Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Analysis of the MODIST Sequence for Selective Proton-Proton Recoupling.

Theoretical and simulated analyses of selective homonuclear dipolar recoupling sequences serve as primary tools for understanding and determining the robustness of these sequences under various conditions. In this article, we investigate the recently proposed first-order dipolar recoupling sequence known as MODIST (Modest Offset Difference Internuclear Selective Transfer). We evaluate the MODIST transfer efficiency, assessing its dependence on rf-field strengths and the number of simulated spins, extending up to 10 spins.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

Background And Objective: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied.

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.

Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology-a strategy that is based on perturbing primary tumor cells from cancer patients-could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs).

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

Methods: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program.

Molecular reshaping of phage-displayed Interleukin-2 at beta chain receptor interface to obtain potent super-agonists with improved developability profiles.

Interleukin-2 (IL-2) engineered versions, with biased immunological functions, have emerged from yeast display and rational design. Here we reshaped the human IL-2 interface with the IL-2 receptor beta chain through the screening of phage-displayed libraries. Multiple beta super-binders were obtained, having increased receptor binding ability and improved developability profiles.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases.

Cognitive-Driven Activities of Daily Living Impairment as a Predictor for Dementia in Parkinson Disease: A Longitudinal Cohort Study.

Background And Objectives: One-third of Parkinson disease (PD) patients with PD-mild cognitive impairment (PD-MCI) convert to dementia within a few years. Markers with a high prognostic value for dementia conversion are needed. Loss of everyday function primarily caused by cognitive dysfunction is the core criterion for the diagnosis of PD dementia, with an onset of more complex instrumental activities of daily living (IADL) dysfunction in the prodromal stage.

Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.

Methods: Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS.

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

Should Ultrasound-Guided High Frequency Focused Ultrasound Be Considered as an Alternative Non-Surgical Treatment of Uterine Fibroids in Non-Asiatic Countries? An Opinion Paper.

Minimally invasive interventions for myomata treatment have gained acceptance due to the possibility of preserving fertility with reduced trauma induced by laparotomy as way of entrance. There are insufficient data regarding outcomes of high intensity focused ultrasound (HIFU) in non-Asiatic women. Therefore, we revised the available evidence to present an expert opinion that could support physicians, patients and policy-makers for considering this approach in other populations.

Inflammatory Monocyte Counts Determine Venous Blood Clot Formation and Resolution.

Background: Monocytes are thought to be involved in venous thrombosis but the role of individual monocyte subpopulations on thrombus formation, clot inflammation, and degradation is an important unresolved issue. We investigate the role of inflammatory Ly6C monocytes in deep vein thrombosis and their potential therapeutic impact.

Methods: Frequencies and compositions of blood monocytes were analyzed by flow cytometry in CCR2 (C-C chemokine receptor type 2) and wild-type mice of different ages and after treatment with the NR4A1 (nuclear receptor group 4 family A member 1, Nur77) agonist CnsB (cytosporone B).

CD127+ CD94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with Crohn's disease.

Phenotypic definition of helper ILC1 and NK cells is problematic due to overlapping markers. Recently we showed the identification of cytotoxic ILC3s characterized by expression of CD94. Here we analyse CD127+ ILCs and NK cells in intestinal lamina propria from healthy donors and Crohn's disease patients and identify two populations of CD127+CD94+ ILCs, designated population A and B, that can be distinguished on the expression of CD117, CD18 and cytotoxic molecules.

Predicting Advanced Balance Ability and Mobility with an Instrumented Timed Up and Go Test.

Extensive test batteries are often needed to obtain a comprehensive picture of a person's functional status. Many test batteries are not suitable for active and healthy adults due to ceiling effects, or require a lot of space, time, and training. The Community Balance and Mobility Scale (CBMS) is considered a gold standard for this population, but the test is complex, as well as time- and resource intensive.

Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation.

Background: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation.