Related Articles

Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies.

Pharmgenomics Pers Med. 2017;10:197-204

Authors: Yamamoto-Furusho JK

Abstract
Inflammatory bowel disease (IBD) is a chronic and heterogeneous disorder characterized by remitting and relapsing periods of activity. Pharmacogenetics refers to the study of the effect of inheritance on individual variation in drug responses. Several drug-related markers in IBD patients have been identified in order to predict the response to medical treatment including biological therapy as well as the reduction of adverse events. In the future, the treatment of IBD should be personalized in its specific profile to provide the most efficacious treatment with lack of adverse events.

PMID: 28603427 [PubMed - in process]

Related Articles

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance.

Mol Cell Biol. 2016 Nov 01;36(21):2715-2727

Authors: Garbacz WG, Lu P, Miller TM, Poloyac SM, Eyre NS, Mayrhofer G, Xu M, Ren S, Xie W

Abstract
The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome.

PMID: 27528620 [PubMed - indexed for MEDLINE]

Matrix exopolysaccharides; The sticky side of biofilm formation.

FEMS Microbiol Lett. 2017 Jun 12;:

Authors: Maunders E, Welch M

Abstract
The Gram-negative pathogen Pseudomonas aeruginosa is found ubiquitously within the environment and is recognised as an opportunistic human pathogen that commonly infects burn wounds and immunocompromised individuals, or patients suffering from the autosomal recessive disorder cystic fibrosis (CF). During chronic infection, P. aeruginosa is thought to form structured aggregates known as biofilms characterised by a self-produced matrix which encases the bacteria, protecting them from anti-microbial attack and the host immune response. In many cases, antibiotics are ineffective at eradicating P. aeruginosa from chronically-infected CF airways. Cyclic-di-GMP has been identified as a key regulator of biofilm formation; however the way in which its effector proteins elicit a change in biofilm formation remains unclear. Identifying regulators of biofilm formation is a key theme of current research and understanding the factors that activate biofilm formation may help to expose potential new drug targets that slow the onset of chronic infection. This minireview outlines the contribution made by exopolysaccharides to biofilm formation, and describes the current understanding of biofilm regulation in P. aeruginosa with a particular focus on CF airway-associated infections.

PMID: 28605431 [PubMed - as supplied by publisher]

Discovery of Two Bacterial Nitric Oxide-Responsive Proteins and Their Roles in Bacterial Biofilm Regulation.

Acc Chem Res. 2017 Jun 12;:

Authors: Hossain S, Nisbett LM, Boon EM

Abstract
Bacterial biofilms form when bacteria adhere to a surface and produce an exopolysaccharide matrix ( Costerton Science 1999 , 284 , 1318 ; Davies Science 1998 , 280 , 295 ; Flemming Nat. Rev. Microbiol. 2010 , 8 , 623 ). Because biofilms are resistant to antibiotics, they are problematic in many aspects of human health and welfare, causing, for instance, persistent fouling of medical implants such as catheters and artificial joints ( Brunetto Chimia 2008 , 62 , 249 ). They are responsible for chronic infections in the lungs of cystic fibrosis patients and in open wounds, such as those associated with burns and diabetes. They are also a major contributor to hospital-acquired infections ( Sievert Infec. Control Hosp. Epidemiol. 2013 , 34 , 1 ; Tatterson Front. Biosci. 2001 , 6 , D890 ). It has been hypothesized that effective methods of biofilm control will have widespread application ( Landini Appl. Microbiol. Biotechnol. 2010 , 86 , 813 ). A promising strategy is to target the mechanisms that drive biofilm dispersal, because dispersal results in biofilm removal and in the restoration of antibiotic sensitivity. First documented in Nitrosomonas europaea ( Schmidt J. Bacteriol. 2004 , 186 , 2781 ) and the cystic fibrosis-associated pathogen Pseudomonas aeruginosa ( Barraud J. Bacteriol. 2006 , 188 , 7344 ; J. Bacteriol. 2009 , 191 , 7333 ), regulation of biofilm formation by nanomolar levels of the diatomic gas nitric oxide (NO) has now been documented in numerous bacteria ( Barraud Microb. Biotechnol. 2009 , 2 , 370 ; McDougald Nat. Rev. Microbiol. 2012 , 10 , 39 ; Arora Biochemistry 2015 , 54 , 3717 ; Barraud Curr. Pharm. Des. 2015 , 21 , 31 ). NO-mediated pathways are, therefore, promising candidates for biofilm regulation. Characterization of the NO sensors and NO-regulated signaling pathways should allow for rational manipulation of these pathways for therapeutic applications. Several laboratories, including our own, have shown that a class of NO sensors called H-NOX (heme-nitric oxide or oxygen binding domain) affects biofilm formation by regulating intracellular cyclic di-GMP concentrations and quorum sensing ( Arora Biochemistry 2015 , 54 , 3717 ; Plate Trends Biochem. Sci. 2013 , 38 , 566 ; Nisbett Biochemistry 2016 , 55 , 4873 ). Many bacteria that respond to NO do not encode an hnoX gene, however. My laboratory has now discovered an additional family of bacterial NO sensors, called NosP (nitric oxide sensing protein). Importantly, NosP domains are widely conserved in bacteria, especially Gram-negative bacteria, where they are encoded as fusions with or in close chromosomal proximity to histidine kinases or cyclic di-GMP synthesis or phosphodiesterase enzyme, consistent with signaling. In this Account, we briefly review NO and H-NOX signaling in bacterial biofilms, describe our discovery of the NosP family, and provide support for its role in biofilm regulation in Pseudomonas aeruginosa, Vibrio cholerae, Legionella pneumophila, and Shewanella oneidensis.

PMID: 28605194 [PubMed - as supplied by publisher]

Evidence of persistence of Prevotella spp. in the cystic fibrosis lung.

J Med Microbiol. 2017 Jun 13;:

Authors: Gilpin DF, Nixon KA, Bull M, McGrath SJ, Sherrard L, Rolain JM, Mahenthiralingam E, Elborn JS, Tunney MM

Abstract
PURPOSE: Prevotella spp. represent a diverse genus of bacteria, frequently identified by both culture and molecular methods in the lungs of patients with chronic respiratory infection. However, their role in the pathogenesis of chronic lung infection is unclear; therefore, a more complete understanding of their molecular epidemiology is required.
METHODOLOGY: Pulsed Field Gel Electrophoresis (PFGE) and Random Amplified Polymorphic DNA (RAPD) assays were developed and used to determine the degree of similarity between sequential isolates (n=42) from cystic fibrosis (CF) patients during periods of clinical stability and exacerbation.
RESULTS: A wide diversity of PFGE and RAPD banding patterns were observed, demonstrating considerable within-genus heterogeneity. In 8/12 (66.7 %) cases, where the same species was identified at sequential time points, pre- and post-antibiotic treatment of an exacerbation, PFGE/RAPD profiles were highly similar or identical. Congruence was observed between PFGE and RAPD (adjusted Rand coefficient, 0.200; adjusted Wallace RAPD->PFGE 0.459, PFGE->RAPD 0.128). Furthermore, some isolates could not be adequately assigned a species name on the basis of 16S rRNA analysis: these isolates had identical PFGE/RAPD profiles to Prevotellahisticola.
CONCLUSION: The similarity in PFGE and RAPD banding patterns observed in sequential CF Prevotella isolates may be indicative of the persistence of this genus in the CF lung. Further work is required to determine the clinical significance of this finding, and to more accurately distinguish differences in pathogenicity between species.

PMID: 28604331 [PubMed - as supplied by publisher]

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CFTR-France, a national relational patient-database for sharing genetic and phenotypic data associated with rare CFTR variants(a).

Hum Mutat. 2017 Jun 12;:

Authors: Claustres M, Theze C, des Georges M, Baux D, Girodon E, Bienvenu T, Audrezet MP, Dugueperoux I, Ferec C, Lalau G, Pagin A, Kitzis A, Thoreau V, Gaston V, Bieth E, Malinge MC, Reboul MP, Fergelot P, Lemonnier L, Mekki C, Fanen P, Bergougnoux A, Sasorith S, Raynal C, Bareil C

Abstract
Most of 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years' experience of CFTR testing, CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles. This article is protected by copyright. All rights reserved.

PMID: 28603918 [PubMed - as supplied by publisher]

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Functional evaluation of breath: spirometry and body plethysmography comparison in people with cystic fibrosis.

J Phys Ther Sci. 2017 May;29(5):799-800

Authors: Villafañe JH, Corbellini C, Balestri E, Dall'Ara S, Bazzocchi F, Bertozzi L

Abstract
[Purpose] The aim of the present study was to establish up-to-date data regarding the lung function of cystic fibrosis (CF) patients. [Subjects and Methods] Forty-eight patients of both genders, with a diagnosis of CF, were recruited. As a result our sample presented, according to the GOLD criteria, 23 patients with mild lung obstruction (FEV1%pred: 89.86), 16 patients with moderate lung obstruction (FEV1%pred: 56.1) and 9 patients with severe obstruction (FEV1%pred: 32.1). [Results] All patients presented normal total lung capacity followed by an important residual volume increase. [Conclusion] Our results were important to illustrate the CF patient's lung functional status and to improve the health system strategy in treating such individuals.

PMID: 28603348 [PubMed - in process]

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Worsening anxiety and depression after initiation of lumacaftor/ivacaftor combination therapy in adolescent females with cystic fibrosis.

J Cyst Fibros. 2017 Jun 08;:

Authors: McKinzie CJ, Goralski JL, Noah TL, Retsch-Bogart GZ, Prieur MB

Abstract
In both phase III studies of LUM/IVA, as well as an extension study, worsening of mental health was not reported as a common side effect. Here we describe five cases in adolescent female patients that suggest a worsening of anxiety or depression associated with its use. In these five patients, two experienced suicidal ideation and three made suicide attempts that resulted in psychiatric hospitalizations.

PMID: 28602538 [PubMed - as supplied by publisher]

[Molecular genetic study of a family affected with punctate palmoplantar keratoderma].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2017 Jun 10;34(3):369-372

Authors: Jia Y, Wang S, Zhu Y, Luo D

Abstract
OBJECTIVE: To analyze the clinical characteristics and causative mutation in an ethnic Han Chinese family affected with punctate palmoplantar keratoderma (PPPK).
METHODS: Clinical characteristics and inheritance pattern of the family were analyzed. Two seriously affected individuals from the family were investigated by whole exome sequencing. Three healthy individuals from the family and 120 non-PPPK individuals were evaluated to validate the result.
RESULTS: The family was characterized by keratotic papules on the palms and soles, which gradually increased in size and number with age and coalesced with each other, particularly over the pressure part of the palms and soles. The family has featured autosomal dominant inheritance. A heterozygous frameshift variant c.419delC in exons of the CELA1 gene was identified in all affected individuals but not among non-affected members.
CONCLUSION: A heterozygous frameshift variant c.419delC in CELA1 gene probably underlies the disease in the family affected with PPPK.

PMID: 28604957 [PubMed - in process]

Genetic diagnosis of Mendelian disorders via RNA sequencing.

Nat Commun. 2017 Jun 12;8:15824

Authors: Kremer LS, Bader DM, Mertes C, Kopajtich R, Pichler G, Iuso A, Haack TB, Graf E, Schwarzmayr T, Terrile C, Koňaříková E, Repp B, Kastenmüller G, Adamski J, Lichtner P, Leonhardt C, Funalot B, Donati A, Tiranti V, Lombes A, Jardel C, Gläser D, Taylor RW, Ghezzi D, Mayr JA, Rötig A, Freisinger P, Distelmaier F, Strom TM, Meitinger T, Gagneur J, Prokisch H

Abstract
Across a variety of Mendelian disorders, ∼50-75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance.

PMID: 28604674 [PubMed - in process]

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Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168.

Front Immunol. 2017;8:576

Authors: Chinn IK, Sanders RP, Stray-Pedersen A, Coban-Akdemir ZH, Kim VH, Dadi H, Roifman CM, Quigg T, Lupski JR, Orange JS, Hanson IC

Abstract
With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these "mendelizing" disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections. Immunologic defects included CD8(+) T cell lymphopenia, decreased T cell proliferative responses to mitogens, hypogammaglobulinemia, and radiation sensitivity. Whole-exome sequencing revealed compound heterozygous variants in ZAP70. Biallelic mutations in ZAP70 are known to produce a spectrum of immune deficiency that includes the T cell abnormalities observed in this patient. Analyses for variants in genes associated with radiation sensitivity identified the presence of a homozygous RNF168 variant of unknown significance. RNF168 deficiency causes radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome and may account for the radiation sensitivity. Thus, the patient was found to have a novel blended phenotype associated with multilocus genomic variation: i.e., separate and distinct genetic defects. These findings further illustrate the clinical utility of applying genomic testing in patients with primary immunodeficiency diseases.

PMID: 28603521 [PubMed - in process]

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Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations.

Eur J Med Genet. 2017 Jun 08;:

Authors: Corbett MA, Turner SJ, Gardner A, Silver J, Stankovich J, Leventer RJ, Derry CP, Carroll R, Ha T, Scheffer IE, Bahlo M, Jackson GD, Mackey DA, Berkovic SF, Gecz J

Abstract
Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected individuals in the family. Identification of COL18A1 mutations in individuals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.

PMID: 28602933 [PubMed - as supplied by publisher]

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Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.

Am J Hum Genet. 2017 Jun 07;:

Authors: Halim D, Brosens E, Muller F, Wangler MF, Beaudet AL, Lupski JR, Akdemir ZHC, Doukas M, Stoop HJ, de Graaf BM, Brouwer RWW, van Ijcken WFJ, Oury JF, Rosenblatt J, Burns AJ, Tibboel D, Hofstra RMW, Alves MM

Abstract
Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs(∗)51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.

PMID: 28602422 [PubMed - as supplied by publisher]

Vedolizumab in pediatric inflammatory bowel disease: a retrospective multi-center experience from the Paediatric IBD Porto group of ESPGHAN.

J Crohns Colitis. 2017 Jun 09;:

Authors: Ledder O, Assa A, Levine A, Escher JC, de Ridder L, Ruemmele F, Shah N, Shaoul R, Wolters VM, Rodrigues A, Uhlig HH, Posovsky C, Kolho KL, Jakobsen C, Cohen S, Shouval DS, de Meij T, Martin-de-Carpi J, Richmond L, Bronsky J, Friedman M, Turner D

Abstract
Background: Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with Inflammatory Bowel Disease (IBD), but the data in pediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-center pediatric IBD cohort.
Method: Retrospective review of children (2-18 years) treated with vedolizumab from 19 centers affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was week 14 corticosteroid-free remission (CFR).
Results: 64 children were included [32 (50%) male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks (IQR 14-38; range 6-116)]; 41 (64%) UC/IBDU and 23 (36%) CD. All were previously treated with anti-TNF (28% primary failure, 53% secondary failure). Week 14 CFR was 37% in UC, and 14% in CD (p=0.06). CFR by last follow-up was 39% in UC and 24% in CD (p=0.24). Ten (17%) children required surgery, 6 of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate (42% vs 35%; p=0.35 at week 22). There were 3 minor drug-related adverse events. Overall 5% achieved endoscopic mucosal healing with 9% achieving stool calprotectin <100mcg/gm.
Conclusion: Vedolizumab was safe and effective in this cohort of pediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared to patients with UC.

PMID: 28605483 [PubMed - as supplied by publisher]

Related Articles

Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies.

Pharmgenomics Pers Med. 2017;10:197-204

Authors: Yamamoto-Furusho JK

Abstract
Inflammatory bowel disease (IBD) is a chronic and heterogeneous disorder characterized by remitting and relapsing periods of activity. Pharmacogenetics refers to the study of the effect of inheritance on individual variation in drug responses. Several drug-related markers in IBD patients have been identified in order to predict the response to medical treatment including biological therapy as well as the reduction of adverse events. In the future, the treatment of IBD should be personalized in its specific profile to provide the most efficacious treatment with lack of adverse events.

PMID: 28603427 [PubMed - in process]

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Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study.

Lancet Haematol. 2017 Jun 08;:

Authors: Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, Jourdan E, Winton E, Silver RT, Schouten HC, Passamonti F, Zweegman S, Talpaz M, Lager J, Shun Z, Mesa RA

Abstract
BACKGROUND: Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT. Furthermore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years. On the basis of this unmet need, we investigated the efficacy and safety of fedratinib, a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis.
METHODS: This single-arm, open-label, non-randomised, phase 2, multicentre study, done at 31 sites in nine countries, enrolled adult patients with a current diagnosis of intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 days of treatment. Other main inclusion criteria were palpable splenomegaly (≥5 cm below the left costal margin), Eastern Cooperative Oncology Group performance status of 2 or less, and life expectancy of 6 months or less. Patients received oral fedratinib at a starting dose of 400 mg once per day, for six consecutive 28-day cycles. The primary endpoint was spleen response (defined as the proportion of patients with a ≥35% reduction in spleen volume as determined by blinded CT and MRI at a central imaging laboratory). We did the primary analysis in the per-protocol population only (patients treated with fedratinib, for whom a baseline and at least one post-baseline spleen volume measurement was available) and the safety analysis in all patients receiving at least one dose of fedratinib. This trial was registered with ClinicalTrials.gov, number NCT01523171.
FINDINGS: Between May 8, 2012, and Aug 29, 2013, 97 patients were enrolled and received at least one dose of fedratinib. Of 83 assessable patients, 46 (55%, 95% CI 44-66) achieved a spleen response. Common grade 3-4 adverse events included anaemia (37 [38%] of 97 patients) and thrombocytopenia (21 [22%] of 97), with 18 (19%) patients discontinuing due to adverse events. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination.
INTERPRETATION: This phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed.
FUNDING: Sanofi.

PMID: 28602585 [PubMed - as supplied by publisher]

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Adverse Events After MMR or MMRV Vaccine in Infants Under Nine Months Old.

Pediatr Infect Dis J. 2016 Aug;35(8):e253-7

Authors: Woo EJ, Winiecki SK, Arya D, Beeler J

Abstract
BACKGROUND: In the United States, measles is resurging, with more than 700 confirmed cases since January 2014. During measles outbreaks, vaccination as early as at 6 months of age is sometimes recommended for infants who are at risk for exposure.
METHODS: We searched the Vaccine Adverse Event Reporting System for reports of measles, mumps and rubella vaccine combined or measles, mumps, rubella and varicella vaccine combined vaccination in children less than 9 months of age. We performed a clinical assessment of each report and summarized the frequency, range, onset time and severity of adverse events.
RESULTS: After excluding 346 reports because they were duplicates or because they contained insufficient information about the child's age or vaccine(s), we retained 204 reports in the analysis, including 35 (17%) that were serious. Among the 169 nonserious reports, more than half (88; 52%) described a vaccination error without any adverse event per se. Other nonserious reports described fever, injection reactions and gastrointestinal symptoms. Serious adverse events included developmental disorders, fever and fussiness. There were 44 reports of fever, but only 4 cases began 5-12 days after immunization, the peak risk window. The vast majority of fever reports listed concomitant vaccines, such as diphtheria and tetanus toxoids, acellular or whole-cell pertussis vaccine.
CONCLUSIONS: This review did not identify any major safety concerns. These findings may facilitate discussions about the risks and benefits of vaccinating infants who are potentially exposed to this life-threatening disease.

PMID: 27167117 [PubMed - indexed for MEDLINE]

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Funding Opportunity PAR-17-313 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages exploratory/developmental research grant applications, proposing the development of innovative, collaborative research projects on brain and other nervous system function and disorders throughout life, relevant to low- and middle-income countries (LMICs). Research on neurological, mental, behavioral, alcohol and substance use disorders may span the full range of science from basic to implementation research. Scientists in the United States (U.S.) or upper-middle income countries (UMICs) are eligible to partner with scientists in LMIC institutions. Scientists in upper middle-income LMICs (UMICs) are also eligible to partner directly with scientists at other LMIC institutions with or without out a US partner. Income categories used are as defined by the World Bank at http://data.worldbank.org/about/country-classifications/country-and-lending-groups.

Funding Opportunity PAR-17-314 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages grant applications for the conduct of innovative, collaborative research projects between U.S. and low- and middle-income country (LMIC) scientists, on brain and other nervous system function and disorders throughout life, relevant to LMICs (including neurological, mental, behavioral, alcohol and substance use disorders and spanning the full range of science from basic to implementation research). Scientists in upper middle-income LMICs (UMICs) are also eligible to partner directly with scientists at other LMIC institutions with or without out a US partner. Income categories are defined by the World Bank at http://data.worldbank.org/about/country-classifications/country-and-lending-groups.