Negative News: Cl- and HCO3- in the Vascular Wall.

Physiology (Bethesda). 2016 09;31(5):370-83

Authors: Boedtkjer E, Matchkov VV, Boedtkjer DM, Aalkjaer C

Abstract
Cl(-) and HCO3 (-) are the most prevalent membrane-permeable anions in the intra- and extracellular spaces of the vascular wall. Outwardly directed electrochemical gradients for Cl(-) and HCO3 (-) permit anion channel opening to depolarize vascular smooth muscle and endothelial cells. Transporters and channels for Cl(-) and HCO3 (-) also modify vascular contractility and structure independently of membrane potential. Transport of HCO3 (-) regulates intracellular pH and thereby modifies the activity of enzymes, ion channels, and receptors. There is also evidence that Cl(-) and HCO3 (-) transport proteins affect gene expression and protein trafficking. Considering the extensive implications of Cl(-) and HCO3 (-) in the vascular wall, it is critical to understand how these ions are transported under physiological conditions and how disturbances in their transport can contribute to disease development. Recently, sensing mechanisms for Cl(-) and HCO3 (-) have been identified in the vascular wall where they modify ion transport and vasomotor function, for instance, during metabolic disturbances. This review discusses current evidence that transport (e.g., via NKCC1, NBCn1, Ca(2+)-activated Cl(-) channels, volume-regulated anion channels, and CFTR) and sensing (e.g., via WNK and RPTPγ) of Cl(-) and HCO3 (-) influence cardiovascular health and disease.

PMID: 27511463 [PubMed - indexed for MEDLINE]

Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB.

J Pediatr Endocrinol Metab. 2017 Mar 17;:

Authors: Zeng Q, Fan Y, Wang L, Huang Z, Gu X, Yu Y

Abstract
BACKGROUND: Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in the NAGLU gene, deficiency of α-N-acetylglucosaminidase, multiple congenital malformations and an increased susceptibility to malignancy. Because of the slow progressive nature of this disease and its atypical symptoms, the misdiagnosis of MPS IIIB is not rare in clinical practice. This misdiagnosis could be avoided by using next-generation sequencing (NGS) techniques, which have been shown to have superior performance for detecting mutations underlying rare inherited disorders in previous studies.
CASE PRESENTATION: Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient's blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in the NAGLU gene of the patient. The two mutations were validated by Sanger sequencing. Our data showed that this patient's c.1562C>T, p.P521L mutation in the NAGLU gene was inherited from his father and c.1705C>A, p.Q569K was from his mother. The diagnosis was further confirmed by an enzymatic activity assay after patient recall and follow-up.
CONCLUSIONS: Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

PMID: 28306536 [PubMed - as supplied by publisher]

The genetics of gastroesophageal adenocarcinoma and the use of circulating cell free DNA for disease detection and monitoring.

Expert Rev Mol Diagn. 2017 Mar 17;:

Authors: Openshaw MR, Richards CJ, Guttery DS, Shaw JA, Thomas AL

Abstract
INTRODUCTION: Gastroesophageal adenocarcinoma (GOA) is a frequently occurring cancer worldwide with a poor clinical outcome. Adenocarcinomas of the oesophagus and gastroesophageal junction have shown a recent increase in frequency, therefore there is need to increase our understanding of GOA in order to improve our ability to detect, monitor and treat the disease. Areas covered: The authors discuss the current classification of GOA in the context of recent changes in incidence. The authors also discuss developments in the understanding of disease biology and recent discoveries from whole genome and whole exome sequencing, and studies in immunotherapy. Finally, the authors discuss the recent developments in the use of circulating tumour DNA (ctDNA). PubMed search terms were in English including "oesophageal/gastric adenocarcinoma", "gastroesophageal junctional tumour", "whole genome/exome sequencing", "immunotherapy" and "circulating tumour DNA". Expert commentary: Shared biological and genetic changes in GOA suggest it can be investigated as a single disease entity with different molecular subtypes. A number of genes are recurrently mutated including TP53, SMAD4, PIK3CA and there are frequent somatic copy number alterations and high levels of chromosomal instability. A subset of these genetic alterations have been detected in ctDNA and may provide an important avenue of research for detecting minimal residual disease and response to chemo- and immunotherapies.

PMID: 28306358 [PubMed - as supplied by publisher]

Changing the Therapeutic Landscape in Non-small Cell Lung Cancers: the Evolution of Comprehensive Molecular Profiling Improves Access to Therapy.

Curr Oncol Rep. 2017 Apr;19(4):24

Authors: Sabari JK, Santini F, Bergagnini I, Lai WV, Arbour KC, Drilon A

Abstract
Targeting genomic alterations has led to a paradigm shift in the treatment of patients with lung cancer. In an effort to better identify potentially actionable alterations that may predict response to FDA-approved and or investigational therapies, many centers have migrated towards performing targeted exome sequencing in patients with stage IV disease. The implementation of next-generation sequencing (NGS) in the evaluation of tumor tissue from patients with NSCLC has led to the discovery of targetable alterations in tumors that previously had no known actionable targets by less comprehensive profiling. An improved understanding of the molecular pathways that drive oncogenesis in NSCLC and a revolution in the technological advances in NGS have led to the development of new therapies through biomarker-driven clinical trials. This review will focus on the advances in molecular profiling that continue to fuel the revolution of precision medicine, identifying targets such as MET exon 14 skipping alterations and select recurrent gene alterations with increasing frequency.

PMID: 28303491 [PubMed - in process]

Ankyrin Repeat and Zinc Finger Domain containing 1 Mutations are associated with Infantile-Onset Inflammatory Bowel Disease.

J Biol Chem. 2017 Mar 16;:

Authors: van Haaften-Visser DY, Harakalova M, Mocholi E, van Montfrans JM, Elkadri A, Rieter E, Fiedler K, van Hasselt PM, Triffaux EM, van Haelst MM, Nijman IJ, Kloosterman WP, Nieuwenhuis EE, Muise AM, Cuppen E, Houwen RH, Coffer PJ

Abstract
Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before two years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in twelve additional IO IBD patients revealed two patients with two mutated Ankyrin Repeat and Zinc Finger Domain containing 1 (ANKZF1) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32_Q87del mutations respectively) and two patients with one mutated ANKZF1 allele. While the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensible role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous ANKZF1 R585Q mutation and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity and this may play a pathogenic role in the development of IO IBD.

PMID: 28302725 [PubMed - as supplied by publisher]

Identification and Characterization of a Missense Mutation in the O-GlcNAc Transferase Gene that Segregates with X-Linked Intellectual Disability.

J Biol Chem. 2017 Mar 16;:

Authors: Vaidyanathan K, Niranjan T, Selvan N, Teo CF, May M, Patel S, Weatherly B, Skinner C, Opitz J, Carey J, Viskochil D, Gecz J, Shaw M, Peng Y, Alexov E, Wang T, Schwartz C, Wells L

Abstract
O-GlcNAc is a regulatory post-translational modification of nucleocytoplasmic proteins that has been implicated in multiple biological processes including transcription. In humans, single genes encode enzymes for its attachment [O-GlcNAc transferase (OGT)] and removal [O-GlcNAcase (OGA)]. An X-chromosome exome screen identified a missense mutation, that encodes an amino acid in the tetratricopeptide repeat, in OGT (759G>T (p.L254F)) that segregates with X-linked intellectual disability (XLID) in an affected family. A decrease in steady-state OGT protein levels were observed in isolated lymphoblastoid cell lines from affected individuals consistent with molecular modeling experiments. Recombinant expression of L254F-OGT demonstrated that the enzyme is active as both a glycosyltransferase and as a HCF-1 protease. Despite the reduction in OGT levels seen in the L254F-OGT individual cells, we observed that steady-state global O-GlcNAc levels remain grossly unaltered. Surprisingly, lymphoblastoids from affected individuals display a marked decrease in steady-state OGA protein and mRNA levels. We observed an enrichment of the OGT-containing transcriptional repressor complex mSin3A-HDAC1 at the proximal promoter region of OGA and correspondingly decreased OGA promoter activity in affected cells. Global transcriptome analysis of L254F-OGT lymphoblastoids compared to controls revealed a small subset of genes that are differentially expressed. Thus, we have begun to unravel the molecular consequences of the 759G>T (p.L254F) mutation in OGT that uncovered a compensation mechanism, albeit imperfect given the phenotype of affected individuals, to maintain steady-state O-GlcNAc levels. Thus, a single amino acid substitution in the regulatory domain (TPR domain) of OGT, which catalyzes the O-GlcNAc post-translational modification of nuclear and cytosolic proteins, appears causal for XLID.

PMID: 28302723 [PubMed - as supplied by publisher]

Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.

Kidney Int. 2017 Mar 14;:

Authors: McMahon GM, Hwang SJ, Clish CB, Tin A, Yang Q, Larson MG, Rhee EP, Li M, CKDGen Consortium, Levy D, O'Donnell CJ, Coresh J, Young JH, Gerszten RE, Fox CS

Abstract
We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m(2)) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.

PMID: 28302371 [PubMed - as supplied by publisher]

Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine.

Genome Med. 2016 12 22;8(1):136

Authors: Nagahashi M, Wakai T, Shimada Y, Ichikawa H, Kameyama H, Kobayashi T, Sakata J, Yagi R, Sato N, Kitagawa Y, Uetake H, Yoshida K, Oki E, Kudo SE, Izutsu H, Kodama K, Nakada M, Tse J, Russell M, Heyer J, Powers W, Sun R, Ring JE, Takabe K, Protopopov A, Ling Y, Okuda S, Lyle S

Abstract
BACKGROUND: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).
METHODS: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.
RESULTS: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.
CONCLUSIONS: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

PMID: 28007036 [PubMed - indexed for MEDLINE]

30-Day Potentially Avoidable Readmissions Due to Adverse Drug Events.

J Patient Saf. 2017 Mar 17;:

Authors: Dalleur O, Beeler PE, Schnipper JL, Donzé J

Abstract
OBJECTIVE: To analyze the patterns of potentially avoidable readmissions due to adverse drug events (ADEs) to identify the most appropriate risk reduction interventions.
METHODS: In this observational study, we analyzed a random sample of 534 potentially avoidable 30-day readmissions from 10,275 consecutive discharges from the medical department of an academic hospital. Readmissions due to ADEs were reviewed to identify the causative drugs and the severity and interventions to prevent them.
RESULTS: Seventy cases (13.1%) of readmission were partially or predominantly due to ADEs, of which, 58 (82.9%) were serious ADEs. Overall, 65 (92.9%) of the ADEs have been confirmed to be preventable. Inappropriate prescribing was identified as the cause of ADE in 34 cases (48.6%) mainly involving diuretics, analgesics, or antithrombotics: misprescribing n = 19 (27.1%), underprescribing n = 8 (11.4%), and overprescribing n = 7 (10.0%). The remaining half of preventable ADEs (n = 36; 51.4%) were related to suboptimal patient monitoring/education, such as adherence issues (n = 6; 8.6%) or lack of monitoring (n = 31; 44.3%). In 64 cases (91.4%), the readmission could have been potentially prevented by better monitoring for drug efficacy/disease control, or for predictable side effect. Thirty-three (97.1%) of the 34 ADEs due to inappropriate prescribing could have also been prevented by better monitoring.
CONCLUSIONS: Adverse drug events accounted for approximately 13% of 30-day preventable readmissions. A half were due to prescription errors involving mainly diuretics, analgesics, or antithrombotics, and the other half were due to suboptimal patient monitoring/education, most frequently with antineoplastics. Both these avoidable causes may represent opportunities to reduce the total drug-related adverse events.

PMID: 28306610 [PubMed - as supplied by publisher]

Adverse Effects of Statins-Reply.

JAMA. 2017 03 14;317(10):1080

Authors: Thompson PD

PMID: 28291889 [PubMed - indexed for MEDLINE]

Adverse Effects of Statins.

JAMA. 2017 03 14;317(10):1079-1080

Authors: Malachowski SJ, Quattlebaum AM, Miladinovic B

PMID: 28291886 [PubMed - indexed for MEDLINE]

Adverse Effects of Statins.

JAMA. 2017 03 14;317(10):1079

Authors: Goldstein LB

PMID: 28291885 [PubMed - indexed for MEDLINE]

Pharmaceuticals and Medical Devices: FDA Oversight.

Issue Brief Health Policy Track Serv. 2016 Dec 27;2016:1-74

Authors: White RS, Thomson Reuters Accelus

PMID: 28252887 [PubMed - indexed for MEDLINE]

Media coverage of statins may have led to 2000 cardiovascular events.

BMJ. 2016 Jun 30;353:i3630

Authors: Galliver M

PMID: 27364525 [PubMed - indexed for MEDLINE]

Authors' reply to Cunningham and Messerli and colleagues.

BMJ. 2016 Jun 07;353:i3141

Authors: Kotecha D, Altman DG, Collins PD, Flather MD

PMID: 27268202 [PubMed - indexed for MEDLINE]

Research into "real world" older patients is needed.

BMJ. 2016 Jun 07;353:i3136

Authors: Cunningham CJ

PMID: 27268071 [PubMed - indexed for MEDLINE]

Adverse effects and tolerability of β blockers.

BMJ. 2016 Jun 07;353:i3142

Authors: Messerli FH, Bangalore S, Grossman E

PMID: 27268029 [PubMed - indexed for MEDLINE]

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab.

Clin J Oncol Nurs. 2016 Apr;20(2):E41-8

Authors: Dawson K, Moran M, Guindon K, Wan H

Abstract
BACKGROUND: In patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, treatment with the glycoengineered, type II anti-CD20 monoclonal antibody obinutuzumab (Gazyva®) (GA101) plus chlorambucil (Leukeran®) was associated with superior outcomes to rituximab (Rituxan®) plus chlorambucil, with a similar safety profile. However, a higher occurrence of infusion-related reactions (IRRs) was reported with obinutuzumab. These reactions typically require additional management.
OBJECTIVES: The focus of this article is to provide oncology nurses and physicians with advice for obinutuzumab IRR management based on clinical trial data and nursing experience.
METHODS: The authors reviewed the published management strategies for IRRs with obinutuzumab that were identified during the phase III CLL11 trial and an expanded access phase IIb study (ML28979). Practical advice for obinutuzumab IRR management was developed based on available clinical trial information and nursing experience.
FINDINGS: IRRs with obinutuzumab are generally manageable. Most IRRs (all grades), and all grade 3-4 IRRs, occurred during the first infusion. Therefore, IRR management could be improved substantially with extra vigilance at this early stage.

PMID: 26991722 [PubMed - indexed for MEDLINE]

Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).

PLoS One. 2017;12(3):e0169687

Authors: Cox AJ, Darbro BW, Laxer RM, Velez G, Bing X, Finer AL, Erives A, Mahajan VB, Bassuk AG, Ferguson PJ

Abstract
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.

PMID: 28301468 [PubMed - in process]

Whole exome sequencing in the Framingham Heart Study identifies rare variation in HYAL2 that influences platelet aggregation.

Thromb Haemost. 2017 Mar 16;:

Authors: Eicher JD, Chen MH, Pitsillides AN, Lin H, Veeraraghavan N, Brody JA, Metcalf GA, Muzny DM, Gibbs RA, Becker DM, Becker LC, Faraday N, Mathias RA, Yanek LR, Boerwinkle E, Cupples LA, Johnson AD

Abstract
Inhibition of platelet reactivity is a common therapeutic strategy in secondary prevention of cardiovascular disease. Genetic and environmental factors influence inter-individual variation in platelet reactivity. Identifying genes that contribute to platelet reactivity can reveal new biological mechanisms and possible therapeutic targets. Here, we examined rare coding variation to identify genes associated with platelet reactivity in a population-based cohort. To do so, we performed whole exome sequencing in the Framingham Heart Study and conducted single variant and gene-based association tests against platelet reactivity to collagen, adenosine diphosphate (ADP), and epinephrine agonists in up to 1,211 individuals. Single variant tests revealed no significant associations (p<1.44×10(-7)), though we observed a suggestive association with previously implicated MRVI1 (rs11042902, p = 1.95×10(-7)). Using gene-based association tests of rare and low-frequency variants, we found significant associations of HYAL2 with increased ADP-induced aggregation (p = 1.07×10(-7)) and GSTZ1 with increased epinephrine-induced aggregation (p = 1.62×10(-6)). HYAL2 also showed suggestive associations with epinephrine-induced aggregation (p = 2.64×10(-5)). The rare variants in the HYAL2 gene-based association included a missense variant (N357S) at a known N-glycosylation site and a nonsense variant (Q406*) that removes a glycophosphatidylinositol (GPI) anchor from the resulting protein. These variants suggest that improper membrane trafficking of HYAL2 influences platelet reactivity. We also observed suggestive associations of AR (p = 7.39×10(-6)) and MAPRE1 (p = 7.26×10(-6)) with ADP-induced reactivity. Our study demonstrates that gene-based tests and other grouping strategies of rare variants are powerful approaches to detect associations in population-based analyses of complex traits not detected by single variant tests and possible new genetic influences on platelet reactivity.

PMID: 28300864 [PubMed - as supplied by publisher]