Insulitis and exocrinitis in autoantibody-positive non-diabetic individuals: role of HLA genotypes.

Context: Type 1 diabetes (T1D) is characterized by the presence of autoantibodies on a genetic background largely determined by HLA class II haplotypes. Stage 1 T1D is characterized by the presence of multiple autoantibodies and normoglycemia.

Objective: To investigate the prevalence of high-risk HLA-DQB1 haplotypes and the extent of islet autoimmunity in pancreatic tissues from non-diabetic organ donors with autoantibodies.

NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity.

NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Rα on ILC1s by downregulating NF-κB signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo.

BaNDyT: Bayesian Network Modeling of Molecular Dynamics Trajectories.

Bayesian network modeling (BN modeling, or BNM) is an interpretable machine learning method for constructing probabilistic graphical models from the data. In recent years, it has been extensively applied to diverse types of biomedical data sets. Concurrently, our ability to perform long-time scale molecular dynamics (MD) simulations on proteins and other materials has increased exponentially.

A lectin produced by a Streptomyces species targets mammalian pancreatic acinar cells in mice and humans.

Lectins are produced in almost all life forms, can interact with targets (glycans) in a cross-kingdom manner and have served as valuable tools for studying glycobiology. Previously, a bacterial lectin, named Streptomyces hemagglutinin (SHA), was found to agglutinate human type B erythrocytes. However, the binding of SHA to mammalian cell types other than human erythrocytes has not been explored.

Informatics strategies for early detection and risk mitigation in pancreatic cancer patients.

This review provides a comprehensive overview of the current landscape in pancreatic cancer (PC) screening, diagnosis, and early detection. This emphasizes the need for targeted screening in high-risk groups, particularly those with familial predispositions and genetic mutations, such as BRCA1, BRCA2, and PALB2. This review highlights the sporadic nature of most PC cases and significant risk factors, including smoking, alcohol consumption, obesity, and diabetes.

CAMKIIδ Reinforces Lipid Metabolism and Promotes the Development of B Cell Lymphoma.

The most prevalent types of lymphomas are B cell lymphomas (BCL). Newer therapies for BCL have improved the prognosis for many patients. However, approximately 30% with aggressive BCL either remain refractory or ultimately relapse.

Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies.

Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood-brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery.

Genetic deficiency or pharmacological inhibition of cGAS-STING signalling suppresses kidney inflammation and fibrosis.

Background And Purpose: Chronic kidney disease (CKD) is characterised by inflammation, which can lead to tubular atrophy and fibrosis. The molecular mechanisms are not well understood. In this study, we investigated the functional role of the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signalling in renal inflammation and fibrosis.

Proteasome inhibition enhances oncolytic reovirus therapy in multiple myeloma independently of its direct cytotoxic effects.

Background: Reovirus (RV) is an oncolytic virus with natural tropism for cancer cells. We previously showed that RV administration in multiple myeloma (MM) patients was safe, but disease control associated with viral replication in the cancer cells was not observed. The combination with proteasome inhibitors (PIs) has shown to enhance RV therapeutic activity, but the mechanisms of action have not been fully elucidated.

TP53 Mutations are Associated with CD19 Negative Relapse and Inferior Outcomes after Blinatumomab in Adults with ALL.

Despite the success of the CD19xCD3 T cell engager blinatumomab in B-cell acute lymphoblastic leukemia (B-ALL), treatment failure is common and can manifest with antigen loss and extramedullary disease (EMD) relapse. To understand the impact of leukemia genetics on outcomes, we reviewed 267 adult patients with B-ALL treated with blinatumomab and used next generation sequencing to identify molecular alterations. Patients received blinatumomab for relapsed/refractory (R/R) disease (n=150), minimal residual disease (MRD+) (n=88), upfront as induction (n=10), or as consolidation in MRD- state (n=19).

Daily sleep and physical activity from accelerometry in adults: Temporal associations and lag effects.

Objectives: Insufficient sleep is linked to various health issues, while physical activity is a protective measure against chronic diseases. Despite the importance of sleep and physical activity for supporting public health, there remains scant research investigating daily and cumulative associations between objectively measured physical activity and sleep. Understanding the associations of physical activity and sleep behaviors over multiple days may inform the efficacy of interventions to synergistically support both behaviors.

Validation of Clinical Dynamic Contrast-Enhanced Magnetic Resonance Imaging Perfusion Modeling and Neoadjuvant Chemotherapy Response Prediction in Breast Cancer Using FDG and Cu-DOTA-Trastuzumab Positron Emission Tomography Studies.

Purpose: Perfusion modeling presents significant opportunities for imaging biomarker development in breast cancer but has historically been held back by the need for data beyond the clinical standard of care (SoC) and uncertainty in the interpretability of results. We aimed to design a perfusion model applicable to breast cancer SoC dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) series with results stable to low temporal resolution imaging, comparable with published results using full-resolution DCE-MRI, and correlative with orthogonal imaging modalities indicative of biophysical markers.

Methods: Subsampled high-temporal-resolution DCE-MRI series were run through our perfusion model and resulting fits were compared for consistency.

DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets.

Introduction: Type 1 diabetic human islet β-cells are deficient in double C 2 like domain beta (DOC2b) protein. Further, DOC2b protects against cytokine-induced pancreatic islet β-cell stress and apoptosis. However, the mechanisms underpinning the protective effects of DOC2b remain unknown.

Single Extracellular VEsicle Nanoscopy-Universal Protocol (SEVEN-UP): Accessible Imaging Platform for Quantitative Characterization of Single Extracellular Vesicles.

Extracellular vesicles (EVs), membrane-encapsulated nanoparticles shed from all cells, are tightly involved in critical cellular functions. Moreover, EVs have recently emerged as exciting therapeutic modalities, delivery vectors, and biomarker sources. However, EVs are difficult to characterize, because they are typically small and heterogeneous in size, origin, and molecular content.

Conformational dynamics and multi-modal interaction of Paxillin with the Focal Adhesion Targeting Domain.

Paxillin (PXN) and focal adhesion kinase (FAK) are two major components of the focal adhesion complex, a multiprotein structure linking the intracellular cytoskeleton to the cell exterior. PXN interacts directly with the C-terminal targeting domain of FAK (FAT) via its intrinsically disordered N-terminal domain. This interaction is necessary and sufficient for localizing FAK to focal adhesions.

Molecular Sentinels: Unveiling the Role of Sirtuins in Prostate Cancer Progression.

Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable with conventional treatments, metastatic PCa is notoriously resistant, highlighting an urgent need for precise biomarkers and innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, a family of NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression in PCa depending on the cellular context.

Human iPSC-derived microglial cells protect neurons from neurodegeneration in long-term cultured adhesion brain organoids.

Brain organoid models have greatly facilitated our understanding of human brain development and disease. However, key brain cell types, such as microglia, are lacking in most brain organoid models. Because microglia have been shown to play important roles in brain development and pathologies, attempts have been made to add microglia to brain organoids through co-culture.

Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML.

BMT CTN 1506 ("MORPHO"; NCT02997202) was a randomized phase 3 study of gilteritinib compared to placebo as maintenance therapy after hematopoietic stem cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary endpoint was to determine the impact on survival of pre- and/or post-HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD.

Phosphoproteomic Profiling Reveals mTOR Signaling in Sustaining Macrophage Phagocytosis of Cancer Cells.

: Macrophage-mediated cancer cell phagocytosis has demonstrated considerable therapeutic potential. While the initiation of phagocytosis, facilitated by interactions between cancer cell surface signals and macrophage receptors, has been characterized, the mechanisms underlying its sustentation and attenuation post-initiation remain poorly understood. : Through comprehensive phosphoproteomic profiling, we interrogated the temporal evolution of the phosphorylation profiles within macrophages during cancer cell phagocytosis.

Multi-omics analysis of long-term cultured human islets.

β-cell dysfunction in pancreatic islets, characterized as either the loss of β-cell mass or the resistance of β-cell to glucose, is the leading cause of progression to diabetes. Islet transplantation became a promising approach to replenish functional β-cell mass. However, not much known about changes in islets used for transplantation after isolation.

Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency.

Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of lipogenesis.

The Hallmarks of Predictive Oncology.

As the field of artificial intelligence evolves rapidly, these hallmarks are intended to capture fundamental, complementary concepts necessary for the progress and timely adoption of predictive modeling in precision oncology. Through these hallmarks, we hope to establish standards and guidelines that enable the symbiotic development of artificial intelligence and precision oncology.