Personalized, autologous neoantigen-specific T cell therapy in metastatic melanoma: a phase 1 trial.

New treatment approaches are warranted for patients with advanced melanoma refractory to immune checkpoint blockade (ICB) or BRAF-targeted therapy. We designed BNT221, a personalized, neoantigen-specific autologous T cell product derived from peripheral blood, and tested this in a 3 + 3 dose-finding study with two dose levels (DLs) in patients with locally advanced or metastatic melanoma, disease progression after ICB, measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1) and, where appropriate, BRAF-targeted therapy.

Single-Cell Multiomics Profiling Reveals Heterogeneity of Müller Cells in the Oxygen-Induced Retinopathy Model.

Purpose: Retinal neovascularization poses heightened risks of vision loss and blindness. Despite its clinical significance, the molecular mechanisms underlying the pathogenesis of retinal neovascularization remain elusive. This study utilized single-cell multiomics profiling in an oxygen-induced retinopathy (OIR) model to comprehensively investigate the intricate molecular landscape of retinal neovascularization.

Coronary Atherosclerotic Plaque Burden Assessment by Computed Tomography and Its Clinical Implications.

Recent studies have demonstrated that coronary plaque burden carries greater prognostic value in predicting adverse atherosclerotic cardiovascular disease outcomes than myocardial ischemia, thereby challenging the existing paradigm. Advances in plaque quantification through both noncontrast and contrast-enhanced computed tomography (CT) methods have led to earlier and more cost-effective detection of coronary disease compared with traditional stress testing. The 2 principal techniques of noninvasive coronary plaque quantification assessment are coronary artery calcium scoring by noncontrast CT and coronary CT angiography, both of which correlate with disease burden on invasive angiography.

A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia.

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells.

Methods: We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP.

Osimertinib after Chemoradiotherapy in Stage III -Mutated NSCLC.

Background: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor () mutation and as adjuvant treatment for resected -mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III -mutated NSCLC.

Methods: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable -mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued.

Negative Selection Allows DNA Mismatch Repair-Deficient Mouse Fibroblasts to Tolerate High Levels of Somatic Mutations.

Substantial numbers of somatic mutations have been found to accumulate with age in different human tissues. Clonal cellular amplification of some of these mutations can cause cancer and other diseases. However, it is as yet unclear if and to what extent an increased burden of random mutations can affect cellular function without clonal amplification.

Single Bolus r-SAK Before Primary PCI for ST-Segment-Elevation Myocardial Infarction.

Background: It is uncertain whether adjunctive thrombolysis is beneficial for patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) within 120 minutes of presentation. This study was to determine whether in patients presenting with ST-segment-elevation myocardial infarction a single bolus recombinant staphylokinase (r-SAK) before timely PCI leads to improved patency of the infarct-related artery and reduces the infarct size.

Methods: This is an open-label, prospective, multicenter, randomized study.

LncRNA Instigates Vascular Inflammation to Aggravate Atherosclerosis.

Background: Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA, , has been implicated in the development of tumors. Nevertheless, the precise role of in cardiovascular diseases, particularly atherosclerosis, has not been thoroughly elucidated.

Analyzing somatic mutations by single-cell whole-genome sequencing.

Somatic mutations are the cause of cancer and have been implicated in other, noncancerous diseases and aging. While clonally expanded mutations can be studied by deep sequencing of bulk DNA, very few somatic mutations expand clonally, and most are unique to each cell. We describe a detailed protocol for single-cell whole-genome sequencing to discover and analyze somatic mutations in tissues and organs.

IL-33 potentiates histaminergic itch.

Background: Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic while receiving maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined.

Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci.

Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio.

Enhanced rare-earth separation with a metal-sensitive lanmodulin dimer.

Technologically critical rare-earth elements are notoriously difficult to separate, owing to their subtle differences in ionic radius and coordination number. The natural lanthanide-binding protein lanmodulin (LanM) is a sustainable alternative to conventional solvent-extraction-based separation. Here we characterize a new LanM, from Hansschlegelia quercus (Hans-LanM), with an oligomeric state sensitive to rare-earth ionic radius, the lanthanum(III)-induced dimer being >100-fold tighter than the dysprosium(III)-induced dimer.

The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Mutations in the PKD1 gene, which encodes polycystin-1 (PC1), account for approximately 78% of cases. PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains.

A Complete Endocannabinoid Signaling System Modulates Synaptic Transmission between Human Induced Pluripotent Stem Cell-Derived Neurons.

The endocannabinoid system (ECS) modulates synaptic function to regulate many aspects of neurophysiology. It adapts to environmental changes and is affected by disease. Thus, the ECS presents an important target for therapeutic development.

AXL targeting restores PD-1 blockade sensitivity of mutant NSCLC through expansion of TCF1 CD8 T cells.

Mutations in in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a () mutation into murine lung adenocarcinomas driven by mutant and loss () resulted in an ICB refractory syngeneic tumor. Mechanistically this occurred because mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1PD-1CD8 T cells, restoring therapeutic response to PD-1 ICB in tumors.

Development and Validation of a Modeling and Calibration Method for Diesel-Like Multistage Combustion Based On a Modified Multi-Wiebe Function.

The stringent regulations of fuel consumption and exhaust emission require further refinement of the control strategy for diesel engines. In the future, the prediction of the in-cylinder combustion process will become necessary to achieve a more dedicated control performance. Hence, a more precise model able to run in a real-time application is required to predict the nature of multiphase Diesel combustion.

Imaging of the Pancreas in New-Onset Diabetes: A Prospective Pilot Study.

Introduction: The aim of this study was to assess the feasibility of cross-sectional imaging for detection of pancreatic cancer (PDAC) in patients with new-onset hyperglycemia and diabetes (NOD).

Methods: We conducted a prospective pilot study from November 2018 to March 2020 within an integrated health system. Patients aged 50-85 years with newly elevated glycemic parameters without a history of diabetes were invited to complete a 3-phase contrast-enhanced computed tomography pancreas protocol scan while participating in the Prospective Study to Establish a NOD Cohort.

Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation.

Vaginal microbiota composition affects many facets of reproductive health. Lactobacillus iners-dominated microbial communities are associated with poorer outcomes, including higher risk of bacterial vaginosis (BV), compared with vaginal microbiota rich in L. crispatus.

Discovery of a new class of integrin antibodies for fibrosis.

Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model.

Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.

Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options.

tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

Rationale: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation.

Objective: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke.

A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer.

Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed.