Prediction of pyrazinamide resistance in using structure-based machine-learning approaches.

Background: Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in , encoding an enzyme that converts pyrazinamide into its active form.

Methods: We curated a dataset of 664 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from published studies and then trained three different machine-learning models to predict pyrazinamide resistance.

Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib.

Feasibility of a Text Messaging-Integrated and Chatbot-Interfaced Self-Management Program for Symptom Control in Patients With Gastrointestinal Cancer Undergoing Chemotherapy: Pilot Mixed Methods Study.

Background: Outpatient chemotherapy often leaves patients to grapple with a range of complex side effects at home. Leveraging tailored evidence-based content to monitor and manage these symptoms remains an untapped potential among patients with gastrointestinal (GI) cancer.

Objective: This study aims to bridge the gap in outpatient chemotherapy care by integrating a cutting-edge text messaging system with a chatbot interface.

Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment: study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma.

Background: Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates.

Methods And Analysis: In a 3+3 dose design, PP is initiated 3 days prior to surgery.

Genomic characterization of early-stage hepatocellular carcinoma patients with Hepatitis B using circulating tumor DNA.

Background: Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology worldwide. Effective early detection strategies may facilitate curative therapies and improve survival. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as potential diagnostic markers of HCC in HBV-infected patients.

Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity.

A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC ∼ 1 μM) Eis inhibitors, which did not inhibit other acetyltransferases.

Molecular surveillance for large outbreaks of tuberculosis in the United States, 2014-2018.

Objective: This study describes characteristics of large tuberculosis (TB) outbreaks in the United States detected using novel molecular surveillance methods during 2014-2016 and followed for 2 years through 2018.

Methods: We developed 4 genotype-based detection algorithms to identify large TB outbreaks of ≥10 cases related by recent transmission during a 3-year period. We used whole-genome sequencing and epidemiologic data to assess evidence of recent transmission among cases.

Mutation of and Implications for Using Whole-Genome Sequencing for Investigating Recent Tuberculosis Transmission.

Tuberculosis (TB) control programs use whole-genome sequencing (WGS) of () for detecting and investigating TB case clusters. Existence of few genomic differences between isolates might indicate TB cases are the result of recent transmission. However, the variable and sometimes long duration of latent infection, combined with uncertainty in the mutation rate during latency, can complicate interpretation of WGS results.

Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from to overcome kanamycin resistance.

Tuberculosis (TB), caused by (), is a deadly bacterial disease. Drug-resistant strains of make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by confers resistance to the second-line antibiotic kanamycin (KAN).

Logically Inferred Tuberculosis Transmission (LITT): A Data Integration Algorithm to Rank Potential Source Cases.

Understanding tuberculosis (TB) transmission chains can help public health staff target their resources to prevent further transmission, but currently there are few tools to automate this process. We have developed the Logically Inferred Tuberculosis Transmission (LITT) algorithm to systematize the integration and analysis of whole-genome sequencing, clinical, and epidemiological data. Based on the work typically performed by hand during a cluster investigation, LITT identifies and ranks potential source cases for each case in a TB cluster.

Multi-agent neoadjuvant chemotherapy improves survival in early-stage pancreatic cancer: A National Cancer Database analysis.

Purpose: To compare overall survival (OS) in patients who underwent surgery for early-stage pancreatic adenocarcinoma (rPca) based on sequence (NAT, neoadjuvant therapy and/or AT, adjuvant therapy) and type (SA, single-agent or MA, multi-agent) of chemotherapy received.

Methods: Using the National Cancer Database, patients with clinical stage I/II rPca diagnosed between 2010 and 2014 were identified and five comparison matches (1: NAT vs. upfront resection (UR); 2: multi-agent neoadjuvant (MA NAT) vs.

Optimising pyrazinamide for the treatment of tuberculosis.

Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.

Molecular Evaluation of Fluoroquinolone Resistance in Serial Mycobacterium tuberculosis Isolates from Individuals Diagnosed with Multidrug-Resistant Tuberculosis.

Fluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Differing levels of resistance are associated with specific mutations within the uinolone-esistance-etermining egion (QRDR) of We sequenced the QRDR from serial isolates of MDR TB patients in the Preserving Effective TB Treatment Study (PETTS) with baseline FQ resistance (FQ) or acquired FQ resistance (FQ) using an Ion Torrent Personal Genome Machine (PGM) to a depth of 10,000× and reported single nucleotide polymorphisms in ≥1% of reads. FQ isolates harbored 15 distinct alleles with 1.

A step towards personalizing next line therapy for resected pancreatic and related cancer patients: A single institution's experience.

Background: There is a lack of precision medicine in pancreatic ductal adenocarcinoma (PDA) and related cancers, and outcomes for patients with this diagnosis remain poor despite decades of research investigating this disease. Therefore, it is necessary to explore novel therapeutic options for these patients who may benefit from personalized therapies.

Objective: Molecular profiling of hepatopancreaticobiliary malignancies at our institution, including but not limited to PDA, was initiated to assess the feasibility of incorporating molecular profiling results into patient oncological therapy planning.

Second-line treatment for metastatic pancreatic cancer.

Pancreatic cancer is the fourth-leading cause of cancer-related death. It is commonly diagnosed at an advanced stage, when no curative options exist. Over the last decade, combination chemotherapy has shown a survival benefit compared with single-agent gemcitabine and has become established as first-line therapy in metastatic pancreatic cancer.

Racial Disparities in Rates of Surgery for Esophageal Cancer: a Study from the National Cancer Database.

Background: Treatment guidelines for stage I-III esophageal cancer indicate that management should include surgery in appropriate patients. Variations in utilization of surgery may contribute to racial differences observed in survival. We sought to identify factors associated with racial disparities in surgical resection of esophageal cancer and evaluate associated survival differences.

Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from .

The enhanced intracellular survival (Eis) protein of () is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of , we designed and optimized structurally unique thieno[2,3-]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy.

Author Correction: Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic.

Background: Atypical Beijing genotype Mycobacterium tuberculosis strains are widespread in South Africa and have acquired resistance to up to 13 drugs on multiple occasions. It is puzzling that these strains have retained fitness and transmissibility despite the potential fitness cost associated with drug resistance mutations.

Methods: We conducted Illumina sequencing of 211 Beijing genotype M.

Isoniazid and Rifampin-Resistance Mutations Associated With Resistance to Second-Line Drugs and With Sputum Culture Conversion.

Background: Mutations in the genes inhA, katG, and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological characteristics.

Methods: In a multicountry prospective cohort study of multidrug-resistant TB, we identified inhA, katG, and rpoB mutations in sputum isolates using the Hain MTBDRplus line probe assay.

Pathogen Genomics in Public Health.

Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more effective investigations of outbreaks of foodborne illnesses, better-targeted tuberculosis control, and more timely and granular influenza surveillance to inform the selection of vaccine strains. In this article, we describe how public health agencies have been adopting pathogen genomics to improve their effectiveness in almost all domains of infectious disease.

Tuberculosis Vaccine Development: Progress in Clinical Evaluation.

Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of the bacille Calmette-Guérin (BCG) vaccine. A safer and more effective vaccine than BCG is urgently required. More than a dozen TB vaccine candidates are under active evaluation in clinical trials aimed to prevent infection, disease, and recurrence.