Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.

Members of the KMT2C/D-KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation.

Prediction of checkpoint inhibitor immunotherapy efficacy for cancer using routine blood tests and clinical data.

Predicting whether a patient with cancer will benefit from immune checkpoint inhibitors (ICIs) without resorting to advanced genomic or immunologic assays is an important clinical need. To address this, we developed and evaluated SCORPIO, a machine learning system that utilizes routine blood tests (complete blood count and comprehensive metabolic profile) alongside clinical characteristics from 9,745 ICI-treated patients across 21 cancer types. SCORPIO was trained on data from 1,628 patients across 17 cancer types from Memorial Sloan Kettering Cancer Center.

Antagonizing NK-1R modulates pain perception following corneal injury.

Substance P (SP) expressed by corneal nerves, is an 11-amino acid long neuropeptide from the tachykinin family, encoded by the Tac1 gene, and binds to neurokinin receptors. SP overexpression is associated with various pathological responses in the cornea including vasodilation, pain, inflammation, and angiogenesis in the normally avascular tissue. This study investigates the role of neurokinin-1 receptor (NK-1R) mediated signaling in nociception, nerve regeneration, and neuronal activation following mechanical corneal injury in mice.

Real-world evaluation of an evidence-based telemental health program for PTSD symptoms.

Blended care therapy (BCT), which augments live, video-based psychotherapy sessions with asynchronous digital tools, has the potential to increase access to evidence-based treatments for posttraumatic stress disorder (PTSD). However, its effectiveness in diverse, real-world settings is not well-understood. This evaluation aimed to assess clinical outcomes of a BCT program for PTSD symptoms.

Effect of Biological Therapy for Psoriasis on the Development of Psoriatic Arthritis: A Population-Based Cohort Study.

Background: Evidence comparing the impact of various biologics for psoriasis on the progression to psoriatic arthritis (PsA) is limited. We therefore assessed the risk of PsA associated with interleukin (IL)-23 inhibitor, IL-17 inhibitor, or IL-12/23 inhibitor use compared with tumor necrosis factor (TNF) inhibitor use among patients with psoriasis.

Methods: This population-based cohort study used the nationwide claims database from South Korea (2007-2023).

Cerebral Oxygen Metabolic Stress in Children and Adults With Large Vessel Vasculopathy Due to Sickle Cell Disease.

Background And Objectives: Large vessel vasculopathy (LVV), or moyamoya syndrome, increases the risk of stroke in patients with sickle cell disease (SCD), yet effective treatments are lacking. In atherosclerotic carotid disease, previous studies demonstrated elevated oxygen extraction fraction (OEF) as a predictor of ipsilateral stroke. In a SCD cohort, we examined hemispheric hemodynamic and oxygen metabolic dysfunction as tissue-based biomarkers of cerebral ischemic risk in patients with LVV.

Profiling immune cell tissue niches in the spatial -omics era.

Immune responses require complex, spatially coordinated interactions between immune cells and their tissue environment. For decades, we have imaged tissue sections to visualize a limited number of immune-related macromolecules in situ, functioning as surrogates for cell types or processes of interest. However, this inevitably provides a limited snapshot of the tissue's immune landscape.

The Enhancement of Regulatory T Cell Maturation and Th1/Th2 Balance through FOXP3 Expression by in an Ovalbumin-Induced Allergic Skin Animal Model.

Chronic allergic skin conditions, including atopic dermatitis (AD), are characterized by pruritus, erythema, xerosis, desquamation, and inflammation, significantly impacting quality of life. Long-term steroid use, while common in treatment, carries the risk of adverse effects. Previous studies have demonstrated the potential of subsp.

Automated quantification of cerebral microbleeds in susceptibility-weighted MRI: association with vascular risk factors, white matter hyperintensity burden, and cognitive function.

Background And Purpose: To train and validate a deep learning (DL)-based segmentation model for cerebral microbleeds (CMB) on susceptibility-weighted MRI; and to find associations between CMB, cognitive impairment, and vascular risk factors.

Materials And Methods: Participants in this single-institution retrospective study underwent brain MRI to evaluate cognitive impairment between January-September 2023. For training the DL model, the nnU-Net framework was used without modifications.

Impact of chemotherapy on patients with mismatch repair deficient advanced endometrial carcinomas-a meta-analysis.

Background: Chemo-immunotherapy is standard of care for women with recurrent or advanced mismatch repair deficient endometrial carcinoma. However, it is uncertain whether patients with mismatch repair deficient advanced or recurrent endometrial carcinoma derive less benefit from chemotherapy than those with mismatch repair proficient endometrial carcinoma.

Methods: We performed a meta-analysis of randomized controlled trials (RCTs) in advanced or recurrent endometrial carcinoma to determine the difference in the benefit of chemotherapy in mismatch repair deficient vs mismatch repair proficient endometrial carcinoma.

Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.

Background: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8 T cells include less differentiated stem-like exhausted T (Tex) cells and terminally exhausted T (Tex) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients.

Prognostic Value of Pulmonary Artery Systolic Pressure in Severe Rheumatic Mitral Stenosis.

Background: Current guidelines recommend intervention for asymptomatic rheumatic mitral stenosis (MS) with mitral valve area ≤1.5 cm based on indicators including pulmonary arterial systolic pressure (PASP) >50 mm Hg and new-onset atrial fibrillation; however, evidence supporting this is lacking.

Methods: This single-center retrospective study included patients with rheumatic MS between 2006 and 2022.

Multidisciplinary management of adult patients with chylothorax: a consensus statement.

The management of chylothorax remains challenging given the limited evidence and significant heterogeneity in practice. In addition, there are no practical guidelines on the optimal approach to manage this complex condition. We convened an international group of 27 experts from 20 institutions across five countries and four specialties (pulmonary, interventional radiology, thoracic surgery and nutrition) with experience and expertise in managing adult patients with chylothorax.

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD).

Blended Phenotype of and Variants With Accelerated Large and Small Artery Crosstalk: A Case Report and Literature Review.

Objectives: Recent advancements in genome research have revealed not only the importance of variants associated with cerebrovascular diseases but also a notably high frequency of carriers harboring multiple variants, presenting with an elusive blended phenotype. In this study, we report the case of a 66-year-old man who experienced 3 stroke episodes over a 4-year period, starting at the age of 62 years. The patient presented with isolated infarcts in the left temporal pole with progressive stenosis in the ipsilateral middle cerebral artery based on large and small artery crosstalk.

Are we closer to achieving precision medicine for migraine treatment? A narrative review.

Background: The term 'precision medicine' encompasses strategies to optimize diagnosis and outcome prediction and to tailor treatment for individual patients, in consideration of their unique characteristics. The greater availability of multifaceted datasets and strategies to model such data have made precision medicine increasingly possible in recent years. Precision medicine is especially needed in the migraine field since the response to migraine treatments is not universal amongst all individuals with migraine.