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Pharmacophore Mapping, In Silico Screening and Molecular Docking to Identify Selective Trypanosoma brucei Pteridine Reductase Inhibitors.

Trypanosoma brucei Pteridine reductase (TbPTR1) is of vital importance and is an established drug target for dreaded Human African trypanosomiasis (HAT). Pharmacophore perception strategy has been employed to identify key chemical features responsible for the biological activity for TbPTR1. The findings suggest that three different pharmacophore features can be associated with T. brucei anti-PTR1 activity namely: H-bond donors (D), Hydrophobic aromatic (H) and Ring aromatic (R). The resulting hypothesis is able to predict the activity of other existing TbPTR1 inhibitors with a correlation coef

Insights from QM/MM Modeling the 3D Structure of the 2009 H1N1 Influenza A Virus Neuraminidase and Its Binding Interactions with Antiviral Drugs.

Control of drug release through the inhibition of neuraminidase-1 has been identified as a potential target for the treatment of H1N1 influenza; however, the drug binding mode of neuraminidase is not yet completely understood. In this work, we propose a model for a neuraminidase-1 complex based on four known X-ray structures of drug/neuraminidase-1 complexes. Specifically, H1N1 neuraminidase-1 complexed with 4 drugs (zanamivir, laninamivir, laninamivir octanoate and oseltamivir) was first investigated using a combined quantum mechanical and molecular mechanical (QM/MM) approach. Based on these

Genetic Variations of ABCC2 Gene Associated with Adverse Drug Reactions to Valproic Acid in Korean Epileptic Patients.

The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was

Significance Analysis of Microarrays (SAM) Offers Clues to Differences Between the Genomes of Adult Philadelphia Positive ALL and the Lymphoid Blast Transformation of CML.

Philadelphia positive malignant disorders are a clinically divergent group of leukemias. These include chronic myeloid leukemia (CML) and de novo acute Philadelphia positive (Ph(+)) leukemia of both myeloid, and lymphoid origin. Recent whole genome screening of Ph(+)ALL in both children and adults identified an almost obligatory cryptic loss of Ikaros, required for the normal B cell maturation. Although similar losses were found in lymphoid blast crisis the genetic background of the transformation in CML is still poorly defined. We used Significance Analysis of Microarrays (SAM) to analyze com

Genetic Analysis of SCN5A in Korean Patients Associated with Atrioventricular Conduction Block.

Recent several studies have shown that the genetic variation of SCN5A is related with atrioventricular conduction block (AVB); no study has yet been published in Koreans. Therefore, to determine the AVB-associated genetic variation in Korean patients, we investigated the genetic variation of SCN5A in Korean patients with AVB and compared with normal control subjects. We enrolled 113 patients with AVB and 80 normal controls with no cardiac symptoms. DNA was isolated from the peripheral blood, and all exons (exon 2-exon 28) except the untranslated region and exon-intron boundaries of the SCN5A g

A Comparative Study on the Constitutive Properties of Marketed Pesticides.

The concept of drug-likeness has been established in the field of drug discovery. Pesticide discovery is also a complicated and rigorous filtering process compared with drug discovery. This study involved investigation of the constitutive properties of 788 marketed pesticides, including 341 herbicides, 182 fungicides, and 265 insecticides. In a comparison of the constitutive properties of different kinds of pesticides and of pesticides from different periods of registration, ClogP, the number of H-bond donors (HBD), and the number of aromatic bonds (ARB) were identified as the most important f

Identification of predictive pathways for non-hodgkin lymphoma prognosis.

Despite decades of intensive research, NHL (non-Hodgkin lymphoma) still remains poorly understood and is largely incurable. Recent molecular studies suggest that genomic variants measured with SNPs (single nucleotide polymorphisms) in genes may have additional predictive power for NHL prognosis beyond clinical risk factors. We analyzed a genetic association study. The prognostic cohort consisted of 346 patients, among whom 138 had DLBCL (diffuse large B-cell lymphoma) and 101 had FL ( follicular lymphoma). For DLBCL, we analyzed 1229 SNPs which represented 122 KEGG pathways. For FL, we analyze

Transporter-mediated Efflux Influences CNS Side Effects: ABCB1, from Antitarget to Target.

We examined the relationship between sedation and orthostatic hypotension, two central side effects and ABCB1 transporter-mediated efflux for a set of 64 launched drugs that are documented as histamine H1 receptor antagonists. This relationship was placed in the context of passive diffusion (estimated using LogP, the octanol/water partition coefficient), receptor affinity, and the adjusted therapeutic daily dose, in order to account for side effect variability. Within this set, CNS permeability was not dependent on passive diffusion, as no significant differences were found for LogP and its pH

Combining clinical and genomic covariates via Cov-TGDR.

Clinical covariates such as age, gender, tumor grade, and smoking history have been extensively used in prediction of disease occurrence and progression. On the other hand, genomic biomarkers selected from microarray measurements may provide an alternative, satisfactory way of disease prediction. Recent studies show that better prediction can be achieved by using both clinical and genomic biomarkers. However, due to different characteristics of clinical and genomic measurements, combining those covariates in disease prediction is very challenging. We propose a new regularization method, Covari

Sequencing of a 'mouse azoospermia' gene panel in azoospermic men: identification of RNF212 and STAG3 mutations as novel genetic causes of meiotic arrest.

STUDY QUESTION: What is the diagnostic potential of next generation sequencing (NGS) based on a 'mouse azoospermia' gene panel in human non- … c and physiological similarities to man. Mouse azoospermia models are available in the Mouse Genome Informatics database (MGI: http://www.informatics.jax.org/). STUDY DESIGN, SIZE, DURATION: The first step was to design of a 'mouse azoospermia' gene panel through the consultation of MGI. The second step was NGS analysis of 175 genes in a group of highly sele …

Techniques for multi-genome synteny analysis to overcome assembly limitations.

Genome scale synteny analysis, the analysis of relative gene-order conservation between species, can provide key insights into evolutionary chromosomal dynamics, rearrangement rates between species, and speciation analysis. With the rapid availability of multiple genomes, there is a need for efficient solutions to aid in comparative syntenic analysis. Current methods rely on homology assessment and multiple alignment based solutions to determine homologs of genetic markers between species and to infer syntenic relationships. One of the primary challenges facing multi-genome syntenic analysis i

Docking unbound proteins with MIAX: a novel algorithm for protein-protein soft docking.

We propose a new methodology for "soft'' docking unbound protein molecules (reported at the isolated state). The methodology is characterized by its simplicity and easiness of embedment in any rigid body docking process based on point complementarity. It is oriented to allow limited free but not unrealistic interpenetration of the side chains of protein surface amino acid residues. The central step to the technique is a filtering process similar to those in image processing. The methodology assists in deletion of atomic-scale details on the surface of the interacting monomers, leading to the e

Toxicity versus potency: elucidation of toxicity properties discriminating between toxins, drugs, and natural compounds.

Within our everyday life we are confronted with a variety of toxic substances. A number of these compounds are already used as lead structures for the development of new drugs, but the amount of toxic substances is still a rich resource of new bioactive compounds. During the identification and development of new potential drugs, risk estimation of health hazards is an essential and topical subject in pharmaceutical industry. To face this challenge, an extensive investigation of known toxic compounds is going to be helpful to estimate the toxicity of potential drugs. "Toxicity properties" found

Robust diagnosis of non-Hodgkin lymphoma phenotypes validated on gene expression data from different laboratories.

A major challenge in cancer diagnosis from microarray data is the need for robust, accurate, classification models which are independent of the analysis techniques used and can combine data from different laboratories. We propose such a classification scheme originally developed for phenotype identification from mass spectrometry data. The method uses a robust multivariate gene selection procedure and combines the results of several machine learning tools trained on raw and pattern data to produce an accurate meta-classifier. We illustrate and validate our method by applying it to gene express

Инфодемиология и инфовелленс множественных склерозов в Италии

Множественный склероз (MS) является хроническим изнурительным заболеванием вероятной аутоиммунной провокационной природы, аэтология которого не в полной мере понята, несмотря на многочисленные усилия и исследования. В этой рукописи мы пересматриваем концепцию < < мультипликаторного склероза 2.0 > > , т.е. использование Интернета пациентами, страдающими MS, для поиска медицинских и связанных с болезнями материалов для целей самообслуживания и саморегулирования, и внедряем основанный на Google Trends подход к мониторингу связанных с MS запросов и поисков в Google, который называется

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… Even if with some limitations and concerns, the Internet and the medical informatics are paving the way for new directions in the field of the epidemiological research, indicating new trends and strategies [ 10 ]. … curriculum wiki: harnessing the power of user-generated content Journal of Pathology Informatics 2010 1 p. 10 10.4103/2153-3539.65428 PMC2929539 20805963 17 Bos L Marsh A Carroll D Gupta S Rees M Patient 2.0 empowerment Proceedings of International Conference on Semantic Web and Web Services (SWWS …

No Sensorization without Representation: Co-designing Tailored Sensorization Plans with Nursing Home Leadership, Direct Care Staff, Residents, and Resident Family Members.

OBJECTIVE: : Although interest in using sensors in long-term care (LTC) settings is growing, little guidance exists on how to engage stakeholders in planning. This study aimed to (1) develop a systematic, community-engaged process for co-designing sensorization plans - defining goals and parameters (e.g., data collection, sharing) to support decision making prior to sensor deployment, (2) apply this process with LTC stakeholders, and (3) examine stakeholder perspectives across sensor approaches. METHODS: : We conducted a multi-phase, multi-method study in a single nursing home that included o

Patient-Provider Distance in Medicare Outpatient Oncology Telehealth Versus Office Visits, 2021-2023: Cross-Sectional Claims Analysis.

In a cross-sectional analysis of traditional Medicare Fee-For-Service beneficiaries aged 66 years or older with outpatient oncology-related encounters, we found that telehealth modestly extended patient-provider geographic reach but largely operated within existing office-based catchments and preserved rural-urban distance gradients. Equitable telehealth policy should target patients with high travel burden while supporting digital access, navigation, and cross-jurisdiction continuity.

Safety and Performance Evaluation of a Clinical Decision Support System for Imatinib Therapeutic Drug Monitoring: In Silico Study.

BACKGROUND: Therapeutic drug monitoring (TDM) aims to optimize clinical outcomes but is hindered by logistical delays and susceptibility to data errors. Integrating model-informed precision dosing with point-of-care testing, fortified by rule-based validation and alerts, forms a transformative clinical decision support system (CDSS) essential for securing this complex workflow. OBJECTIVE: This study evaluates, in silico, the effectiveness of a rule-based CDSS for imatinib in detecting data-quality issues and optimizing therapeutic dosing, compared with a human TDM expert. METHODS: We simulat

Augmenting electronic health records for adverse event detection.

OBJECTIVE: Adverse events (AEs) resulting from medical interventions are significant contributors to patient morbidity, mortality, and healthcare costs. Detection of these events using electronic health records (EHRs) can facilitate timely clinical interventions. However, effective detection remains challenging due to severe class imbalance, missing labels, and the complexity of EHR records. Classical machine learning approaches frequently underperform due to insufficient representation of minority adverse event classes and limited capacity to capture interactions among patient demographics, a