Related Articles

Analysis of gene repair tracts from Cas9/gRNA double-stranded breaks in the human CFTR gene.

Sci Rep. 2016 08 25;6:32230

Authors: Hollywood JA, Lee CM, Scallan MF, Harrison PT

Abstract
To maximise the efficiency of template-dependent gene editing, most studies describe programmable and/or RNA-guided endonucleases that make a double-stranded break at, or close to, the target sequence to be modified. The rationale for this design strategy is that most gene repair tracts will be very short. Here, we describe a CRISPR Cas9/gRNA selection-free strategy which uses deep sequencing to characterise repair tracts from a donor plasmid containing seven nucleotide differences across a 216 bp target region in the human CFTR gene. We found that 90% of the template-dependent repair tracts were >100 bp in length with equal numbers of uni-directional and bi-directional repair tracts. The occurrence of long repair tracts suggests that a single gRNA could be used with variants of the same template to create or correct specific mutations within a 200 bp range, the size of ~80% of human exons. The selection-free strategy used here also allowed detection of non-homologous end joining events in many of the homology-directed repair tracts. This indicates a need to modify the donor, possibly by silent changes in the PAM sequence, to prevent creation of a second double-stranded break in an allele that has already been correctly edited by homology-directed repair.

PMID: 27557525 [PubMed - indexed for MEDLINE]

Common and rare variants genetic association analysis of cigarettes per day among ever smokers in COPD cases and controls.

Nicotine Tob Res. 2018 May 15;:

Authors: Lutz SM, Frederiksen B, Begum F, McDonald ML, Cho MH, Hobbs B, Parker MM, DeMeo DL, Hersh CP, Eringher M, Young K, Jiang L, Foreman MG, Kinney GL, Make BJ, Lomas DA, Bakke P, Gulsvik A, Crapo JD, Silverman EK, Beaty TH, Hokanson JE, ECLIPSE and COPDGene Investigators

Abstract
Introduction: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown.
Methods: We performed genome-wide association analyses for average cigarettes per day (CPD) across the COPDGene Non-Hispanic White (NHW) (n=6,659) and African American (AA) (n=3,260), GenKOLS (n=1,671), and ECLIPSE (n=1,942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status.
Results: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p=1.78x10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4 p=1.95x10-6; CYP2A7 p=7.50x10-5; CYP2B6 4.04x10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms (SNPs) in chromosome 15q25 were nominally associated in both NHW COPD cases (Beta=0.11, p=5.58x10-4) and controls (Beta=0.12, p=3.86x10-5). For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p=5.2x10-4).
Conclusions: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls.
IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. While the genetic effect sizes for these SNPs on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker.

PMID: 29767774 [PubMed - as supplied by publisher]

DNAJC3 mutation in Thai familial type 2 diabetes mellitus.

Int J Mol Med. 2018 May 14;:

Authors: Kulanuwat S, Tangjittipokin W, Jungtrakoon P, Chanprasert C, Sujjitjoon J, Binnima N, Yenchitsomanus PT, Plengvidhya N

Abstract
Type 2 diabetes mellitus (T2D) is a heterogeneous disease, with certain cases presenting an autosomal dominant type. The rare coding variants of disease‑causing genes in T2D remain mostly unclear. The present study aimed to identify the disease‑causing gene conducting whole exome sequencing in a Thai T2D family with an autosomal dominant transmission of T2D with no evidence of mutations in known maturity‑onset diabetes of the young (MODY) genes. Candidate variants were selected according to certain criteria of mutation prediction programs, followed by segregation analysis with diabetes in the family. The results demonstrated that, of the 68,817 variants obtained, 122 were considered as candidate variants subsequent to the filtering processes. Genotyping of these variants revealed that DnaJ homolog subfamily C member 3 (DNAJC3) p.H238N segregated with diabetes in the family. This mutation was also identified in another proband from the autosomal dominant T2D family without mutation in known MODY genes and was segregated with diabetes. This variant was also identified in 14/1,000 older‑onset T2D patients [minor allele frequency (MAF)=0.007], 2/500 non‑diabetic controls (MAF=0.002) and 3 prediabetic individuals who were previously classified as non‑diabetic controls. In silico mutagenesis and protein modeling of p.H238N revealed changes of the polar contacts across the tetratricopeptide repeat (TPR) motif and TPR subdomains, which may affect the protein tertiary structure. Furthermore, the expression of DNAJC3 H238N protein was 0.68±0.08 fold (P<0.05) lower when compared with that of the wild‑type, possibly due to protein instability. Thus, DNAJC3 p.H238N is likely to be a variant causing diabetes.

PMID: 29767246 [PubMed - as supplied by publisher]

Related Articles

Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness.

Genet Med. 2018 May 15;:

Authors: Stark Z, Schofield D, Martyn M, Rynehart L, Shrestha R, Alam K, Lunke S, Tan TY, Gaff CL, White SM

Abstract
PURPOSE: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses.
METHODS: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES).
RESULTS: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing.
CONCLUSION: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.

PMID: 29765138 [PubMed - as supplied by publisher]

Related Articles

Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy.

J Med Genet. 2018 May 15;:

Authors: Langer Y, Aran A, Gulsuner S, Abu Libdeh B, Renbaum P, Brunetti D, Teixeira PF, Walsh T, Zeligson S, Ruotolo R, Beeri R, Dweikat I, Shahrour M, Weinberg-Shukron A, Zahdeh F, Baruffini E, Glaser E, King MC, Levy-Lahad E, Zeviani M, Segel R

Abstract
OBJECTIVE: To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy.
METHODS: Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast.
RESULTS: Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids.
CONCLUSION: PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.

PMID: 29764912 [PubMed - as supplied by publisher]

Related Articles

Case Report: Identification of an HNF1B p.Arg527Gln mutation in a Maltese patient with atypical early onset diabetes and diabetic nephropathy.

BMC Endocr Disord. 2018 May 15;18(1):28

Authors: Pace NP, Craus J, Felice A, Vassallo J

Abstract
BACKGROUND: The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1β mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy. HNF1β-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of HNF1β mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported.
CASE PRESENTATION: An obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband's phenotype. A rare missense mutation at a highly conserved site in exon 8 of HNF1β was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in-silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course.
CONCLUSION: This report highlights several atypical features in a proband with atypical diabetes associated with an HNF1β missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes.

PMID: 29764441 [PubMed - in process]

Related Articles

COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

BMC Nephrol. 2018 May 16;19(1):114

Authors: Voskarides K, Papagregoriou G, Hadjipanagi D, Petrou I, Savva I, Elia A, Athanasiou Y, Pastelli A, Kkolou M, Hadjigavriel M, Stavrou C, Pierides A, Deltas C

Abstract
BACKGROUND: About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD).
METHODS: Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis.
RESULTS: In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts.
CONCLUSIONS: A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.

PMID: 29764427 [PubMed - in process]

Related Articles

VAReporter: variant reporter for cancer research of massive parallel sequencing.

BMC Genomics. 2018 May 09;19(Suppl 2):86

Authors: Huang PJ, Lee CC, Chiu LY, Huang KY, Yeh YM, Yang CY, Chiu CH, Tang P

Abstract
BACKGROUND: High throughput sequencing technologies have been an increasingly critical aspect of precision medicine owing to a better identification of disease targets, which contributes to improved health care cost and clinical outcomes. In particular, disease-oriented targeted enrichment sequencing is becoming a widely-accepted application for diagnostic purposes, which can interrogate known diagnostic variants as well as identify novel biomarkers from panels of entire human coding exome or disease-associated genes.
RESULTS: We introduce a workflow named VAReporter to facilitate the management of variant assessment in disease-targeted sequencing, the identification of pathogenic variants, the interpretation of biological effects and the prioritization of clinically actionable targets. State-of-art algorithms that account for mutation phenotypes are used to rank the importance of mutated genes through visual analytic strategies. We established an extensive annotation source by integrating a wide variety of biomedical databases and followed the American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation and reporting of sequence variations.
CONCLUSIONS: In summary, VAReporter is the first web server designed to provide a "one-stop" resource for individual's diagnosis and large-scale cohort studies, and is freely available at http://rnd.cgu.edu.tw/vareporter .

PMID: 29764369 [PubMed - in process]

Related Articles

DEPDC5 mutations in familial and sporadic focal epilepsy.

Clin Genet. 2017 Oct;92(4):397-404

Authors: Tsai MH, Chan CK, Chang YC, Yu YT, Chuang ST, Fan WL, Li SC, Fu TY, Chang WN, Liou CW, Chuang YC, Ng CC, Hwang DY, Lim KS

Abstract
BACKGROUND AND AIMS: Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.
MATERIALS AND METHODS: We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.
RESULTS: We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene.
DISCUSSION AND CONCLUSIONS: Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.

PMID: 28170089 [PubMed - indexed for MEDLINE]

Related Articles

Genotype and phenotype in 12 additional individuals with SATB2-associated syndrome.

Clin Genet. 2017 Oct;92(4):423-429

Authors: Zarate YA, Kalsner L, Basinger A, Jones JR, Li C, Szybowska M, Xu ZL, Vergano S, Caffrey AR, Gonzalez CV, Dubbs H, Zackai E, Millan F, Telegrafi A, Baskin B, Person R, Fish JL, Everman DB

Abstract
SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.

PMID: 28139846 [PubMed - indexed for MEDLINE]

Anti-glioma effects of Caffeic acid phenethyl ester and Dasatinib combination therapy in an in vivo rat glioma model.

Anticancer Agents Med Chem. 2018 May 15;:

Authors: Balkhi H, Haq E, Guler T, Sana S

Abstract
BACKGROUND: Caffeic acid phenethyl ester and Dasatinib in combination, when used in congruous proportions and durations, present an antitumor potential for glioma in vitro, suggesting a high therapeutic potential for glioma treatment.
OBJECTIVE: In the present study, we addressed the question whether CAPE and Dasatinib target multiple pathways involved in tumor growth, proliferation and development on an in vivo rat model of glioma.
METHODS: Expression analysis of proteins thought to be mediating proliferation, cell motility, angiogenesis, and invasion was carried out to delineate the antineoplastic action of CAPE and Dasatinib.
RESULTS: CAPE and Dasatinib modulates the expression of proteins having potential interactive crosstalk with major oncogenic pathways involved in glioma progression. Our results showed that combination treatment modulates the expression of p53 in group co-administered with CAPE and Dasatinib after glioma induction in comparison to group induced with glioma only. EGFR and PCNA expression were significantly altered in the co-treated group in comparison to the glioma-induced group. The effects of CAPE and Dasatinib treatment were further evaluated on AKT pathway by Western blot analysis, the co-treated group showed a significant reduction in expression of AKT. The histopathological analysis further backed the antiproliferative and anti invasive effects of CAPE and Dasatinib.
CONCLUSION: This study in totality suggests that the combinational therapy remarkably reduces the proliferation of glioma cells in vivo, suggesting that CAPE and Dasatinib therapy could be exploited for the management of gliomas without showing drug-related resistances and side effects, suggesting a high therapeutic potential of the therapy in glioma.

PMID: 29766825 [PubMed - as supplied by publisher]

Related Articles

Successful administration of BI 695501, an adalimumab biosimilar, using an autoinjector (AI): results from a Phase II open-label clinical study (VOLTAIRE®-RL).

Expert Opin Drug Deliv. 2018 May 15;:1-4

Authors: Cohen S, Klimiuk PA, Krahnke T, Assudani D

Abstract
BACKGROUND: This study examined the patient handling experience and self-injection success of patients with rheumatoid arthritis (RA) administering BI 695501 using an AI.
METHODS: This Phase II, 7-week, open-label, interventional study (NCT02636907) included adult patients with moderately to severely active RA not adequately controlled by DMARDs, with no experience of self-injecting with AI/pen. Patients self-injected BI 695501 via AI every 2 weeks in the AI Assessment Period (AAP). Training was given on first injection; AI handling events were recorded. Percentage of self-injection success was the primary end point. Patients could enter a 42-week pre-filled syringe (PFS) safety extension.
RESULTS: The AAP was completed by 73/77 patients. In total, 216/218 (99.1%) self-injections on Days 15, 29, and 43, were successful. Nine (11.7%) patients had drug-related adverse events (AEs). Two patients reported four serious AEs (SAEs), none drug-related. Overall (in the AAP and PFS extension), 28 (36.4%) patients had drug-related AEs; nine patients had SAEs, one was considered drug-related. Five (6.5%) patients reported injection-site reactions in the AAP; 13 (18.1%) in the PFS extension.
CONCLUSIONS: After training, almost all patients were successfully able to self-administer BI 695501 using an AI. BI 695501 via AI (and via PFS in the extension) was well tolerated.
CLINICAL TRIAL REGISTRATION: NCT02636907.

PMID: 29764238 [PubMed - as supplied by publisher]

Related Articles

The safety and efficacy of transarterial chemoembolization combined with sorafenib and sorafenib mono-therapy in patients with BCLC stage B/C hepatocellular carcinoma.

BMC Cancer. 2017 Sep 12;17(1):645

Authors: Wu FX, Chen J, Bai T, Zhu SL, Yang TB, Qi LN, Zou L, Li ZH, Ye JZ, Li LQ

Abstract
BACKGROUND: Sorafenib and transarterial chemoembolization (TACE) are recommended therapies for advanced hepatocellular carcinoma (HCC), but their combined efficacy remains unclear.
METHODS: Between August 2004 and November 2014, 104 patients with BCLC stage B/C HCC were enrolled at the Affiliated Tumor Hospital of Guangxi Medical University, China. Forty-eight patients were treated with sorafenib alone (sorafenib group) and 56 with TACE plus sorafenib (TACE + sorafenib group). Baseline demographic/clinical data were collected. The primary outcomes were median overall survival (OS) and progression-free survival (PFS). Secondary outcomes were overall response rate (ORR) and sorafenib-related adverse events (AEs). Baseline characteristics associated with disease prognosis were identified using multivariate Cox hazards regression.
RESULTS: The mean age of the 104 patients (94 males; 90.38%) was 49.02 ± 12.29 years. Of the baseline data, only albumin level (P = 0.028) and Child-Pugh class (P = 0.017) differed significantly between groups. Median OS did not differ significantly between the sorafenib and TACE + sorafenib groups (18.0 vs. 22.0 months, P = 0.223). Median PFS was significantly shorter in the sorafenib group than that in the TACE + sorafenib group (6.0 vs. 8.0 months, P = 0.004). Six months after treatments, the ORRs were similar between the sorafenib and TACE + sorafenib groups (12.50% vs. 18.75%, P = 0.425). The rates of grade III-IV adverse events in sorafenib and TACE + sorafenib groups were 29.2% vs. 23.2%, respectively. TACE plus sorafenib treatment (HR = 0.498, 95% CI = 0.278-0.892), no vascular invasion (HR = 0.354, 95% CI = 0.183-0.685) and Child-Pugh class A (HR = 0.308, 95% CI = 0.141-0.674) were significantly associated with better OS, while a larger tumor number was predictive of poorer OS (HR = 1.286, 95% CI = 1.031-1.604). TACE plus sorafenib treatment (HR = 0.461, 95% CI = 0.273-0.780) and no vascular invasion (HR = 0.557, 95% CI = 0.314-0.988) were significantly associated with better PFS.
CONCLUSIONS: Compared with sorafenib alone, combining TACE with sorafenib might prolong survival and delay disease progression in patients with advanced HCC.

PMID: 28899349 [PubMed - indexed for MEDLINE]

Related Articles

Discovering associations between adverse drug events using pattern structures and ontologies.

J Biomed Semantics. 2017 Aug 22;8(1):29

Authors: Personeni G, Bresso E, Devignes MD, Dumontier M, Smaïl-Tabbone M, Coulet A

Abstract
BACKGROUND: Patient data, such as electronic health records or adverse event reporting systems, constitute an essential resource for studying Adverse Drug Events (ADEs). We explore an original approach to identify frequently associated ADEs in subgroups of patients.
RESULTS: Because ADEs have complex manifestations, we use formal concept analysis and its pattern structures, a mathematical framework that allows generalization using domain knowledge formalized in medical ontologies. Results obtained with three different settings and two different datasets show that this approach is flexible and allows extraction of association rules at various levels of generalization.
CONCLUSIONS: The chosen approach permits an expressive representation of a patient ADEs. Extracted association rules point to distinct ADEs that occur in a same group of patients, and could serve as a basis for a recommandation system. The proposed representation is flexible and can be extended to make use of additional ontologies and various patient records.

PMID: 28830518 [PubMed - indexed for MEDLINE]

Related Articles

The prescribing cascade revisited.

Lancet. 2017 05 06;389(10081):1778-1780

Authors: Rochon PA, Gurwitz JH

PMID: 28495154 [PubMed - indexed for MEDLINE]

Related Articles

Gastrointestinal tract as a side-effect target of medications.

Przegl Lek. 2016;73(9):652-8

Authors: Domagała-Rodacka R, Cibor D, Szczeklik K, Rodacki T, Mach T, Owczarek D

Abstract
World Health Organization (WHO) defines adverse drug reaction (ADR) as “a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function”. ADRs are a serious problem of contemporary pharmacotherapy. Expenditures for treatment of ADRs in the United States may cost up to 30.1 billion dollars annually. Factors affecting the development of ADRs are: age, gender, body weight, polypharmacy. About 10% of ADRs is associated with gastrointestinal tract (GIT). ADR can affect every part of GIT. Xerostomia is the most common ADR occurring in oral cavity. ADRs affecting esophagus include irritation and inflammation of the mucosa. Approximately one-third of all cases of esophageal inflammation results from administration of non-steroid anti-inflammatory drugs (NSAIDs). The main cause of ulcerations involving stomach and small intestine are NSAIDs. Drug-induced diarrheas are the most common adverse effect accounting for approximately 7% of all observed cases of ADRs. They may be triggered by antibiotics, magnesium salts, laxatives and others. On the other hand, some groups of medications may induce constipation. These drugs comprise opioids, diuretics, calcium channel blockers, cholinolytics and others. Proton pump inhibitors, metformin, orlistat and colesevelam may lead to restricted absorption of certain vitamins and minerals. Physicians’ knowledge about most popular and well documented ADRs can improve patients’ safety and make pharmacotherapy more comfortable for them.

PMID: 29688675 [PubMed - indexed for MEDLINE]

31 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/05/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Funding Opportunity RFA-FD-18-025 from the NIH Guide for Grants and Contracts. The primary objective of this effort is to provide supporting research, identify key issues, and convene appropriate subject matter experts to help inform major initiatives for process improvement and regulatory science related to FDA commitments under the 2018 reauthorization of the Prescription Drug User Fee Act (PDUFA VI) and the 21st Century Cures Act legislation.

Notice NOT-OD-18-181 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-180 from the NIH Guide for Grants and Contracts