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Concerted changes in Epithelium and Stroma: a multi-scale, multi-omics analysis of progression from Barrett\u27s Esophagus to adenocarcinoma.
No full textEsophageal adenocarcinoma arises from Barrett\u27s esophagus, a metaplastic condition. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue mechanics and spatial proteomics of the paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, in 107 samples from 26 patients in two independent cohorts, defined shared and patient-specific progression characteristics. Metaplastic replacement of epithelial cell composition and architecture was paralleled by changes in stromal cells, extracellular matrix (ECM) and tissue stiffness. This change in pre-cancerous metaplasia was already accompanied by appearance of fibroblasts with the molecular characteristics of carcinoma-associated fibroblasts. These fibroblasts produced the immunosuppressive protein POSTN, whose expression shifted from vascular to stromal cells, consistent with the emergence of an immunosuppressive microenvironment evident in cell neighborhoods enriched for immunoregulatory NK and Treg cells. Thus, Barrett\u27s esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporate stromal reprogramming
Metabolic modeling reveals determinants of synbiotic efficacy in a human intervention trial.
No full textSynbiotic interventions show variable effects across individuals, likely driven by ecological interactions with the endogenous microbiota and the host diet. Rationally predicting individual-specific success or failure of probiotic and prebiotic interventions remains an outstanding challenge. In this study, we leverage microbial community-scale metabolic models (MCMMs) to predict probiotic engraftment and shifts in microbiota-mediated short-chain fatty acid (SCFA) production in response to a synbiotic intervention. Using data from a placebo-controlled synbiotic intervention trial, involving a cocktail of five probiotic strains and the prebiotic inulin, we validate model engraftment predictions with quantitative PCR (qPCR), demonstrating that MCMMs accurately predict probiotic engraftment outcomes in the treatment group with over 85% accuracy. Engraftment varied by species, with Akkermansia muciniphila and Bifidobacterium infantis displaying higher engraftment rates than Clostridium beijerinckii, Anaerobutyricum hallii, and Clostridium butyricum. Furthermore, MCMMs predicted significant increases in butyrate and propionate production following synbiotic treatment. MCMM-predicted changes in propionate production in the treatment group were negatively associated with changes in C-reactive protein (CRP), a blood marker of systemic inflammation, from baseline to 12 weeks after the synbiotic intervention. Finally, we explore MCMM-predicted responses to a wider range of synbiotic combinations in a larger observational cohort, suggesting that personalized prebiotic selection can augment probiotic efficacy. These findings highlight the potential of metabolic modeling to inform precision microbiome therapeutics
Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer.
No full textIdentifying molecular drivers in triple-negative breast cancer (TNBC) is crucial. While HER2-low expression predicts response to novel antibody-drug conjugates, its biological influence on TNBC biology is unknown. We performed a comprehensive multi-omics analysis, integrating genomic, epigenomic, transcriptomic, and proteomic profiling to characterize HER2-low TNBC. We generated genome-wide DNA methylation profiles from a multi-institutional cohort and integrated our data with three independent cohorts (TCGA, SCAN-B, I-SPY2). TNBC cases were categorized as HER2-zero (IHC 0) or HER2-low TNBC (IHC 1+/2+, ISH non-amplified). Among 506 patients (HER2-low, n = 288; HER2-zero, n = 218), HER2-low TNBC exhibited significantly lower tumor mutational burden (P = 0.02). Epigenetic analysis identified 5287 differentially methylated sites, with consistent hypermethylation of HLA genes in HER2-low tumors. Transcriptomic analyses revealed significant downregulation of genes enriched in immune response pathways (e.g., leukocyte activation, T-cell signaling) in HER2-low TNBC (adjusted P \u3c 0.001). Immune cell deconvolution showed reduced immune cell infiltration in the HER2-low tumor microenvironment (P = 0.002). Higher expression of five immune-related genes, downregulated in HER2-low, correlated with improved relapse-free (HR = 0.52; P \u3c 0.001) and overall survival (HR = 0.36; P \u3c 0.001). HER2-low TNBC tumors display distinct molecular features compared to HER2-zero, imparting an immune-evasive phenotype. These findings provide critical insights into the unique biology of HER2-low TNBC, warranting further clinical investigation
ASNR Consensus Statement: Integrating Neuro-PET Interpretation into Neuroradiology Training and Practice.
No full textBACKGROUND: Molecular imaging, particularly positron emission tomography (PET), has significantly advanced the diagnosis and management of disease by visualizing biological processes at a cellular and molecular level. PET imaging of the brain, spine, and head/neck, summarized under the umbrella term Neuro-PET, enables noninvasive diagnosis and monitoring of diseases such as dementia, epilepsy, cancer, movement, or autoimmune disorders. The rising prevalence of these conditions, as well as new treatment options necessitating response assessment, are expected to escalate Neuro-PET imaging volumes, with projections for a significant increase in the need for specialized imaging services. This increasing clinical need highlights existing workforce shortages and underscores the need for neuroradiologists to acquire proficiency in molecular imaging. This expanded role seeks to address the growing demand. To this end, we propose a rigorous, structured, patient-centered, and collaborative framework for expanding neuroradiologists\u27 training and practice to include Neuro-PET interpretation.
METHODS: This ASNR consensus statement outlines competency recommendations, training pathways, and implementation strategies to incorporate Neuro-PET into neuroradiology practice. This approach is based on existing guidelines and was informed by survey data from neuroradiologists and molecular imaging subspecialists revealing current practice patterns and training needs. For neuroradiology fellows, structured training encompasses hands-on Neuro-PET imaging experience, understanding the biologic and molecular basis of radiopharmaceuticals used in Neuro-PET, and integrating molecular insights with anatomical data. Neuroradiologists beyond fellowship can undertake practice-based curriculum involving supervised case interpretation, standardized reader training courses, continuing medical education (CME), and peer review.
KEY MESSAGE: Neuroradiologists, with their in-depth expertise of central nervous system structure and function, are well positioned to meld molecular imaging data with traditional anatomical findings. They can achieve competency and should be granted practice privileges in interpreting Neuro-PET studies through a comprehensive combination of structured training, hands-on clinical experience, and documented CME hours.
ABBREVIATIONS: PET = positron emission tomography; CME = continuing medical education; ACR= American College of Radiology
Treatment of NSCLC after chemoimmunotherapy - are we making headway?
No full textThe treatment landscape of non-small-cell lung cancer (NSCLC) has evolved considerably with the integration of immune-checkpoint inhibitors (ICIs) into first-line regimens. However, the majority of patients will ultimately have primary resistance or develop secondary resistance, driven by a complex interplay of intrinsic tumour biology and adaptive changes within the tumour microenvironment (TME), which can be further amplified by host-related factors such as dysbiosis and organ-specific conditions. Despite these heterogeneous origins, most mechanisms of resistance to ICIs lead to an immunosuppressive TME as the final common pathway. Consequently, current strategies designed to overcome resistance aim to restore antitumour immunity via antibody-based therapies (including bispecific antibodies, T cell engagers and antibody-drug conjugates), targeted therapies, adoptive cell therapies, therapeutic vaccines or intratumoural immunotherapies. Although substantial progress has been made in identifying potential biomarkers associated with immune resistance, the clinical relevance of many of these observations remains limited. Biomarker-driven studies using adaptive, hypothesis-generating designs might offer a promising path forward by navigating the complexity of resistance and enabling the timely evaluation of novel therapeutic concepts. In this Review, we summarize the latest advances in addressing resistance to ICIs in patients with advanced-stage NSCLC and provide insights into emerging clinical strategies and future research directions
Gastroduodenal Artery Aneurysm Causing Obstructive Jaundice and Acute Cholangitis.
No full textGastroduodenal artery aneurysms (GDAA) are a rare but potentially life-threatening vascular condition. They can vary in presentation from being found incidentally on imaging to devastating rupture. We describe a case of 2 gastroduodenal aneurysms causing obstructive jaundice and acute cholangitis in an elderly woman, which was treated with coil embolization.rupture. GDAA of any size should be highly considered for treatment given the high mortality of eventual rupture
Genes associated with genetic and rare lung diseases and the risk of lung cancer.
No full textBACKGROUND: We investigated whether markers, genes or terms of the
METHODS: Genes of interest were extracted from
RESULTS: The marker rs56113850 (OR=0.893, 95%CI: 0.862-0.924) was associated with lung cancer (p=1.2×10
CONCLUSIONS: Genes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data
Associations between donor-derived cell-free DNA dynamics and clinical outcomes after kidney allograft rejection: A prospective, multicenter study.
No full textActive rejection (AR) remains a major risk factor for graft dysfunction and loss. Donor-derived cell-free DNA (dd-cfDNA) is a dynamic, noninvasive biomarker for AR. We hypothesized that dd-cfDNA monitoring post-rejection may enable physicians to stratify patients into those with more and less favorable prognoses. This prospective multicenter study of kidney transplant recipients (KTRs) with biopsy-proven AR (BPAR) monitored dd-cfDNA for 8 weeks following diagnosis and recorded clinical outcomes at 12 months. Patients were classified using dd-cfDNA trends; trends were then associated with outcomes. Negative outcomes comprised graft loss, subsequent BPAR, post-biopsy donor-specific antibody, and/or lack of resolution of renal dysfunction. Out of 488 KTRs, 66 with BPAR were analyzed (T cell-mediated rejection, n = 37; antibody-mediated rejection, n = 24; and mixed rejection, n = 5). A total of 76% experienced negative outcomes, and 24% experienced positive outcomes. Four distinct dd-cfDNA trends were identified: 2 with a favorable prognosis (n = 25) and 2 with an unfavorable prognosis (n = 41). Among patients with a favorable prognosis, the odds of experiencing positive outcomes were 60× higher (P = 3.18 × 10-7) and of experiencing resolving kidney dysfunction at 1 year were 13× higher (P = 2.15 × 10-5). Among KTRs with BPAR, post-rejection dd-cfDNA trends were statistically associated with outcomes, suggesting that dd-cfDNA may help physicians manage patients post-BPAR
Transcatheter Repair of Ventricular Septal Defect Post Myocardial Infarction at a Community Hospital: A Case Study.
No full textVentricular septal defect (VSD) is a rare complication following a myocardial infarction (MI), with a very high mortality rate if left untreated. Traditionally, surgical repair has been used to treat VSDs, but even in those cases, it has poor outcomes. This case shows a middle-aged woman who suffered an MI complicated by a VSD successfully treated with a transcatheter approach to repair the defect. The procedure was performed at a non-teaching community hospital with a small cardiology team. This case highlights the emerging use and success of non-invasive repair in post MI-associated VSD
