Fulvestrant Versus Anastrozole in Endocrine Therapy-Naïve Women With Hormone Receptor-Positive Advanced Breast Cancer: Final Overall Survival in the Phase III FALCON Trial.

The randomized phase III FALCON trial demonstrated significant improvement in progression-free survival (PFS) with fulvestrant versus anastrozole in postmenopausal women with endocrine therapy-naïve, hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Herein, the prespecified final overall survival (OS) analysis is reported. After the primary PFS analysis, data were collected on survival, serious adverse events, and health-related quality of life.

Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer's disease.

Background: PSEN1, PSEN2, and APP mutations cause Alzheimer's disease (AD) with an early age at onset (AAO) and progressive cognitive decline. PSEN1 mutations are more common and generally have an earlier AAO; however, certain PSEN1 mutations cause a later AAO, similar to those observed in PSEN2 and APP.

Methods: We examined whether common disease endotypes exist across these mutations with a later AAO (~ 55 years) using hiPSC-derived neurons from familial Alzheimer's disease (FAD) patients harboring mutations in PSEN1, PSEN2, and APP and mechanistically characterized by integrating RNA-seq and ATAC-seq.

System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans.

We performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity.

Tumor suppressor NME1/NM23-H1 modulates DNA binding of NF-κB RelA.

The dimeric NF-κB family of transcription factors activates transcription by binding sequence-specifically to DNA response elements known as κB sites, located within the promoters and enhancers of their target genes. While most NF-κB remain inactive in the cytoplasm of unstimulated cells, a small amount of RelA, one of its members, persists in the nucleus, ensuring low-level expression of genes essential for homeostasis. Several cofactors have been identified that aid in DNA binding of RelA.

The molecular chronology of mammary epithelial cell fate switching.

The adult mammary gland is maintained by lineage-restricted progenitor cells through pregnancy, lactation, involution, and menopause. Injury resolution, transplantation-associated mammary gland reconstitution, and tumorigenesis are unique exceptions, wherein mammary basal cells gain the ability to reprogram to a luminal state. Here, we leverage newly developed cell-identity reporter mouse strains, and time-resolved single-cell epigenetic and transcriptomic analyses to decipher the molecular programs underlying basal-to-luminal fate switching .

Tumor suppressor NME1/NM23-H1 modulates DNA binding of NF-κB RelA.

The dimeric NF-κB family of transcription factors activates transcription by binding sequence-specifically to DNA response elements known as κB sites, located within the promoters and enhancers of their target genes. While most NF-κB remain inactive in the cytoplasm of unstimulated cells, a small amount of RelA, one of its members, persists in the nucleus, ensuring low-level expression of genes essential for homeostasis. Several cofactors have been identified that aid in DNA binding of RelA.

Study of Respiratory Symptoms and Pulmonary Function among Neem Oil Industry Workers.

This study aims to investigate the pulmonary functions and respiratory symptoms of workers in the neem oil extraction industry in Tamil Nadu, India, who are exposed to neem oil dust and chemicalsin their occupational environment. Fifty male workers from the exposed group and 50 male workers from the non-exposed group to neem dust and chemicals were investigated for this study. A modified respiratory assessment questionnaire based on the American Thoracic Society (ATS) standard and portable hand-held spirometry were used to assess their respiratory symptoms and pulmonary function.

Single-cell transcriptomics reveals stage- and side-specificity of gene modules in colorectal cancer.

Background: An understanding of mechanisms underlying colorectal cancer (CRC) development and progression is yet to be fully elucidated. This study aims to employ network theoretic approaches to analyse single cell transcriptomic data from CRC to better characterize its progression and sided-ness.

Methods: We utilized a recently published single-cell RNA sequencing data (GEO-GSE178341) and parsed the cell X gene data by stage and side (right and left colon).

Generation of 'semi-guided' cortical organoids with complex neural oscillations.

Temporal development of neural electrophysiology follows genetic programming, similar to cellular maturation and organization during development. The emergent properties of this electrophysiological development, namely neural oscillations, can be used to characterize brain development. Recently, we utilized the innate programming encoded in the human genome to generate functionally mature cortical organoids.

Assessment of pulmonary function and respiratory symptoms among INDIAN textile sizing mill workers.

Background: Textile-sizing mill workers are exposed to various hazards in the sizing units during their working hours and are at risk of acquiring lung impairments due to the usage of sizing chemicals in the sizing process.

Objective: The main aim of this study is to assess the influence of cotton dust and sizing agents on lung function and breathing difficulties among Indian textile sizing mill workers.

Methods: This cross-sectional study was carried out at a textile-sizing mill from August 2022 to September 2022.

Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease.

Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance.

Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time.

Modeling transcriptional regulation of the cell cycle using a novel cybernetic-inspired approach.

Quantitative understanding of cellular processes, such as cell cycle and differentiation, is impeded by various forms of complexity ranging from myriad molecular players and their multilevel regulatory interactions, cellular evolution with multiple intermediate stages, lack of elucidation of cause-effect relationships among the many system players, and the computational complexity associated with the profusion of variables and parameters. In this paper, we present a modeling framework based on the cybernetic concept that biological regulation is inspired by objectives embedding rational strategies for dimension reduction, process stage specification through the system dynamics, and innovative causal association of regulatory events with the ability to predict the evolution of the dynamical system. The elementary step of the modeling strategy involves stage-specific objective functions that are computationally determined from experiments, augmented with dynamical network computations involving endpoint objective functions, mutual information, change-point detection, and maximal clique centrality.

MetGENE: gene-centric metabolomics information retrieval tool.

Background: Biomedical research often involves contextual integration of multimodal and multiomic data in search of mechanisms for improved diagnosis, treatment, and monitoring. Researchers need to access information from diverse sources, comprising data in various and sometimes incongruent formats. The downstream processing of the data to decipher mechanisms by reconstructing networks and developing quantitative models warrants considerable effort.

Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease.

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al.

LIPID MAPS: update to databases and tools for the lipidomics community.

LIPID MAPS (LIPID Metabolites and Pathways Strategy), www.lipidmaps.org, provides a systematic and standardized approach to organizing lipid structural and biochemical data.

Endotype Characterization Reveals Mechanistic Differences Across Brain Regions in Sporadic Alzheimer's Disease.

Background: While Alzheimer's disease (AD) pathology is associated with altered brain structure, it is not clear whether gene expression changes mirror the onset and evolution of pathology in distinct brain regions. Deciphering the mechanisms which cause the differential manifestation of the disease across different regions has the potential to help early diagnosis.

Objective: We aimed to identify common and unique endotypes and their regulation in tangle-free neurons in sporadic AD (SAD) across six brain regions: entorhinal cortex (EC), hippocampus (HC), medial temporal gyrus (MTG), posterior cingulate (PC), superior frontal gyrus (SFG), and visual cortex (VCX).

The Janus face of proliferating plasmablasts in dengue and COVID-19 infections.

Introduction: B cells play an integral role in the immune response to both dengue fever and COVID-19. Prior scRNAseq analyses of peripheral plasmablasts in COVID-19 have revealed a heterogeneous population with distinct cell subsets associated with proliferation; prior studies in patients with dengue fever have likewise shown the presence of proliferative pre-plasmablasts in the circulation. These findings may have implications for disease severity.

Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes.

Background & Aims: Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.

Methods: We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls.

Temporal transcriptional control of neural induction in human induced pluripotent stem cells.

Introduction: Neural induction of human induced pluripotent stem cells represents a critical switch in cell state during which pluripotency is lost and commitment to a neural lineage is initiated. Although many of the key transcription factors involved in neural induction are known, we know little of the temporal and causal relationships that are required for this state transition.

Methods: Here, we have carried out a longitudinal analysis of the transcriptome of human iPSCs undergoing neural induction.