example.ipynb

{
 "cells": [
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "### Example of PubMed Clustering"
   ]
  },
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "This notebook shows an example of using this project."
   ]
  },
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "*Step 1:* Imports."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 1,
   "metadata": {},
   "outputs": [],
   "source": [
    "import os\n",
    "from pubmed_clustering import PubMedClustering"
   ]
  },
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "*Step 2:* Logging."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 2,
   "metadata": {},
   "outputs": [],
   "source": [
    "import logging\n",
    "\n",
    "logger = logging.basicConfig(level=logging.DEBUG, format='%(asctime)s %(levelname)-5s %(message)s')"
   ]
  },
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "*Step 3:* Initializing the class.\n",
    "\n",
    "Parameters:\n",
    "- `pubmed_ids` (required): This parameter contains either a list of PMID strings, a string containing comma-separated PMIDs or the disk location to a text file containing a list of PMIDs. If it is a disk location, ensure the `is_file` flag is set to `True`.\n",
    "- `is_file` (optional): Boolean flag to specify if `pubmed_ids` is a text file that should be read. Default: `False`.\n",
    "- `metamap` (optional): Location of MetaMap binary. Without MetaMap, the pre-processing will not run and the program will terminate. Default: `/opt/public_mm/bin/metamap16`.\n",
    "- `email` (optional): Email ID. Required to query PubMed using the BioPython library. Default: `\"Your.Name.Here@example.org\"`.\n",
    "- `labels` (optional): Either a dictionary containing PMID -> cluster pairs or a location to a text file that of the form `PMID\\tlabel`. If it is a text file, ensure the flag `labels_is_file` is set to `True`. Default: `None`.\n",
    "- `labels_is_file` (optional): Boolean flag to specify if `pubmed_ids` is a text file that should be read. Default: `False`.\n",
    "- `write_to_file` (optional): Boolean flag to specify if the output should be written to a file where each line is of the form `PMID\\tlabel`. Default `False`.\n",
    "- `output_file` (optional): Location of output file. If not specified and `write_to_file` and `is_file` is set, `output_file` will be set to `pubmed_ids`, with `_clustered` appended to its end."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "metadata": {},
   "outputs": [],
   "source": [
    "clus1 = PubMedClustering(os.path.join('./data', 'pmids_gold_set_unlabeled.txt'),\n",
    "                         metamap='/opt/public_mm/bin/metamap16', email=\"This.Is.My@Email.org\", is_file=True,\n",
    "                         labels=os.path.join('./data', 'pmids_gold_set_labeled.txt'), labels_is_file=True, \n",
    "                         write_to_file=True)"
   ]
  },
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "*Step 4:* Running the pipeline."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 4,
   "metadata": {
    "scrolled": true
   },
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "2018-11-28 14:57:20,472 INFO  Fetching articles and abstracts from PubMed\n",
      "2018-11-28 14:57:21,980 INFO  Parsing fetched PubMed articles\n",
      "2018-11-28 14:57:22,332 INFO  Parsed all PubMed articles\n",
      "2018-11-28 14:57:22,333 INFO  Processing all documents with MetaMap\n",
      "2018-11-28 14:57:22,334 INFO  0 of 69 documents processed with MetaMap\n",
      "2018-11-28 14:57:40,042 INFO  10 of 69 documents processed with MetaMap\n",
      "2018-11-28 14:57:56,688 INFO  20 of 69 documents processed with MetaMap\n",
      "2018-11-28 14:58:15,108 INFO  30 of 69 documents processed with MetaMap\n",
      "2018-11-28 14:58:35,814 INFO  40 of 69 documents processed with MetaMap\n",
      "2018-11-28 14:58:58,595 INFO  50 of 69 documents processed with MetaMap\n",
      "2018-11-28 14:59:18,155 INFO  60 of 69 documents processed with MetaMap\n",
      "2018-11-28 14:59:41,633 INFO  All documents processed with MetaMap\n",
      "2018-11-28 14:59:41,634 INFO  Creating dictionary\n",
      "2018-11-28 14:59:41,635 INFO  adding document #0 to Dictionary(0 unique tokens: [])\n",
      "2018-11-28 14:59:41,637 INFO  built Dictionary(172 unique tokens: ['male', 'noonan', 'syndrome', 'turner', 'bardet']...) from 69 documents (total 2065 corpus positions)\n",
      "2018-11-28 14:59:41,638 INFO  Filtering low occurence words from dictionary\n",
      "2018-11-28 14:59:41,639 INFO  discarding 120 tokens: [('chronic', 2), ('laurence', 1), ('moon', 1), ('stage', 2), ('autonomic', 1), ('episode', 1), ('hypotensive', 1), ('nervous', 1), ('system', 1), ('body', 1)]...\n",
      "2018-11-28 14:59:41,639 INFO  keeping 52 tokens which were in no less than 3 and no more than 69 (=100.0%) documents\n",
      "2018-11-28 14:59:41,640 DEBUG rebuilding dictionary, shrinking gaps\n",
      "2018-11-28 14:59:41,641 INFO  resulting dictionary: Dictionary(52 unique tokens: ['male', 'noonan', 'syndrome', 'turner', 'bardet']...)\n",
      "2018-11-28 14:59:41,641 DEBUG rebuilding dictionary, shrinking gaps\n",
      "2018-11-28 14:59:41,643 INFO  Creating a corpus\n",
      "2018-11-28 14:59:41,648 INFO  Creating a TF-IDF model\n",
      "2018-11-28 14:59:41,649 INFO  collecting document frequencies\n",
      "2018-11-28 14:59:41,650 INFO  PROGRESS: processing document #0\n",
      "2018-11-28 14:59:41,652 INFO  calculating IDF weights for 69 documents and 51 features (479 matrix non-zeros)\n",
      "2018-11-28 14:59:41,653 INFO  Calculating document matrix\n",
      "2018-11-28 14:59:41,654 INFO  Document vector for 0 of 69 documents calculated\n",
      "2018-11-28 14:59:41,656 INFO  Document vector for 10 of 69 documents calculated\n",
      "2018-11-28 14:59:41,662 INFO  Document vector for 20 of 69 documents calculated\n",
      "2018-11-28 14:59:41,664 INFO  Document vector for 30 of 69 documents calculated\n",
      "2018-11-28 14:59:41,666 INFO  Document vector for 40 of 69 documents calculated\n",
      "2018-11-28 14:59:41,668 INFO  Document vector for 50 of 69 documents calculated\n",
      "2018-11-28 14:59:41,669 INFO  Document vector for 60 of 69 documents calculated\n",
      "2018-11-28 14:59:41,672 INFO  Document matrix calculated\n",
      "2018-11-28 14:59:41,673 INFO  Performing clustering on the document matrix\n",
      "2018-11-28 14:59:41,712 INFO  Clustering performed\n",
      "2018-11-28 14:59:41,713 INFO  Clustering results saved to object\n",
      "2018-11-28 14:59:41,713 INFO  Reading ground truth labels\n",
      "2018-11-28 14:59:41,715 INFO  Calculating purity\n",
      "2018-11-28 14:59:41,716 INFO  Purity calculated and stored\n",
      "2018-11-28 14:59:41,716 INFO  Calculating F-measure\n",
      "2018-11-28 14:59:41,717 INFO  Precision, recall and F-measure calculated and stored\n",
      "2018-11-28 14:59:41,717 INFO  Writing to file\n",
      "2018-11-28 14:59:41,720 INFO  Output written to file\n"
     ]
    }
   ],
   "source": [
    "clus1.run()"
   ]
  },
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "*Step 5:* Observing results."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "metadata": {
    "scrolled": true
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "PMID: 8001324\n",
      "Document text: Noonan syndrome. An update and review for the primary pediatrician.\n",
      "Cluster: 2\n",
      "PMID: 8270381\n",
      "Document text: Clinical aspects of renal involvement in Bardet-Biedl syndrome. \n",
      "The Bardet-Biedl syndrome (BBS), which consists of polydactyly, obesity, mental retardation, pigmentary retinopathy and hypogonadism has been known since 1922, but due to the great similarity to the clinical manifestations of the Laurence-Moon syndrome (LMS) there is a considerable terminological confusion in the medical literature. An attempt is made at clarifying the problem. Four children from two families have been observed. There were inter- and intrafamilial variabilities of the expression and severity of the particular features, but retinopathy and structural and/or functional abnormalities were found in 100%. The combination of the two can serve as an easy clinical screening for diagnosis of the disease. Renal involvement is considered to be a cardinal feature of the syndrome. The most common and earliest symptoms are polydypso-polyuria and reduced concentrating ability, which may lead to some diagnostic difficulties, especially in infancy. Three children have end-stage renal disease and two of them are on maintenance haemodialysis, which they tolerate well.\n",
      "Cluster: 6\n",
      "PMID: 8667262\n",
      "Document text: Anomalies in the permanent dentition and other oral findings in 29 individuals with Laurence-Moon-Bardet-Biedl syndrome. \n",
      "This paper reports a clinical and roentgenological examination of the teeth, jaws and saliva of 29 Scandinavian individuals with Laurence-Moon-Bardet-Biedl (LMBB) syndrome, whose cardinal signs are retinal dystrophy, polydactyly, obesity, hypogenitalism and mental retardation. All subjects had at least three of these signs, including retinal dystrophy. Compared with normal subjects, the group had statistically significantly higher frequencies of hypodontia, small teeth and short roots. In addition, the saliva showed a buffering capacity higher than normal. In conclusion, there seem to exist disturbances of both dental and skeletal formation in the LMBB syndrome.\n",
      "Cluster: 6\n",
      "PMID: 8712208\n",
      "Document text: Midodrine efficacy and pharmacokinetics in a patient with recurrent intradialytic hypotension. \n",
      "Recurrent intradialytic hypotension, a complication of hemodialysis, is a consequence of an inadequate compensatory response or a paradoxic response to ultrafiltration-induced volume reduction. We report the use of midodrine, an alpha agonist, in an 18-year-old man with Bardet-Biedl syndrome and recurrent intradialytic hypotension. The clinical features of the intradialytic hypotensive spells are consistent with a paradoxic withdrawal of sympathetic activity, although an underlying abnormality in autonomic dysfunction cannot be excluded. Midodrine significantly increased the intradialytic blood pressure and decreased the intradialytic hypotensive episodes requiring intervention. The pharmacokinetic characteristics of the prodrug midodrine and the active metabolite de-glymidodrine in this patient with end-stage renal disease approximate those reported for patients with normal renal function. However, the prolonged terminal half-life for the active metabolite, de-glymidodrine, warrants careful administration in patients with renal failure.\n",
      "Cluster: 6\n",
      "PMID: 10022033\n",
      "Document text: Basic and clinical studies on ApoE gene typing by line probe assay (LiPA) as a biological marker for Alzheimer's disease and related disorders: multicenter study in Japan. \n",
      "The fundamental reagent capability and clinical significance of ApoE gene typing has been investigated. The result of each test shows that the reagent capability satisfied the expected standard. Four-hundred thirty-nine samples classified into three groups (Alzheimer's disease (AD), other types of dementia and nondementia) were measured to examine the clinical significance. The rate of epsilon 4 genotype of each group was 31.5%, 14.6%, 10.4%, respectively. The AD group had a higher rate than the other groups (p < 0.001). The measurement of ApoE genotype is suggested to be useful as one of the guidelines in the diagnosis of AD.\n",
      "Cluster: 0\n",
      "PMID: 10025425\n",
      "Document text: Neurofibrillary pathology in Alzheimer disease with Lewy bodies: two subgroups. \n",
      "While NFT frequency is reportedly reduced in AD+DLB, we often encounter abundant neocortical NFTs in such cases and decided to investigate this discrepancy.\n",
      "To compare neurofibrillary tangle (NFT) frequency in Alzheimer disease with concomitant dementia with Lewy bodies (AD+DLB) with NFT frequency in \"pure\" AD.\n",
      "Neurofibrillary tangle frequency, as well as regional staging of neurofibrillary degeneration modified from Braak, was scored in 160 autopsy cases of primary dementia (80 AD+DLB cases and 80 pure AD cases).\n",
      "Neurofibrillary tangle and modified Braak scores were lower in AD+DLB, as reported previously. Yet, neocortical NFT scores assumed markedly different patterns in the 2 groups (P = .001). In pure AD, NFT scores of \"frequent\" were predominant: more cases exhibited frequent than moderate or sparse NFTs. In AD+DLB, the distribution of NFT scores was bimodal: NFTs were either frequent or few to absent. Neocortical NFT scores in the AD+DLB group tended to parallel the severity of other types of tau cytopathology (neuropil threads and tau-positive plaque neurites).\n",
      "Cases of AD+DLB may be divided into 2 subgroups based on the extent of neocortical neurofibrillary pathology. These findings could have implications for disease pathogenesis and treatment.\n",
      "Cluster: 0\n",
      "PMID: 10025444\n",
      "Document text: In vivo brain concentrations of N-acetyl compounds, creatine, and choline in Alzheimer disease. \n",
      "Alzheimer disease (AD) and normal aging result in cortical gray matter volume deficits. The extent to which the remaining cortex is functionally compromised can be estimated in vivo with magnetic resonance spectroscopic imaging.\n",
      "To assess the effects of age and dementia on gray matter and white matter concentrations of 3 metabolites visible in the proton spectrum: N-acetyl compounds, present only in living neurons; creatine plus phosphocreatine, reflecting high-energy phosphate metabolism; and choline, increasing with membrane synthesis and degradation.\n",
      "Fifteen healthy young individuals, 19 healthy elderly individuals, and 16 patients with AD underwent 3-dimensional magnetic resonance spectroscopic imaging and memory and language testing.\n",
      "Gray matter N-acetyl compound concentrations (signal intensity corrected for the amount of brain tissue contributing to the magnetic resonance spectroscopic imaging signal) was significantly reduced only in patients with AD, even though both the AD and elderly control groups had substantial gray matter volume deficits relative to the young control group. Both the healthy elderly and AD groups had abnormally high gray matter creatine plus phosphocreatine concentrations. Gray matter choline concentrations were higher in the elderly than the younger controls, and even higher in the AD group than in the elderly control group. Functional significance of these findings was supported by correlations between poorer performance on recognition memory tests and lower gray matter N-acetyl compounds in elderly controls and higher gray matter creatine plus phosphocreatine and choline concentrations in patients with AD.\n",
      "Cortical gray matter volume deficits in patients with AD are accompanied by disease-related increases in gray matter choline concentrations suggestive of cellular degeneration and reduced N-acetyl compound concentrations, with possible effects on behavioral function.\n",
      "Cluster: 0\n",
      "PMID: 10025576\n",
      "Document text: Increased tau in the cerebrospinal fluid of patients with frontotemporal dementia and Alzheimer's disease. \n",
      "Cerebrospinal fluid (CSF) concentrations of tau protein were measured using an enzyme-linked immunosorbent assay which measures both normal and hyperphosphorylated tau. Levels of CSF tau were measured in 17 patients with Alzheimer's disease and 23 patients with frontotemporal dementia, and were compared to age-matched healthy controls. The CSF tau concentration in control subjects was 198+/-49 pg/ml and no relationship was found between age and CSF tau concentrations in these subjects. CSF tau concentrations were significantly raised in patients with both Alzheimer's disease and frontotemporal dementia when compared to healthy controls (802+/-381 pg/ml, P<0.001; 612+/-382 pg/ml, P<0.05, respectively). In neither disease did CSF tau correlate with disease severity as assessed by the Mini Mental State Examination score (MMSE). This study shows that CSF tau is significantly raised in patients with frontotemporal dementia.\n",
      "Cluster: 0\n",
      "PMID: 12677556\n",
      "Document text: Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. \n",
      "Bardet-Biedl syndrome is a genetically and clinically heterogeneous disorder caused by mutations in at least seven loci (BBS1-7), five of which are cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis. To date, four of the five known BBS loci have been implicated in this mode of oligogenic disease transmission. We present a comprehensive analysis of the spectrum, distribution, and involvement in non-Mendelian trait transmission of mutant alleles in BBS1, the most common BBS locus. Analyses of 259 independent families segregating a BBS phenotype indicate that BBS1 participates in complex inheritance and that, in different families, mutations in BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as at unknown loci, to cause the phenotype. Consistent with this model, we identified homozygous M390R alleles, the most frequent BBS1 mutation, in asymptomatic individuals in two families. Moreover, our statistical analyses indicate that the prevalence of the M390R allele in the general population is consistent with an oligogenic rather than a recessive model of disease transmission. The distribution of BBS oligogenic alleles also indicates that all BBS loci might interact genetically with each other, but some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other.\n",
      "Cluster: 1\n",
      "PMID: 15231740\n",
      "Document text: Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. \n",
      "Bardet-Biedl syndrome (BBS) is a genetically heterogeneous developmental disorder whose molecular basis is largely unknown. Here, we show that mutations in the Caenorhabditis elegans bbs-7 and bbs-8 genes cause structural and functional defects in cilia. C. elegans BBS proteins localize predominantly at the base of cilia, and like proteins involved in intraflagellar transport (IFT), a process necessary for cilia biogenesis and maintenance, move bidirectionally along the ciliary axoneme. Importantly, we demonstrate that BBS-7 and BBS-8 are required for the normal localization/motility of the IFT proteins OSM-5/Polaris and CHE-11, and to a notably lesser extent, CHE-2. We propose that BBS proteins play important, selective roles in the assembly and/or function of IFT particle components. Our findings also suggest that some of the cardinal and secondary symptoms of BBS, such as obesity, diabetes, cardiomyopathy, and learning defects may result from cilia dysfunction.\n",
      "Cluster: 6\n",
      "PMID: 17574030\n",
      "Document text: A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. \n",
      "Primary cilium dysfunction underlies the pathogenesis of Bardet-Biedl syndrome (BBS), a genetic disorder whose symptoms include obesity, retinal degeneration, and nephropathy. However, despite the identification of 12 BBS genes, the molecular basis of BBS remains elusive. Here we identify a complex composed of seven highly conserved BBS proteins. This complex, the BBSome, localizes to nonmembranous centriolar satellites in the cytoplasm but also to the membrane of the cilium. Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Strikingly, Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Conversely, preventing Rab8(GTP) production blocks ciliation in cells and yields characteristic BBS phenotypes in zebrafish. Our data reveal that BBS may be caused by defects in vesicular transport to the cilium.\n",
      "Cluster: 1\n",
      "PMID: 20578946\n",
      "Document text: PTPN11 and KRAS gene analysis in patients with Noonan and Noonan-like syndromes. \n",
      "Noonan and Noonan-like syndromes are disorders of dysregulation of the rat sarcoma viral oncogene homolog (RAS)-mitogen-activated protein kinase signaling pathway. In Noonan syndrome (NS), four genes of this pathway (PTPN11, SOS1, RAF1, and KRAS) are responsible for roughly 70% of the cases. We analyzed PTPN11 and KRAS genes by bidirectional sequencing in 95 probands with NS and 29 with Noonan-like syndromes, including previously reported patients already screened for PTPN11 gene mutations. In the new patients with NS, 20/46 (43%) showed a PTPN11 gene mutation, two of them novel. In our total cohort, patients with NS and a PTPN11 mutation presented significantly higher prevalence of short stature (p = 0.03) and pulmonary valve stenosis (p = 0.01), and lower prevalence of hypertrophic cardiomyopathy (p = 0.01). Only a single gene alteration, of uncertain role, was found in the KRAS gene in an NS patient also presenting a PTPN11 gene mutation. We further analyzed the influence in clinical variability of three frequent polymorphisms found in the KRAS gene and no statistically significant difference was observed among the frequency of clinical findings regarding the studied polymorphisms.\n",
      "Cluster: 2\n",
      "PMID: 21246219\n",
      "Document text: Phenotypic variability of Bardet-Biedl syndrome: focusing on the kidney. \n",
      "Bardet-Biedl syndrome (BBS) is a multisystemic developmental disorder diagnosed on the basis of the presence of obesity, retinal defects, polydactyly, hypogonadism, renal dysfunction, and learning disabilities. The syndrome is genetically heterogeneous with 14 BBS genes identified to date. Since the cloning of the first gene in 2000, a combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology. Pleiotropy of ciliopathy phenotypes and complex genetic interactions between causal and modifying alleles of ciliary genes contribute to phenotypic variability. In particular, kidney disease in BBS is clinically heterogeneous, but is now recognized as a cardinal feature and a major cause of mortality in BBS.\n",
      "Cluster: 6\n",
      "PMID: 21263000\n",
      "Document text: Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. \n",
      "Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras-mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome.\n",
      "Cluster: 2\n",
      "PMID: 21263000\n",
      "Document text: Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. \n",
      "Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras-mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome.\n",
      "Cluster: 2\n",
      "PMID: 21549079\n",
      "Document text: Neurofibromatosis-Noonan syndrome: case report and clinicopathogenic review of the Neurofibromatosis-Noonan syndrome and RAS-MAPK pathway. \n",
      "Neurofibromatosis-Noonan syndrome is an entity that combines both features of Noonan syndrome and Neurofibromatosis type 1. This phenotypic overlap can be explained by the involvement of the RAS-MAPK pathway (mitogen-activated protein kinase) in both disorders. We report the case of a 17-year-old boy with Neurofibromatosis 1 with Noonan-like features, who complained of the progressive appearance of blue-gray lesions on his back.\n",
      "Cluster: 3\n",
      "PMID: 21706501\n",
      "Document text: Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype. \n",
      "To define sonographic criteria that may improve the prenatal diagnosis of Noonan syndrome by targeted DNA testing.\n",
      "We searched our Fetal Medicine Unit records for all cases with a final diagnosis of Noonan syndrome. A literature review was undertaken to identify the sonographic features of Noonan syndrome fetuses. Information was pooled to define the most common features.\n",
      "In our database, we identified three cases of Noonan syndrome. The diagnosis was suspected prenatally in two of them. Thirty-nine cases were identified in the literature. In the presented cases we show that suspicion of Noonan syndrome should arise when, after an increased nuchal translucency, ultrasound investigation in the second trimester shows a persistant nuchal fold (NF) or cystic hygroma in combination with at least one of the following features: hydrops fetalis, pleural effusion, cardiac anomalies, polyhydramnios or specific facial abnormalities.\n",
      "Prenatal ultrasound findings in Noonan syndrome can be subtle and aspecific, but when specific characteristics are present additional targeted DNA analysis is indicated.\n",
      "Copyright © 2011 John Wiley & Sons, Ltd.\n",
      "Cluster: 2\n",
      "PMID: 22011734\n",
      "Document text: Rosette forming glioneuronal tumor in association with Noonan syndrome: pathobiological implications. \n",
      "Noonan syndrome, a distinctive syndrome characterized by dysmorphism, cardiac abnormalities and developmental delay, has been associated with a number of malignancies, however, only a few cases of primary glial or glioneuronal neoplasms have been reported. We report here the case of an 18-year-old with Noonan syndrome who developed a rosette forming glioneuronal tumor of the posterior fossa. The tumor demonstrated strong pERK immunoreactivity, suggesting MAPK/ERK pathway activation. Molecular testing did not reveal BRAF rearrangements (fusion transcripts) by PCR or a BRAFV600E mutation by sequencing. We review the literature regarding the molecular pathogenesis of Noonan syndrome and primary brain tumors, and consider the intriguing link between their common molecular pathways.\n",
      "Cluster: 2\n",
      "PMID: 23211900\n",
      "Document text: Case report: Noonan-like multiple central giant cell granuloma syndrome. \n",
      "The purpose of this report was to: summarize the care of a child between the ages of 12 to 16 years old born with Noonan-like central giant cell syndrome and unrelated common variable immune deficiency; provide information on the dental management of patients with Noonan's syndrome;  and present a brief discussion of the recent associated genetic findings. A review of the common features of Noonan syndrome and Noonan-like central giant cell syndrome is also provided.\n",
      "Cluster: 2\n",
      "PMID: 23239255\n",
      "Document text: Association between Noonan syndrome and Chiari I malformation: a case-based update. \n",
      "Chiari I malformations (CM-I) have been associated with a variety of developmental abnormalities in the literature. A few cases of CM-I in patients with Noonan syndrome (NS) have been reported; however, opinion remains divided as to whether the observed association is coincidental.\n",
      "Six previous cases of CM-I in patients with NS have been described in the literature. Many of these had other neurological abnormalities; however, neurological problems are not a prominent part of earlier descriptions of NS. A statistically significant association between NS and CM-I is difficult to obtain at present due to availability and logistical issues with scanning many asymptomatic patients. Although we believe a link exists between CM-I and NS, there is little understanding on how NS may cause CM-I. The most logical cause would be posterior fossa abnormality; however, the most common genetic mutation in NS tends to cause frontal and facial abnormalities, and the posterior fossa tends to be relatively spared. Other genetic mutations may also affect the posterior cranium and thus create the appropriate conditions for a CM-I to develop.\n",
      "We report a case of CM-I in a 9-year-old patient with Noonan syndrome, severe scoliosis and syringomyelia.\n",
      "We believe that CM-I is a part of Noonan syndrome; however, statistical validation of this opinion is necessary.\n",
      "Cluster: 2\n",
      "PMID: 23716571\n",
      "Document text: Bardet-Biedl syndrome proteins control the cilia length through regulation of actin polymerization. \n",
      "Primary cilia are cellular appendages important for signal transduction and sensing the environment. Bardet-Biedl syndrome proteins form a complex that is important for several cytoskeleton-related processes such as ciliogenesis, cell migration and division. However, the mechanisms by which BBS proteins may regulate the cytoskeleton remain unclear. We discovered that Bbs4- and Bbs6-deficient renal medullary cells display a characteristic behaviour comprising poor migration, adhesion and division with an inability to form lamellipodial and filopodial extensions. Moreover, fewer mutant cells were ciliated [48% ± 6 for wild-type (WT) cells versus 23% ± 7 for Bbs4 null cells; P < 0.0001] and their cilia were shorter (2.55 μm ± 0.41 for WT cells versus 2.16 μm ± 0.23 for Bbs4 null cells; P < 0.0001). While the microtubular cytoskeleton and cortical actin were intact, actin stress fibre formation was severely disrupted, forming abnormal apical stress fibre aggregates. Furthermore, we observed over-abundant focal adhesions (FAs) in Bbs4-, Bbs6- and Bbs8-deficient cells. In view of these findings and the role of RhoA in regulation of actin filament polymerization, we showed that RhoA-GTP levels were highly upregulated in the absence of Bbs proteins. Upon treatment of Bbs4-deficient cells with chemical inhibitors of RhoA, we were able to restore the cilia length and number as well as the integrity of the actin cytoskeleton. Together these findings indicate that Bbs proteins play a central role in the regulation of the actin cytoskeleton and control the cilia length through alteration of RhoA levels.\n",
      "Cluster: 1\n",
      "PMID: 23954459\n",
      "Document text: Spinal neurofibromatosis in a family with classical neurofibromatosis type 1 and a novel NF1 gene mutation. \n",
      "Familial spinal neurofibromatosis (FSNF) is a rare form of neurofibromatosis type 1 (NF1) characterized by multiple, histologically proven neurofibromas of the spinal roots leaving no intact segments and associated neurofibromas of major peripheral nerves. It is sometimes associated with other NF1 stigmata. Most patients have NF1 gene mutations. We describe a patient who fulfilled the diagnostic criteria for spinal neurofibromatosis and belonged to a family in which other affected members exhibited classical NF1 stigmata. A novel missense (c.7109 T>A; p.Val2370Asp) mutation in exon 39 of the NF1 gene was present in the affected family members. The family displayed extreme phenotypic variability in the spectrum of NF1. To our knowledge, this is the first patient with spinal neurofibromatosis in the context of classical NF1 with an NF1 gene mutation. The term FSNF is inaccurate as this condition simply reflects the typical autosomal dominant pattern of NF1 inheritance with phenotypoc variability and does not encompass patients with sporadic disease or those in the context of a classical NF1 phenotype as reported in the present family. The term could be replaced by \"spinal neurofibromatosis\".\n",
      "Copyright © 2013 Elsevier Ltd. All rights reserved.\n",
      "Cluster: 3\n",
      "PMID: 24032991\n",
      "Document text: Congenital giant plexiform neurofibroma with occipital calvarial dysplasia in association with meningoencephalocele in neurofibromatosis Type 1 and segmental neurofibromatosis: report of 2 cases. \n",
      "Giant plexiform neurofibroma (GPNF) of the scalp is an extremely rare lesion reported in association with neurofibromatosis. Occipital location of GPNF is even more infrequent, especially in association with occipital dysplasia (OD). The authors report 2 pediatric cases of GPNF associated with OD. The first case had an associated meningoencephalocele, and the second had large vascular channels within the lesion and the dominant ipsilateral transverse sinus lying in the center of the calvarial defect. The authors present these 2 unusual cases with a review of literature and discuss the radiological findings, theories of etiopathogenesis of the OD, and management dilemmas.\n",
      "Cluster: 3\n",
      "PMID: 24316073\n",
      "Document text: Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. \n",
      "Human monogenic obesity syndromes, including Bardet-Biedl syndrome (BBS), implicate neuronal primary cilia in regulation of energy homeostasis. Cilia in hypothalamic neurons have been hypothesized to sense and regulate systemic energy status, but the molecular mechanism of this signaling remains unknown. Here, we report a comprehensive localization screen of 42 G-protein-coupled receptors (GPCR) revealing seven ciliary GPCRs, including the neuropeptide Y (NPY) receptors NPY2R and NPY5R. We show that mice modeling BBS disease or obese tubby mice fail to localize NPY2R to cilia in the hypothalamus and that BBS mutant mice fail to activate c-fos or decrease food intake in response to the NPY2R ligand PYY3-36. We find that cells with ciliary NPY2R show augmented PYY3-36-dependent cAMP signaling. Our data demonstrate that ciliary targeting of NPY receptors is important for controlling energy balance in mammals, revealing a physiologically defined ligand-receptor pathway signaling within neuronal cilia. \n",
      "Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.\n",
      "Cluster: 1\n",
      "PMID: 24611735\n",
      "Document text: Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome. \n",
      "Bardet-Biedl syndrome is a rare ciliopathy characterized by retinal dystrophy, obesity, intellectual disability, polydactyly, hypogonadism and renal impairment. Patients are at high risk of cardiovascular disease. Mutations in BBS1 and BBS10 account for more than half of those with molecular confirmation of the diagnosis. To elucidate genotype-phenotype correlations with respect to cardiovascular risk indicators 50 patients with mutations in BBS1 were compared with 19 patients harbouring BBS10 mutations. All patients had truncating, missense or compound missense/truncating mutations. The effect of genotype and mutation type was analysed. C-reactive protein was higher in those with mutations in BBS10 and homozygous truncating mutations (p = 0.013 and p = 0.002, respectively). Patients with mutations in BBS10 had higher levels of C peptide than those with mutations in BBS1 (p = 0.043). Triglyceride levels were significantly elevated in patients with homozygous truncating mutations (p = 0.048). Gamma glutamyl transferase was higher in patients with homozygous truncating mutations (p = 0.007) and heterozygous missense and truncating mutations (p = 0.002) than those with homozygous missense mutations. The results are compared with clinical cardiovascular risk factors. Patients with missense mutations in BBS1 have lower biochemical cardiovascular disease markers compared with patients with BBS10 and other BBS1 mutations. This could contribute to stratification of the clinical service.\n",
      "© 2014 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.\n",
      "Cluster: 1\n",
      "PMID: 24619745\n",
      "Document text: Triple-negative breast carcinoma: current and emerging concepts. \n",
      "Triple-negative breast cancer is regarded as an aggressive disease that affects a young patient population and for which effective targeted therapy is not yet available.\n",
      "Intense efforts have been made to gain a better understanding of this heterogeneous group of tumors from the histologic to the genomic and molecular levels.\n",
      "Progress has been made, including the ability to subtype these tumors and the discovery of biomarkers toward which current therapeutic efforts are focused. Many novel targets under exploration have the potential to affect the clinical course of this disease.\n",
      "This article reviews the current concepts regarding the clinicopathologic features of triple-negative breast carcinoma, its histologic subtypes, molecular classification, the prognostic and therapeutic potential of biomarkers, and emerging targeted therapies.\n",
      "Cluster: 4\n",
      "PMID: 24695551\n",
      "Document text: Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model. \n",
      "Bardet-Biedl syndrome (BBS) is a genetically heterogeneous inherited human disorder displaying a pleotropic phenotype. Many of the symptoms characterized in the human disease have been reproduced in animal models carrying deletions or knock-in mutations of genes causal for the disorder. Thinning of the cerebral cortex, enlargement of the lateral and third ventricles, and structural changes in cilia are among the pathologies documented in these animal models. Ciliopathy is of particular interest in light of recent studies that have implicated primary neuronal cilia (PNC) in neuronal signal transduction. In the present investigation, we tested the hypothesis that areas of the brain responsible for learning and memory formation would differentially exhibit PNC abnormalities in animals carrying a deletion of the Bbs4 gene (Bbs4-/-). Immunohistochemical localization of adenylyl cyclase-III (ACIII), a marker restricted to PNC, revealed dramatic alterations in PNC morphology and a statistically significant reduction in number of immunopositive cilia in the hippocampus and amygdala of Bbs4-/- mice compared to wild type (WT) littermates. Western blot analysis confirmed the decrease of ACIII levels in the hippocampus and amygdala of Bbs4-/- mice, and electron microscopy demonstrated pathological alterations of PNC in the hippocampus and amygdala. Importantly, no neuronal loss was found within the subregions of amygdala and hippocampus sampled in Bbs4-/- mice and there were no statistically significant alterations of ACIII immunopositive cilia in other areas of the brain not known to contribute to the BBS phenotype. Considered with data documenting a role of cilia in signal transduction these findings support the conclusion that alterations in cilia structure or neurochemical phenotypes may contribute to the cognitive deficits observed in the Bbs4-/- mouse mode.\n",
      "Cluster: 1\n",
      "PMID: 24939608\n",
      "Document text: Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity.\n",
      "Cluster: 2\n",
      "PMID: 25008444\n",
      "Document text: Mosaic generalized neurofibromatosis 1: report of two cases. \n",
      "We report two cases of mosaic generalized neurofibromatosis 1 (NF1) and review the history of the classification of segmental neurofibromatosis (SNF; Ricardi type NF-V). Somatic mutations giving rise to limited disease, such as segmental neurofibromatosis are manifestations of mosaicism. If the mutation occurs before tissue differentiation, the clinical phenotype will be generalized disease. Mutations that occur later in development give rise to disease that is confined to a single region.\n",
      "Segmental neurofibromatosis is caused by a somatic mutation of neurofibromatosis type 1, and should not be regarded as a distinct entity from neurofibromatosis 1. Cases previously referred to as unilateral or bilateral segmental neurofibromatosis are now best referred to as mosaic generalized or mosaic localized neurofibromatosis 1.\n",
      "Cluster: 3\n",
      "PMID: 25458167\n",
      "Document text: Bardet-Biedl syndrome and a large concha bullosa pyocele. \n",
      "Bardet-Biedl syndrome is a rare disease involving rode cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism and renal anomalies, symptoms caused by immotile cilia dysfunction. We report the first case of this syndrome in a teenager with an endonasal mass secondary to pyocele of a concha bullosa. The patient was treated successfully with endoscopic sinus surgery. Nasal obstruction secondary to a middle turbinate pyocele in Bardet-Biedl syndrome has not been described before. The pediatrician and the rhinologist should take this entity into consideration when investigating patients with Bardet-Biedl syndrome and sinonasal symptoms. \n",
      "Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.\n",
      "Cluster: 1\n",
      "PMID: 25672202\n",
      "Document text: Laurence Moon Bardet Biedl Syndrome with anaemia. \n",
      "Laurence Moon Bardet Biedl Syndrome is a rare genetic disorder. Consanguineous marriage is usually the common cause. Principal features of Bardet Biedl Syndrome are red cone dystrophy, obesity, polydactyl, hypogonadism and renal anomalies. The diagnosis was overlooked in our patient until he came in our hospital. We here report an infrequent case of autosomal recessive disorder with Anaemia.\n",
      "Cluster: 1\n",
      "PMID: 25682074\n",
      "Document text: Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. \n",
      "Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone and HER2 receptors. The gene expression profiles of TNBCs are similar to those of breast tumours in women with BRCA1 mutations. Reports to date indicate that up to 20 % of TNBC patients harbour germline BRCA mutations; however, the prevalence of BRCA mutations in TNBC patients varies widely between countries and from study to study. We studied 774 women with triple-negative breast cancer, diagnosed on average at age 58.0 years. Samples of genomic DNA were provided by the Australian Breast Cancer Tissue Bank (ABCTB) (439 patients) and by the Department of Genetics and Pathology of the Pomeranian Medical University (335 patients). The entire coding regions and the exon-intron boundaries of BRCA1 and BRCA2 were amplified and sequenced by next-generation sequencing. We identified a BRCA1 or BRCA2 mutation in 74 of 774 (9.6 %) triple-negative patients. The mutation prevalence was 9.3 % in Australia and was 9.9 % in Poland. In both countries, the mean age of diagnoses of BRCA1 mutation carriers was significantly lower than that of non-carriers, while the age of onset of BRCA2 mutation carriers was similar to that of non-carriers. In the Australian cohort, 59 % of the mutation-positive patients did not have a family history of breast or ovarian cancer, and would not have qualified for genetic testing. The triple-negative phenotype should be added as a criterion to genetic screening guidelines.\n",
      "Cluster: 4\n",
      "PMID: 25752562\n",
      "Document text: Radiation therapy in the locoregional treatment of triple-negative breast cancer. \n",
      "This Review assesses the relevant data and controversies regarding the use of radiotherapy for, and locoregional management of, women with triple-negative breast cancer (TNBC). In view of the strong association between BRCA1 and TNBC, knowledge of baseline mutation status can be useful to guide locoregional treatment decisions. TNBC is not a contraindication for breast conservation therapy because data suggest increased locoregional recurrence risks (relative to luminal subtypes) with breast conservation therapy or mastectomy. Although a boost to the tumour bed should routinely be considered after whole breast radiation therapy, TNBC should not be the sole indication for post-mastectomy radiation, and accelerated delivery methods for TNBC should be offered on clinical trials. Preliminary data implying a relative radioresistance for TNBC do not imply radiation omission because radiation provides an absolute locoregional risk reduction. At present, the integration of subtypes in locoregional management decisions is still in its infancy. Until level 1 data supporting treatment decisions based on subtypes are available, standard locoregional management principles should be adhered to. \n",
      "Copyright © 2015 Elsevier Ltd. All rights reserved.\n",
      "Cluster: 4\n",
      "PMID: 26103456\n",
      "Document text: Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins. \n",
      "Insulin and its receptor are critical for the regulation of metabolic functions, but the mechanisms underlying insulin receptor (IR) trafficking to the plasma membrane are not well understood. Here, we show that Bardet Biedl Syndrome (BBS) proteins are necessary for IR localization to the cell surface. We demonstrate that the IR interacts physically with BBS proteins, and reducing the expression of BBS proteins perturbs IR expression in the cell surface. We show the consequence of disrupting BBS proteins for whole body insulin action and glucose metabolism using mice lacking different BBS genes. These findings demonstrate the importance of BBS proteins in underlying IR cell surface expression. Our data identify defects in trafficking and localization of the IR as a novel mechanism accounting for the insulin resistance commonly associated with human BBS. This is supported by the reduced surface expression of the IR in fibroblasts derived from patients bearing the M390R mutation in the BBS1 gene.\n",
      "Cluster: 1\n",
      "PMID: 26201402\n",
      "Document text: Androgen Receptor Biology in Triple Negative Breast Cancer: a Case for Classification as AR+ or Quadruple Negative Disease. \n",
      "Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) amplification. Due to the absence of these receptors, TNBC does not respond to traditional endocrine or HER2-targeted therapies that improve patient prognosis in other breast cancer subtypes. TNBC has a poor prognosis, and currently, there are no effective targeted therapies. Some TNBC tumors express androgen receptor (AR) and may benefit from AR-targeted therapies. Here, we review the literature on AR in TNBC and propose that TNBC be further sub-classified as either AR+ TNBC or quadruple negative breast cancer since targeting AR may represent a viable therapeutic option for a subset of TNBC.\n",
      "Cluster: 4\n",
      "PMID: 26273192\n",
      "Document text: The role of taxanes in triple-negative breast cancer: literature review. \n",
      "Breast cancer (BC) is the most frequent tumor worldwide. Triple-negative BCs are characterized by the negative estrogen and progesterone receptors and negative HER2, and represent 15% of all BCs. In this review, data on the use of taxanes in triple-negative BCs are analyzed, concluding they are effective in any clinical setting (neoadjuvant, adjuvant, and metastatic). Further, the role of nab-paclitaxel (formulation of albumin-bound paclitaxel) in these tumors is also evaluated. The available data show the clinical potential of nab-paclitaxel based combinations in terms of long-duration response, increased survival, and better quality of life of patients with triple-negative metastatic BC. The ongoing trials will give further information on the better management of this type of tumor.\n",
      "Cluster: 5\n",
      "PMID: 26568208\n",
      "Document text: Circulating tumor DNA for triple-negative breast cancer diagnosis and treatment decisions. \n",
      "Triple-negative breast cancer (TNBC) is a highly aggressive disease characterized by a high number of relapses and poor overall survival. The heterogeneity of the disease and the limited treatment options compared to other breast cancer subtypes mainly explain these clinical outcomes. New biomarkers are urgently needed to improve the management of TNBC. Circulating tumor DNA, identified by tumor-related molecular alterations, could be used in the context of non-invasive \"liquid biopsy\" and help in TNBC diagnosis and treatment decisions. In this review, we discuss the key issues related to the potential of circulating tumor DNA to improve the management of this disease and the future steps to overcome before its implementation into clinical routine within the next 5 years.\n",
      "Cluster: 4\n",
      "PMID: 26586152\n",
      "Document text: Value of MRI olfactory bulb evaluation in the assessment of olfactory dysfunction in Bardet-Biedl syndrome. \n",
      "Olfactory bulb (OB) volume evaluation by magnetic resonance imaging (MRI) has been demonstrated to be related to olfactory dysfunction in many different diseases. Olfactory dysfunction is often overlooked in Bardet-Biedl syndrome (BBS) patients and is rarely objectively evaluated by MRI. We present a series of 20 BBS patients with olfactory dysfunction. The OB was evaluated separately and blindly by two radiologists (SR and SM) with 3 Tesla MRI imaging comparatively to 12 normal control subjects by global visual evaluation and by quantitative measurement of OB volume. In the 12 control cases OB visual evaluation was considered as normal in all cases for radiologist (SR) and in 10 cases for radiologist (SM). In the 20 BBS patients, OB visual evaluation was considered as abnormal in 18 cases for SR and in all cases for SM. OB volumetric evaluation for SR and SM in BBS patients was able to provide significant correlation between BBS and olfactory dysfunction. This study indicates that OB volume evaluation by MRI imaging like structural MRI scan for gray matter modifications demonstrates that olfactory dysfunction in BBS patients is a constant and cardinal symptom integrated in a genetical syndrome with peripheral and central olfactory structure alterations.\n",
      "© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.\n",
      "Cluster: 6\n",
      "PMID: 26820943\n",
      "Document text: Immunohistochemistry for Triple-Negative Breast Cancer. \n",
      "Triple-negative breast cancers are a heterogeneous group of tumors that are, as yet, not entirely understood. Although triple-negative carcinomas are strictly defined as invasive carcinomas lacking expression of estrogen receptor, progesterone receptor, and HER2, some use the terms triple-negative and basal-like cancer synonymously. It should be noted that these are not entirely equivalent. Nevertheless, it has been shown that a panel of immunohistochemical markers can be used as a surrogate for genomic profiling and thus to identify basal-like breast cancers. We describe the panels of immunohistochemical markers that can be applied and how to interpret these markers herein.\n",
      "Cluster: 5\n",
      "PMID: 26846096\n",
      "Document text: Homozygosity mapping identified a novel protein truncating mutation (p.Ser100Leufs*24) of the BBS9 gene in a consanguineous Pakistani family with Bardet Biedl syndrome. \n",
      "Bardet Biedl Syndrome (BBS) is a rare condition of multi-organ dysfunction with characteristic clinical features of retinal degeneration, truncal obesity, postaxial polydactyly, genital anomaly, intellectual disability and renal dysfunction. It is a hetero-genetic disorder and nineteen BBS genes have been discovered so far.\n",
      "Whole genome SNP genotyping was performed by using CytoScan® 750 K array (Affymetrix). Subsequently, the segregation of the disease locus in the whole family was carried out by genotyping STS markers within the homozygous interval. Finally, the mutation analysis was performed by Sanger DNA sequencing.\n",
      "In the present molecular study a consanguineous Pakistani family, with autosomal recessive BBS, was analyzed. The clinical analysis of affected individuals presented with synpolydactyly, obesity, intellectual disability, renal abnormality and retinitis pigmentosa. The presented phenotype was consistent with the major features of BBS syndrome. Homozygosity mapping identified a common homozygous interval within the known BBS9 locus. Sequence analysis of BBS9/PTHB1 gene revealed a single base deletion of c.299delC (p.Ser100Leufs*24) in exon 4. This frame-shift mutation presumably leads to a 122 amino acid truncated protein with complete loss of its C-terminal PTHB1 domain in combination with a partial loss of the N-terminal PTHB1 domain as well. BBS9/PTHB1 gene mutations have been shown to be associated with BBS syndrome and to the best of our knowledge this study reports the first Pakistani family linked to the BBS9 gene.\n",
      "Our molecular findings expand the mutational spectrum of BBS9 gene and also explain the genetic heterogeneity of Pakistan families with BBS syndrome. The growing number of mutations in BBS genes in combination with a detailed phenotypical description of patients will be helpful for genotype-phenotype correlation, targeted genetic diagnosis, prenatal screening and carrier testing of familial and non-familial BBS patients.\n",
      "Cluster: 1\n",
      "PMID: 26925684\n",
      "Document text: Response of Triple Negative Breast Cancer to Neoadjuvant Chemotherapy: Correlation between Ki-67 Expression and Pathological Response. \n",
      "Triple-negative breast cancers constitute about 15% of all cases, but despite their higher response to neoadjuvant chemotherapy, the tumors are very aggressive and associated with a poor prognosis as well as a higher risk of early recurrence. This study was retrospectively performed on 101 patients with stage II and III invasive breast cancer who received 6-8 cycles of neo-adjuvant chemotherapy. Out of the total, 23 were in the triple negative breast cancer subgroup. Nuclear Ki-67 expression in both the large cohort group (n=101) and triple negative breast cancer subgroup (n=23) and its relation to the pathological response were evaluated. The purpose of the study was to identify the predictive value of nuclear protein Ki-67 expression among patients with invasive breast cancers, involving the triple negative breast cancer subgroup, treated with neoadjuvant chemotherapy in correlation to the rate of pathological complete response. The proliferation marker Ki-67 expression was highest in the triple negative breast cancer subgroup. No appreciable difference in the rate of Ki-67 expression in triple negative breast cancer subgroup using either a cutoff of 14% or 35%. Triple negative breast cancer subgroup showed lower rates of pathological complete response. Achievement of pathological complete response was significantly correlated with smaller tumor size and higher Ki-67 expression. The majority of triple negative breast cancer cases achieved pathological partial response. The study concluded that Ki-67 is a useful tool to predict chemosensitivity in the setting of neoadjuvant chemotherapy for invasive breast cancer but not for the triple negative breast cancer subgroup.\n",
      "Cluster: 4\n",
      "PMID: 26952712\n",
      "Document text: Hypertrophic neuropathy in Noonan syndrome with multiple lentigines. \n",
      "RASopathies comprise several genetic syndromes with mainly cardio-facial-cutaneous manifestations. We report a patient with Noonan syndrome with multiple lentigines (NSML) due to a PTPN11 (p.Thr468Met) mutation associated with hypertrophic neuropathy of lumbar plexus in an adult woman, initially referred for neuropathic pain. Differential diagnosis of neurofibromatosis type 1 (NF1) and other RASopathies is difficult without molecular testing. © 2016 Wiley Periodicals, Inc.\n",
      "© 2016 Wiley Periodicals, Inc.\n",
      "Cluster: 3\n",
      "PMID: 26968398\n",
      "Document text: Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer. \n",
      "Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/β-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC.\n",
      "Cluster: 4\n",
      "PMID: 27015557\n",
      "Document text: Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin. \n",
      "Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR- TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients.\n",
      "Cluster: 4\n",
      "PMID: 27241659\n",
      "Document text: Plexiform neurofibromatosis type 1.\n",
      "Cluster: 3\n",
      "PMID: 27442694\n",
      "Document text: Polydactyly and obesity - the clinical manifestation of ciliopathy: a boy with Bardet-Biedl syndrome. \n",
      "The prevalence of obesity in children is still rising all over the world. The most common reason for significant weight gain is a high-calorie diet and decreased physical activity. However, apart from environmental factors, genetic predisposition plays a crucial role in the pathomechanism of obesity. We present the case of a boy with pathological obesity and Bardet-Biedl syndrome (BBS). BBS is a ciliopathy, a heterogeneous group of rare disorders associated with defects in primary cilia. Other clinical signs and symptoms of BBS are: polydactyly, hypertension, hyperlipidemia, hypogonadotrophic hypogonadism, intellectual disability, rod-cone dystrophy, genitourinary and renal abnormalities.\n",
      "genetic factors of rapid weight gain should be taken into consideration in a child with obesity. Polydactyly can be associated with ciliopathy. A patient with Bardet-Biedl syndrome requires multi-specialist care.\n",
      "Cluster: 1\n",
      "PMID: 27488999\n",
      "Document text: Renal phenotype in Bardet-Biedl syndrome: a combined defect of urinary concentration and dilution is associated with defective urinary AQP2 and UMOD excretion. \n",
      "The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml·min-1·1.73 m-2 Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling.\n",
      "Copyright © 2016 the American Physiological Society.\n",
      "Cluster: 1\n",
      "PMID: 27571505\n",
      "Document text: Oral healthcare management in Bardet Biedl syndrome. \n",
      "Bardet Biedl syndrome is a rare autosomal recessive disorder with variable clinical presentation and challenging diagnosis. Recognition of orofacial features might help in the diagnosis. Dental management of affected patients might be complicated by renal, cardiac, metabolic, neurosensory, and cognitive defects.\n",
      "© 2016 Special Care Dentistry Association and Wiley Periodicals, Inc.\n",
      "Cluster: 1\n",
      "PMID: 27580659\n",
      "Document text: Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer. \n",
      "Patients diagnosed with triple-negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study, in silico analysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, which is a driver of tumor metastasis and resistance and a target for cancer vaccine approaches. Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions. A strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. Two brachyury-targeting cancer vaccines are currently undergoing clinical evaluation; the data presented here provide rationale for using brachyury-targeting immunotherapy approaches for the treatment of TNBC.\n",
      "© 2016 Society for Endocrinology.\n",
      "Cluster: 5\n",
      "PMID: 27888421\n",
      "Document text: Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer. \n",
      "The current American Joint Committee on Cancer (AJCC) staging manual uses tumor size, lymph node, and metastatic status to stage breast cancer across different subtypes. We examined the prognosis of triple-negative breast cancer (TNBC) versus non-TNBC within the same stages and sub-stages to evaluate whether TNBC had worse prognosis than non-TNBC.\n",
      "We reviewed the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) data and identified 158,358 patients diagnosed with breast cancer from 2010 to 2012. The overall survival (OS) time and breast cancer cause-specific survival time were compared between patients with TNBC and non-TNBC in each stage and sub-stages. The results were validated using a dataset of 2049 patients with longer follow-up from our institution.\n",
      "Compared with patients with non-TNBC, patients with TNBC had worse OS and breast cancer cause-specific survival time in every stage and sub-stage in univariate and multivariate analyses adjusting for age, race, tumor grade, and surgery and radiation treatments in the SEER data. The worse OS time in patients with TNBC was validated in our institutional dataset.\n",
      "Patients with TNBC have worse survival than patients with non-TNBC. The new AJCC staging manual should consider breast cancer biomarker information.\n",
      "Cluster: 4\n",
      "PMID: 28101798\n",
      "Document text: miR-10b, miR-26a, miR-146a And miR-153 Expression in Triple Negative Vs Non Triple Negative Breast Cancer: Potential Biomarkers. \n",
      "MicroRNAs (miRNAs) are small non-coding RNAs composed of 18-25 nucleotides that can post-transcriptionally regulate gene expression and have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. About 1000 genes in humans encode miRNAs, which account for approximately 3% of the human genome, and up to 30% of human protein coding genes may be regulated by miRNAs. The objective of this article is to evaluate the expression profile of four miRNAs previously implicated in triple negative breast cancer: miR-10b, miR-26a, miR-146a and miR-153, and to determine their possible interaction in triple negative and non triple negative breast cancer based on clinical outcome and the expression of BRCA1. 24 triple-negative and 13 non triple negative breast cancer cases, were studied by q-RT-PCR and immunohistochemistry to determine the expression of the four studied miRNAs and the BRCA1 protein, respectively. We observed that the BRCA1 protein was absent in 62.5% of the triple negative cases. Besides, the miR-146a and miR-26a were over expressed in triple negative breast cancer. These two miRNAs, miR-10b and miR-153 were significantly associated to lymph node metastases occurrence in triple negative breast carcinoma. All the analyzed microRNAs were not associated with the expression of BRCA1 in our conditions. Our work provides evidence that miR-146a, miR-26a, miR-10b and miR-153 could be defined as biomarkers in triple negative breast cancer to predict lymph node metastases (LNM).\n",
      "Cluster: 5\n",
      "PMID: 28174811\n",
      "Document text: Ovarian teratomas in a patient with Bardet-Biedl syndrome, a rare association. \n",
      "Bardet-Biedl syndrome (BBS) represents a rare ciliopathy recessive autosomal inherited. The main clinical features are retinal dystrophy, postaxial polydactyly, obesity, different degrees of cognitive deficit, renal impairment, hypogonadism and genital malformations. The genetic explanation consists in BBS genes mutations, which encode modified proteins, altering the function of the immotile cilia. As a multitude of BBS genes mutations were described, the phenotypic aspect of these disorders varies according to that. We present the case of a 22 years old female patient, known with BBS since the age of 11 and which was diagnosed and operated for bilateral ovarian dermoid cysts, at the age of 21. We did not find a similar case in literature, regarding the association between the two disorders. We consider that our case points towards the importance of periodic imagistic evaluations [magnetic resonance imaging (MRI), computed tomography (CT) or ultrasound] of these patients, not only clinical and biological. Usually, the moment they are diagnosed with hypogonadism or genital malformations (in childhood or adolescence), the genital evaluation is neglected thereafter. We also consider that our therapeutic approach can be helpful in other similar clinical situations. Another important conclusion is represented by the importance of genetic counseling of the relatives of a BBS patient, unfortunately insufficiently provided in our region.\n",
      "Cluster: 6\n",
      "PMID: 28198380\n",
      "Document text: A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth. \n",
      "Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative. PAK4 is also overexpressed in other types of cancer, making it a promising drug target. However, its inhibition is complicated by the fact that PAK4 has both kinase-dependent and -independent functions. Here we investigate a new clinical compound KPT-9274, which has been shown to inhibit PAK4 and NAMPT. We find that KPT-9274 (and its analog, KPT-8752) can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. These compounds also block the growth of the breast cancer cells in vitro, and stimulate apoptosis. Most importantly, oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. Our results indicate that KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy.\n",
      "Cluster: 4\n",
      "PMID: 28211982\n",
      "Document text: The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype. \n",
      "We report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern-sparse, thin, and with slow growing-, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy-PPP1CB-related Noonan syndrome with loose anagen hair-shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. © 2017 Wiley Periodicals, Inc.\n",
      "© 2017 Wiley Periodicals, Inc.\n",
      "Cluster: 2\n",
      "PMID: 28267727\n",
      "Document text: Why axing TPP was a lost opportunity for biotech.\n",
      "Cluster: 6\n",
      "PMID: 28296849\n",
      "Document text: The Epilepsy Dilemma.\n",
      "Cluster: 6\n",
      "PMID: 28377481\n",
      "Document text: Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer. \n",
      "Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer.Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized.Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4+ and HLA-DRB1*1501-restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples.Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer. Clin Cancer Res; 23(15); 4347-53. ©2017 AACR.\n",
      "©2017 American Association for Cancer Research.\n",
      "Cluster: 5\n",
      "PMID: 28618888\n",
      "Document text: Moonlight.\n",
      "Cluster: 6\n",
      "PMID: 28618929\n",
      "Document text: Anti-tumorigenic effects of a novel digitoxin derivative on both estrogen receptor-positive and triple-negative breast cancer cells. \n",
      "While there are targeted treatments for triple positive breast cancers, lack of specific biomarkers for triple-negative breast cancers (TNBC) has hindered the development of therapies for this subset of cancers. In this study, we evaluated the anticancer properties of cardiac glycoside Digitoxin (Dtx) and its synthetic analog MonoD on breast cancer cell lines MCF-7 (estrogen receptor-positive breast cancer) and MDA-MB-468 (triple-negative breast cancer). Both cardiac glycosides, at concentrations within the therapeutic range, increased the fraction of cells in the G0/G1 phase of the cell cycle, decreased viability, and inhibited the migration of MCF-7 and MDA-MB-468 cells. Both cardiac glycosides increased production of superoxide and induced apoptosis in both cell types. Reduced protein levels of nuclear factor kappa B and IkappaB kinase-beta were found in cardiac glycoside-treated cells, indicating that the cellular effects of these compounds are mediated via nuclear factor kappa B pathway. This study demonstrates the cytotoxic potential of digitoxin, and more importantly its synthetic analog MonoD, in the treatment of triple-positive breast cancer and more importantly the aggressive triple-negative breast cancer. Collectively, this study provides a basis for the reevaluation of cardiac glycosides in the treatment of breast cancer and more importantly reveals their potential in the treatment of triple-negative breast cancers.\n",
      "Cluster: 4\n",
      "PMID: 28653902\n",
      "Document text: NF-κB as the main node of resistance to receptor tyrosine kinase inhibitors in triple-negative breast cancer. \n",
      "Graphical abstract Although accounting for merely a minute portion of diagnosed breast cancers, disproportionate number of deaths and associated low survival rate of patients have made triple-negative breast cancer to be considered as the most lethal breast cancer subtype. More importantly, intrinsic or developed resistance to chemotherapeutic regimens and disappointing outcomes of trials associated with many newly developed agents are other obstacles in establishment of a durable response in these patients. Interestingly, these happen despite the outstanding preclinical outcomes observed by these agents, most importantly among them, targeted receptor tyrosine kinase inhibitors. Pursuing these disappointing outcomes, especially in the case of targeted receptor tyrosine kinase inhibitors, many researches have focused on identification of the hidden factors involved. Highly inflammatory, rich in reactive oxygen species, and hypoxic microenvironment of triple-negative breast cancer tumors and the involving mediators were the first suggestions for observed resistance and poor clinical outcomes of targeted receptor tyrosine kinase inhibitors. Interestingly, for all aberrantly expressed mediators observed in microenvironment, downstream pathways converge in a common node, nothing but the nuclear factor-κB, the insidious factor proposed to be the cause of many events opposing achievement of a desired outcome. In first section of current review, we describe the signaling pathways underlying activation of receptor tyrosine kinases and their convergence at the nuclear factor-κB node, and in next section, we demonstrate how unique hypoxic, inflammatory, rich in free-radical microenvironment of triple-negative breast cancer exacerbate pathways in which otherwise could become mostly suppressed by receptor tyrosine kinase inhibitors.\n",
      "Cluster: 4\n",
      "PMID: 28911804\n",
      "Document text: Case report: Left ventricular noncompaction cardiomyopathy and RASopathies. \n",
      "The following is a case report of 6 patients with Noonan syndrome (NS) and/or a related RASsopathy that also have evidence of left ventricular noncompaction cardiomyopathy (LVNC). Noonan syndrome,a type of RASopathy, is an autosomal dominant disorder that is typically associated with congenital heart defects and hypertrophic cardiomyopathy. There have been minimal reports of Noonan syndrome or other RASopathy and the association of LVNC. This report promulgates 6 nonrelated cases of Noonan syndrome or unspecified RASopathy and LVNC.\n",
      "Copyright © 2017 Elsevier Masson SAS. All rights reserved.\n",
      "Cluster: 2\n",
      "PMID: 28958991\n",
      "Document text: Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer. \n",
      "Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose-response measures of cell viability, an EC50 value was calculated for each cellular phenotype and each PARP inhibitor. The EC50 values for both 53BP1 metrics strongly correlated with IC50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle-associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. Mol Cancer Ther; 16(12); 2892-901. ©2017 AACR.\n",
      "©2017 American Association for Cancer Research.\n",
      "Cluster: 5\n",
      "PMID: 29039417\n",
      "Document text: Protein interaction perturbation profiling at amino-acid resolution. \n",
      "The identification of genomic variants in healthy and diseased individuals continues to rapidly outpace our ability to functionally annotate these variants. Techniques that both systematically assay the functional consequences of nucleotide-resolution variation and can scale to hundreds of genes are urgently required. We designed a sensitive yeast two-hybrid-based 'off switch' for positive selection of interaction-disruptive variants from complex genetic libraries. Combined with massively parallel programmed mutagenesis and a sequencing readout, this method enables systematic profiling of protein-interaction determinants at amino-acid resolution. We defined >1,000 interaction-disrupting amino acid mutations across eight subunits of the BBSome, the major human cilia protein complex associated with the pleiotropic genetic disorder Bardet-Biedl syndrome. These high-resolution interaction-perturbation profiles provide a framework for interpreting patient-derived mutations across the entire protein complex and thus highlight how the impact of disease variation on interactome networks can be systematically assessed.\n",
      "Cluster: 1\n",
      "PMID: 29271604\n",
      "Document text: The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor. \n",
      "Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.\n",
      "© 2017 Wiley Periodicals, Inc.\n",
      "Cluster: 2\n",
      "PMID: 30391405\n",
      "Document text: Epirubicin-loaded polymeric micelles effectively treat axillary lymph nodes metastasis of breast cancer through selective accumulation and pH-triggered drug release. \n",
      "Suppression of axillary lymph node metastasis (ALNM) is an important goal in the treatment of breast cancer. While several therapies directed to ALNM have been evaluated, effective and safe treatments for ALNM in triple negative breast cancer (TNBC) have not been established yet, especially against initial/small metastases. Here, we demonstrated the therapeutic effect of an anthracycline drug, epirubicin (EPI)-loaded polymeric micelles equipped with pH-triggered drug release property (EPI/m) against ALNM of TNBC. EPI/m effectively inhibited the spread of the primary tumor and the growth of ALNM, through selective accumulation and penetration in both primary tumor and vascularized ALNM, as well as efficient drug activation triggered by the intratumoral acidic environment. Furthermore, we revealed that the improvement of the activated drug distribution of EPI/m contributed to dose-dependent enhancement of the antitumor effect through expansion of the therapeutic window. These findings highlight the utility of pH-responsive property in EPI/m for the treatment of ALNM in TNBC.\n",
      "Copyright © 2018 Elsevier B.V. All rights reserved.\n",
      "Cluster: 5\n",
      "PMID: 30397860\n",
      "Document text: In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model. \n",
      "Monocarboxylate transporter 1 (MCT1), also known as a L-lactate transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression. AR-C155858 inhibited the cellular L-lactate uptake and cellular proliferation at low nanomolar potencies (IC50 values of 25.0 ± 4.2 and 20.2 ± 0.2 nM, respectively). In the xenograft 4T1 mouse model of immunocompetent animals, AR-C155858 (10 mg/kg i.p. once daily) had no effect on tumor volume and weight. Treatment with AR-C155858 resulted in slightly increased tumor lactate concentrations; however, the changes were not statistically significant. AR-C155858 was well tolerated, as demonstrated by the unchanged body weight and blood lactate concentrations. Average blood and tumor AR-C155858 concentrations (110 ± 22 and 574 ± 245 nM, respectively), 24 h after the last dose, were well above the IC50 values. These data indicate that AR-C155858 penetrated 4T1 xenograft tumors and was present at high concentrations but was ineffective in decreasing tumor growth. Evaluations of AR-C155858 in other preclinical models of breast cancer are needed to further assess its efficacy.\n",
      "Cluster: 5\n",
      "PMID: 30405852\n",
      "Document text: Oestrogen Inhibits VEGF Expression And Angiogenesis In Triple-Negative Breast Cancer By Activating GPER-1. \n",
      "Triple-negative breast cancer (TNBC) is the most malignant type of breast cancer with ample vascularisation and high vascular endothelial growth factor (VEGF) expression. The sex steroid hormone oestrogen is involved in several cellular activities associated with TNBC regulation. However, the role of oestrogen in VEGF expression and angiogenesis in TNBC remains unclear. In this study, we found that treatment with 17β-oestradiol (E2) inhibited VEGF mRNA and protein expression in the TNBC cell lines MDA-MB-468 and MDA-MB-436. To further elaborate on the phenomenon of E2-regulated angiogenesis, we showed that conditioned medium from the TNBC cell line MDA-MB-468 treated with E2 inhibits the tube formation ability of human umbilical vein endothelial cells (HUVECs). Additionally, the G-protein-coupled oestrogen receptor-1 (GPER-1)-specific agonist G-1 has a function similar to that of E2. While G-15, the selective antagonist of GPER-1, notably reversed the inhibitory effects of E2 and G-1 on VEGF expression and tube formation, suggesting that GPER-1 is involved in the E2-induced angiogenesis suppression in TNBC cells. Moreover, E2 inhibited in vivo tumour growth and angiogenesis and reduced the expression levels of VEGF, NF-κB/p65, STAT3, and the endothelial marker CD34 in MDA-MB-468 xenograft tumours. Our findings provide important evidence that E2 can inhibit VEGF expression and angiogenesis in TNBC by activating GPER-1, offering additional insight into tumour angiogenesis and targets for drug intervention in TNBC.\n",
      "Cluster: 6\n",
      "PMID: 30419345\n",
      "Document text: Recent Advances in the Research of Immunotherapy for Triple-Negative Breast Cancer. \n",
      "Triple-negative breast cancer (TNBC) refers to cancers that are low in expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tends to behave more aggressively than other types of breast cancer. Unlike other breast cancer subtypes (ie, ER-positive, HER2-positive subtypes), there are no approved targeted treatments available, other than the administration of chemotherapy. Immunotherapy is a new kind of treatment approach for TNBC when compared with the surgical treatment, chemotherapy, endocrine therapy, and molecular targeting therapy. The present article reviews the research progresses of immunotherapy for TNBC in recent years. The full text structure covers molecular classification of TNBC, active immunotherapy of TNBC, passive immunotherapy of TNBC, oncolytic immunotherapy and the prospect of immunotherapy for TNBC.\n",
      "Copyright © 2018 Elsevier B.V. All rights reserved.\n",
      "Cluster: 5\n",
      "PMID: 30419349\n",
      "Document text: DEPDC1, negatively regulated by miR-26b, facilitates cell proliferation via the up-regulation of FOXM1 expression in TNBC. \n",
      "Triple negative breast cancer (TNBC), characterized by lack of estrogen receptors, progesterone hormone receptors, and HER2 overexpression, is a more aggressive high grade tumor and not sensitive to current targeted drugs. The clinical prognosis of TNBC is poorer than other types of breast cancer, and there is no effective therapy strategy until now. Thus, it is necessary to determine important factors involved in regulating the progression of TNBC. In this study, we found DEPDC1 was up-regulated in the tissues of TNBC compared with their paired peritumoral tissues. DEPDC1 over-expression facilitated cell proliferation and tumor growth through increasing the expression of FOXM1 in TNBC cells. Conversely, knockdown of DEPDC1 had the opposite effects. Moreover, miR-26b, acting as a tumor suppressor in TNBC, directly repressed the expression of DEPDC1 and mitigated its promotive effects on cell growth and colony formation. These results indicate that DEPDC1, negatively regulated by miR-26b, promotes cell proliferation and tumor growth via up-regulating FOXM1 expression, implying an important underlying mechanism of regulating the progression of TNBC.\n",
      "Copyright © 2018. Published by Elsevier B.V.\n",
      "Cluster: 4\n"
     ]
    }
   ],
   "source": [
    "for document in clus1.documents:\n",
    "    print('PMID:', document['pmid'])\n",
    "    print('Document text:', document['all_text'].strip()) \n",
    "    print('Cluster:', clus1.clustering_results_dict[document['pmid']])"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "0.9004329004329004"
      ]
     },
     "execution_count": 6,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "clus1.precision"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "0.9288043478260869"
      ]
     },
     "execution_count": 7,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "clus1.recall"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 8,
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "0.9143986037281078"
      ]
     },
     "execution_count": 8,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "clus1.f_measure"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 9,
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "0.9117647058823529"
      ]
     },
     "execution_count": 9,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "clus1.purity"
   ]
  },
  {
   "cell_type": "markdown",
   "metadata": {},
   "source": [
    "If running without labels:"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 10,
   "metadata": {},
   "outputs": [],
   "source": [
    "clus2 = PubMedClustering(os.path.join('./data', 'pmids_test_set_unlabeled.txt'),\n",
    "                            metamap='/opt/public_mm/bin/metamap16', email=\"This.Is.My@Email.org\", is_file=True)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 11,
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "2018-11-28 14:59:41,783 INFO  Fetching articles and abstracts from PubMed\n",
      "2018-11-28 14:59:42,976 INFO  Parsing fetched PubMed articles\n",
      "2018-11-28 14:59:43,252 INFO  Parsed all PubMed articles\n",
      "2018-11-28 14:59:43,253 INFO  Processing all documents with MetaMap\n",
      "2018-11-28 14:59:43,254 INFO  0 of 36 documents processed with MetaMap\n",
      "2018-11-28 15:00:05,498 INFO  10 of 36 documents processed with MetaMap\n",
      "2018-11-28 15:00:24,033 INFO  20 of 36 documents processed with MetaMap\n",
      "2018-11-28 15:00:43,814 INFO  30 of 36 documents processed with MetaMap\n",
      "2018-11-28 15:00:58,169 INFO  All documents processed with MetaMap\n",
      "2018-11-28 15:00:58,170 INFO  Creating dictionary\n",
      "2018-11-28 15:00:58,171 INFO  adding document #0 to Dictionary(0 unique tokens: [])\n",
      "2018-11-28 15:00:58,173 INFO  built Dictionary(122 unique tokens: ['cancer', 'carcinoma', 'colon', 'colorectal', 'hereditary']...) from 36 documents (total 1401 corpus positions)\n",
      "2018-11-28 15:00:58,173 INFO  Filtering low occurence words from dictionary\n",
      "2018-11-28 15:00:58,174 INFO  discarding 86 tokens: [('colon', 2), ('polyps', 2), ('alzheimer', 1), ('amyotrophic', 2), ('arrest', 1), ('cardiac', 2), ('lateral', 2), ('metabolic', 1), ('sclerosis', 2), ('recessive', 1)]...\n",
      "2018-11-28 15:00:58,175 INFO  keeping 36 tokens which were in no less than 3 and no more than 36 (=100.0%) documents\n",
      "2018-11-28 15:00:58,176 DEBUG rebuilding dictionary, shrinking gaps\n",
      "2018-11-28 15:00:58,177 INFO  resulting dictionary: Dictionary(36 unique tokens: ['cancer', 'carcinoma', 'colorectal', 'hereditary', 'malignant']...)\n",
      "2018-11-28 15:00:58,177 DEBUG rebuilding dictionary, shrinking gaps\n",
      "2018-11-28 15:00:58,178 INFO  Creating a corpus\n",
      "2018-11-28 15:00:58,180 INFO  Creating a TF-IDF model\n",
      "2018-11-28 15:00:58,183 INFO  collecting document frequencies\n",
      "2018-11-28 15:00:58,184 INFO  PROGRESS: processing document #0\n",
      "2018-11-28 15:00:58,185 INFO  calculating IDF weights for 36 documents and 35 features (284 matrix non-zeros)\n",
      "2018-11-28 15:00:58,185 INFO  Calculating document matrix\n",
      "2018-11-28 15:00:58,186 INFO  Document vector for 0 of 36 documents calculated\n",
      "2018-11-28 15:00:58,187 INFO  Document vector for 10 of 36 documents calculated\n",
      "2018-11-28 15:00:58,188 INFO  Document vector for 20 of 36 documents calculated\n",
      "2018-11-28 15:00:58,190 INFO  Document vector for 30 of 36 documents calculated\n",
      "2018-11-28 15:00:58,192 INFO  Document matrix calculated\n",
      "2018-11-28 15:00:58,193 INFO  Performing clustering on the document matrix\n",
      "2018-11-28 15:00:58,237 INFO  Clustering performed\n",
      "2018-11-28 15:00:58,238 INFO  Clustering results saved to object\n"
     ]
    }
   ],
   "source": [
    "clus2.run()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 13,
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "PMID: 14707528\n",
      "Document text: Are there socio-economic inequalities in age of resection of colorectal cancer in people with HNPCC? \n",
      "The relationship between socio-economic status and health has been consistently reported and is thought to be causal. Socio-economic inequalities are present in the incidence of and mortality from cancer in general, but not in the incidence of colorectal cancer in particular. However, there are socio-economic gradients in mortality from colorectal cancer. The socio-economic distribution of incidence of and mortality from colorectal cancer in individuals with hereditary non-polyposis colon cancer (Lynch syndrome) is not known. It is possible that increased awareness of and access to screening for colorectal cancer amongst this group of individuals reduces the socio-economic gradients seen in the population as a whole. We investigated the relationship between socio-economic status and age of resection of colorectal cancer in a cohort of individuals with hereditary non-polyposis colon cancer. More affluent individuals tended to undergo surgical resection for colorectal cancers earlier in their lives than less affluent individuals. This relationship was bordering on statistical significance. This trend probably represents socio-economic variations in access to treatment. In addition, age based diagnostic criteria for hereditary non-polyposis colon cancer may, inadvertently, accentuate socio-economic inequalities in outcome.\n",
      "Cluster: 3\n",
      "PMID: 24523674\n",
      "Document text: The role of miRNA in motor neuron disease. \n",
      "microRNA is a subset of endogenous non-coding RNA. It binds to partially complementary sequences in mRNAs and inhibits mRNA translation by either blocking translational machinery or degrading mRNAs. It is involved in various cellular processes including cell cycle, development, metabolism, and synaptic plasticity. Dysregulation of miRNA expression and function is reported in various diseases including cancer, metabolic disorders as well as neurological disorders. In nervous system, miRNA related pathways play a very important role in development and function of neuronal cells. Moreover, numerous evidences suggest that dysregulated miRNA related pathways contribute to pathology of neurological disorders such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Here, we review current knowledge about the role of miRNAs in motor neuron disorders, especially about two common diseases: SMA and ALS.\n",
      "Cluster: 0\n",
      "PMID: 24533984\n",
      "Document text: hnRNP M facilitates exon 7 inclusion of SMN2 pre-mRNA in spinal muscular atrophy by targeting an enhancer on exon 7. \n",
      "Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease, which causes death of motor neurons in the anterior horn of the spinal cord. Genetic cause of SMA is the deletion or mutation of SMN1 gene, which encodes the SMN protein. Although SMA patients include SMN2 gene, a duplicate of SMN1 gene, predominant production of exon 7 skipped isoform from SMN2 pre-mRNA, fails to rescue SMA patients. Here we show that hnRNP M, a member of hnRNP protein family, when knocked down, promotes exon 7 skipping of both SMN2 and SMN1 pre-mRNA. By contrast, overexpression of hnRNP M promotes exon 7 inclusion of both SMN2 and SMN1 pre-mRNA. Significantly, hnRNP M promotes exon 7 inclusion in SMA patient cells. Thus, we conclude that hnRNP M promotes exon 7 inclusion of both SMN1 and SMN2 pre-mRNA. We also demonstrate that hnRNP M contacts an enhancer on exon 7, which was previously shown to provide binding site for tra2β. We present evidence that hnRNP M and tra2β contact overlapped sequence on exon 7 but with slightly different RNA sequence requirements. In addition, hnRNP M promotes U2AF65 recruitment on the flanking intron of exon 7. We conclude that hnRNP M promotes exon 7 inclusion of SMN1 and SMN2 pre-mRNA through targeting an enhancer on exon 7 through recruiting U2AF65. Our results provide a clue that hnRNP M is a potential therapeutic target for SMA. \n",
      "Copyright © 2014 Elsevier B.V. All rights reserved.\n",
      "Cluster: 1\n",
      "PMID: 24705136\n",
      "Document text: Zebrafish models of human motor neuron diseases: advantages and limitations. \n",
      "Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs. \n",
      "Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.\n",
      "Cluster: 0\n",
      "PMID: 24715477\n",
      "Document text: The high frequency of genetic diseases in hypotonic infants referred by neuropediatrics. \n",
      "Neonatal hypotonia is a relatively common cause of consultation in daily pediatric practice. It is part of the clinical presentation of a large group of heterogeneous diseases, many of which have an important and classifiable genetic background. Identification of the specific disorder can help optimize the management and treatment of the patient and inform genetic counseling for the family, and therefore input from clinical geneticists is critical at the earliest stages of medical management. Here we present 30 patients with hypotonia of unknown etiology referred by a neuropediatrician to clinical genetics. Clinical, genetic, and molecular evaluation of each patient was performed. Sixty-nine percent of the patients included in the study had a genetic disease, including eight with Prader-Willi syndrome, three with spinal muscular atrophy, one with Rett syndrome, and one with Sotos syndrome harboring a previously undescribed mutation. Our data demonstrate that a multidisciplinary approach used from the outset that includes molecular analysis can help improve diagnosis and management of hypotonic infants.\n",
      "© 2014 Wiley Periodicals, Inc.\n",
      "Cluster: 1\n",
      "PMID: 24769255\n",
      "Document text: SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease. \n",
      "At the post-transcriptional level, expression of protein-coding genes is controlled by a series of RNA regulatory events including nuclear processing of primary transcripts, transport of mature mRNAs to specific cellular compartments, translation and ultimately, turnover. These processes are orchestrated through the dynamic association of mRNAs with RNA binding proteins and ribonucleoprotein (RNP) complexes. Accurate formation of RNPs in vivo is fundamentally important to cellular development and function, and its impairment often leads to human disease. The survival motor neuron (SMN) protein is key to this biological paradigm: SMN is essential for the biogenesis of various RNPs that function in mRNA processing, and genetic mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP assembly. We discuss advances in our understanding of SMN activity as a chaperone of RNPs and how disruption of SMN-dependent RNA pathways can cause motor neuron disease. \n",
      "Copyright © 2014 Elsevier Ltd. All rights reserved.\n",
      "Cluster: 0\n",
      "PMID: 25080519\n",
      "Document text: Observational study of spinal muscular atrophy type I and implications for clinical trials. \n",
      "Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I).\n",
      "Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered.\n",
      "Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1-22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p=0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n=10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21-2.33, p=0.02).\n",
      "Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.\n",
      "© 2014 American Academy of Neurology.\n",
      "Cluster: 0\n",
      "PMID: 25711197\n",
      "Document text: Lynch Syndrome: A Primer for Urologists and Panel Recommendations. \n",
      "Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a common genetic disease. The predisposition of patients with Lynch syndrome to urological cancer, particularly upper tract urothelial carcinoma, is underappreciated. Urologists may be involved in several aspects of care involving Lynch syndrome, including identifying undiagnosed patients, surveillance of those with established Lynch syndrome or screening family members, in addition to treating patients with Lynch syndrome in whom upper tract urothelial carcinoma develops. We sought to increase awareness in the urological community about Lynch syndrome and provide some guidance where little currently exists.\n",
      "Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement we reviewed the available published literature and guidelines from 1998 to 2014 on Lynch syndrome and its association with upper tract urothelial carcinoma. Recommendations based on the literature and the consensus of expert opinion are provided.\n",
      "No randomized or prospective study has been done to evaluate Lynch syndrome in the setting of urological cancer. All data were based on retrospective studies. Lynch syndrome is an autosomal dominant genetic disease caused by germline mutations in 4 mismatch repair genes, leading to the accumulation of DNA errors in microsatellite regions. Upper tract urothelial carcinoma develops in up to 28% of patients with known Lynch syndrome. The diagnosis of Lynch syndrome is established by clinical criteria, tumor tissue testing and genetic evaluation. Urologists should suspect Lynch syndrome when a patient with upper tract urothelial carcinoma presents before age 60 years or meets the 3-2-1 rule. Screening patients with Lynch syndrome for upper tract urothelial carcinoma presents a particular challenge. While no ideal screening test exists, at a minimum routine urinalysis is recommended using the American Urological Association guideline of 3 or more red blood cells per high power field as a trigger for further assessment. Upper tract urothelial carcinoma associated with Lynch syndrome presents at a younger age than sporadic upper tract urothelial carcinoma. It shows a higher proportion of ureteral cancer with a female preponderance and a possible predisposition to bilaterality.\n",
      "Lynch syndrome is a common genetic disease that is an underappreciated cause of upper tract urothelial carcinoma and possibly other urological cancers. Optimal screening for upper tract urothelial carcinoma in this population is unclear. Further study is needed to identify the best screening test and interval of testing. Urologists should consider routine tissue testing of de novo upper tract urothelial carcinoma tissue in individuals at risk.\n",
      "Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.\n",
      "Cluster: 3\n",
      "PMID: 26077881\n",
      "Document text: Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome. \n",
      "The short rib polydactyly syndromes (SRPSs) are a heterogeneous group of autosomal recessive, perinatal lethal skeletal disorders characterized primarily by short, horizontal ribs, short limbs and polydactyly. Mutations in several genes affecting intraflagellar transport (IFT) cause SRPS but they do not account for all cases. Here we identify an additional SRPS gene and further unravel the functional basis for IFT. We perform whole-exome sequencing and identify mutations in a new disease-producing gene, cytoplasmic dynein-2 light intermediate chain 1, DYNC2LI1, segregating with disease in three families. Using primary fibroblasts, we show that DYNC2LI1 is essential for dynein-2 complex stability and that mutations in DYNC2LI1 result in variable length, including hyperelongated, cilia, Hedgehog pathway impairment and ciliary IFT accumulations. The findings in this study expand our understanding of SRPS locus heterogeneity and demonstrate the importance of DYNC2LI1 in dynein-2 complex stability, cilium function, Hedgehog regulation and skeletogenesis.\n",
      "Cluster: 2\n",
      "PMID: 26098911\n",
      "Document text: Deletion of IFT80 Impairs Epiphyseal and Articular Cartilage Formation Due to Disruption of Chondrocyte Differentiation. \n",
      "Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development. Partial loss of IFT80 function leads Jeune asphyxiating thoracic dystrophy (JATD) or short-rib polydactyly (SRP) syndrome type III, displaying narrow thoracic cavity and multiple cartilage anomalies. However, it is unknown how IFT80 regulates cartilage formation. To define the role and mechanism of IFT80 in chondrocyte function and cartilage formation, we generated a Col2α1; IFT80f/f mouse model by crossing IFT80f/f mice with inducible Col2α1-CreER mice, and deleted IFT80 in chondrocyte lineage by injection of tamoxifen into the mice in embryonic or postnatal stage. Loss of IFT80 in the embryonic stage resulted in short limbs at birth. Histological studies showed that IFT80-deficient mice have shortened cartilage with marked changes in cellular morphology and organization in the resting, proliferative, pre-hypertrophic, and hypertrophic zones. Moreover, deletion of IFT80 in the postnatal stage led to mouse stunted growth with shortened growth plate but thickened articular cartilage. Defects of ciliogenesis were found in the cartilage of IFT80-deficient mice and primary IFT80-deficient chondrocytes. Further study showed that chondrogenic differentiation was significantly inhibited in IFT80-deficient mice due to reduced hedgehog (Hh) signaling and increased Wnt signaling activities. These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation.\n",
      "Cluster: 2\n",
      "PMID: 26309352\n",
      "Document text: Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer. \n",
      "Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.\n",
      "Cluster: 3\n",
      "PMID: 26642845\n",
      "Document text: Tumor islands and spread through air spaces: Distinct patterns of invasion in lung adenocarcinoma. \n",
      "Lung adenocarcinoma is a highly heterogeneous disease and the heterogeneity is associated with various patient outcomes even in early-stage tumors. In order to improve prognostic and predictive values, the IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification was put forth in 2011 and it has been adopted in the recently published World Health Organization (WHO) classification of Tumours of the Lung, Pleura, Thymus and Heart 4th edition 2015, and lung adenocarcinomas are classified based on the predominant pattern. The performance of the classification in stratifying patient outcomes after resection of Stage I tumors and predicting molecular alterations has been confirmed by several studies. It also includes the category of minimally invasive adenocarcinoma (MIA) that predicts 100% 5-year recurrence free survival after curative resection similar to adenocarcinoma in situ. The diagnosis of MIA is based on not only size of the invasive component but also the absence of aggressive morphologic features such as pleural and/or lymphovascular invasion. Importantly, the WHO 2015 classification has introduced the concept of air space invasion and includes it as the exclusion criteria for MIA. The air space invasion consists of tumor islands and spread through air spaces (STAS). In this review, we will discuss the two entities and their clinical implications. \n",
      "© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.\n",
      "Cluster: 7\n",
      "PMID: 26895074\n",
      "Document text: Mismatch repair deficiency testing in clinical practice. \n",
      "Lynch syndrome, an autosomal dominant inherited disorder, is caused by inactivating mutations involving DNA mismatch repair (MMR) genes. This leads to profound genetic instability, including microsatellite instability (MSI) and increased risk for cancer development, particularly colon and endometrial malignancies. Clinical testing of tumor tissues for the presence of MMR gene deficiency is standard practice in clinical oncology, with immunohistochemistry and PCR-based microsatellite instability analysis used as screening tests to identify potential Lynch syndrome families. The ultimate diagnosis of Lynch syndrome requires documentation of mutation within one of the four MMR genes (MLH1, PMS2, MSH2 and MSH6) or EPCAM, currently achieved by comprehensive sequencing analysis of germline DNA. In this review, the genetic basis of Lynch syndrome, methodologies of MMR deficiency testing, and current diagnostic algorithms in the clinical management of Lynch syndrome, are discussed.\n",
      "Cluster: 3\n",
      "PMID: 27466187\n",
      "Document text: An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome. \n",
      "The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.\n",
      "© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.\n",
      "Cluster: 2\n",
      "PMID: 27496117\n",
      "Document text: Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. \n",
      "This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers.\n",
      "Copyright © 2016 by the National Comprehensive Cancer Network.\n",
      "Cluster: 3\n",
      "PMID: 27903974\n",
      "Document text: LncRNAs are altered in lung squamous cell carcinoma and lung adenocarcinoma. \n",
      "Long non-coding RNAs (lncRNAs) have been implicated in pathogenesis of various cancers, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). We used cBioPortal to analyze lncRNA alteration frequencies and their ability to predict overall survival (OS) using 504 LUSC and 522 LUAD samples from The Cancer Genome Atlas (TCGA) database. In LUSC, 624 lncRNAs had alteration rates > 1% and 64 > 10%. In LUAD 625 lncRNAs had alteration rates > 1% and 36 > 10%. Among those, 620 lncRNAs had alteration frequencies > 1% in both LUSC and LUAD, while 22 were LUSC-specific and 23 were LUAD-specific. Twenty lncRNAs had alteration frequencies > 10% in both LUSC and LUAD, while 44 were LUSC-specific and 16 were LUAD specific. Genome ontology and pathway analyses produced similar results for LUSC and LUAD. Two lncRNAs (IGF2BP2-AS1 and DGCR5) correlated with better OS in LUSC, and three (MIR31HG, CDKN2A-AS1 and LINC01600) predicted poor OS in LUAD. Chip-seq and luciferase reporter assays identified potential IGF2BP2-AS1, DGCR5 and LINC01600 promoters and enhancers. This study presented lncRNA landscapes and revealed differentially expressed, highly altered lncRNAs in LUSC and LUAD. LncRNAs that act as oncogenes and lncRNA-regulating transcription factors provide novel targets for anti-lung cancer therapeutics.\n",
      "Cluster: 7\n",
      "PMID: 28105432\n",
      "Document text: The Hedgehog Signaling Networks in Lung Cancer: The Mechanisms and Roles in Tumor Progression and Implications for Cancer Therapy. \n",
      "Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.\n",
      "Cluster: 4\n",
      "PMID: 28118799\n",
      "Document text: Lung cancer and miRNAs: a possible remedy for anti-metastatic, therapeutic and diagnostic applications. \n",
      "Lung cancer still accounts for the leading cause of cancer-related deaths worldwide and despite the emerging advances in diagnostic and therapeutic techniques it remains to be a serious global public health concern. Micro-ribonucleic acids (microRNAs) are responsible for invasion and metastasis of various tumors including lung cancer which underscores the necessity of understanding their functions. Areas covered: Herein, we aim to summarize the recent advances made in our understanding of the miRNAs with special reference to lung cancer. Moreover, the role of miRNAs in crucial cellular processes will be elucidated. Various applications of the miRNAs would be explained and different kinds of them would be discussed to delineate their significance in lung cancer biology, therapy and diagnosis. Expert commentary: the miRNA study in the field of respiratory disease and specially lung cancer has emerged lately. Given the several miRNAs, which are in the clinical trials, this field is passing through its maturation phase which ultimately could rise to a robust tool for lung cancer therapy, diagnosis and prevention.\n",
      "Cluster: 4\n",
      "PMID: 28400947\n",
      "Document text: Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia. \n",
      "Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function.\n",
      "Herein we describe mutations in IFT43, a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described IFT43 mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the IFT43 SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43.\n",
      "This study defines a new IFT43-associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors.\n",
      "Cluster: 2\n",
      "PMID: 28403077\n",
      "Document text: High expression of CD8 predicts favorable prognosis in patients with lung adenocarcinoma: A cohort study. \n",
      "Lung carcinoma is the most common cause of malignant death worldwide. CD8 T cells, as critical elements in antitumor immunity, could function as good prognostic indicators in various kinds of cancers such as renal cell carcinoma and colorectal cancer, but its prognostic role in lung adenocarcinoma is still unclear. The objective of this study was to explore the prognostic role of CD8 expression in lung adenocarcinoma.Paired tumor and adjacent noncancerous tissues were obtained from 102 patients with lung adenocarcinoma, and CD8 expression of these samples was examined by immunohistochemistry. We evaluated the relationships between the expression of CD8 and pathological grade, TNM stage, clinical stage, as well as overall survival (OS).Expression of CD8 was significantly increased in lung adenocarcinoma compared with that in adjacent lung adenocarcinoma (P < .001). CD8 expression was negatively correlated with pathological grade (r = -0.216, P = .022) and N stage (r = -0.372, P < .001), while no statistical correlation with T stage, or clinical stage. Importantly, OS was numerically increased in patients with high expression of CD8 than the group of intermediate and low CD8 expression (P = .12). Furthermore, CD8 could significantly increase OS (P = .043, HR: .713, 95%CI: .515-.989) by univariate Cox's proportional hazards regression analysis.Our data indicated that expression of CD8, as a protective factor, is correlated with the outcome of patients with lung adenocarcinoma. Furthermore, CD8 might be a novel prognostic biological marker for patients with lung adenocarcinoma.\n",
      "Cluster: 7\n",
      "PMID: 28623644\n",
      "Document text: Increased AAA-TOB3 correlates with lymph node metastasis and advanced stage of lung adenocarcinoma. \n",
      "This study was to investigate the differential mitochondrial protein expressions in human lung adenocarcinoma and provide preliminary data for further exploration of the carcinogenic mechanism.\n",
      "Total proteins of A549 and 16HBE mitochondria were extracted through 2D polyacrylamide gel electrophoresis (2-DE). The differential mitochondria proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and were further confirmed by Western blot, immunoelectron microscopy and immunohistochemistry (IHC) in A549 cells as well as lung adenocarcinoma tissues.\n",
      "A total of 41 differentially expressed protein spots were found in A549 mitochondria. Of them, 15 proteins were highly expressed and 26 proteins were lowly expressed in the mitochondria of A549 (by more than 1.5 times). Among the 15 more highly expressed proteins, AAA-TOB3 (by more than 3 times) was highly expressed in the mitochondria of A549 compared with the 16HBE, by LC-MS/MS identification. High electron density and clear circular colloidal gold-marked AAA-TOB3 particles were observed in the A549 cells via immunoelectron microscopy. Besides, AAA-TOB3 was confirmed to be elevated in lung adenocarcinoma by Western blot and IHC. Moreover, increased AAA-TOB3 correlated with lymph node metastasis and advanced stage of lung adenocarcinoma (p<0.05).\n",
      "AAA-TOB3 was highly expressed in lung adenocarcinoma, and the up-regulation of AAA-TOB3 correlated with lymph node metastasis and advanced stage of lung adenocarcinoma, which suggested that it could serve as a potential molecular marker for lung adenocarcinoma.\n",
      "Cluster: 7\n",
      "PMID: 28696559\n",
      "Document text: Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). \n",
      "Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominant cancer syndrome that confers an elevated risk of early-onset colorectal cancer (CRC) and increased lifetime risk for other cancers of the endometrium, stomach, small intestine, hepatobiliary system, kidney, ureter, and ovary. Lynch syndrome accounts for up to 3% of all CRC, making it the most common hereditary colorectal cancer syndrome. Germline mutations in methyl-directed mismatch repair (MMR) genes give rise to microsatellite instability (MSI) in tumor DNA. Lynch syndrome is most frequently caused by pathogrenic variants in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Germline mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with Lynch syndrome. Pathogenic vatiants in MSH6 have been reported in approximately 7-10% of families with Lynch syndrome. Pathogenic variants in PMS2 account for fewer than 5% of mutations in families with Lynch syndrome. This unit presents a comprehensive molecular genetic testing strategy for Lynch syndrome including MSI analysis, next generation sequencing (NGS)-based targeted sequence analysis, PCR-based Sanger sequencing and microarray-based comparative genomic hybridization (array-CGH). © 2017 by John Wiley & Sons, Inc.\n",
      "Copyright © 2017 John Wiley & Sons, Inc.\n",
      "Cluster: 3\n",
      "PMID: 28699072\n",
      "Document text: Expending Role of Microsatellite Instability in Diagnosis and Treatment of Colorectal Cancers. \n",
      "Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2.\n",
      "Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov . Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers.\n",
      "Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy.\n",
      "Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.\n",
      "Cluster: 3\n",
      "PMID: 28720066\n",
      "Document text: High expression of SLC34A2 is a favorable prognostic marker in lung adenocarcinoma patients. \n",
      "Dysregulation of SLC34A2 (NaPi2b) in tumors has attracted wide attention, but its expression and function in non-small cell lung cancer remains unclear. By examining its expression in lung adenocarcinoma and correlation to patient outcome, we aimed to explore its prognostic and therapeutic values in this deadly disease. Overall, 175 cases of lung adenocarcinoma sample were included in this study. Histological subtyping of them was diagnosed according to standards of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011. Protein expression of SLC34A2 and anaplastic lymphoma kinase in these samples was determined by immunohistochemistry. Epidermal growth factor receptor mutations were examined using amplification refractory mutation system. Statistical analysis was performed using software of Pearson's correlation coefficient. High expression of SLC34A2 was identified in about 2/3 patients and correlated with significantly better patient's overall survival. Epidermal growth factor receptor mutations were detected in about 53% of patients with no statistically significant difference to patient's overall survival. Anaplastic lymphoma kinase rearrangement was found in 8 out of 175 patients, harboring this abnormality leads to shorter overall survival. No correlation has been found between SLC34A2 expression and epidermal growth factor receptor mutation or anaplastic lymphoma kinase rearrangements in lung adenocarcinoma. High expression of SLC34A2 is present in about 3/4 lung adenocarcinoma samples and predicts better outcome. Since it is a membrane protein, antibody-based drugs targeting this marker might bring new resolution to this deadly disease.\n",
      "Cluster: 7\n",
      "PMID: 28834269\n",
      "Document text: Prognostic significance of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of stage I lung adenocarcinoma: A retrospective study based on analysis of 110 Chinese patients. \n",
      "The aim of this study was to investigate the relationship between predominant subtype, classification, and prognosis in Chinese stage I lung adenocarcinoma patients according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) International Multidisciplinary Lung Adenocarcinoma Classification.\n",
      "Between 2000 and 2010, 110 patients with stage I lung adenocarcinoma underwent surgery at Xuanwu Hospital. Two pathologists independently reclassified all resected specimens according to the IASLC/ATS/ERS classification. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis.\n",
      "There were no cases of adenocarcinoma in situ, and three cases of minimally invasive adenocarcinoma. There were 107 cases of invasive adenocarcinoma: 12 lepidic, 32 acinar, 30 papillary, 18 micropapillary, and 15 solid predominant subtypes. Patients with micropapillary and solid predominant tumors had significantly poorer disease-free survival compared to those with other subtypes of predominant tumors (P = 0.021). Multivariate analysis revealed that the new classification (P = 0.003) and T stage (P = 0.034) were independent predictors of disease-free and overall survival, respectively.\n",
      "The predominant subtype in the primary tumor was associated with prognosis in resected stage I lung adenocarcinoma.\n",
      "© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\n",
      "Cluster: 7\n",
      "PMID: 29060458\n",
      "Document text: Improved microRNA biomarkers for pathological stages in lung adenocarcinoma via clustering of dysregulated microRNA-target associations. \n",
      "Most of cancer-related deaths are due to lung cancer, and there is a need for reliable prognosis biomarkers to predict stages in lung adenocarcinoma cases. Recently, microRNAs are found to have potential as both biomarkers and therapeutic targets for lung cancer. As evidence suggests microRNA dysregulations are implicated in many cancer malignancies, it is important to consider the changes in miRNA-target associations among different lung cancer biological states. We proposed a novel clustering strategy to identify groups of miRNAs with similar dysregulated targets. Then, we incorporated the learned clusters of miRNA as prior knowledge to a Sparse Group Lasso classifier to improve classification results, thereby leading to more relevant selection of microRNA biomarkers. We apply the method to the TCGA Lung Adenocarcinoma dataset. In cross-validation tests, the AUC rate for each stages is 1.0, 0.71, 0.68, 0.64, and 0.90 for normal, Stage I, Stage II, Stage III, and Stage IV, respectively. Among the candidate miRNAs selected in the model, 87% are reported to be related to Lung Adenocarcinoma. Further result demonstrates that clustering miRNAs by considering the dysregulation between miRNAs and mRNA targets leads to biomarkers with higher precision and recall rate to known lung adenocarcinoma miRNAs.\n",
      "Cluster: 7\n",
      "PMID: 29261648\n",
      "Document text: Regulation of the cohesin-loading factor NIPBL: Role of the lncRNA NIPBL-AS1 and identification of a distal enhancer element. \n",
      "Cohesin is crucial for genome stability, cell division, transcription and chromatin organization. Its functions critically depend on NIPBL, the cohesin-loader protein that is found to be mutated in >60% of the cases of Cornelia de Lange syndrome (CdLS). Other mutations are described in the cohesin subunits SMC1A, RAD21, SMC3 and the HDAC8 protein. In 25-30% of CdLS cases no mutation in the known CdLS genes is detected. Until now, functional elements in the noncoding genome were not characterized in the molecular etiology of CdLS and therefore are excluded from mutation screening, although the impact of such mutations has now been recognized for a wide range of diseases. We have identified different elements of the noncoding genome involved in regulation of the NIPBL gene. NIPBL-AS1 is a long non-coding RNA transcribed upstream and antisense to NIPBL. By knockdown and transcription blocking experiments, we could show that not the NIPBL-AS1 gene product, but its actual transcription is important to regulate NIPBL expression levels. This reveals a possibility to boost the transcriptional activity of the NIPBL gene by interfering with the NIPBL-AS1 lncRNA. Further, we have identified a novel distal enhancer regulating both NIPBL and NIPBL-AS1. Deletion of the enhancer using CRISPR genome editing in HEK293T cells reduces expression of NIPBL, NIPBL-AS1 as well as genes found to be dysregulated in CdLS.\n",
      "Cluster: 0\n",
      "PMID: 29279609\n",
      "Document text: Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome. \n",
      "Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.\n",
      "Cluster: 6\n",
      "PMID: 29348408\n",
      "Document text: NIPBL+/- haploinsufficiency reveals a constellation of transcriptome disruptions in the pluripotent and cardiac states. \n",
      "Cornelia de Lange syndrome (CdLS) is a complex disorder with multiple structural and developmental defects caused by mutations in structural and regulatory proteins involved in the cohesin complex. NIPBL, a cohesin regulatory protein, has been identified as a critical protein responsible for the orchestration of transcriptomic regulatory networks necessary for embryonic development. Mutations in NIPBL are responsible for the majority of cases of CdLS. Through RNA-sequencing of human induced pluripotent stem cells and in vitro-derived cardiomyocytes, we identified hundreds of mRNAs, pseudogenes, and non-coding RNAs with altered expression in NIPBL+/- patient-derived cells. We demonstrate that NIPBL haploinsufficiency leads to upregulation of gene sets identified in functions related to nucleosome, chromatin assembly, RNA modification and downregulation of Wnt signaling, cholesterol biosynthesis and vesicular transport in iPSC and cardiomyocytes. Mutations in NIPBL result in the dysregulation of many genes responsible for normal heart development likely resulting in the variety of structural cardiac defects observed in the CdLS population.\n",
      "Cluster: 5\n",
      "PMID: 29379197\n",
      "Document text: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome. \n",
      "We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.\n",
      "Cluster: 6\n",
      "PMID: 29860495\n",
      "Document text: Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo. \n",
      "Cornelia de Lange syndrome (CdLS) is a rare disease characterized by cognitive impairment, multisystemic alterations and premature aging. Furthermore, CdLS cells display gene expression dysregulation and genomic instability. Here, we demonstrated that treatment with antioxidant drugs, such as ascorbic acid and riboceine, reduced the level of genomic instability and extended the in vitro lifespan of CdLS cell lines. We also found that antioxidant treatment partially rescued the phenotype of a zebrafish model of CdLS. Gene expression profiling showed that antioxidant drugs caused dysregulation of gene transcription; notably, a number of genes coding for the zinc finger (ZNF)-containing Krueppel-associated box (KRAB) protein domain (KRAB-ZNF) were found to be downregulated. Taken together, these data suggest that antioxidant drugs have the potential to ameliorate the developmental phenotype of CdLS.\n",
      "Cluster: 1\n",
      "PMID: 29982567\n",
      "Document text: Mutation of FOP/FGFR1OP in mice recapitulates human short rib-polydactyly ciliopathy. \n",
      "Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. A total of 436 skeletal dysplasias are listed in the 2015 revised version of the nosology and classification of genetic skeletal disorders, of which nearly 20% are still genetically and molecularly uncharacterized. We report the clinical and molecular characterization of a lethal skeletal dysplasia of the short-rib group caused by mutation of the mouse Fop gene. Fop encodes a centrosomal and centriolar satellite (CS) protein. We show that Fop mutation perturbs ciliogenesis in vivo and that this leads to the alteration of the Hedgehog signaling pathway. Fop mutation reduces CSs movements and affects pericentriolar material composition, which probably participates to the ciliogenesis defect. This study highlights the role of a centrosome and CSs protein producing phenotypes in mice that recapitulate a short rib-polydactyly syndrome when mutated.\n",
      "Cluster: 2\n",
      "PMID: 30418046\n",
      "Document text: NFIX downregulation independently predicts poor prognosis in lung adenocarcinoma, but not in squamous cell carcinoma. \n",
      "To study the expression profile of NFIX, its prognostic value and the mechanism of its dysregulation in lung adenocarcinoma (LUAD). Patients & materials: A retrospective study was performed by using data from the Cancer Genome Atlas and the Human Protein Atlas.\n",
      "High NFIX RNA expression was an independent prognostic factor of favorable overall survival (HR: 0.687, 95% CI: 0.496-0.951; p = 0.024) and recurrence-free survival (HR: 0.700, 95% CI: 0.493-0.994, p = 0.046) in LUAD, but not in lung squamous cell carcinoma. NFIX DNA hypermethylation was associated with significantly decreased NFIX expression and shorter overall survival and recurrence-free survival in LUAD.\n",
      " NFIX downregulation might independently predict poor prognosis in LUAD. DNA hypermethylation might be an important cause of the downregulation.\n",
      "Cluster: 7\n",
      "PMID: 30419062\n",
      "Document text: Association of specific gene mutations derived from machine learning with survival in lung adenocarcinoma. \n",
      "Lung cancer is the second most common cancer in the United States and the leading cause of mortality in cancer patients. Biomarkers predicting survival of patients with lung cancer have a profound effect on patient prognosis and treatment. However, predictive biomarkers for survival and their relevance for lung cancer are not been well known yet. The objective of this study was to perform machine learning with data from The Cancer Genome Atlas of patients with lung adenocarcinoma (LUAD) to find survival-specific gene mutations that could be used as survival-predicting biomarkers. To identify survival-specific mutations according to various clinical factors, four feature selection methods (information gain, chi-squared test, minimum redundancy maximum relevance, and correlation) were used. Extracted survival-specific mutations of LUAD were applied individually or as a group for Kaplan-Meier survival analysis. Mutations in MMRN2 and GMPPA were significantly associated with patient mortality while those in ZNF560 and SETX were associated with patient survival. Mutations in DNAJC2 and MMRN2 showed significant negative association with overall survival while mutations in ZNF560 showed significant positive association with overall survival. Mutations in MMRN2 showed significant negative association with disease-free survival while mutations in DRD3 and ZNF560 showed positive associated with disease-free survival. Mutations in DRD3, SETX, and ZNF560 showed significant positive association with survival in patients with LUAD while the opposite was true for mutations in DNAJC2, GMPPA, and MMRN2. These gene mutations were also found in other cohorts of LUAD, lung squamous cell carcinoma, and small cell lung cancer. In LUAD of Pan-Lung Cancer cohort, mutations in GMPPA, DNAJC2, and MMRN2 showed significant negative associations with survival of patients while mutations in DRD3 and SETX showed significant positive association with survival. In this study, machine learning was conducted to obtain information necessary to discover specific gene mutations associated with the survival of patients with LUAD. Mutations in the above six genes could predict survival rate and disease-free survival rate in patients with LUAD. Thus, they are important biomarker candidates for prognosis.\n",
      "Cluster: 7\n",
      "PMID: 30419347\n",
      "Document text: Estrogen-independent Myc overexpression confers endocrine therapy resistance on breast cancer cells expressing ERαY537S and ERαD538G mutations. \n",
      "Approximately 30% of metastatic breast cancers harbor estrogen receptor α (ERα) mutations associated with resistance to endocrine therapy and reduced survival. Consistent with their constitutive proliferation, T47D and MCF7 cells in which wild-type ERα is replaced by the most common mutations, ERαY537S and ERαD538G, exhibit partially estrogen-independent gene expression. A novel invasion/dissociation/rebinding assay demonstrated that the mutant cells have a higher tendency to dissociate from invasion sites and rebind to a second site. Compared to ERαD538G breast tumors, ERαY537S tumors exhibited a dramatic increase in lung metastasis. Transcriptome analysis showed that the ERαY537S and ERαD538G mutations each elicit a unique gene expression profile. Gene set enrichment analysis showed Myc target pathways are highly induced in mutant cells. Moreover, chromatin immunoprecipitation showed constitutive, fulvestrant-resistant, recruitment of ERα mutants to the Myc enhancer region, resulting in estrogen-independent Myc overexpression in mutant cells and tumors. Knockdown and virus transduction showed Myc is necessary and sufficient for ligand-independent proliferation of the mutant cells but had no effect on metastasis-related phenotypes. Thus, Myc plays a key role in aggressive proliferation-related phenotypes exhibited by breast cancer cells expressing ERα mutations.\n",
      "Copyright © 2018 Elsevier B.V. All rights reserved.\n",
      "Cluster: 4\n",
      "PMID: 30419558\n",
      "Document text: Neutrophil to Lymphocyte Ratio as a Prognostic Factor in European Patients with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Treated with Tyrosine Kinase Inhibitors. \n",
      "A high neutrophil to lymphocyte ratio (NLR) has been associated with adverse outcomes in non-small cell lung cancer (NSCLC). However, information on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC is scarce, and most of the studies published have been conducted in Asian populations. We aimed to assess the influence of pretreatment NLR on progression-free survival (PFS) and overall survival (OS) in Western European patients treated with EGFR tyrosine kinase inhibitors (TKIs).\n",
      "A retrospective evaluation of 41 patients with EGFR-mutant advanced NSCLC treated with EGFR TKIs between June 2010 and May 2016 was carried out. The association between several prognostic factors including pretreatment NLR and survival was analyzed.\n",
      "Median PFS and OS were 10.58 and 20.84 months, respectively. OS for patients with a high NLR was 7.4 months, compared to 24.6 months for patients with a low NLR (p = 0.0122). In multivariate analysis, poor performance status (ECOG PS ≥ 2) and presence of ≥ 3 metastatic locations were identified as significant independent prognostic factors for worse PFS. For OS, unfavorable prognostic factors were a high NLR and central nervous system metastasis at diagnosis.\n",
      "Pretreatment NLR is an independent prognostic factor for OS in Western European patients with EGFR-mutant NSCLC treated with EGFR TKIs.\n",
      "© 2018 S. Karger GmbH, Freiburg.\n",
      "Cluster: 4\n"
     ]
    }
   ],
   "source": [
    "for document in clus2.documents:\n",
    "    print('PMID:', document['pmid'])\n",
    "    print('Document text:', document['all_text'].strip()) \n",
    "    print('Cluster:', clus2.clustering_results_dict[document['pmid']])"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "metadata": {},
   "outputs": [],
   "source": []
  }
 ],
 "metadata": {
  "kernelspec": {
   "display_name": "Python 3",
   "language": "python",
   "name": "python3"
  },
  "language_info": {
   "codemirror_mode": {
    "name": "ipython",
    "version": 3
   },
   "file_extension": ".py",
   "mimetype": "text/x-python",
   "name": "python",
   "nbconvert_exporter": "python",
   "pygments_lexer": "ipython3",
   "version": "3.6.6"
  }
 },
 "nbformat": 4,
 "nbformat_minor": 2
}