Utilizing Patient-Derived Xenografts to Model Precision Oncology for Biliary Tract Cancer.

Purpose: Biliary tract cancers, which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant biliary tract cancer models that recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in biliary tract cancers to create a resource for modeling precision oncology.

A Gold Standard-Derived Modular Barcoding Approach to Cancer Transcriptomics.

A challenge with studying cancer transcriptomes is in distilling the wealth of information down into manageable portions of information. In this resource, we develop an approach that creates and assembles cancer type-specific gene expression modules into flexible barcodes, allowing for adaptation to a wide variety of uses. Specifically, we propose that modules derived organically from high-quality gold standards such as The Cancer Genome Atlas (TCGA) can accurately capture and describe functionally related genes that are relevant to specific cancer types.

KRAS Allelic Variants in Biliary Tract Cancers.

Importance: Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation.

Objectives: To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants.

Comprehensive Immunogenomic Profiling of /-Altered Cholangiocarcinoma.

Purpose: Isocitrate dehydrogenase ()/ genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of mutated iCCA is largely unknown.

Methods: Comprehensive genomic profiling (CGP) was performed on 3,067 cases of advanced iCCA. Tumor mutational burden (TMB), PD-L1 expression (Dako 22C3), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) as a surrogate marker for homologous recombination deficiency were examined.

Preventing zoonotic and zooanthroponotic disease transmission at wild great ape sites: Recommendations from qualitative research at Bwindi Impenetrable National Park.

Employees at wild great ape sites are at high risk of transmitting infectious diseases to endangered great apes. Because of the significant amount of time employees spend near great apes, they are a priority population for the prevention and treatment of zoonotic and zooanthroponotic spillover and need adequate preventive and curative healthcare. Qualitative, semi-structured interviews with 46 staff (rangers and porters) at Bwindi Impenetrable National Park, Uganda (BINP) and key informants from five other wild great ape sites around the world were performed.

The use of bubble charts in analyzing second stage cesarean delivery rates.

Background: The incidence of second stage cesarean delivery has been rising globally because of the failure or the anticipated difficulty of performing instrumental delivery. Yet, the best way to interpret the figure and its optimal rate remain to be determined. This is because it is strongly influenced by the practice of other 2 modes of birth, namely cesarean delivery performed before reaching the second stage and assisted vaginal birth during the second stage.

The use of bubble charts in analyzing the global second-stage cesarean delivery rates: a systematic review.

Objective: This study aimed to systematically review the worldwide second-stage cesarean delivery rate concerning pre-second-stage cesarean delivery and assisted vaginal birth rates.

Data Sources: PubMed, Medline Ovid, EBSCOhost, Embase, Scopus, and Google Scholar were queried from inception to February 2023, with the following terms: "full dilatation," "second stage," and "cesarean," with their word variations. Furthermore, an additional cohort of 353,434 cases from our recently published study was included.

Is detection of enteropathogens and human or animal faecal markers in the environment associated with subsequent child enteric infections and growth: an individual participant data meta-analysis.

Background: Quantifying contributions of environmental faecal contamination to child diarrhoea and growth faltering can illuminate causal mechanisms behind modest health benefits in recent water, sanitation, and hygiene (WASH) trials. We aimed to assess associations between environmental detection of enteropathogens and human or animal microbial source tracking markers (MSTM) and subsequent child health outcomes.

Methods: In this individual participant data meta-analysis we searched we searched PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus for WASH intervention studies with a prospective design and concurrent control that measured enteropathogens or MSTM in environmental samples, or both, and subsequently measured enteric infections, diarrhoea, or height-for-age Z-scores (HAZ) in children younger than 5 years.

Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma.

Background & Aims: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA).

Methods: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed.

USP1 promotes cholangiocarcinoma progression by deubiquitinating PARP1 to prevent its proteasomal degradation.

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate.

Menstrual, fertility and psychological impacts after uterine compression sutures for postpartum hemorrhage: a prospective cohort study.

Background: Uterine compression suture is an important conservative surgical technique in managing atonic postpartum hemorrhage. In this study, we aim to evaluate the subsequent menstrual, fertility and psychological outcomes after uterine compression sutures.

Methods: This was a prospective cohort study between 2009 and 2022 conducted in a tertiary obstetric unit (6000 deliveries per year) in Hong Kong SAR.

Effects of water, sanitation, and hygiene interventions on detection of enteropathogens and host-specific faecal markers in the environment: a systematic review and individual participant data meta-analysis.

Background: Water, sanitation, and hygiene (WASH) improvements are promoted to reduce diarrhoea in low-income countries. However, trials from the past 5 years have found mixed effects of household-level and community-level WASH interventions on child health. Measuring pathogens and host-specific faecal markers in the environment can help investigate causal pathways between WASH and health by quantifying whether and by how much interventions reduce environmental exposure to enteric pathogens and faecal contamination from human and different animal sources.

Multiplatform Analysis of Intratumoral PTEN Heterogeneity in Melanoma.

Loss of protein expression of the tumor suppressor PTEN is associated with increased cancer aggressiveness, decreased tumor immune infiltration, and resistance to immune and targeted therapies in melanoma. We assessed a unique cohort of eight melanoma samples with focal loss of PTEN protein expression to understand the features and mechanisms of PTEN loss in this disease. We compared the PTEN-negative (PTEN[-]) areas to their adjacent PTEN-positive (PTEN[+]) areas using DNA sequencing, DNA methylation, RNA expression, digital spatial profiling, and immunohistochemical platforms.

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma.

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression.

Comprehensive microRNA analysis across genome-edited colorectal cancer organoid models reveals miR-24 as a candidate regulator of cell survival.

Somatic mutations drive colorectal cancer (CRC) by disrupting gene regulatory mechanisms. Distinct combinations of mutations can result in unique changes to regulatory mechanisms leading to variability in the efficacy of therapeutics. MicroRNAs are important regulators of gene expression, and their activity can be altered by oncogenic mutations.

Identification of Clinical Risk Factors Affecting Patient-Physician Communication.

Introduction: Patient satisfaction is an important indicator of quality in health care and is linked to clinical outcomes, patient retention, and professional satisfaction. Patients admitted to the hospital from the emergency department may not understand their diagnosis, reason for admission or plan of care, which can adversely impact their hospital experience. We aim to identify risk factors that contribute to poor patient-physician communication and to assess the effects of raising awareness of these issues to hospital providers.

Influence of community-level sanitation coverage and population density on environmental fecal contamination and child health in a longitudinal cohort in rural Bangladesh.

Background: Household-level sanitation interventions have had limited effects on child health or environmental contamination, potentially due to low community coverage. Higher community-level coverage with safely managed sanitation can reduce opportunities for disease transmission.

Methods: We estimated associations between community sanitation coverage, environmental fecal contamination, and child health among 360 compounds in the control arm of the WASH Benefits trial in rural Bangladesh (NCT01590095).

Incidence of neonatal sepsis after universal antenatal culture-based screening of group B streptococcus and intrapartum antibiotics: A multicentre retrospective cohort study.

Objective: To compare the incidences of early and late-onset neonatal sepsis, including group B streptococcus (GBS) and Escherichia coli (E. coli) before and after implementation of universal screening and intrapartum antibiotics prophylaxis (IAP).

Design: Retrospective cohort study.

Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6.

Unlabelled: KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint.

Environmental Persistence of the World's Most Burdensome Infectious and Parasitic Diseases.

Humans live in complex socio-ecological systems where we interact with parasites and pathogens that spend time in abiotic and biotic environmental reservoirs (e.g., water, air, soil, other vertebrate hosts, vectors, intermediate hosts).

Cost-Efficient Sequence-Based Nonextensible Oligonucleotide in Real-Time PCR and High-Throughput Sequencing.

Molecular detection of disease-associated mutations, especially those with low abundance, is essential for academic research and clinical diagnosis. Certain variant detection methods reach satisfactory sensitivity and specificity in detecting rare mutations based on the introduction of blocking oligos to prevent the amplification of wild-type or unwanted templates, thus selectively amplifying and enriching the mutations. These blocking oligos usually suppress PCR amplification through the 3' chemical modifications, with high price, slow synthesis, and reduced purity.

Characterizing Behaviors Associated with Enteric Pathogen Exposure among Infants in Rural Ecuador through Structured Observations.

The relative importance of environmental pathways that results in enteropathogen transmission may vary by context. However, measurement of contact events between individuals and the environment remains a challenge, especially for infants and young children who may use their mouth and hands to explore their environment. Using a mixed-method approach, we combined 1) semistructured observations to characterize key behaviors associated with enteric pathogen exposure and 2) structured observations using Livetrak, a customized software application, to quantify the frequency and duration of contacts events among infants in rural Ecuador.