Dissecting Genotype-Environment interactions with functional implications for parental selection in Cannabis Breeding.

As climate variability continues to impact agricultural systems, identifying genetic factors that contribute to environmental adaptation will be essential for optimizing breeding strategies for the development of climate resilient varieties. Through human cultivation and naturalization, Cannabis sativa has dispersed globally, adapting to a range of environmental conditions across various climates and latitudes. We combined raw data from multiple public sources to conduct an Environmental Genomic Selection (EGS) analysis on 149 C.

A Mendelian randomization study of the effect of body mass index on 52 causes of death among 125 000 Mexican adults with admixed ancestry.

Background: Persistent hyperglycaemia in diabetes can cause weight loss, distorting the association of adiposity with mortality. We estimated the lifelong associations of genetically predicted body mass index (BMI) with 52 causes of death among 125 003 Mexican adults, in whom persistent hyperglycaemia in diabetes was common.

Methods: A trans-ancestry genetic instrument for BMI (from 724 BMI-associated single-nucleotide polymorphisms) estimated the causal relevance of BMI to mortality before age 75 years, stratified by sex and adjusted for age and underlying ancestry structure, using a one-sample Mendelian randomization (MR) approach.

BLID is a drug-responsive target of FOXO3a and multi-omics analysis reveals survival mechanisms and therapeutic vulnerabilities in BLID-deficient breast cancer cells.

BH-3 like motif containing inducer of cell death (BLID) is a known prognostic factor in breast cancer. The aim of the present study was to determine the significance of BLID in the outcomes of chemotherapy and mechanisms affected in BLID-deficient breast cancer cells. Reverse transcription-PCR, reverse transcription-quantitative PCR, dual-luciferase reporter and chromatin immunoprecipitation assays were used to determine the effects of drugs on BLID expression and binding of forkhead box protein O3a (FOXO3a) to the BLID promoter.

Risk thresholds for soft versus hard cardiovascular disease outcome models for initiating statin therapy among Chinese adults: a cost-utility analysis.

Background: Current guidelines for atherosclerotic cardiovascular disease (ASCVD) primary prevention mostly recommend risk scores that predict risk of non-fatal myocardial infarction, fatal ischemic heart disease (IHD), and fatal or non-fatal ischemic stroke (hard outcomes), ignoring the burden from other non-fatal IHD outcomes. We explored the optimal risk thresholds for statin initiation using non-laboratory-based soft and hard ASCVD outcome models and compared the cost-utility of such models in the Chinese population.

Methods: We constructed Markov cohort models to estimate the incidence of ASCVD events, costs, and quality-adjusted life years (QALYs) over a lifetime from a social perspective.

Buenos Aires Breast Cancer Symposium 2024: bridging basic and clinical research in breast cancer.

The second edition of the Buenos Aires Breast Cancer Symposium (BA-BCS), the first to be held in person, took place from September 3rd to 6th, 2024, in Buenos Aires, Argentina. Nineteen scientists from Brazil, Canada, the United States, the United Kingdom, Denmark, Germany, and Spain, along with six Argentine experts, shared and discussed their recent findings with the audience. Young researchers had the opportunity to present their results through either mini-oral presentations or posters, facilitating oneon-one interactions and the potential for new collaborations.

GDF15 and its receptors as pathways mediating smoking related weight change.

Background: Smokers have lower body weight than non-smokers, while smoking cessation results in weight gain. Understanding the mechanisms involved can help identify potential therapeutic targets to enhance smoking cessation.

Methods: We measured plasma levels of growth/differentiation factor 15 (GDF15), a stress-responsive protein, and its two receptors (proto-oncogene tyrosine-protein kinase receptor Ret [RET], GDNF family receptor alpha-like [GFRAL]) among 3936 Chinese adults (mean BMI 24.

Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer.

Background: Despite significant improvements in the outcome of Estrogen Receptor (ER) α-positive breast cancer (BC) following the use of endocrine therapies, resistance remains a major challenge. Clinical studies proved that obesity, in addition to promote BC progression, is associated with a reduced efficacy to these treatments, but mechanisms remain unclear.

Methods: We used co-culture systems followed by validation through an ‘ex vivo’ model of human mammary obese (Ob) adipocytes and obese endocrine-resistant metastatic Patient-Derived Organoids (PDOs).

Effect of supplementation with vitamin D on biochemical markers of iron status and erythropoiesis in older people: BEST-D trial.

Previous observational studies suggested that vitamin D may control the absorption of iron (Fe) by inhibition of hepcidin, but the causal relevance of these associations is uncertain. Using placebo-controlled randomisation, we assessed the effects of supplementation with vitamin D on biochemical markers of Fe status and erythropoiesis in community-dwelling older people living in the UK. The BEST-D trial, designed to establish the optimum dose of vitamin D3 for future trials, had 305 participants, aged 65 years or older, randomly allocated to 4000 IU vitamin D3 ( 102), 2000 IU vitamin D3 ( 102) or matching placebo ( 101).

iDDN: determining trans-omics network structure and rewiring with integrative differential dependency networks.

Motivation: Mapping the gene networks that drive disease progression allows identifying molecules that rectify the network by normalizing pivotal regulatory elements. Upon mechanistic validation, these upstream normalizers represent attractive targets for developing therapeutic interventions to prevent the initiation or interrupt the pathways of disease progression. Differential network analysis aims to detect significant rewiring of regulatory network structures under different conditions.

Proteome-Wide Genetic Study in East Asians and Europeans Identified Multiple Therapeutic Targets for Ischemic Stroke.

Background: Analyses of genomic and proteomics data in prospective biobank studies in diverse populations may discover novel or repurposing drug targets for stroke.

Methods: We extracted individual -protein quantitative trait locus for 2923 proteins measured using Olink Explore panel from a genome-wide association study in prospective China Kadoorie Biobank and UK Biobank, both established ≈20 years ago. These -protein quantitative trait loci were used in ancestry-specific 2-sample Mendelian randomization analyses of ischemic stroke (IS) in East Asians (n=22 664 cases) and Europeans (n=62 100 cases).

Causal Relevance of Lp(a) for Coronary Heart Disease and Stroke Types in East Asian and European Ancestry Populations: A Mendelian Randomization Study.

Background: Elevated plasma levels of Lp(a) [lipoprotein(a)] are a causal risk factor for coronary heart disease and stroke in European individuals, but the causal relevance of Lp(a) for different stroke types and in East Asian individuals with different Lp(a) genetic architecture is uncertain.

Methods: We measured plasma levels of Lp(a) in a nested case-control study of 18 174 adults (mean [SD] age, 57 [10] years; 49% female) in the China Kadoorie Biobank (CKB) and performed a genome-wide association analysis to identify genetic variants affecting Lp(a) levels, with replication in ancestry-specific subsets in UK Biobank. We further performed 2-sample Mendelian randomization analyses, associating ancestry-specific Lp(a)-associated instrumental variants derived from CKB or from published data in European individuals with risk of myocardial infarction (n=17 091), ischemic stroke (IS [n=29 233]) and its subtypes, or intracerebral hemorrhage (n=5845) in East Asian and European individuals using available data from CKB and genome-wide association analysis consortia.

Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.

Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions.

Molecular mechanisms underlying TXNIP's anti-tumor role in breast cancer, including interaction with a novel, pro-tumor partner: CAST.

Thioredoxin-interacting protein (TXNIP) plays a pivotal role in glucose metabolism and redox signaling. Its emerging function as a potent suppressor of cell proliferation in various cancer contexts underscores its importance in cancer development. In a previous study, we found TXNIP activation by UNC0642, an inhibitor of histone methyltransferase G9A, significantly inhibited MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo.

BLIMP-1-dependent differentiation of T follicular helper cells into Foxp3 T regulatory type 1 cells.

T-regulatory-type-1 (TR1) cells are a subset of interleukin-10-producing but Foxp3 Treg cells that arise in response to chronic antigenic stimulation. We have shown that systemic delivery of autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII)-coated nanoparticles (pMHCII-NP) triggers the formation of large pools of disease-suppressing Foxp3 TR1 cells from cognate T-follicular helper (TFH) cell precursors. Here we show that, upon treatment withdrawal, these Foxp3 TR1 cells spontaneously differentiate into a novel immunoregulatory Foxp3 TR1 subset that inherits epigenetic and transcriptional hallmarks of their precursors, including clonotypic T-cell receptors, and is distinct from other Foxp3 Treg subsets.

Acute Impact of Nonoptimal Ambient Temperatures on Plasma Levels of 3000 Proteins in Chinese Adults.

Nonoptimal ambient temperatures (i.e., cold and heat) are leading environmental determinants of major diseases worldwide, but the underlying pathological mechanisms are still poorly understood.

Comparative studies of 2168 plasma proteins measured by two affinity-based platforms in 4000 Chinese adults.

Proteomics offers unique insights into human biology and drug development, but few studies have directly compared the utility of different proteomics platforms. We measured plasma levels of 2168 proteins in 3976 Chinese adults using both Olink Explore and SomaScan platforms. The correlation of protein levels between platforms was modest (median rho = 0.

Bayesian identification of differentially expressed isoforms using a novel joint model of RNA-seq data.

We develop a Bayesian approach, BayesIso, to identify differentially expressed isoforms from RNA-seq data. The approach features a novel joint model of the sample variability and the deferential state of isoforms. Specifically, the within-sample variability and the between-sample variability of each isoform are modeled by a Poisson-Lognormal model and a Gamma-Gamma model, respectively.

A Guide to Breast Cancer Research: An Introduction.

"A Guide to Breast Cancer Research: From Cells and Molecular Mechanisms to Therapy" is designed as a comprehensive reference for early career investigators and postgraduate students. This book aims to provide a broad overview of contemporary breast cancer research. It covers key areas including development and cancer, metastasis and immunology, subtypes, signalling, therapy, and resistance.

Can we utilise the circadian clock to target cancer stem cells?

The 24-hourly circadian clock has been implicated in the regulation of multiple cancer hallmarks and characteristics. Cancer stem cells (CSCs) are a small but significant population of cells within many cancers, characterised by their self-renewal and clonogenic capacities. Increasing evidence points to CSCs having prominent roles in metastasis and drug resistance.

Risk prediction of ischemic heart disease using plasma proteomics, conventional risk factors and polygenic scores in Chinese and European adults.

Plasma proteomics could enhance risk prediction for multiple diseases beyond conventional risk factors or polygenic scores (PS). To assess utility of proteomics for risk prediction of ischemic heart disease (IHD) compared with conventional risk factors and PS in Chinese and European populations. A nested case-cohort study measured plasma levels of 2923 proteins using Olink Explore panel in ~ 4000 Chinese adults (1976 incident IHD cases and 2001 sub-cohort controls).

Embracing the informative missingness and silent gene in analyzing biologically diverse samples.

Bioinformatics software tools are essential to identify informative molecular features that define different phenotypic sample groups. Among the most fundamental and interrelated tasks are missing value imputation, signature gene detection, and differential pattern visualization. However, many commonly used analytics tools can be problematic when handling biologically diverse samples if either informative missingness possess high missing rates with mixed missing mechanisms, or multiple sample groups are compared and visualized in parallel.

SUMOylation regulates the aggressiveness of breast cancer-associated fibroblasts.

Background: Cancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer.

Proteo-genomic analyses in relatively lean Chinese adults identify proteins and pathways that affect general and central adiposity levels.

Adiposity is an established risk factor for multiple diseases, but the causal relationships of different adiposity types with circulating protein biomarkers have not been systematically investigated. We examine the causal associations of general and central adiposity with 2923 plasma proteins among 3977 Chinese adults (mean BMI = 23.9 kg/m²).

Conventional and genetic associations of BMI with major vascular and non-vascular disease incidence and mortality in a relatively lean Chinese population: U-shaped relationship revisited.

Background: Higher body mass index (BMI) is associated with higher incidence of cardiovascular and some non-cardiovascular diseases (CVDs/non-CVDs). However, uncertainty remains about its associations with mortality, particularly at lower BMI levels.

Methods: The prospective China Kadoorie Biobank recruited >512 000 adults aged 30-79 years in 2004-08 and genotyped a random subset of 76 000 participants.

Measured and genetically predicted protein levels and cardiovascular diseases in UK Biobank and China Kadoorie Biobank.

Several large-scale studies have measured plasma levels of the proteome in individuals with cardiovascular diseases (CVDs). However, since the majority of such proteins are interrelated, it is difficult for observational studies to distinguish which proteins are likely to be of etiological relevance. Here we evaluate whether plasma levels of 2,919 proteins measured in 52,164 UK Biobank participants are associated with incident myocardial infarction, ischemic stroke or heart failure.