Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma.

Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4 T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL.

Cardiovascular Events Associated with CDK4/6 Inhibitors: A Safety Meta-Analysis of Randomized Controlled Trials and a Pharmacovigilance Study of the FAERS Database.

Background: CDK4/6 inhibitors are highly valued, but the incidence of cardiovascular adverse events (CVAEs) associated with CDK4/6 inhibitors is not clear.

Objective: Our aim was therefore to assess the risk of developing CVAEs associated with CDK4/6 inhibitors, by conducting a systematic review and meta-analysis of randomized controlled trials (RCTs), along with a pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS) database.

Methods: Eligible CVAEs were extracted from the ClinicalTrials.

Enhancing transcription-replication conflict targets ecDNA-positive cancers.

Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments.

Prospective single-arm trial on feasibility and safety of an endoscopic robotic system for colonic endoscopic submucosal dissection.

Background: The development of the EndoMaster "Endoluminal Access Surgical Efficacy" (EASE) system aims to enhance the safety and efficacy of colonic endoscopic submucosal dissection (ESD) through two flexible robotic arms. This is the first clinical trial to evaluate the performance of colorectal ESD using EndoMaster.

Method: Patients with early mucosal colorectal neoplasia that was not suitable for en bloc resection with snare-based techniques were recruited.

Mechanical release of homogenous proteins from supramolecular gels.

A long-standing challenge is how to formulate proteins and vaccines to retain function during storage and transport and to remove the burdens of cold-chain management. Any solution must be practical to use, with the protein being released or applied using clinically relevant triggers. Advanced biologic therapies are distributed cold, using substantial energy, limiting equitable distribution in low-resource countries and placing responsibility on the user for correct storage and handling.

Artificial Intelligence Outcome Prediction in Neonates with Encephalopathy (AI-OPiNE).

Purpose To develop a deep learning algorithm to predict 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy using MRI and basic clinical data. Materials and Methods In this study, MRI data of term neonates with encephalopathy in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial (ClinicalTrials.gov: NCT02811263), who were enrolled from 17 institutions between January 25, 2017, and October 9, 2019, were retrospectively analyzed.

Unravelling the complex interplay of factors behind exercise limitations and physical inactivity in COPD.

Exercise limitation and physical inactivity are known treatable traits for people with COPD. Maximising exercise capacity and keeping people physically active improves health status and survival rates among people with COPD. However, managing these two treatable traits can be extremely challenging for clinicians due to the complex intersectionality of factors influencing an individual's capacity, opportunity and motivation to engage in physical activity.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus.

Precise prediction of phase-separation key residues by machine learning.

Understanding intracellular phase separation is crucial for deciphering transcriptional control, cell fate transitions, and disease mechanisms. However, the key residues, which impact phase separation the most for protein phase separation function have remained elusive. We develop PSPHunter, which can precisely predict these key residues based on machine learning scheme.

Exponential Combination of and Intracellular Peptide Libraries Identifies a Selective ATF3 Inhibitor.

Activating transcription factor 3 (ATF3) is an activation transcription factor/cyclic adenosine monophosphate (cAMP) responsive element-binding (CREB) protein family member. It is recognized as an important regulator of cancer progression by repressing expression of key inflammatory factors such as interferon-γ and chemokine (C-C motif) ligand 4 (CCL4). Here, we describe a novel library screening approach that probes individual leucine zipper components before combining them to search exponentially larger sequence spaces not normally accessible to intracellular screening.

RSPSSL: A novel high-fidelity Raman spectral preprocessing scheme to enhance biomedical applications and chemical resolution visualization.

Raman spectroscopy has tremendous potential for material analysis with its molecular fingerprinting capability in many branches of science and technology. It is also an emerging omics technique for metabolic profiling to shape precision medicine. However, precisely attributing vibration peaks coupled with specific environmental, instrumental, and specimen noise is problematic.

Evaluation of Continuous Infusion Vancomycin in a Pediatric Hematology/Oncology Population.

Background: Continuous infusion vancomycin (CIV) may benefit children who are unable to achieve therapeutic concentrations with intermittent vancomycin dosing and may facilitate outpatient administration by alleviating the burden of frequent dosing intervals. Previous studies have used variable dosing regimens and steady-state concentration goals. The purpose of this study was to evaluate the total daily dose (TDD) of CIV required to achieve therapeutic steady-state concentrations of 15-25 µg/mL in pediatric hematology/oncology patients.

Methotrexate Inhibits the Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptor Binding Domain to the Host-Cell Angiotensin-Converting Enzyme-2 (ACE-2) Receptor.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus mutates, finding effective drugs becomes more challenging. In this study, we use ultrasensitive frequency locked microtoroid optical resonators in combination with screening to search for COVID-19 drugs that can stop the virus from attaching to the human angiotensin-converting enzyme 2 (hACE2) receptor in the lungs. We found 29 promising candidates that could block the binding site and selected four of them that were likely to bind very strongly.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

Background: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.

Refined preferences of prioritizers improve intelligent diagnosis for Mendelian diseases.

Phenotype-guided gene prioritizers have proved a highly efficient approach to identifying causal genes for Mendelian diseases. In our previous study, we preliminarily evaluated the performance of ten prioritizers. However, all the selected software was run based on default settings and singleton mode.

A Tandem-Affinity Purification Method for Identification of Primary Intracellular Drug-Binding Proteins.

In the field of drug discovery, understanding how small molecule drugs interact with cellular components is crucial. Our study introduces a novel methodology to uncover primary drug targets using andem ffinity urification for identification of rug-inding roteins (TAP-DBP). Central to our approach is the generation of a FLAG-hemagglutinin (HA)-tagged chimeric protein featuring the FKBP12(F36V) adaptor protein and the TurboID enzyme.

Treatment of moderate-to-severe alopecia areata in patients over the age of 65 years with baricitinib.

Baricitinib is a Janus kinase inhibitor that has been approved by the US Food and Drugs Administration for the treatment of severe alopecia areata (AA) in adults. However, the clinical trials that demonstrated the efficacy of baricitinib in the treatment of severe AA did not include men aged > 60 years or women aged > 70 years. We retrospectively assessed the efficacy and safety of baricitinib in 14 patients aged ≥ 65 years with moderate-to-severe AA.

DockOpt: A Tool for Automatic Optimization of Docking Models.

Molecular docking is a widely used technique for leveraging protein structure for ligand discovery, but it remains difficult to utilize due to limitations that have not been adequately addressed. Despite some progress toward automation, docking still requires expert guidance, hindering its adoption by a broader range of investigators. To make docking more accessible, we developed a new utility called DockOpt, which automates the creation, evaluation, and optimization of docking models prior to their deployment in large-scale prospective screens.

Endoplasmic Reticulum Protein 72 Regulates Integrin Mac-1 Activity to Influence Neutrophil Recruitment.

Background: Integrins mediate the adhesion, crawling, and migration of neutrophils during vascular inflammation. Thiol exchange is important in the regulation of integrin functions. ERp72 (endoplasmic reticulum-resident protein 72) is a member of the thiol isomerase family responsible for the catalysis of disulfide rearrangement.

Therapeutic Potential for Beta-3 Adrenoreceptor Agonists in Peripheral Arterial Disease and Diabetic Foot Ulcers.

Annually, peripheral arterial disease is estimated to cost over USD 21 billion and diabetic foot disease an estimated at USD 9-13 billion. Mirabegron is a TGA-approved beta-3 adrenoreceptor agonist, shown to be safe and effective in the treatment of overactive bladder syndrome by stimulating bladder smooth muscle relaxation. In this review, we discuss the potential use of beta-3 adrenoreceptor agonists as therapeutic agents repurposed for peripheral arterial disease and diabetic foot ulcers.

Clinical Outcomes of Deferred Lesions by IVUS Versus FFR-Guided Treatment Decision.

Background: There are limited data regarding the safety of deferral of percutaneous coronary intervention based on intravascular ultrasound (IVUS) findings. The current study sought to compare the prognosis between deferred lesions based on IVUS and fractional flow reserve (FFR)-guided treatment decision.

Methods: This study is a post hoc analysis of the FLAVOUR randomized trial (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients With Intermediate Stenosis) that compared 2-year clinical outcomes between IVUS- and FFR-guided treatment decision on intermediate coronary artery lesions using predefined criteria.

Circular single-stranded DNA as switchable vector for gene expression in mammalian cells.

Synthetic gene networks in mammalian cells are currently limited to either protein-based transcription factors or RNA-based regulators. Here, we demonstrate a regulatory approach based on circular single-stranded DNA (Css DNA), which can be used as an efficient expression vector with switchable activity, enabling gene regulation in mammalian cells. The Css DNA is transformed into its double-stranded form via DNA replication and used as vectors encoding a variety of different proteins in a wide range of cell lines as well as in mice.

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer.

Background: Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown.

Methods: In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less.

Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir.

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL with an enthalpy-driven thermodynamic binding signature.