Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors.

Int J Cancer. 2018 Feb 16;:

Authors: Liew PL, Huang RL, Weng YC, Fang CL, Hui-Ming Huang T, Lai HC

Abstract
Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remain uncertain. We analyzed the methylomic profiles of six benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs), and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process, and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma, and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC, or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second-generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous-type-specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC. This article is protected by copyright. All rights reserved.

PMID: 29451304 [PubMed - as supplied by publisher]

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.

Diabetologia. 2018 Feb 15;:

Authors: Habeb AM, Flanagan SE, Zulali MA, Abdullah MA, Pomahačová R, Boyadzhiev V, Colindres LE, Godoy GV, Vasanthi T, Al Saif R, Setoodeh A, Haghighi A, Haghighi A, Shaalan Y, International Neonatal Diabetes Consortium, Hattersley AT, Ellard S, De Franco E

Abstract
AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes.
METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.
RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day.
CONCLUSIONS/INTERPRETATION: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent.
DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).

PMID: 29450569 [PubMed - as supplied by publisher]

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

Addict Behav Rep. 2017 Dec;6:8-14

Authors: Ettienne EB, Chapman E, Maneno M, Ofoegbu A, Wilson B, Settles-Reaves B, Clarke M, Dunston G, Rosenblatt K

Abstract
Introduction: Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes.
Methods: We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management.
Results: At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing.
Conclusion: Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

PMID: 29450233 [PubMed]

Therapeutic Lowering of Lipoprotein(a): A Role for Pharmacogenetics?

Circ Genom Precis Med. 2018 Feb;11(2):e002052

Authors: Boffa MB, Koschinsky ML

PMID: 29449330 [PubMed - in process]

First experience in Switzerland in Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease enrolled in a lumacaftor-ivacaftor therapy trial - preliminary results.

Swiss Med Wkly. 2018 Feb 16;148:w14593

Authors: Murer C, Huber LC, Kurowski T, Hirt A, Robinson CA, Bürgi U, Benden C

Abstract
AIMS OF THE STUDY: Cystic fibrosis is the most common genetic disorder in Caucasians. The combination of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector lumacaftor / potentiator ivacaftor (LUM/IVA) has been shown to increase forced expiratory volume in 1 second (FEV1) moderately, but predominantly reduce acute exacerbation rate (AER) in Phe508del homozygous cystic fibrosis patients; however, patients with FEV1 <40% predicted were excluded from studies. We used LUM/IVA on a "compassionate use" basis in cystic fibrosis patients with end-stage pulmonary disease. Our aim was to evaluate if this patient cohort tolerates LUM/IVA treatment and if there is clinical stabilisation. Lung transplantation (LTX) is the ultimate treatment option for these patients despite maximal therapy. If LTX candidates stabilise clinically, conditions for LTX, when it is indicated, improve. This is particularly important in countries such as Switzerland with a low organ donation rate and long waiting times for suitable donor organs.
METHODS: We included all patients from the Adult Cystic Fibrosis Centre at the University Hospital Zurich with Phe508del homozygous genotype and a predicted FEV1 <40% or being evaluated or already listed for LTX. Clinical outcome data comprised AER, 6-minute walking distance (6-MWD), FEV1, forced vital capacity (FVC), mid-expiratory flow (MEF 25-75%), sweat chloride, body mass index (BMI) and quality of life. Respiratory-related adverse events (RAEs) were recorded. LUM/IVA treatment was initiated at a low dose and the dose increased stepwise.
RESULTS: Twenty patients were on trial with LUM/IVA; at the cut-off date, 6-month follow-up was complete for 10 patients. RAEs were severe and occurred early. The dropout rate due to RAE or lack of clinical success was 20%. Median AER decreased from 2.5 in the 6 months pre-treatment to 1 during the observation period. FEV1 increased from 32 to 34.5% predicted, p = 0.292. The 6-MWD increased by a median 33 m (p = 0.6086). Sweat chloride decreased significantly by a median of 25 mmol/l (p = 0.0003). Median BMI increased from 19 to 19.9 kg/m2 (p = 0.1488). At the cut-off, three previously listed patients were paused on the transplant waiting list.
CONCLUSION: Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease tolerated LUM/IVA, although RAEs occurred early and were severe. This positive finding was probably due to the stepwise dose increases. There was clinical benefit mainly from reduction in AER and stabilisation of lung function. We propose that all suitable Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease should have a trial of LUM/IVA treatment in experienced centres.

PMID: 29451946 [PubMed - in process]

Aquagenic Wrinkling of the Palms in Patients with Cystic Fibrosis.

Br J Dermatol. 2018 Feb 16;:

Authors: Kaiser H, Brustad N, Pressler T, Bygum A

Abstract
Aquagenic wrinkling of the palms (AWP) is a condition characterized by oedema, confluent white papules and excessive wrinkling of the palms after few minutes exposure to water. The phenomenon may be associated with pain, numbness and pruritus1,2 . It was first noticed and described in 1974 in children with cystic fibrosis (CF) by a paediatrician R.B. Elliott3 . This article is protected by copyright. All rights reserved.

PMID: 29451691 [PubMed - as supplied by publisher]

CFTR mutation enhances Dishevelled degradation and results in impairment of Wnt-dependent hematopoiesis.

Cell Death Dis. 2018 Feb 15;9(3):275

Authors: Sun H, Wang Y, Zhang J, Chen Y, Liu Y, Lin Z, Liu M, Sheng K, Liao H, Tsang KS, Zhang X, Jiang X, Xu W, Mao M, Chan HC

Abstract
Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) with a multitude of clinical manifestations. Some CF patients develop clinically significant anemia, suggesting that CFTR may regulate hematopoiesis. Here, we report that cftr mutant zebrafish model exhibits primitive and definitive hematopoietic defects with impaired Wnt signaling. Cftr is found to interact, via its PDZ-binding domain (PDZBD), with Dishevelled (Dvl), a key component of Wnt signaling required for hematopoietic progenitor specification, thus protecting Dvl from Dapper1 (Dpr1)-induced lysosomal degradation. Defective hematopoiesis and impaired Wnt signaling in cftr mutant can be rescued by overexpression of wild-type or channel function-defective G551D mutant CFTR with an intact PDZBD, but not Cftr with mutations in the PDZBD. Analysis of human database ( http://r2.amc.nl ) shows that CFTR is positively correlated with DVL2 and Wnt-related hematopoietic factors in human blood system. The results reveal a previously unrecognized role of CFTR, which is independent of its channel function, in regulating DVL degradation and thus Wnt signaling required for hematopoiesis in both zebrafish and humans, providing an explanation for the anemic phenotype of CF patients.

PMID: 29449653 [PubMed - in process]

Lung clearance index to monitor treatment response in pulmonary exacerbations in preschool children with cystic fibrosis.

Thorax. 2018 Feb 15;:

Authors: Rayment JH, Stanojevic S, Davis SD, Retsch-Bogart G, Ratjen F

Abstract
BACKGROUND: Antibiotic treatment for pulmonary symptoms in preschool children with cystic fibrosis (CF) varies among clinicians. The lung clearance index (LCI) is sensitive to early CF lung disease, but its utility to monitor pulmonary exacerbations in young children has not been assessed.
OBJECTIVE: We aim to (1) understand how LCI changes during lower respiratory tract symptoms relative to a recent clinically stable measurement, (2) determine whether LCI can identify antibiotic treatment response and (3) compare LCI changes to changes in spirometric indices.
METHODS: LCI and spirometry were measured at quarterly clinic visits over a 12-month period in preschool children with CF. Symptomatic visits were identified and classified as treated or untreated. Treatment response was estimated using propensity score matching methods.
RESULTS: 104 symptomatic visits were identified in 78 participants. LCI increased from baseline in both treated (mean relative change +23.8% (95% CI 16.2 to 31.4)) and untreated symptomatic visits (mean relative change +11.2% (95% CI 2.4 to 19.9)). A significant antibiotic treatment effect was observed when LCI was used as the outcome measure (average treatment effect -15.5% (95% CI -25.4 to -5.6)) but not for z-score FEV1.
CONCLUSION: LCI significantly deteriorated with pulmonary symptoms relative to baseline and improved with antibiotic treatment. These data suggest that LCI may have a role in the routine clinical care of preschool children with CF.

PMID: 29449440 [PubMed - as supplied by publisher]

Genome Sequences of 12 Pseudomonas lundensis Strains Isolated from the Lungs of Humans.

Genome Announc. 2018 Feb 15;6(7):

Authors: Scales BS, Erb-Downward JR, Falkowski NR, LiPuma JJ, Huffnagle GB

Abstract
We report here the first complete genome sequence of a human Pseudomonas lundensis isolate, strain AU1044, and the draft genomes of 11 other clinical P. lundensis strains, isolated from the lungs of cystic fibrosis patients. The genome of strain AU1044 is 4.81 Mb and encodes seven 16S rRNAs.

PMID: 29449399 [PubMed]

Antimicrobial activity of a novel bioengineered honey against non-typeable Haemophilus influenzae biofilms: an in vitro study.

J Clin Pathol. 2018 Feb 15;:

Authors: Newby RS, Dryden M, Allan RN, Salib RJ

Abstract
The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) plays an important role in many chronic respiratory diseases including otitis media, chronic rhinosinusitis, cystic fibrosis and chronic obstructive pulmonary disease. Biofilm formation has been implicated in NTHi colonisation, persistence of infection and recalcitrance towards antimicrobials. There is therefore a pressing need for the development of novel treatment strategies that are effective against NTHi biofilm-associated diseases. SurgihoneyRO is a honey-based product that has been bioengineered to enable the slow release of H2O2, a reactive oxygen species to which H. influenzae is susceptible. Treatment of established NTHi biofilms with SurgihoneyRO significantly reduced biofilm viability through enhanced H2O2 production and was shown to be more effective than the conventional antibiotic co-amoxiclav.

PMID: 29449345 [PubMed - as supplied by publisher]

Structural variation in SBDS gene, with loss of exon 3, in two Shwachman-Diamond patients.

Blood Cells Mol Dis. 2016 09;60:33-5

Authors: Minelli A, Nacci L, Valli R, Pietrocola G, Ramenghi U, Locatelli F, Brescia L, Nicolis E, Cipolli M, Danesino C

PMID: 27519942 [PubMed - indexed for MEDLINE]

Variant in human POFUT1 reduces enzymatic activity and likely causes a recessive microcephaly, global developmental delay with cardiac and vascular features.

Glycobiology. 2018 Feb 14;:

Authors: Takeuchi H, Wong D, Schneider M, Freeze HH, Takeuchi M, Berardinelli SJ, Ito A, Lee H, Nelson SF, Haltiwanger RS

Abstract
Protein O-fucosyltransferase-1 (POFUT1) adds O-fucose monosaccharides to epidermal growth factor-like (EGF) repeats found on approximately 100 mammalian proteins, including Notch receptors. Haploinsufficiency of POFUT1 has been linked to adult-onset Dowling Degos Disease (DDD) with hyperpigmentation defects. Homozygous deletion of mouse Pofut1 results in embryonic lethality with severe Notch-like phenotypes including defects in somitogenesis, cardiogenesis, vasculogenesis, and neurogenesis, but the extent to which POFUT1 is required for normal human development is not yet understood. Here we report a patient with a congenital syndrome consisting of severe global developmental delay, microcephaly, heart defects, failure to thrive, and liver disease with a previously unreported homozygous NM_015352.1: c.485 C>T variant (p.Ser162Leu) in POFUT1 detected by exome sequencing. Both parents are heterozygotes and neither manifests any signs of DDD. No other detected variant explained the phenotype. This variant eliminated a conserved N-glycosylation sequon at Asn160 in POFUT1 and profoundly decreased POFUT1 activity in patient fibroblasts compared to control fibroblasts. Purified p.Ser162Leu mutant protein also showed much lower POFUT1 activity with a lower affinity for EGF acceptor substrate than wild type POFUT1. Eliminating the N-glycan sequon by replacing Asn160 with Gln had little effect on POFUT1 activity, suggesting that loss of the glycan is not responsible for the defect. Furthermore, the p.Ser162Leu mutant showed weaker ability to rescue Notch activity in cell-based assays. These results suggest that this N-glycan of POFUT1 is not required for its proper enzymatic function, and that the p.Ser162Leu mutation of POFUT1 likely causes global developmental delay, microcephaly with vascular and cardiac defects.

PMID: 29452367 [PubMed - as supplied by publisher]

Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients.

PLoS One. 2018;13(2):e0188869

Authors: Ji H, Li D, Wu Y, Zhang Q, Gu Q, Xie H, Ji T, Wang H, Zhao L, Zhao H, Yang Y, Feng H, Xiong H, Ji J, Yang Z, Kou L, Li M, Bao X, Chang X, Zhang Y, Li L, Li H, Niu Z, Wu X, Xiao J, Jiang Y, Wang J

Abstract
OBJECTIVE: Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population.
METHODS: 119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing.
RESULTS: Clinical and genetic features of hypomyelinating disorders were revealed. Nine different hypomyelinating disorders were identified in 119 patients: Pelizaeus-Merzbacher disease (94, 79%), Pelizaeus-Merzbacher-like disease (10, 8%), hypomyelination with atrophy of the basal ganglia and cerebellum (3, 3%), GM1 gangliosidosis (5, 4%), GM2 gangliosidosis (3, 3%), trichothiodystrophy (1, 1%), Pol III-related leukodystrophy (1, 1%), hypomyelinating leukodystrophy type 9 (1, 1%), and chromosome 18q deletion syndrome (1, 1%). Of the sample, 94% (112/119) of the patients were genetically diagnosed, including 111 with mutations distributing across 9 genes including PLP1, GJC2, TUBB4A, GLB1, HEXA, HEXB, ERCC2, POLR3A, and RARS and 1 with mosaic chromosomal change of 46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18. Eighteen novel mutations were discovered. Mutations in POLR3A and RARS were first identified in Chinese patients with Pol III-related leukodystrophy and hypomyelinating leukodystrophy, respectively.
SIGNIFICANCE: This is the first report on clinical and genetic features of hypomyelinating disorders with a large sample of patients in Chinese population, identifying 18 novel mutations especially mutations in POLR3A and RARS in Chinese patients, expanding clinical and genetic spectrums of hypomyelinating disorders.

PMID: 29451896 [PubMed - in process]

Genetic Investigation of 93 Families with Microphthalmia or Posterior Microphthalmos.

Clin Genet. 2018 Feb 16;:

Authors: Patel N, Khan AO, Alsahli S, Abdel-Salam G, Nowilaty SR, Mansour AM, Nabil A, Al-Owain M, Sogati S, Salih MA, Kamal AM, Alsharif H, Alsaif H, Alzahrani SS, Abdulwahab F, Ibrahim N, Hashem M, Faquih T, Shah ZA, Abouelhoda M, Monies D, Dasouki M, Shaheen R, Majid S, Aldahmesh MA, Alkuraya FS

Abstract
Microphthalmia is a developmental eye defect that is highly variable in severity and in its potential for systemic association. Despite the discovery of many disease genes in microphthalmia, at least 50% of patients remain undiagnosed genetically. Here, we describe a cohort of 147 patients (93 families) from our highly consanguineous population with various forms of microphthalmia (including the distinct entity of posterior microphthalmos) that were investigated using a next-generation sequencing multi-gene panel (i-panel) as well as whole exome sequencing (WES) and molecular karyotyping. A potentially causal mutation was identified in the majority of the cohort with microphthalmia (61%) and posterior microphthalmos (82%). The identified mutations (55 point mutations, 15 of which are novel) spanned 24 known disease genes, some of which have not or only very rarely been linked to microphthalmia (PAX6, SLC18A2, DSC3 and CNKSR1). Our study has also identified interesting candidate variants in two genes that have not been linked to human diseases (MYO10 and ZNF219), which we present here as novel candidates for microphthalmia. In addition to revealing novel phenotypic aspects of microphthalmia, this study expands its allelic and locus heterogeneity and highlights the need for expanded testing of patients with this condition.

PMID: 29450879 [PubMed - as supplied by publisher]

Novel homozygous variants in ATCAY, MCOLN1, and SACS in complex neurological disorders.

Parkinsonism Relat Disord. 2018 Feb 06;:

Authors: Manzoor H, Brüggemann N, Hussain HMJ, Bäumer T, Hinrichs F, Wajid M, Münchau A, Naz S, Lohmann K

Abstract
BACKGROUND: Neurological disorders comprise a large group of clinically and genetically heterogeneous disorders, many of which have a genetic cause. In addition to a detailed neurological examination, exome sequencing is being increasingly used as a complementary diagnostic tool to identify the underlying genetic cause in patients with unclear, supposedly genetically determined disorders.
OBJECTIVE: To identify the genetic cause of a complex movement disorder in five consanguineous Pakistani families.
METHODS: We included five consanguineous Pakistani families with complex recessively inherited movement disorders. Clinical investigation including videotaping was carried out in a total of 59 family members (4-21 per family) and MRI in six patients. Exome sequencing was performed in 4-5 family members per pedigree to explore the underlying genetic cause.
RESULTS: Patients presented a wide spectrum of neurological symptoms including ataxia and/or dystonia. We identified three novel homozygous, segregating variants in ATCAY (p.Pro200Profs*20), MCOLN1 (p.Ile184Thr), and SACS (p.Asn3040Lysfs*4) in three of the families. Thus, we were able to identify the likely cause of the disease in a considerable number of families (60%) with the relatively simple and nowadays widely available method of exome sequencing. Of note, close collaboration of neurologists and geneticists was instrumental for proper data interpretation.
CONCLUSIONS: We expand the phenotypic, genotypic, and ethnical spectrum of mutations in these genes. Our findings alert neurologists that rare genetic causes should be considered in complex phenotypes regardless of ethnicity.

PMID: 29449188 [PubMed - as supplied by publisher]

Identification of a novel homozygous TRAPPC9 gene mutation causing non-syndromic intellectual disability, speech disorder, and secondary microcephaly.

Am J Med Genet B Neuropsychiatr Genet. 2017 Dec;174(8):839-845

Authors: Abbasi AA, Blaesius K, Hu H, Latif Z, Picker-Minh S, Khan MN, Farooq S, Khan MA, Kaindl AM

Abstract
TRAPPC9 gene mutations have been linked recently to autosomal recessive mental retardation 13 (MRT13; MIM#613192) with only eight families reported world-wide. We assessed patients from two consanguineous pedigrees of Pakistani descent with non-syndromic intellectual disability and postnatal microcephaly through whole exome sequencing (WES) and cosegregation analysis. Here we report six further patients from two pedigrees with homozygous TRAPPC9 gene mutations, the novel nonsense mutation c.2065G>T (p.E689*) and the previously identified nonsense mutation c.1423C>T (p.R475*). We provide an overview of previously reported clinical features and highlight common symptoms and variability of MRT13. Common findings are intellectual disability and absent speech, and frequently microcephaly, motor delay and pathological findings on MRI including diminished cerebral white matter volume are present. Mutations in TRAPPC9 should be considered in non-syndromic autosomal recessive intellectual disability with severe speech disorder.

PMID: 29031008 [PubMed - indexed for MEDLINE]

Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance.

Am J Med Genet B Neuropsychiatr Genet. 2017 Dec;174(8):817-827

Authors: Kos MZ, Carless MA, Peralta J, Curran JE, Quillen EE, Almeida M, Blackburn A, Blondell L, Roalf DR, Pogue-Geile MF, Gur RC, Göring HHH, Nimgaonkar VL, Gur RE, Almasy L

Abstract
Schizophrenia is a serious mental illness, involving disruptions in thought and behavior, with a worldwide prevalence of about one percent. Although highly heritable, much of the genetic liability of schizophrenia is yet to be explained. We searched for susceptibility loci in multiplex, multigenerational families affected by schizophrenia, targeting protein-altering variation with in silico predicted functional effects. Exome sequencing was performed on 136 samples from eight European-American families, including 23 individuals diagnosed with schizophrenia or schizoaffective disorder. In total, 11,878 non-synonymous variants from 6,396 genes were tested for their association with schizophrenia spectrum disorders. Pathway enrichment analyses were conducted on gene-based test results, protein-protein interaction (PPI) networks, and epistatic effects. Using a significance threshold of FDR < 0.1, association was detected for rs10941112 (p = 2.1 × 10-5 ; q-value = 0.073) in AMACR, a gene involved in fatty acid metabolism and previously implicated in schizophrenia, with significant cis effects on gene expression (p = 5.5 × 10-4 ), including brain tissue data from the Genotype-Tissue Expression project (minimum p = 6.0 × 10-5 ). A second SNP, rs10378 located in TMEM176A, also shows risk effects in the exome data (p = 2.8 × 10-5 ; q-value = 0.073). PPIs among our top gene-based association results (p < 0.05; n = 359 genes) reveal significant enrichment of genes involved in NCAM-mediated neurite outgrowth (p = 3.0 × 10-5 ), while exome-wide SNP-SNP interaction effects for rs10941112 and rs10378 indicate a potential role for kinase-mediated signaling involved in memory and learning. In conclusion, these association results implicate AMACR and TMEM176A in schizophrenia risk, whose effects may be modulated by genes involved in synaptic plasticity and neurocognitive performance.

PMID: 28902459 [PubMed - indexed for MEDLINE]

Clinical research: Inequality in medicine.

Nature. 2017 10 04;550(7674):S18-S19

Authors: Nowogrodzki A

PMID: 28976953 [PubMed - indexed for MEDLINE]

Integrating natural language processing expertise with patient safety event review committees to improve the analysis of medication events.

Int J Med Inform. 2017 Aug;104:120-125

Authors: Fong A, Harriott N, Walters DM, Foley H, Morrissey R, Ratwani RR

Abstract
OBJECTIVES: Many healthcare providers have implemented patient safety event reporting systems to better understand and improve patient safety. Reviewing and analyzing these reports is often time consuming and resource intensive because of both the quantity of reports and length of free-text descriptions in the reports.
METHODS: Natural language processing (NLP) experts collaborated with clinical experts on a patient safety committee to assist in the identification and analysis of medication related patient safety events. Different NLP algorithmic approaches were developed to identify four types of medication related patient safety events and the models were compared.
RESULTS: Well performing NLP models were generated to categorize medication related events into pharmacy delivery delays, dispensing errors, Pyxis discrepancies, and prescriber errors with receiver operating characteristic areas under the curve of 0.96, 0.87, 0.96, and 0.81 respectively. We also found that modeling the brief without the resolution text generally improved model performance. These models were integrated into a dashboard visualization to support the patient safety committee review process.
CONCLUSIONS: We demonstrate the capabilities of various NLP models and the use of two text inclusion strategies at categorizing medication related patient safety events. The NLP models and visualization could be used to improve the efficiency of patient safety event data review and analysis.

PMID: 28529113 [PubMed - indexed for MEDLINE]

Efficacy and safety of weekly intravenous nanoparticle albumin-bound paclitaxel for non-small cell lung cancer patients who have failed at least two prior systemic treatments.

Thorac Cancer. 2017 May;8(3):138-146

Authors: Duan J, Hao Y, Wan R, Yu S, Bai H, An T, Zhao J, Wang Z, Zhuo M, Wang J

Abstract
BACKGROUND: The study was conducted to evaluate the efficacy and safety of weekly intravenous nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) treatment in patients with advanced non-small-cell lung cancer (NSCLC) who have undergone multi-line therapy, and to investigate the association of secreted protein acidic and rich in cysteine (SPARC) expression status with clinical outcome.
METHODS: Sixty-four patients who received NAB-paclitaxel treatment (130 mg/m2 on days 1 and 8 of a 21 day cycle) as third line or further systemic treatment from 1 May 2011 to 30 June 2014 were included in this retrospective analysis. Tumor tissue was available in 28 patients for analysis of SPARC expression by immunohistochemistry.
RESULTS: Sixty-two patients had response evaluation and complete survival follow-up data; 83.9% received the weekly NAB-paclitaxel as fourth-line treatment or beyond. The objective response and disease control rates (n = 62) were 16.1% (10/62) and 64.5% (40/62), respectively. The median progression-free and overall survival rates were 3.7 (95% confidence interval 2.6-4.8) and 9.8 months (95% confidence interval 6.9-12.8), respectively. Previous treatment with taxane did not affect the response to NAB-paclitaxel. The main grade 3-4 toxicities experienced were neutropenia (9.4%) and leukopenia (7.8%). Patients with SPARC expression in tumor stroma but not in cancer cells had poorer progression-free survival compared with those with negative SPARC expression in tumor stroma cells (3.3 vs. 5.0 months, P = 0.036).
CONCLUSION: Weekly NAB-paclitaxel might be effective for heavily pretreated NSCLC patients. SPARC expression in tumor stroma cells might be a potential negative predictor of NAB-paclitaxel.

PMID: 28304139 [PubMed - indexed for MEDLINE]