Non-Canonical TERT Activity Initiates Osteogenesis in Calcific Aortic Valve Disease.

Background: Calcific aortic valve disease is the pathological remodeling of valve leaflets. The initial steps in valve leaflet osteogenic reprogramming are not fully understood. As TERT (telomerase reverse transcriptase) overexpression primes mesenchymal stem cells to differentiate into osteoblasts, we investigated whether TERT contributes to the osteogenic reprogramming of valve interstitial cells.

A phase II study of ramucirumab and somatostatin analog therapy in patients with advanced neuroendocrine tumors.

Objectives: Well-differentiated neuroendocrine tumors (NET) are highly vascular tumors characterized by their expression of vascular endothelial growth factor (VEGF). This trial investigated the activity of ramucirumab, a monoclonal antibody that targets VEGF receptor-2 (VEGFR-2) and inhibits activity of VEGF, in combination with somatostatin analog therapy in patients (pts) with advanced extra-pancreatic NET.

Methods: We conducted a single-arm phase II trial enrolling pts with advanced, progressive extra-pancreatic NET.

Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

The inherent antigen cross-reactivity of the T cell receptor (TCR) is balanced by high specificity. Surprisingly, TCR specificity often manifests in ways not easily interpreted from static structures. Here we show that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen and its wild-type (WT) counterpart emerges from distinct motions within the HLA-A3 peptide binding groove that vary with the identity of the peptide's first primary anchor.

A National Physician Survey Examining Switching From Sulfonylureas or Insulin to Newer Diabetes Medications.

This study was a national survey of U.S. physicians in general medicine, geriatrics, or endocrinology who were asked what medication change they would make for adults with type 2 diabetes taking sulfonylureas or insulin with an A1C below their individualized goal.

Bile acid diarrhea in patients with chronic diarrhea. Current appraisal and recommendations for clinical practice.

Bile Acid Diarrhea (BAD) is a common cause of chronic diarrhea, often accompanied by urgency, occasional fecal incontinence, abdominal pain, and fatigue. A nationwide survey has shown limited awareness of BAD within the Italian medical community, prompting a panel of experts to develop a Position Paper that outlines the most practical and cost-saving diagnostic investigations and treatments for this frequently overlooked condition. The document provides an overview of the epidemiology, pathophysiology, clinical manifestations, and classification of the different types of Bile Acid Diarrhea (BAD).

Passage of the HIV capsid cracks the nuclear pore.

Upon infection, human immunodeficiency virus type 1 (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T cells and macrophages. The capsid enters the nuclear pore complex (NPC), driven by interactions with numerous phenylalanine-glycine (FG)-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown, however.

Defective Mammary Epithelial Outgrowth in Transgenic EKAREV-NLS Mice: Correction via Estrogen Supplementation and Genetic Background Modification.

Fluorescent biosensors offer a powerful tool for tracking and quantifying protein activity in living systems with high temporospatial resolution. However, the expression of genetically encoded fluorescent proteins can interfere with endogenous signaling pathways, potentially leading to developmental and physiological abnormalities. The EKAREV-NLS mouse model, which carries a FRET-based biosensor for monitoring extracellular signal-regulated kinase (ERK) activity, has been widely utilized both in vivo and in vitro across various cell types and organs.

Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated.

Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost.

Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic's evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate's contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.

Diabetic foot ulcer in the Western Pacific Region: Current data on ulceration rates and microbial profiles, gaps and charting strategies.

The Western Pacific Region hosts the largest proportion of people with diabetes. Despite being a key diabetes-related complication, diabetic foot ulcer has been neglected in both prevention and treatment efforts. This narrative review highlights available data on the burden (either prevalence or incidence), as well as microbial profiles of diabetic foot ulcers in the Western Pacific Region, identifies data gaps, and discusses strategies to address these gaps.

Ex vivo assessment of human neutrophil motility and migration.

Neutrophils are pivotal in orchestrating tumor-induced systemic inflammation and are increasingly recognized for their critical involvement in both the initiation and progression of cancer. A fundamental facet of neutrophil biology is their migratory capacity, which enables them to extravasate and infiltrate tumors in other tissues, where they carry out essential effector functions. Unraveling the intricate mechanisms of neutrophil motility and migration is crucial for comprehending immune responses and inflammatory processes, shedding light on their substantial contribution to cancer progression.

Biomarkers of RV Dysfunction in HFrEF Identified by Direct Tissue Proteomics: Extracellular Proteins Fibromodulin and Fibulin-5.

Background: Right ventricular dysfunction (RVD) is common in patients with heart failure with reduced ejection fraction, and it is associated with poor prognosis. However, no biomarker reflecting RVD is available for routine clinical use.

Methods: Proteomic analysis of myocardium from the left ventricle and right ventricle (RV) of patients with heart failure with reduced ejection fraction with (n=10) and without RVD (n=10) who underwent heart transplantation was performed.

Maralixibat Reduces Serum Bile Acids and Improves Cholestatic Pruritus in Adolescents With Alagille Syndrome.

Background: Alagille syndrome (ALGS) is a multisystem cholestatic disorder. Maralixibat is approved for the treatment of cholestatic pruritus in ALGS with limited data in adults.

Methods: Participants were included if they received ≥ 2 doses of maralixibat at age ≥ 16 years in one of the three previously published maralixibat ALGS clinical trials.

Prevalence of "weak B" phenotypes and their evaluation and differentiation in healthy blood donor population in Eastern India.

Background: Examples of group B red cells that react weakly or not at all with anti-B have been described. Subgroups of B such as B, B, B, and B are rare and are less frequently reported. We studied the frequency of subgroups of B in our healthy blood donor population and serologically characterized and differentiated these subgroups.

Association of Alzheimer's Disease Polygenic Risk Score with Concussion Severity and Recovery Metrics.

Background: Identification of genetic alleles associated with both Alzheimer's disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed.

Objective: We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset.

Short-Term Warm-Water Immersion for Improving Whole-Body Heat Loss in Older Men.

Purpose: Exercise-induced heat acclimation can mitigate age-related reductions in heat-loss capacity, though performing repeated bouts of strenuous exercise in the heat may be untenable for many older adults. While short-term passive heat acclimation (e.g.

Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function.

Myelin loss induces neural dysfunction and contributes to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that restore neural function are clinical imperatives. Here, we use in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice.

Neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in women with early HER2-positive breast cancer: the randomized phase 2 ABCSG-52/ATHENE trial.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no.

Language and Attention Networks Have Distinct Roles in Language Improvement Following an Intensive Comprehensive Aphasia Program.

Background: Attention is known to play an important role in language, and attentional deficits have been associated with language impairments in people with aphasia (PWA). A prior study by our laboratory indicated that behavioral measures for PWA participating in an intensive comprehensive aphasia program (ICAP) clustered into 1 language and 1 attention-related factor, with each factor correlated with independent resting state functional connectivity (rsFC) networks. The present study includes additional attention measures and participants to better assess the relationship between attention, language, and rsFC.

Evaluation of a Deep Learning Denoising Algorithm for Dose Reduction in Whole-Body Photon-Counting CT Imaging: A Cadaveric Study.

Rationale And Objectives: Photon Counting CT (PCCT) offers advanced imaging capabilities with potential for substantial radiation dose reduction; however, achieving this without compromising image quality remains a challenge due to increased noise at lower doses. This study aims to evaluate the effectiveness of a deep learning (DL)-based denoising algorithm in maintaining diagnostic image quality in whole-body PCCT imaging at reduced radiation levels, using real intraindividual cadaveric scans.

Materials And Methods: Twenty-four cadaveric human bodies underwent whole-body CT scans on a PCCT scanner (NAEOTOM Alpha, Siemens Healthineers) at four different dose levels (100%, 50%, 25%, and 10% mAs).

Photodegradation, kinetics and non-linear error functions of methylene blue dye using SrZrO perovskite photocatalyst.

The degradation of methylene blue dye-contaminated wastewater via photocatalysis is an efficient approach towards environmental remediation. The SrZrO perovskite photocatalyst was synthesized using the modified Pechini sol-gel method, and characterized using XRD, FESEM, FTIR, and UV-visible spectrophotometer. Crystallite size obtained by the Scherrer and Williamson-Hall methods were 45.

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia.

X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert.

IL-33-activated ILC2s induce tertiary lymphoid structures in pancreatic cancer.

Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LTβ receptor (LTβR) pathway, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues, induces TLSs.

Targeting protein-ligand neosurfaces with a generalizable deep learning tool.

Molecular recognition events between proteins drive biological processes in living systems. However, higher levels of mechanistic regulation have emerged, in which protein-protein interactions are conditioned to small molecules. Despite recent advances, computational tools for the design of new chemically induced protein interactions have remained a challenging task for the field.

De novo designed proteins neutralize lethal snake venom toxins.

Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity. At present, the only available treatments for snakebites consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs.