Giant cell tumours in fingers among the Inuit population in Greenland.

Int J Circumpolar Health. 2016;75:31285

Authors: Duelund N, Hougaard K

Abstract
OBJECTIVE: Giant cell tumours (GCTs) of the tendon sheets in fingers are rare. We therefore find it of interest to report on 5 cases identified in the Inuit population in Greenland within 16 months prior to this study.
MATERIAL AND METHODS: The Inuit account for 56,000 people of the total population in Greenland. From November 2010 to 16 months prior to this study, we diagnosed 5 cases (0.6% of all orthopaedic operations) with a GCT of the flexor tendon sheet of a finger. The patients were aged between 10 and 54 years, and 4 were women. All of them had noticed slow-growing tumours over 3 or more years and were referred for a suspected ganglion.
RESULTS: In two cases, the tumour was located at the distal interphalangeal (DIP) joint in the thumb and in one case at the third finger. Two other patients had tumours at the metacarpophalangeal (MCP) joint of the third finger and the thumb, respectively; one of these two had a communicating tumour to the DIP joint. The last patient had two tumours on the same finger, one at the MCP joint and the other at the DIP joint. In one case, the tumour had also eroded the cortex of the first phalanx of the thumb, and the largest tumour measured 5 cm.
CONCLUSION: GCTs of the flexor tendon sheets in fingers are rare. It could be a coincidence that we have seen 5 cases within a short period of time. It is not possible to identify past cases through a register. A tumour in a finger is not the most common location for a ganglion, especially not at the DIP level. Therefore, a large tumour at this location is more likely to be a GCT.

PMID: 27052154 [PubMed - indexed for MEDLINE]

Correction: A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics.

PLoS One. 2017;12(2):e0172595

Authors: Mizzi C, Dalabira E, Kumuthini J, Dzimiri N, Balogh I, Başak N, Böhm R, Borg J, Borgiani P, Bozina N, Bruckmueller H, Burzynska B, Carracedo A, Cascorbi I, Deltas C, Dolzan V, Fenech A, Grech G, Kasiulevicius V, Kádaši Ľ, Kučinskas V, Khusnutdinova E, Loukas YL, Macek M, Makukh H, Mathijssen R, Mitropoulos K, Mitropoulou C, Novelli G, Papantoni I, Pavlovic S, Saglio G, Sertić J, Stojiljkovic M, Stubbs AP, Squassina A, Torres M, Turnovec M, van Schaik RH, Voskarides K, Wakil SM, Werk A, Del Zompo M, Zukic B, Katsila T, Lee MT, Motsinger-Rief A, Mc Leod HL, van der Spek PJ, Patrinos GP

Abstract
[This corrects the article DOI: 10.1371/journal.pone.0162866.].

PMID: 28207884 [PubMed - in process]

Prevalence of clinically actionable genotypes and medication exposure of older adults in the community.

Pharmgenomics Pers Med. 2017;10:17-27

Authors: Daneshi N, Holliday E, Hancock S, Schneider JJ, Scott RJ, Attia J, Milward EA

Abstract
This study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus using microarray data for 2121 participants (55-85 years) from the Australian Hunter Community Study (HCS). At least 74% of participants (95% confidence interval [CI]: 72%-76%) had strong level evidence for at least one medium- or high-risk actionable genotype that would trigger a change in standard therapy under current international recommendations. About 14% of these participants (95% CI: 12%-16%) were taking medication potentially affected by the genotype in question. Furthermore, ~2.6% of all participants with medication data (95% CI: 1.4%-3.8%) had a high-risk clinically actionable genotype for a medication to which they were exposed. This represents a considerable number of people at the population level. Although relationships between genotype and health outcomes remain contentious, pharmacogenotyping of multiple variants simultaneously may have considerable potential to improve medication safety and efficacy for older people in the community.

PMID: 28203101 [PubMed - in process]

Optimising the use of medicines to reduce acute kidney injury in children and babies.

Pharmacol Ther. 2017 Feb 12;:

Authors: Oni L, Hawcutt DB, Turner MA, Beresford MW, McWilliam S, Barton C, Park BK, Murray P, Wilm B, Copple I, Floyd R, Peak M, Sharma A, Antoine DJ

Abstract
The majority of medications in children are administered in an unlicensed or off-label manner. Paediatricians are obliged to prescribe using the limited evidence available. The 2007 EU regulation on the use of paediatric drugs means pharmaceutical companies are now obliged to (and receive incentives for) contributing to paediatric drug data and carrying out paediatric clinical trials. This is important, as the efficacy and adverse effect profiles of medicines vary across childhood. Additionally, there are significant age-related changes in the pharmacodynamic and pharmacokinetic activity of many drugs. This may be related to physiological (differential expressions of cytochrome P450 enzymes or variable glomerular filtration rates at different ages for example) and psychological (increasing autonomy and risk perception in teenage years) changes. Increasing numbers of children are surviving life-threatening childhood conditions due to medical advances. This means there is an increasing population who are at risk of the consequences of the long-term, early exposure to nephrotoxic agents. The kidney is an organ that is particularly vulnerable to damage as a consequence of drugs. Drug-induced acute kidney injury (AKI) episodes in children and babies are principally due to non-steroidal anti-inflammatory drugs, antibiotics or chemotherapeutic agents. The renal tubules are vulnerable to injury because of their concentrating ability and high-energy hypoxic environment. This review focuses on drug-induced AKI and the methods to minimise its effect, including general management plus the role of child-specific pharmacokinetic data, the use of pharmacogenomics and early detection of AKI using urinary biomarkers and electronic triggers.

PMID: 28202365 [PubMed - as supplied by publisher]

Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis.

PLoS Genet. 2017 Feb;13(2):e1006508

Authors: Skwark MJ, Croucher NJ, Puranen S, Chewapreecha C, Pesonen M, Xu YY, Turner P, Harris SR, Beres SB, Musser JM, Parkhill J, Bentley SD, Aurell E, Corander J

Abstract
Recent advances in the scale and diversity of population genomic datasets for bacteria now provide the potential for genome-wide patterns of co-evolution to be studied at the resolution of individual bases. Here we describe a new statistical method, genomeDCA, which uses recent advances in computational structural biology to identify the polymorphic loci under the strongest co-evolutionary pressures. We apply genomeDCA to two large population data sets representing the major human pathogens Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A Streptococcus). For pneumococcus we identified 5,199 putative epistatic interactions between 1,936 sites. Over three-quarters of the links were between sites within the pbp2x, pbp1a and pbp2b genes, the sequences of which are critical in determining non-susceptibility to beta-lactam antibiotics. A network-based analysis found these genes were also coupled to that encoding dihydrofolate reductase, changes to which underlie trimethoprim resistance. Distinct from these antibiotic resistance genes, a large network component of 384 protein coding sequences encompassed many genes critical in basic cellular functions, while another distinct component included genes associated with virulence. The group A Streptococcus (GAS) data set population represents a clonal population with relatively little genetic variation and a high level of linkage disequilibrium across the genome. Despite this, we were able to pinpoint two RNA pseudouridine synthases, which were each strongly linked to a separate set of loci across the chromosome, representing biologically plausible targets of co-selection. The population genomic analysis method applied here identifies statistically significantly co-evolving locus pairs, potentially arising from fitness selection interdependence reflecting underlying protein-protein interactions, or genes whose product activities contribute to the same phenotype. This discovery approach greatly enhances the future potential of epistasis analysis for systems biology, and can complement genome-wide association studies as a means of formulating hypotheses for targeted experimental work.

PMID: 28207813 [PubMed - in process]

Physiological, metabolic and biotechnological features of extremely thermophilic microorganisms.

Wiley Interdiscip Rev Syst Biol Med. 2017 Feb 16;:

Authors: Counts JA, Zeldes BM, Lee LL, Straub CT, Adams MW, Kelly RM

Abstract
The current upper thermal limit for life as we know it is approximately 120°C. Microorganisms that grow optimally at temperatures of 75°C and above are usually referred to as 'extreme thermophiles' and include both bacteria and archaea. For over a century, there has been great scientific curiosity in the basic tenets that support life in thermal biotopes on earth and potentially on other solar bodies. Extreme thermophiles can be aerobes, anaerobes, autotrophs, heterotrophs, or chemolithotrophs, and are found in diverse environments including shallow marine fissures, deep sea hydrothermal vents, terrestrial hot springs-basically, anywhere there is hot water. Initial efforts to study extreme thermophiles faced challenges with their isolation from difficult to access locales, problems with their cultivation in laboratories, and lack of molecular tools. Fortunately, because of their relatively small genomes, many extreme thermophiles were among the first organisms to be sequenced, thereby opening up the application of systems biology-based methods to probe their unique physiological, metabolic and biotechnological features. The bacterial genera Caldicellulosiruptor, Thermotoga and Thermus, and the archaea belonging to the orders Thermococcales and Sulfolobales, are among the most studied extreme thermophiles to date. The recent emergence of genetic tools for many of these organisms provides the opportunity to move beyond basic discovery and manipulation to biotechnologically relevant applications of metabolic engineering. For further resources related to this article, please visit the WIREs website.

PMID: 28206708 [PubMed - as supplied by publisher]

Identification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis.

Cell Oncol (Dordr). 2017 Feb 15;:

Authors: Giulietti M, Occhipinti G, Principato G, Piva F

Abstract
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal prognosis which is, among others, due to a lack of suitable biomarkers and therapeutic targets. Previously, basic gene expression analysis methods have been used for their identification, but recently new algorithms have been developed allowing more comprehensive data analyses. Among them, weighted gene co-expression network analysis (WGCNA) has already been applied to several cancer types with promising results.
METHODS: We applied WGCNA to miRNA expression data from PDAC patients. Specifically, we processed microarray-based expression data of 2555 miRNAs in serum from 100 PDAC patients and 150 healthy subjects. We identified network modules of co-expressed miRNAs in the healthy subject dataset and verified their preservation in the PDAC dataset. In the non-preserved modules, we selected key miRNAs and carried out functional enrichment analyses of their experimentally known target genes. Finally, we tested their prognostic significance using overall survival analyses.
RESULTS: Through WGCNA we identified several miRNAs that discriminate healthy subjects from PDAC patients and that, therefore, may play critical roles in PDAC development. At a functional level, we found that they regulate p53, FoxO and ErbB associated cellular signalling pathways, as well as cell cycle progression and various genes known to be involved in PDAC development. Some miRNAs were also found to serve as novel prognostic biomarkers, whereas others have previously already been proposed as such, thereby validating the WGCNA approach. In addition, we found that these novel data may explain at least some of our previous PDAC gene expression analysis results.
CONCLUSIONS: We identified several miRNAs critical for PDAC development using WGCNA. These miRNAs may serve as biomarkers for PDAC diagnosis/prognosis and patient stratification, and as putative novel therapeutic targets.

PMID: 28205147 [PubMed - as supplied by publisher]

Modeling the Genetic Regulation of Cancer Metabolism: Interplay Between Glycolysis and Oxidative Phosphorylation.

Cancer Res. 2017 Feb 15;:

Authors: Yu L, Lu M, Jia D, Ma J, Ben-Jacob E, Levine H, Kaipparettu BA, Onuchic JN

Abstract
Abnormal metabolism is a hallmark of cancer, yet its regulation remains poorly understood. Cancer cells were considered to utilize primarily glycolysis for ATP production, referred to as the Warburg effect. However, recent evidence suggests that oxidative phosphorylation (OXPHOS) plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and OXPHOS. Integrating information from literature, we constructed a regulatory network of genes and metabolites from which we extracted a core circuit containing HIF-1, AMPK, and ROS. Our circuit analysis showed that while normal cells have an oxidative state and a glycolytic state, cancer cells can access a hybrid state with both metabolic modes coexisting. This was due to higher ROS production and/or oncogene activation, such as RAS, MYC, and c-SRC. Guided by the model, we developed two signatures consisting of AMPK and HIF-1 downstream genes, respectively, to quantify the activity of glycolysis and OXPHOS. By applying the AMPK and HIF-1 signatures to TCGA patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma, we confirmed an anti-correlation between AMPK and HIF-1 activities and the association of metabolic states with oncogenes. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism.

PMID: 28202516 [PubMed - as supplied by publisher]

An integrative metabolomics and transcriptomics study to identify metabolic alterations in aged skin of humans in vivo.

BMC Genomics. 2017 Feb 15;18(1):169

Authors: Kuehne A, Hildebrand J, Soehle J, Wenck H, Terstegen L, Gallinat S, Knott A, Winnefeld M, Zamboni N

Abstract
BACKGROUND: Aging human skin undergoes significant morphological and functional changes such as wrinkle formation, reduced wound healing capacity, and altered epidermal barrier function. Besides known age-related alterations like DNA-methylation changes, metabolic adaptations have been recently linked to impaired skin function in elder humans. Understanding of these metabolic adaptations in aged skin is of special interest to devise topical treatments that potentially reverse or alleviate age-dependent skin deterioration and the occurrence of skin disorders.
RESULTS: We investigated the global metabolic adaptions in human skin during aging with a combined transcriptomic and metabolomic approach applied to epidermal tissue samples of young and old human volunteers. Our analysis confirmed known age-dependent metabolic alterations, e.g. reduction of coenzyme Q10 levels, and also revealed novel age effects that are seemingly important for skin maintenance. Integration of donor-matched transcriptome and metabolome data highlighted transcriptionally-driven alterations of metabolism during aging such as altered activity in upper glycolysis and glycerolipid biosynthesis or decreased protein and polyamine biosynthesis. Together, we identified several age-dependent metabolic alterations that might affect cellular signaling, epidermal barrier function, and skin structure and morphology.
CONCLUSIONS: Our study provides a global resource on the metabolic adaptations and its transcriptional regulation during aging of human skin. Thus, it represents a first step towards an understanding of the impact of metabolism on impaired skin function in aged humans and therefore will potentially lead to improved treatments of age related skin disorders.

PMID: 28201987 [PubMed - in process]

Exploring targeted therapy of osteosarcoma using proteomics data.

Onco Targets Ther. 2017;10:565-577

Authors: Chaiyawat P, Settakorn J, Sangsin A, Teeyakasem P, Klangjorhor J, Soongkhaw A, Pruksakorn D

Abstract
Despite multimodal therapeutic treatments of osteosarcoma (OS), some patients develop resistance to currently available regimens and eventually end up with recurrent or metastatic outcomes. Many attempts have been made to discover effective drugs for improving outcome; however, due to the heterogeneity of the disease, new therapeutic options have not yet been identified. This study aims to explore potential targeted therapy related to protein profiles of OS. In this review of proteomics studies, we extracted data on differentially expressed proteins (DEPs) from archived literature in PubMed and our in-house repository. The data were divided into three experimental groups, DEPs in 1) OS/OB: OS vs osteoblastic (OB) cells, 2) metastasis: metastatic vs non-metastatic sublines plus fresh tissues from primary OS with and without pulmonary metastasis, and 3) chemoresistance: spheroid (higher chemoresistance) vs monolayer cells plus fresh tissues from biopsies from good and poor responders. All up-regulated protein entities in the list of DEPs were sorted and cross-referenced with identifiers of targets of US Food and Drug Administration (FDA)-approved agents and chemical inhibitors. We found that many targets of FDA-approved antineoplastic agents, mainly a group of epigenetic regulators, kinases, and proteasomes, were highly expressed in OS cells. Additionally, some overexpressed proteins were targets of FDA-approved non-cancer drugs, including immunosuppressive and antiarrhythmic drugs. The resulting list of chemical agents showed that some transferase enzyme inhibitors might have anticancer activity. We also explored common targets of OS/OB and metastasis groups, including amidophosphoribosyltransferase (PPAT), l-lactate dehydrogenase B chain (LDHB), and pyruvate kinase M2 (PKM2) as well as the common target of all categories, cathepsin D (CTSD). This study demonstrates the benefits of a text mining approach to exploring therapeutic targets related to protein expression patterns. These results suggest possible repurposing of some FDA-approved medicines for the treatment of OS and using chemical inhibitors in drug screening tests.

PMID: 28203090 [PubMed - in process]

Interacting TCP and NLP transcription factors control plant responses to nitrate availability.

Proc Natl Acad Sci U S A. 2017 Feb 15;:

Authors: Guan P, Ripoll JJ, Wang R, Vuong L, Bailey-Steinitz LJ, Ye D, Crawford NM

Abstract
Plants have evolved adaptive strategies that involve transcriptional networks to cope with and survive environmental challenges. Key transcriptional regulators that mediate responses to environmental fluctuations in nitrate have been identified; however, little is known about how these regulators interact to orchestrate nitrogen (N) responses and cell-cycle regulation. Here we report that teosinte branched1/cycloidea/proliferating cell factor1-20 (TCP20) and NIN-like protein (NLP) transcription factors NLP6 and NLP7, which act as activators of nitrate assimilatory genes, bind to adjacent sites in the upstream promoter region of the nitrate reductase gene, NIA1, and physically interact under continuous nitrate and N-starvation conditions. Regions of these proteins necessary for these interactions were found to include the type I/II Phox and Bem1p (PB1) domains of NLP6&7, a protein-interaction module conserved in animals for nutrient signaling, and the histidine- and glutamine-rich domain of TCP20, which is conserved across plant species. Under N starvation, TCP20-NLP6&7 heterodimers accumulate in the nucleus, and this coincides with TCP20 and NLP6&7-dependent up-regulation of nitrate assimilation and signaling genes and down-regulation of the G2/M cell-cycle marker gene, CYCB1;1 TCP20 and NLP6&7 also support root meristem growth under N starvation. These findings provide insights into how plants coordinate responses to nitrate availability, linking nitrate assimilation and signaling with cell-cycle progression.

PMID: 28202720 [PubMed - as supplied by publisher]

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Systematic analyses of drugs and disease indications in RepurposeDB reveal pharmacological, biological and epidemiological factors influencing drug repositioning.

Brief Bioinform. 2017 Feb 15;:

Authors: Shameer K, Glicksberg BS, Hodos R, Johnson KW, Badgeley MA, Readhead B, Tomlinson MS, O'Connor T, Miotto R, Kidd BA, Chen R, Ma'ayan A, Dudley JT

PMID: 28200013 [PubMed - as supplied by publisher]

DeSigN: connecting gene expression with therapeutics for drug repurposing and development.

BMC Genomics. 2017 Jan 25;18(Suppl 1):934

Authors: Lee BK, Tiong KH, Chang JK, Liew CS, Abdul Rahman ZA, Tan AC, Khang TF, Cheong SC

Abstract
BACKGROUND: The drug discovery and development pipeline is a long and arduous process that inevitably hampers rapid drug development. Therefore, strategies to improve the efficiency of drug development are urgently needed to enable effective drugs to enter the clinic. Precision medicine has demonstrated that genetic features of cancer cells can be used for predicting drug response, and emerging evidence suggest that gene-drug connections could be predicted more accurately by exploring the cumulative effects of many genes simultaneously.
RESULTS: We developed DeSigN, a web-based tool for predicting drug efficacy against cancer cell lines using gene expression patterns. The algorithm correlates phenotype-specific gene signatures derived from differentially expressed genes with pre-defined gene expression profiles associated with drug response data (IC50) from 140 drugs. DeSigN successfully predicted the right drug sensitivity outcome in four published GEO studies. Additionally, it predicted bosutinib, a Src/Abl kinase inhibitor, as a sensitive inhibitor for oral squamous cell carcinoma (OSCC) cell lines. In vitro validation of bosutinib in OSCC cell lines demonstrated that indeed, these cell lines were sensitive to bosutinib with IC50 of 0.8-1.2 μM. As further confirmation, we demonstrated experimentally that bosutinib has anti-proliferative activity in OSCC cell lines, demonstrating that DeSigN was able to robustly predict drug that could be beneficial for tumour control.
CONCLUSIONS: DeSigN is a robust method that is useful for the identification of candidate drugs using an input gene signature obtained from gene expression analysis. This user-friendly platform could be used to identify drugs with unanticipated efficacy against cancer cell lines of interest, and therefore could be used for the repurposing of drugs, thus improving the efficiency of drug development.

PMID: 28198666 [PubMed - in process]

Repositioning of amprenavir as a novel extracellular signal-regulated kinase-2 inhibitor and apoptosis inducer in MCF-7 human breast cancer.

Int J Oncol. 2017 Jan 24;:

Authors: Jiang W, Li X, Li T, Wang H, Shi W, Qi P, Li C, Chen J, Bao J, Huang G, Wang Y

Abstract
Computational drug repositioning by virtually screening existing drugs for additional therapeutic usage could efficiently accelerate anticancer drug discovery. Herein, a library of 1447 Food and Drug Administration (FDA)-approved small molecule drugs was screened in silico for inhibitors of extracellular signal-regulated kinase 2 (ERK2). Then, in vitro kinase assay demonstrated amprenavir, a HIV-1 protease inhibitor, as a potential kinase inhibitor of ERK2. The in vivo kinase assay indicated that amprenavir could inhibit ERK2-mediated phosphorylation of BimEL at Ser69. Amprenavir could suppress this phosphorylation in MCF-7 cells, which may further facilitate the association of BimEL with several pro-survival molecules. Additionally, inhibition of ERK2-BimEL signaling pathway by amprenavir could contribute to its anti-proliferative and apoptosis-inducing activity in MCF-7 cells. Finally, in vivo tumor growth and immunohistochemical studies confirmed that amprenavir remarkably suppressed tumor proliferation and induce apoptosis in MCF-7 xenografts. Taken together, amprenavir can effectively inhibit the kinase activity of ERK2, and thus induces apoptosis and inhibits tumor growth in human MCF-7 cancer cells both in vitro and in vivo, making amprenavir a promising candidate for future anticancer therapeutics.

PMID: 28197631 [PubMed - as supplied by publisher]

Mefloquine and its oxazolidine derivative compound are active against drug-resistant Mycobacterium tuberculosis strains and in a murine model of tuberculosis infection.

Int J Antimicrob Agents. 2016 Aug;48(2):203-7

Authors: Rodrigues-Junior VS, Villela AD, Gonçalves RS, Abbadi BL, Trindade RV, López-Gavín A, Tudó G, González-Martín J, Basso LA, de Souza MV, Campos MM, Santos DS

Abstract
Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. In this work, we demonstrate for the first time the activities of mefloquine and its oxazolidine derivative compound 1E in a murine model of TB infection following administration of both drugs by the oral route. The effects of associations between mefloquine or 1E with the clinically used antituberculosis drugs isoniazid, rifampicin, ethambutol, moxifloxacin and streptomycin were also investigated. Importantly, combination of mefloquine with isoniazid and of 1E with streptomycin showed a two-fold decrease in their minimum inhibitory concentrations (MICs). Moreover, no tested combinations demonstrated antagonist interactions. Here we describe novel evidence on the activity of mefloquine and 1E against a series of quinolone-resistant M. tuberculosis strains. These data show MICs against quinolone-resistant strains (0.5-8 µg/mL) similar to or lower than those previously reported for multidrug-resistant strains. Taking these results together, we can suggest the use of mefloquine or 1E in combination with clinically available drugs, especially in the case of resistant forms of TB.

PMID: 27364701 [PubMed - indexed for MEDLINE]

Clinical pharmacogenetics implementation consortium (cpic) guideline for pharmacogenetics-guided warfarin dosing: 2017 update.

Clin Pharmacol Ther. 2017 Feb 15;:

Authors: Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, Lee MT, Gage BF, Kimmel SE, Perera MA, Anderson JL, Pirmohamed M, Klein TE, Limdi NA, Cavallari LH, Wadelius M

Abstract
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry. This article is protected by copyright. All rights reserved.

PMID: 28198005 [PubMed - as supplied by publisher]

Beyond cystic fibrosis transmembrane conductance regulator (CFTR) single channel kinetics: implications for therapeutic intervention.

J Physiol. 2017 Feb 15;595(4):1015-1016

Authors: McNicholas CM

PMID: 28198020 [PubMed - in process]

Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.

Leukemia. 2017 Feb 15;:

Authors: Ratnaparkhe M, Hlevnjak M, Kolb T, Jauch A, Maass KK, Devens F, Rode A, Hovestadt V, Korshunov A, Pastorczak A, Mlynarski W, Sungalee S, Korbel J, Hoell J, Fischer U, Milde T, Kramm C, Nathrath M, Chrzanowska K, Tausch E, Takagi M, Taga T, Constantini S, Loeffen J, Meijerink J, Zielen S, Gohring G, Schlegelberger B, Maass E, Siebert R, Kunz J, Kulozik AE, Worst B, Jones DT, Pfister SM, Zapatka M, Lichter P, Ernst A

Abstract
Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared to tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.Leukemia accepted article preview online, 15 February 2017. doi:10.1038/leu.2017.55.

PMID: 28196983 [PubMed - as supplied by publisher]

Vardenafil reduces macrophage pro-inflammatory overresponses in Cystic Fibrosis through PDE5- and CFTR-dependent mechanisms.

Clin Sci (Lond). 2017 Feb 14;:

Authors: Noel S, Panin N, Beka M, Dhooghe B, Huaux F, Leal T

Abstract
Chronic inflammation that progressively disrupts the lung tissue is a hallmark of Cystic Fibrosis (CF). In mice, vardenafil, an inhibitor of phosphodiesterase type 5 (PDE5), restores transepithelial ion transport and corrects mislocalization of the most common CF mutation, F508del-CFTR. It also reduces lung pro-inflammatory responses in mice and in patients with CF. To test the hypothesis that macrophages are target effector cells of the immunomodulatory effect of vardenafil, we isolated lung macrophages from mice homozygous for the F508del mutation or invalidated for the cftr gene and from their corresponding wild-type littermates. We then evaluated the effect of vardenafil on the classical M1 polarization, mirroring release of pro-inflammatory cytokines. We confirmed that macrophages from different body compartments express CFTR and showed that vardenafil targets the cells through PDE5- and CFTR-dependent mechanisms. In the presence of the F508del mutation, vardenafil downregulated overresponses of the M1 markers, tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (NOS)-2. Our study identifies lung macrophages as target cells of the anti-inflammatory effect of vardenafil in CF and supports the view that the drug is potentially beneficial for treating CF as it combines rescue of CFTR protein and anti-inflammatory properties.

PMID: 28196856 [PubMed - as supplied by publisher]