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Bis-biguanide dihydrochloride inhibits intracellular replication of M. tuberculosis and controls infection in mice.

Sci Rep. 2016 09 07;6:32725

Authors: Shen H, Wang F, Zeng G, Shen L, Cheng H, Huang D, Wang R, Rong L, Chen ZW

Abstract
While there is an urgent need to develop new and effective drugs for treatment of tuberculosis (TB) and multi-drug resistant TB (MDR-TB), repurposing FDA (U.S. Food and Drug Administration) -approved drugs for development of anti-TB agents may decrease time and effort from bench to bedside. Here, we employed host cell-based high throughput screening (HTS) assay to screen and characterize FDA-approved, off-patent library drugs for anti-Mycobacterium tuberculosis (MTB) activities. The cell-based HTS allowed us to identify an anti-cancer drug of bis-biguanide dihydrochloride (BBD) as potent anti-mycobacteria agent. Further characterization showed that BBD could inhibit intracellular and extracellular growth of M. smegmatis and slow-growing M. bovis BCG. BBD also potently inhibited replication of clinically-isolated MTB and MDR-TB strains. The proof-of-concept study showed that BBD treatment of MTB-infected mice could significantly decrease CFU counts in the lung and spleen. Notably, comparative evaluation showed that MTB CFU counts in BBD-treated mice were lower than those in rifampicin-treated mice. No apparent BBD side effects were found in BBD-treated mice. Thus, our findings support further studies to develop BBD as a new and effective drug against TB and MDR-TB.

PMID: 27601302 [PubMed - indexed for MEDLINE]

Small-Molecule Inhibitors Disrupt let-7 Oligouridylation and Release the Selective Blockade of let-7 Processing by LIN28.

Cell Rep. 2018 Jun 05;23(10):3091-3101

Authors: Wang L, Rowe RG, Jaimes A, Yu C, Nam Y, Pearson DS, Zhang J, Xie X, Marion W, Heffron GJ, Daley GQ, Sliz P

Abstract
LIN28 is an RNA-binding protein that regulates the maturation of the let-7 family of microRNAs by bipartite interactions with let-7 precursors through its two distinct cold shock and zinc-knuckle domains. Through inhibition of let-7 biogenesis, LIN28 functions as a pluripotency factor, as well as a driver of tumorigenesis. Here, we report a fluorescence polarization assay to identify small-molecule inhibitors for both domains of LIN28 involved in let-7 interactions. Of 101,017 compounds screened, six inhibit LIN28:let-7 binding and impair LIN28-mediated let-7 oligouridylation. Upon further characterization, we demonstrate that the LIN28 inhibitor TPEN destabilizes the zinc-knuckle domain of LIN28, while LI71 binds the cold shock domain to suppress LIN28's activity against let-7 in leukemia cells and embryonic stem cells. Our results demonstrate selective pharmacologic inhibition of individual domains of LIN28 and provide a foundation for therapeutic inhibition of the let-7 biogenesis pathway in LIN28-driven diseases.

PMID: 29874593 [PubMed - in process]

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Berry syndrome: a rare cardiac malformation with extra-cardiac findings.

Sci China Life Sci. 2017 07;60(7):772-774

Authors: Li J, Yang Y, Duan X, Jin L, Zheng L, Zhang X, Wei H, Sun Y, Zhang X, Li P, Yang J, Ma N, Wang F

PMID: 28646472 [PubMed - indexed for MEDLINE]

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Analysis of diagnosis and treatment of lipoblastomatosis.

Sci China Life Sci. 2017 07;60(7):778-780

Authors: Mo Z, Xie X, Wang H, Qin H, Han W, Li X

PMID: 28639103 [PubMed - indexed for MEDLINE]

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The challenge and promise of rare disease diagnosis in China.

Sci China Life Sci. 2017 07;60(7):681-685

Authors: Ni X, Shi T

PMID: 28623543 [PubMed - indexed for MEDLINE]

Simultaneous Discrimination of Single-Base Mismatch and Full Match Using a Label-Free Single-Molecule Strategy.

Anal Chem. 2018 Jun 06;:

Authors: Yang Q, Ai T, Lv Y, Huang Y, Geng J, Xiao D, Zhou C

Abstract
Identification of single-base mismatches has found wide applications in disease diagnosis, pharmacogenetics and population genetics. However, there is still a great challenge in the simultaneous discrimination of single-base mismatch and full match. Combined with a nanopore electrochemical sensor, a shared-stem structure of molecular beacon (MB) was designed that did not need the labeling, but achieved an enhanced signal-to-background ratio (SBR) of ~10E4, high thermodynamic stability to bind with target sequences and a fast hybridization rate. Fully matched and single-base mismatched sequences were simultaneously discriminated at the single-molecule level, which is expected to have potential applications ranging from the quick detection, early clinical diagnostics to point-of-care research.

PMID: 29874049 [PubMed - as supplied by publisher]

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Identification of a Genomic Region Between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).

Clin Cancer Res. 2018 Jun 05;:

Authors: Li M, Mulkey F, Jiang C, O'Neill BH, Schneider BP, Shen F, Friedman PN, Momozawa Y, Kubo M, Niedzwiecki D, Hochster HS, Lenz HJ, Atkins JN, Rugo HS, Halabi S, Kelly WK, McLeod HL, Innocenti F, Ratain MJ, Venook A, Owzar K, Kroetz D

Abstract
PURPOSE: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.
EXPERIMENTAL DESIGN: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 bevacizumab-treated patients (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.
RESULTS: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01, OR 2.4) and systolic blood pressure > 180 mmHg (P = 0.02, OR 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03, OR 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.
CONCLUSIONS: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension.

PMID: 29871907 [PubMed - as supplied by publisher]

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Expression profiling and functional annotation of noncoding genes across 11 distinct organs in rat development.

Sci Rep. 2016 12 09;6:38575

Authors: Wen Z, Chen G, Zhu S, Zhu J, Li B, Song Y, Li S, Shi L, Zheng Y, Li M

Abstract
Accumulating evidence suggests that noncoding RNAs (ncRNAs) have important regulatory functions. However, lacking of functional annotations for ncRNAs hampered us from carrying out the subsequent functional or predictive research. Here we dissected the expression profiles of 3,458 rat noncoding genes using rat bodymap RNA-sequencing data consisting of 11 solid organs over four developmental stages (juvenile, adolescent, adult and aged) from both sexes, and conducted a comprehensive analysis of differentially expressed noncoding genes (DEnGs) between various conditions. We then constructed a co-expression network between protein-coding and noncoding genes to infer biological functions of noncoding genes. Modules of interest were linked to online databases including DAVID for functional annotation and pathway analysis. Our results indicated that noncoding genes are functionally enriched through pathways similar to those of protein-coding genes. Terms about development of the immune system were enriched with genes from age-related modules, whereas terms about sexual reproduction were enriched with genes in sex-related modules. We also built connection networks on some significant modules to visualize the interactions and regulatory relationship between protein-coding and noncoding genes. Our study could improve our understanding and facilitate a deeper investigation on organ/age/sex-related regulatory events of noncoding genes, which may lead to a superior preclinical model for drug development and translational medicine.

PMID: 27934932 [PubMed - indexed for MEDLINE]

A Bond-Fluctuation Model of Translational Dynamics of Chain-like Particles through Mucosal Scaffolds.

Biophys J. 2018 Jun 05;114(11):2732-2742

Authors: Bajd F, Serša I

Abstract
Mucus scaffolds represent one of the most common barriers in targeted drug delivery and can remarkably reduce the outcome of pharmacological therapies. An efficient transport of drug particles through a mucus barrier is a precondition for an efficient drug delivery. Understanding the transport mechanism is particularly important for treatment of disorders such as cystic fibrosis. These are characterized by an onset of high-density mucus scaffolds imposing an increased steric filtering. In this study, we employed the bond-fluctuation model to analyze the effect of steric interactions on slowing the translational dynamics of compound chain-like particles traversing through scaffolds of different configurations (regular isotropic and anisotropic versus irregular random). The model, which accounts for both the geometry-imposed steric interaction as well as the intrachain steric interaction between the chain subunits, yields a transient subdiffusive motional pattern persists between the short-time and long-time Gaussian diffusion limits. The motion is analyzed in terms of a mean-squared displacement, diffusion coefficient, and radius of gyration. With higher levels of restriction or larger particles, the subdiffusive motional regime persists longer. The study also demonstrates that an important feature of the motion is also geometry-induced chain accommodation. The presented model is generic and could also be applied to studying the translational dynamics of other particles with more complex architecture such as dendrites or chain-decorated nanoparticles.

PMID: 29874621 [PubMed - in process]

Unusual presentation of cystic fibrosis as diffuse dermatitis.

Indian J Dermatol Venereol Leprol. 2018 Jun 04;:

Authors: Bonfim BS, Mota LR, Almeida CG, de Brito Aguiar AP, Ferreira de Lima RLL, de Mattos ÂP, Souza EL

PMID: 29873311 [PubMed - as supplied by publisher]

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Impact of PEGylation on the mucolytic activity of recombinant human deoxyribonuclease I in cystic fibrosis sputum.

Clin Sci (Lond). 2018 Jun 05;:

Authors: Guichard MJ, Kinoo D, Aubriot AS, Bauwens N, Gougué J, Vermeulen F, Lebecque P, Leal T, Vanbever R

Abstract
Highly viscous mucus and its impaired clearance characterize the lungs of patients with cystic fibrosis (CF). Pulmonary secretions of patients with CF display increased concentrations of high molecular weight components such as DNA and actin. Recombinant human deoxyribonuclease I (rhDNase) delivered by inhalation cleaves DNA filaments contained in respiratory secretions and thins them. However, rapid clearance of rhDNase from the lungs implies a daily administration and thereby a high therapy burden and a reduced patient compliance. A PEGylated version of rhDNase could sustain the presence of the protein within the lungs and reduce its administration frequency. Here, we evaluated the enzymatic activity of rhDNase conjugated to a two-arm 40 kDa polyethylene glycol (PEG) in CF sputa. Rheology data indicated that both rhDNase and PEG40-rhDNase presented similar mucolytic activity in CF sputa, independently of the purulence of the sputum samples as well as of their DNA, actin and ions contents. The macroscopic appearance of the samples correlated with the DNA content of the sputa: the more purulent the sample, the higher the DNA concentration. Finally, quantification of the enzymes in CF sputa following rheology measurement suggests that PEGylation largely increases the stability of rhDNase in CF respiratory secretions since 24-fold more PEG40-rhDNase than rhDNase was recovered from the samples. The present results are considered positive and provide support to the continuation of the research on a long-acting version of rhDNase to treat CF lung disease.

PMID: 29871879 [PubMed - as supplied by publisher]

Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family.

Mult Scler. 2018 Jun 01;:1352458518777202

Authors: Mescheriakova JY, Verkerk AJ, Amin N, Uitterlinden AG, van Duijn CM, Hintzen RQ

Abstract
BACKGROUND: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS.
OBJECTIVE: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations.
METHODS: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls.
RESULTS: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8-2.4), p = 0.31).
CONCLUSION: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk.

PMID: 29873607 [PubMed - as supplied by publisher]

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Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease.

Pharmacol Rev. 2018 Jul;70(3):446-474

Authors: Squires KE, Montañez-Miranda C, Pandya RR, Torres MP, Hepler JR

Abstract
Regulators of G protein signaling (RGS) proteins modulate the physiologic actions of many neurotransmitters, hormones, and other signaling molecules. Human RGS proteins comprise a family of 20 canonical proteins that bind directly to G protein-coupled receptors/G protein complexes to limit the lifetime of their signaling events, which regulate all aspects of cell and organ physiology. Genetic variations account for diverse human traits and individual predispositions to disease. RGS proteins contribute to many complex polygenic human traits and pathologies such as hypertension, atherosclerosis, schizophrenia, depression, addiction, cancers, and many others. Recent analysis indicates that most human diseases are due to extremely rare genetic variants. In this study, we summarize physiologic roles for RGS proteins and links to human diseases/traits and report rare variants found within each human RGS protein exome sequence derived from global population studies. Each RGS sequence is analyzed using recently described bioinformatics and proteomic tools for measures of missense tolerance ratio paired with combined annotation-dependent depletion scores, and protein post-translational modification (PTM) alignment cluster analysis. We highlight selected variants within the well-studied RGS domain that likely disrupt RGS protein functions and provide comprehensive variant and PTM data for each RGS protein for future study. We propose that rare variants in functionally sensitive regions of RGS proteins confer profound change-of-function phenotypes that may contribute, in newly appreciated ways, to complex human diseases and/or traits. This information provides investigators with a valuable database to explore variation in RGS protein function, and for targeting RGS proteins as future therapeutic targets.

PMID: 29871944 [PubMed - in process]

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Rapid and effective response of the R222Q SCN5A to quinidine treatment in a patient with Purkinje-related ventricular arrhythmia and familial dilated cardiomyopathy: a case report.

BMC Med Genet. 2018 Jun 05;19(1):94

Authors: Zakrzewska-Koperska J, Franaszczyk M, Bilińska Z, Truszkowska G, Karczmarz M, Szumowski Ł, Zieliński T, Płoski R, Bilińska M

Abstract
BACKGROUND: Mutations of the SCN5A gene are reported in 2-4% of patients with dilated cardiomyopathy (DCM). In such cases, DCM is associated with different rhythm disturbances such as the multifocal ectopic Purkinje-related premature contractions and atrial fibrillation. Arrhythmia often occurs at a young age and is the first symptom of heart disease.
CASE PRESENTATION: We present the case of 55-year old male with a 30-year history of heart failure (HF) in the course of familial DCM and complex ventricular tachyarrhythmias, which constituted 50-80% of the whole rhythm. The patient was qualified for heart transplantation because of the increasing symptoms of HF. We revealed the heterozygotic R222Q mutation in SCN5A by means of whole exome sequencing. After the quinidine treatment, a rapid and significant reduction of ventricular tachyarrhythmias and an improvement in the myocardial function were observed and this effect remained constant in the 2.5-year follow-up. This effect was observed even in the presence of concomitant coronary artery disease.
CONCLUSIONS: Patients with familial DCM and Purkinje-related ventricular arrhythmias should be offered genetic screening. The quinidine treatment for the SCN5A R222Q mutation can be life saving for patients.

PMID: 29871609 [PubMed - in process]

Evaluation of accuracy of IHI Trigger Tool in identifying adverse drug events: a prospective observational study.

Br J Clin Pharmacol. 2018 Jun 06;:

Authors: das Dores Graciano Silva M, Martins MAP, de Gouvêa Viana L, Passaglia LG, de Menezes RR, de Queiroz Oliveira JA, da Silva JLP, Ribeiro ALP

Abstract
AIMS: Adverse drug events (ADEs) can seriously compromise the safety and quality of care provided to hospitalized patients, requiring the adoption of accurate methods to monitor them. We sought to prospectively evaluate the accuracy of the triggers proposed by the Institute for Healthcare Improvement (IHI) for identifying ADEs.
METHODS: A prospective study was conducted in a public university hospital, in 2015, with patients ≥18 years. Triggers proposed by IHI and clinical alterations suspected to be ADEs were searched daily. The number of days in which the patient was hospitalized was considered as unit of measure to evaluate the accuracy of each trigger.
RESULTS: Three hundred patients were included in this study. Mean age was 56.3 years (standard deviation (SD) 16.0), and 154 (51.3%) were female. The frequency of patients with ADEs was 24.7% and with at least one trigger was 53.3%. From those patients who had at least one trigger, the most frequent triggers were antiemetics (57.5%) and "abrupt medication stop" (31.8%). Triggers' sensitivity ranged from 0.3 to11.8 % and the positive predictive value ranged from 1.2 to 27.3%. Specificity and negative predictive value were greater than 86%. Most patients identified by the presence of triggers did not have ADEs (64.4%). No triggers were identified in 40 (38.5%) ADEs.
CONCLUSIONS: IHI Trigger Tool did not show good accuracy in detecting ADEs in this prospective study. The adoption of combined strategies could enhance effectiveness in identifying patient safety flaws. Further discussion might contribute to improve trigger usefulness in clinical practice.

PMID: 29874704 [PubMed - as supplied by publisher]

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Effect of Low-Dose Vs Standard-Dose Valganciclovir in the Prevention of Cytomegalovirus Disease in Kidney Transplantation Recipients: A Systemic Review and Meta-Analysis.

Transplant Proc. 2018 Jun 02;:

Authors: Hwang SD, Lee JH, Lee SW, Kim JK, Kim MJ, Song JH

Abstract
BACKGROUND: Valganciclovir is widely used to prevent post-transplant cytomegalovirus (CMV) infection in kidney transplant patients. However, the currently used dose remains controversial because the continuous use of this drug decreases kidney function and can induce leukopenia.
OBJECTIVE: The purpose of this study was to measure the appropriate dose of valganciclovir required to prevent CMV infection.
METHODS: A systematic review and meta-analysis were performed by using a random effects model. The Cochrane Central Register, MEDLINE, EMBASE, and PubMed databases were searched up to April 15, 2017. We conducted analysis on low-dose (450 mg) and standard-dose (900 mg) valganciclovir groups.
RESULTS: After completion of the research, the analysis revealed that the glomerular filtration rate, graft loss, tacrolimus level, antibody-mediated rejection, and fungal and Candida infection rates did not differ between the 2 groups. However, the incidence of CMV tended to decrease in the low-dose group (0.584 [95% confidence interval [CI], 0.352-0.967]; P = .036). The biopsy-proven rejection rate decreased by 0.427 times in the low-dose group compared with the standard-dose group (95% CI, 0.274-0.667; P = .002). Furthermore, the incidence of leukopenia decreased by 0.371 times in the low-dose group compared with the standard-dose group (95% CI, 0.264-0.523; P = .001).
CONCLUSIONS: The 450-mg dose of valganciclovir effectively prevented post-transplantation CMV infection and decreased drug-induced side effects such as leukopenia. In the future, the lower dose of valganciclovir should be considered to prevent CMV infection and enhance cost-effectiveness.

PMID: 29871773 [PubMed - as supplied by publisher]

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Cognitive Effects of Androgen Deprivation Therapy in Men With Advanced Prostate Cancer.

Urology. 2017 05;103:167-172

Authors: Gunlusoy B, Ceylan Y, Koskderelioglu A, Gedizlioglu M, Degirmenci T, Ortan P, Kozacioglu Z

Abstract
OBJECTIVE: To evaluate the prostate cancer effects of androgen deprivation therapy (ADT) by using a systematic set of methods to calculate specific cognitive functions in men with locally advanced or metastatic prostate cancer.
MATERIALS AND METHODS: From April 2014 to February 2016, a prospective, comparative study was done to evaluate the cognitive effects of hormone therapy. Group 1 consisted of 78 patients with locally advanced or metastatic prostate cancer who received complete ADT treatment continuously for 12 months and group 2 (control group) consisted of 78 patients who underwent radical prostatectomy without any additional treatment. The Montreal Cognitive Assessment (MoCA) test and the Frontal Assessment Battery (FAB) test with Turkish language version were used to evaluate multiple domains of cognitive function.
RESULTS: Post-treatment results of both tests revealed that patients in group 1 achieved lower mean total scores than group 2. In MoCA test, the deficits were especially prominent in the areas of language ability and short-term memory capacity (P < .05 and P < .05). No significant differences could be identified between groups in respect to attention, executive functions, visuospatial abilities, abstract thinking, calculating abilities, and orientation. In FAB test, the deficits were especially prominent in the areas of mental flexibility and inhibitory control (P < .05 and P < .05). No significant differences could be identified between groups in conceptualization, motor series, conflicting instructions, and environmental autonomy.
CONCLUSION: ADT affects cognitive functions such as language ability, short-term memory capacity, mental flexibility, and inhibitory control. Urologists should keep in mind these side effects and inform the patients and their families for the early symptoms of cognitive dysfunction.

PMID: 28188757 [PubMed - indexed for MEDLINE]

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A Predictive Model for Toxicity Effects Assessment of Biotransformed Hepatic Drugs Using Iterative Sampling Method.

Sci Rep. 2016 12 09;6:38660

Authors: Tharwat A, Moemen YS, Hassanien AE

Abstract
Measuring toxicity is one of the main steps in drug development. Hence, there is a high demand for computational models to predict the toxicity effects of the potential drugs. In this study, we used a dataset, which consists of four toxicity effects:mutagenic, tumorigenic, irritant and reproductive effects. The proposed model consists of three phases. In the first phase, rough set-based methods are used to select the most discriminative features for reducing the classification time and improving the classification performance. Due to the imbalanced class distribution, in the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling and Synthetic Minority Oversampling Technique are used to solve the problem of imbalanced datasets. ITerative Sampling (ITS) method is proposed to avoid the limitations of those methods. ITS method has two steps. The first step (sampling step) iteratively modifies the prior distribution of the minority and majority classes. In the second step, a data cleaning method is used to remove the overlapping that is produced from the first step. In the third phase, Bagging classifier is used to classify an unknown drug into toxic or non-toxic. The experimental results proved that the proposed model performed well in classifying the unknown samples according to all toxic effects in the imbalanced datasets.

PMID: 27934950 [PubMed - indexed for MEDLINE]

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Funding Opportunity PAR-18-822 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to invite applications for support of innovative clinical and preclinical/non-clinical research to improve our understanding of disease mechanisms in tuberculosis meningitis (TBM) and to improve therapy in the presence or absence of human immunodeficiency virus (HIV) co-infection.