HMGA2 Expression Predicts Subtype, Survival, and Treatment Outcome in Pancreatic Ductal Adenocarcinoma.

Purpose: To establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance.

Experimental Design: We identified high expression of HMGA2 in basal PDAC cells in a scRNAseq Atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classical marker GATA6, in a cohort of 580 PDAC samples with multiplex immunohistochemistry.

Divergence in Regulatory Regions and Gene Duplications May Underlie Chronobiological Adaptation in Desert Tortoises.

Many cellular processes and organismal behaviours are time-dependent, and asynchrony of these phenomena can facilitate speciation through reinforcement mechanisms. The Mojave and Sonoran desert tortoises (Gopherus agassizii and G. morafkai respectively) reside in adjoining deserts with distinct seasonal rainfall patterns and they exhibit asynchronous winter brumation and reproductive behaviours.

Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity.

Necroptosis can promote antigen-specific immune responses, suggesting induced necroptosis as a therapeutic approach for cancer. Here we sought to determine the mechanism of immune activation but found the necroptosis mediators RIPK3 and MLKL dispensable for tumor growth in genetic and implantable models of breast or lung cancer. Surprisingly, inducing necroptosis within established breast tumors generates a myeloid suppressive microenvironment that inhibits T cell function, promotes tumor growth, and reduces survival.

Targeting dendritic cells to drive PDAC immunotherapy response.

Pancreatic adenocarcinoma (PDAC) has been historically unresponsive to immunotherapy, predominantly due to lower antigen loads and a lack of tumor-infiltrating dendritic cells (DCs) and T cells. A recent study by Mahadevan and colleagues demonstrates that increasing DC infiltration through use of an engineered DC1 vaccine can sensitize PDAC to immunotherapy.

Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.

Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance.

Temporal changes in HIV-related stigma and sexual behaviours: An examination of 22 African countries.

Despite non-trivial success against the HIV epidemic, health experts in Sub-Saharan Africa (SSA) remain concerned about new infections, stigma attitudes, and increasing rates of higher-risk sexual behaviours (HRSBs). Although this concern has produced voluminous scholarship on the behavioural consequences of belonging to stigmatised populations, scholars have only recently examined the behavioural consequences of . Existing work generally finds a positive relationship between stigmatising beliefs and the practice of HRSBs.

M3NetFlow: A novel multi-scale multi-hop graph AI model for integrative multi-omic data analysis.

Multi-omic data-driven studies, characterizing complex disease signaling system from multiple levels, are at the forefront of precision medicine and healthcare. The integration and interpretation of multi-omic data are essential for identifying molecular targets and deciphering core signaling pathways of complex diseases. However, it remains an open problem due the large number of biomarkers and complex interactions among them.

Brain-Engrafted Monocyte-derived Macrophages from Blood and Skull-Bone Marrow Exhibit Distinct Identities from Microglia.

Microglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and to persist throughout life without much contribution from definitive hematopoiesis. Here, using lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and characteristics of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation, and defined the core transcriptional signatures of brain-engrafted MDMs. Lineage tracing mouse models revealed that MDMs transiently express CD206 during brain engraftment as CD206 microglia precursors in the YS.

High sugar diet alters immune function and the gut microbiome in juvenile green iguanas (Iguana iguana).

The present work aimed to study whether a high sugar diet can alter immune responses and the gut microbiome in green iguanas. Thirty-six iguanas were split into four treatment groups using a 2×2 design. Iguanas received either a sugar-supplemented diet or a control diet, and either a lipopolysaccharide (LPS) injection or a phosphate-buffered saline (PBS) injection.

Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors.

Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC.

Effects of thermophily-relevant temperature variation and sex on digestive performance in pythons.

Different physiological performances are often optimized at slightly varying temperatures, which can lead to ectotherms selecting higher body temperatures during certain physiological efforts (e.g., digestion, reproduction).

Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer.

Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition.

Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers.

Hydration state does not affect selected body temperature during gravidity or gravidity duration in pythons (Antaresia childreni).

The embryonic development of many ectothermic species are highly sensitive to temperature and typically have a higher thermal optima than do most other physiological processes. Thus, female ectotherms often maintain a higher and more carefully controlled body temperature when she is supporting developing embryos (early development in oviparous species, throughout development in viviparous species). Considering the positive correlation between body temperature and evaporative water loss, this response could potentially exacerbate female water imbalance in water-limited environments, suggesting that female water balance and egg development may be in conflict.

"RIPping" off Pancreas Cancer's Blockage of Immune Surveillance.

MHC-I downregulation is correlated with immunotherapy resistance in PDAC, but efficient strategies to increase cell-surface MHC-I are still lacking. This study by Sang, Zhou, Chen, Yu, and colleagues identified inhibition of tumor-intrinsic RIPK2 as a pharmacologic target to block the degradation of MHC-I on tumor cells and improved PDAC responses to anti-PD-1 immunotherapy. See related article by Sang et al.

Lack of Dosage Balance and Incomplete Dosage Compensation in the ZZ/ZW Gila Monster (Heloderma suspectum) Revealed by De Novo Genome Assembly.

Reptiles exhibit a variety of modes of sex determination, including both temperature-dependent and genetic mechanisms. Among those species with genetic sex determination, sex chromosomes of varying heterogamety (XX/XY and ZZ/ZW) have been observed with different degrees of differentiation. Karyotype studies have demonstrated that Gila monsters (Heloderma suspectum) have ZZ/ZW sex determination and this system is likely homologous to the ZZ/ZW system in the Komodo dragon (Varanus komodoensis), but little else is known about their sex chromosomes.

Chemokine Receptor 2 Targeted PET/CT Imaging Distant Metastases in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and treatment-refractory malignancies. The lack of an effective screening tool results in the majority of patients being diagnosed at late stages, which underscores the urgent need to develop more sensitive and specific imaging modalities, particularly in detecting occult metastases, to aid clinical decision-making. The tumor microenvironment of PDAC is heavily infiltrated with myeloid-derived suppressor cells (MDSCs) that express C-C chemokine receptor type 2 (CCR2).

sc2MeNetDrug: A computational tool to uncover inter-cell signaling targets and identify relevant drugs based on single cell RNA-seq data.

Single-cell RNA sequencing (scRNA-seq) is a powerful technology to investigate the transcriptional programs in stromal, immune, and disease cells, like tumor cells or neurons within the Alzheimer's Disease (AD) brain or tumor microenvironment (ME) or niche. Cell-cell communications within ME play important roles in disease progression and immunotherapy response and are novel and critical therapeutic targets. Though many tools of scRNA-seq analysis have been developed to investigate the heterogeneity and sub-populations of cells, few were designed for uncovering cell-cell communications of ME and predicting the potentially effective drugs to inhibit the communications.

Pancreatic Cancer's PD1-Roadblock: When T-Cell Reinvigoration Is Not Enough.

PD1-blockade combinations in pancreatic ductal adenocarcinoma have been poorly effective, and the underlying reasons for this are unknown. A recent study revealed that chemoradiation plus PD1-blockade reinvigorates tumor-specific T cells; however, this T-cell activation is accompanied with exaggerated NFκB signaling, which may limit productive tumor-controlling immunity. See related article by Ali et al.

Corticosterone and immune responses to dehydration in squamate reptiles.

Many environments present some degree of seasonal water limitations; organisms that live in such environments must be adapted to survive periods without permanent water access. Often this involves the ability to tolerate dehydration, which can have adverse physiological effects and is typically considered a physiological stressor. While having many functions, the hormone corticosterone (CORT) is often released in response to stressors, yet increasing plasma CORT while dehydrated could be considered maladaptive, especially for species that experience predictable bouts of dehydration and have related coping mechanisms.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples.