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Linezolid-Containing Treatment Regimens for Tuberculosis in Children.

Pediatr Infect Dis J. 2018 May 10;:

Authors: Prieto LM, Santiago B, Del Rosal T, Carazo B, Jiménez AB, Pérez-Gorricho B, Rubio F, Tagarro A, Blázquez D, Moreno-Pérez D, Mellado MJ, Baquero-Artigao F, Spanish Paediatric TB Research Network (pTBred)

Abstract
BACKGROUND: In recent years there is an increasing interest in the use of linezolid for the treatment of tuberculosis (TB).
METHODS: Patients under 18 years of age who received linezolid within the Spanish Pediatric TB Network (pTBred) from 2001 to 2016 were retrospectively included. Treatment characteristics, adverse events (AEs) and outcomes were analyzed.
RESULTS: Fifteen children were included (53% male) with a median age of 3.6 years (IQR: 1.6-6.2). Median follow up was 54 months (IQR: 38-76). The reasons for linezolid use were drug-resistant TB (DR-TB) in eight (53%) patients, drug-induced liver injury (DILI) in five (33%) patients and chronic liver disease (CLD) in two (13%) patients. Four children (26%) were on immunosuppressive therapy when TB was diagnosed. Five children (33%) were diagnosed with extrapulmonary TB. The median duration of linezolid treatment was 13 months (IQR: 7.5-17). Nine patients had 13 linezolid-related AEs. Hematologic toxicity was observed in eight patients (53%) and gastrointestinal intolerance in 3 patients (20%). In two patients linezolid dose was reduced and in two patients linezolid was discontinued because of AEs. A 2- year-old girl went back to her country of birth and was lost to follow-up. No relapses were observed among the other 14 patients (93%).
CONCLUSIONS: Linezolid may be considered when treating children with drug resistant TB but also in the cases of patients with chronic liver disease or drug induced liver injury. However, AEs should be closely monitored. Further studies are needed to determine the optimum dosage and the optimal duration of linezolid treatment in children.

PMID: 29750764 [PubMed - as supplied by publisher]

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A phase I study of nintedanib combined with cisplatin/gemcitabine as first-line therapy for advanced squamous non-small cell lung cancer (LUME-Lung 3).

Lung Cancer. 2018 Jun;120:27-33

Authors: Forster M, Hackshaw A, De Pas T, Cobo M, Garrido P, Summers Y, Dingemans AC, Flynn M, Schnell D, von Wangenheim U, Loembé AB, Kaiser R, Lee SM

Abstract
BACKGROUND: There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated.
MATERIALS AND METHODS: A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2-7, 9-21) were given for 4-6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine maximum tolerated dose (MTD) based on occurrence of dose-limiting toxicities (DLTs) during Cycle 1. DLTs were primarily defined as drug-related non-hematologic (Grade ≥3) or hematologic (Grade 4) AEs.
RESULTS: Sixteen patients were treated with nintedanib; n = 4 for 150 mg bid, n = 12 for 200 mg bid. No DLTs were observed in Cycle 1; therefore, the MTD was 200 mg bid. In subsequent cycles, two patients had DLTs: renal failure and reduced blood magnesium levels. The most common AEs were gastrointestinal. Three patients discontinued last study medication due to AEs and one had a nintedanib dose reduction. No relevant PK interactions were observed. Five patients had partial responses (31.3%) and eight had stable disease (50.0%); disease control rate was 81.3%. There were three long-term survivors (17-35 months).
CONCLUSIONS: The safety profile of nintedanib 200 mg bid plus cisplatin/gemcitabine was manageable, with AEs consistent with previous observations. PK data demonstrated no interaction, and preliminary antitumor activity was observed.

PMID: 29748012 [PubMed - in process]

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Comparison of lacosamide versus sodium valproate in status epilepticus: A pilot study.

Epilepsy Behav. 2017 Nov;76:110-113

Authors: Misra UK, Dubey D, Kalita J

Abstract
PURPOSE: The purpose of this study was to compare the efficacy and safety of lacosamide (LCM) and sodium valproate (SVA) in lorazepam (LOR)-resistant SE.
METHODS: Patients with LOR-resistant SE were randomized to intravenous LCM 400mg at the rate of 60mg/kg/min or SVA 30mg/kg at the rate of 100mg/min. The SE severity score (STESS), duration of SE and its etiology, and MRI findings were noted. Primary outcome was seizure cessation for 1h, and secondary outcomes were 24h seizure remission, in-hospital death, and severe adverse events (SAE).
RESULTS: Sixty-six patients were included, and their median age was 40 (range 18-90) years. Thirty-three patients each received LCM and SVA. Their demographic, clinical, STESS, etiology, and MRI findings were not significantly different. One-hour seizure remission was not significantly different between LCM and SVA groups (66.7% vs 69.7%; P=0.79). Twenty-four-hour seizure freedom was insignificantly higher in SVA (20, 66.6%) compared with LCM group (15, 45.5%). Death (10 vs 12) and composite side effects (4 vs 6) were also not significantly different in LCM and SVA groups. LCM was associated with hypotension and bradycardia (1 patient), and SVA with liver dysfunction (6).
CONCLUSION: In patients with LOR-resistant SE, both LCM and SVA have comparable efficacy and safety.

PMID: 28919386 [PubMed - indexed for MEDLINE]

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[Cross sectional study of comorbidities and concomitant medications in a cohort of human immunodeficiency virus-infected patients].

Aten Primaria. 2017 May;49(5):286-293

Authors: García Gonzalo MA, Santamaría Mas MI, Pascual Tomé L, Ibarguren Pinilla M, Rodríguez-Arrondo F

Abstract
AIM: To assess the prevalence of comorbidities, concomitant therapies and adverse effects associated with the medication in a cohort of patients with HIV infection.
DESIGN: Multicentre cross-sectional study.
SETTINGS: Infectious Diseases or Internal Medicine outpatient Clinics of 3 hospitals in the Basque Country.
PARTICIPANTS: During a 3 month period, patients with the following inclusion criteria were randomly selected: HIV infection, age>18years, antiretroviral treatment (ART) for at least 6months, and no changes in ART in the previous 4weeks. A total of 224 patients (of the 225 expected) were included.
MEASUREMENTS: Data were collected using a form, and include, epidemiological and anthropometric data, data related to HIV infection, comorbidities, current therapies, and adverse effects.
RESULTS: Of the 224 patients, 95.5% had at least one comorbidity, the most common being HCV infection (51.3%), dyslipidaemia (37.9%), diabetes mellitus or impaired fasting glucose (21.9%), and hypertension (21.9%). A total of 155 patients (69.2%) were taking concomitant medication: anxiolytics (21.4%), antihypertensives (19.6%), proton pump inhibitors (17.9%), statins (17%), and antidepressants (16.5%). Adverse effects (AE) were observed in 62.9% of subjects, the most common being, changes in body fat distribution (32.6%) and gastrointestinal (24.1%).
CONCLUSIONS: Patients with HIV infection are getting older, with more comorbidities, with very frequent use of concomitant treatments, and high number of adverse effects. This requires a multidisciplinary approach and a coordinated effort within the Primary Care setting.

PMID: 27720238 [PubMed - indexed for MEDLINE]

Notice NOT-OD-18-179 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-782 from the NIH Guide for Grants and Contracts. The NIH Research Education Program (R25) supports research education activities in the mission areas of the NIH. The over-arching goal of this NINDS R25 program is to support educational activities that complement and/or enhance the training of a workforce to meet the nations biomedical, behavioral and clinical research needs.

Funding Opportunity PAR-18-781 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support the use of Collaborative Cross (CC) mouse lines to advance understanding of the host genetics involved in immune regulation and function and to further develop CC mouse lines that more faithfully reproduce human immune responses. Research areas supported by this FOA include: immune system development, function or regulation; mechanisms governing immune response to infectious pathogens, vaccines or adjuvants; host susceptibility factors and mechanisms of pathogen-induced immunopathology; and immune mechanisms involved in the development and progression of immune-mediated diseases, such as allergy/asthma, autoimmunity, primary immunodeficiency, inflammation, and cell/organ/tissue transplant rejection or tolerance.

Funding Opportunity RFA-NS-18-032 from the NIH Guide for Grants and Contracts. The purpose of the NINDS Research Program Award (RPA) is to provide longer-term support and increased flexibility to Program Directors (PDs) /Principal Investigators (PIs) whose records of research achievement demonstrate their ability to make major contributions to neuroscience. RPAs will support the overall research programs of NINDS-funded investigators for up to 8 years, at a level commensurate with a PD/PIs recent NINDS support (Part 2, Section II) This greater funding stability will provide eligible investigators at nearly all career stages increased freedom and flexibility, allowing them to be more adventurous in their research, take greater risks, embark upon research that breaks new ground, undertake research projects that require a longer timeframe, and/or extend previous discoveries in new directions. Research supported through the RPA must be within the scope of the NINDS mission (http://www.ninds.nih.gov/about_ninds/mission.htm). Research activities outside of the NINDS mission, or traditionally supported by another NIH Institute or Center will not be considered through this program. Other anticipated benefits of the RPA include: A more stable funding environment, facilitating the pursuit of longer term research goals; Flexible funding, enabling investigators to pursue research opportunities as they arise, not tied to specific aims; Reduced time spent writing grant applications and managing multiple grant awards, thereby allowing investigators to spend more time conducting and overseeing research; and More time for PDs/PIs to mentor junior scientists. Eligibility to apply through this FOA is limited to investigators who currently have at least one active NINDS R01 or R01 equivalent grant (defined as R01, R37, R56, DP1 or DP2 awards) due to expire in FY18 or FY19. Applicants must also have received R01, R00, or R01 equivalent grant support from NINDS in each of the past 5 years), with no more than one of those years in a no cost ext

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High-Throughput Flow Cytometry Identifies Small-Molecule Inhibitors for Drug Repurposing in T-ALL.

SLAS Discov. 2018 May 01;:2472555218774248

Authors: Perez DR, Nickl CK, Waller A, Delgado-Martin C, Woods T, Sharma ND, Hermiston ML, Loh ML, Hunger SP, Winter SS, Chigaev A, Edwards B, Sklar LA, Matlawska-Wasowska K

Abstract
Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute lymphoblastic leukemia (T-ALL). In this study, we used a high-throughput flow cytometry (HTFC) approach to test a collection of small-molecule inhibitors, including 26 FDA-approved tyrosine kinase inhibitors in a panel of T-ALL cell lines and patient-derived xenografts. Because hypoxia is known to cause resistance to chemotherapy, we developed a synthetic niche that mimics the low oxygen levels found in leukemic bone marrow to evaluate the effects of hypoxia on the tested inhibitors. Drug sensitivity screening was performed using the Agilent BioCel automated liquid handling system integrated with the HyperCyt HT flow cytometry platform, and the uptake of propidium iodide was used as an indication of cell viability. The HTFC dose-response testing identified several compounds that were efficacious in both normal and hypoxic conditions. This study shows that some clinically approved kinase inhibitors target T-ALL in the hypoxic niche of the bone marrow.

PMID: 29746793 [PubMed - as supplied by publisher]

Multi-target drug repositioning by bipartite block-wise sparse multi-task learning.

BMC Syst Biol. 2018 Apr 24;12(Suppl 4):55

Authors: Li L, He X, Borgwardt K

Abstract
BACKGROUND: Finding potential drug targets is a crucial step in drug discovery and development. Recently, resources such as the Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 database provide gene expression profiles induced by various chemical and genetic perturbations and thereby make it possible to analyze the relationship between compounds and gene targets at a genome-wide scale. Current approaches for comparing the expression profiles are based on pairwise connectivity mapping analysis. However, this method makes the simple assumption that the effect of a drug treatment is similar to knocking down its single target gene. Since many compounds can bind multiple targets, the pairwise mapping ignores the combined effects of multiple targets, and therefore fails to detect many potential targets of the compounds.
RESULTS: We propose an algorithm to find sets of gene knock-downs that induce gene expression changes similar to a drug treatment. Assuming that the effects of gene knock-downs are additive, we propose a novel bipartite block-wise sparse multi-task learning model with super-graph structure (BBSS-MTL) for multi-target drug repositioning that overcomes the restrictive assumptions of connectivity mapping analysis.
CONCLUSIONS: The proposed method BBSS-MTL is more accurate for predicting potential drug targets than the simple pairwise connectivity mapping analysis on five datasets generated from different cancer cell lines.
AVAILABILITY: The code can be obtained at http://gr.xjtu.edu.cn/web/liminli/codes .

PMID: 29745839 [PubMed - in process]

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Repurposing drugs in oncology (ReDO)-selective PDE5 inhibitors as anti-cancer agents.

Ecancermedicalscience. 2018;12:824

Authors: Pantziarka P, Sukhatme V, Crispino S, Bouche G, Meheus L, Sukhatme VP

Abstract
Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of cancers. In particular, evidence is presented that these drugs have potent immunomodulatory activity that warrants clinical study in combination with check-point inhibition.

PMID: 29743944 [PubMed]

Related Articles

Non-coding RNA in cystic fibrosis.

Biochem Soc Trans. 2018 May 09;:

Authors: Glasgow AMA, De Santi C, Greene CM

Abstract
Non-coding RNAs (ncRNAs) are an abundant class of RNAs that include small ncRNAs, long non-coding RNAs (lncRNA) and pseudogenes. The human ncRNA atlas includes thousands of these specialised RNA molecules that are further subcategorised based on their size or function. Two of the more well-known and widely studied ncRNA species are microRNAs (miRNAs) and lncRNAs. These are regulatory RNAs and their altered expression has been implicated in the pathogenesis of a variety of human diseases. Failure to express a functional cystic fibrosis (CF) transmembrane receptor (CFTR) chloride ion channel in epithelial cells underpins CF. Secondary to the CFTR defect, it is known that other pathways can be altered and these may contribute to the pathophysiology of CF lung disease in particular. For example, quantitative alterations in expression of some ncRNAs are associated with CF. In recent years, there has been a series of published studies exploring ncRNA expression and function in CF. The majority have focussed principally on miRNAs, with just a handful of reports to date on lncRNAs. The present study reviews what is currently known about ncRNA expression and function in CF, and discusses the possibility of applying this knowledge to the clinical management of CF in the near future.

PMID: 29743276 [PubMed - as supplied by publisher]

Related Articles

CFTR/ENaC dependent regulation of membrane potential during human sperm capacitation is initiated by bicarbonate uptake through NBC.

J Biol Chem. 2018 May 09;:

Authors: Puga Molina LC, Pinto NA, Torres NI, Gonzalez-Cota AL, Luque GM, Balestrini PA, Romarowski A, Krapf D, Santi CM, Trevino CL, Darszon A, Buffone MG

Abstract
To fertilize an egg, sperm must reside in the female reproductive tract to undergo several maturational changes that are collectively referred to as capacitation. From a molecular point of view, the HCO3--dependent activation of the atypical soluble adenylyl cyclase (ADCY10) is one of the first events that occurs during capacitation and leads to the subsequent cAMP-dependent activation of protein kinase A (PKA). Capacitation is also accompanied by hyperpolarization of the sperm plasma membrane. We previously reported that PKA activation is necessary for CFTR (Cystic Fibrosis Transmembrane Conductance Regulator Channel) activity and for the modulation of membrane potential (Em). However, the main HCO3- transporters involved in the initial transport and the PKA-dependent Em changes are not well known nor characterized. Here, we analyzed how the activity of CFTR regulates Em during capacitation and examined its relationship with an electrogenic Na+/HCO3- cotransporter (NBC) and epithelial Na+ channels (ENaCs). We observed that inhibition of both CFTR and NBC decreased HCO3- influx, resulting in lower PKA activity, and that events downstream the cAMP-activation of PKA are essential for the regulation of Em. Addition of a permeable cAMP analog partially rescued the inhibitory effects caused by these inhibitors. HCO3-  also produced a rapid membrane hyperpolarization mediated by ENaC channels, which contribute to the regulation of Em during capacitation. Altogether, we demonstrate for the first time, that NBC cotransporters and ENaC channels are essential in the CFTR-dependent activation of the cAMP/PKA signaling pathway and Em regulation during human sperm capacitation.

PMID: 29743243 [PubMed - as supplied by publisher]

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Adult patients' experiences of symptom management during pulmonary exacerbations in cystic fibrosis: A thematic synthesis of qualitative research.

Chronic Illn. 2018 Jan 01;:1742395318772647

Authors: Schmid-Mohler G, Yorke J, Spirig R, Benden C, Caress AL

Abstract
Objective The aim of this review was to describe how patients experience an exacerbation of cystic fibrosis in terms of symptom management. Methods A systematic literature search was performed in MEDLINE, CINAHL, EMBASE, PSYCINFO and ASSIA. Studies were included that contained any direct quotes or summaries of quotes from patients with cystic fibrosis aged 16 or older and were related to symptom experience and management during an exacerbation. Framework analysis, guided by Symptom Management Theory, was used to present the findings. Results The review included 18 qualitative studies. In addition to physiological symptoms, patients highlighted the significant role of psychological symptoms. Delayed help-seeking was a common first response. Participants choose their self-management strategies taking both physiological and psychological symptoms into account. Maintaining normality was an important short-term outcome for patients, leading to conflict with health professionals. Patients' symptom management during exacerbation was greatly influenced by the structure of cystic fibrosis care. Discussion Our findings provide an initial understanding of factors influencing patient self-management during an exacerbation. The transferal of these findings into clinical practice will provide a basis for shared goal setting and intervention planning. In addition, our findings have implications for future development of patient-reported outcome measures and intervention research.

PMID: 29742923 [PubMed - as supplied by publisher]

Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer.

DNA Repair (Amst). 2018 Apr 26;66-67:50-63

Authors: Das R, Kundu S, Laskar S, Choudhury Y, Ghosh SK

Abstract
Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition. Whole exome sequencing was performed in Ion Proton™ platform on 15 case-control samples from the HNC-prevalent states of Manipur, Mizoram, and Nagaland. Variant annotation was done in Ion Reporter™ as well as wANNOVAR. Subsequent statistical and bioinformatics analysis identified significant exonic and intronic variants associated with HNC. Amongst our observed variants, 78.6% occurred in ExAC, 94% reported in dbSNP and 5.8% & 9.3% variants were present in ClinVar and HGMD, respectively. The total variants were dispersed among 199 genes with DSBR and FA pathway being the most mutated pathways. The allelic association test suggested that the intronic variants in HLTF and RAD52 gene significantly associated (P < 0.05) with the risk (OR > 5), while intronic variants in PARP4, RECQL5, EXO1 and PER1 genes and exonic variant in TDP2 gene showed protection (OR < 1) for HNC. MDR analysis proposed the exonic variants in MSH6, BRCA2, PALB2 and TP53 genes and intronic variant in RECQL5 genetic region working together during certain phase of DNA repair mechanism for HNC causation. In addition, other intronic and 3'UTR variations caused modifications in the transcription factor binding sites and miRNA target sites associated with HNC. Large-scale validation in NE Indian population, in-depth structure prediction and subsequent simulation of our recognized polymorphisms is necessary to identify true causal variants related to HNC.

PMID: 29747023 [PubMed - as supplied by publisher]

Related Articles

Widespread and debilitating hemangiomas in a patient with enchondromatosis and D-2-hydroxyglutaric aciduria.

Skeletal Radiol. 2018 May 10;:

Authors: Yeetong P, Phewplung T, Kamolvisit W, Suphapeetiporn K, Shotelersuk V

Abstract
Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) (OMIM 614875) is a severe chondrodysplasia combined with a urinary excretion of D-2-hydroxyglutaric acid. Here, we reported the tenth case of this disease. A 15-year-old boy had symmetric radiolulencies in the metaphyses of the long bones suggesting enchondromatosis and platyspondyly. Remarkably, he manifested widespread cavernous hemangiomas including scalp, lips, tongue, larynx, and prepuce, with the onset of 3 years of age. Hemangiomas at the larynx had caused dyspnea and those in the oral cavity led to recurrent bleeding, requiring several surgical removals. These multiple and debilitating hemangiomas have never been previously reported in patients with MC-HGA. Mutation analyses including Sanger sequencing of genes involving in enchondromatosis and the metabolic pathway of D-2-hydroxyglutarate including PTHR1, D2HGDH, HOT, and IDH1, as well as whole-exome sequencing for proband-parent trio analysis and paired blood versus hemangioma studies showed no pathogenic variants. In summary, we reported the tenth patient with MC-HGA who manifested widespread and debilitating hemangiomas in several organs, expanding the clinical spectrum of MC-HGA.

PMID: 29744569 [PubMed - as supplied by publisher]