Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors.

Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35.

Endothelial cells derived extracellular vesicles promote diabetic arterial calcification via circ_0008362/miR-1251-5p/Runx2 axial.

Introduction: Arterial calcification, an independent predictor of cardiovascular events, increases morbidity and mortality in patients with diabetes mellitus (DM), but its mechanisms remain unclear. Extracellular vesicles (EVs) play an important role in intercellular communication. The study investigates the role and potential mechanisms of EVs derived from endothelial cells (ECs) in regulating vascular smooth muscle cell (VSMC) calcification under high glucose (HG) condition, with a goal of developing effective prevention and treatment strategies for diabetic arterial calcification.

Discovery of Imidazo[1,2-]pyrazine Derivatives as Potent ENPP1 Inhibitors.

ENPP1 acts as a negative regulator of the cGAS-STING pathway through the hydrolysis of 2'3'-cGAMP. Inhibitors of ENPP1 are regarded as promising agents for stimulating the immune response in cancer immunotherapy. This study describes the identification and optimization of imidazo[1,2-]pyrazine derivative as a highly potent and selective ENPP1 inhibitor.

Case report: Thyroid metastasis from hepatocellular carcinoma: a rare case with diffuse solid occupancy and unusual imaging findings.

Background: Thyroid metastasis represents a rare occurrence, with commonly observed primary tumors originating from renal cell carcinoma, malignant neoplasms of the gastrointestinal tract, lungs, and breast. However, the metastasis of hepatocellular carcinoma to the thyroid gland remains infrequent. Previous investigations have consistently demonstrated an unfavorable prognosis for patients with malignancies that have metastasized to the thyroid.

Coronary Microvascular Dysfunction and Diffuse Myocardial Fibrosis in Patients With Type 2 Diabetes Using Quantitative Perfusion MRI.

Background: Imaging techniques that quantitatively and automatically measure changes in the myocardial microcirculation in patients with diabetes are lacking.

Purpose: To detect diabetic myocardial microvascular complications using a novel automatic quantitative perfusion MRI technique, and to explore the relationship between myocardial microcirculation dysfunction and fibrosis.

Study Type: Prospective.

Targeting JMJD1C to selectively disrupt tumor T cell fitness enhances antitumor immunity.

Regulatory T (T) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving T cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral T cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral T cell-specific epigenetic regulators have been unexplored.

Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application.

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability.

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS.

KRAS, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRAS PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRAS PROTACs.

Endovascular Thrombectomy for a Progressive Stroke Patient With a High-Burden Carotid Free-Floating Thrombus.

Carotid free-floating thrombus (FFT) is a rare cause of acute ischemic events. The optimal management of carotid FFT remains unclear. The optimal and individualized management of carotid FFT should be determined based on the underlying etiology, clinical manifestation, and imaging characteristics.

Residual inflammatory risk predicts long-term outcomes following stenting for symptomatic intracranial atherosclerotic stenosis.

Background And Purpose: Residual inflammatory risk (RIR) can predict the unfavourable outcomes in patients with minor ischaemic stroke. However, the impact of preprocedural RIR on long-term outcomes in patients with symptomatic intracranial atherosclerotic stenosis (sICAS) who underwent stenting remains understudied.

Methods: This retrospective, single-centre cohort study evaluated consecutive patients with severe sICAS who underwent intracranial stenting.

Sequence-based drug design as a concept in computational drug design.

Drug development based on target proteins has been a successful approach in recent decades. However, the conventional structure-based drug design (SBDD) pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, we propose a sequence-to-drug concept for computational drug design based on protein sequence information by end-to-end differentiable learning.

Examining the impact of , , and on the quality of soy sauce: a comprehensive review of microbial population dynamics in fermentation.

Soy sauce is a popular fermented seasoning due to its distinct flavor and rich umami taste. Its traditional production involves two stages: solid-state fermentation and moromi (brine fermentation). During moromi, the dominant microbial population in the soy sauce mash changes, which is called microbial succession and is essential for the formation of soy sauce flavor compounds.

Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial.

SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned.

High-Resolution Magnetic Resonance Imaging in Endovascular Treatment of Vertebrobasilar Junction Stenosis.

Introduction: Vertebrobasilar junction (VBJ) stenosis is a challenge in endovascular treatment due to structural variants and complexities. The role of high-resolution magnetic resonance imaging (HRMRI) in endovascular treatment for patients with severe VBJ stenosis is uncertain.

Case Report: Four patients with symptomatic VBJ stenosis underwent HRMRI of the vessel wall before endovascular treatment.

Association between basilar artery stenosis features, vertebral artery stenosis and perforator stroke after stenting.

Background And Purpose: We investigated the relationship between basilar artery (BA) atherosclerotic stenosis features and vertebral artery (VA) stenosis and explored whether BA stenosis features are associated with perforator stroke after stenting.

Methods: Patients with BA stenosis who underwent HRMRI and DSA were recruited. Patients were divided into proximal BA stenosis and middle-or-distal BA stenosis groups, and then subgroup analyses were performed based on whether they had VA stenosis.

Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers.

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151.

Predictors of hyperperfusion syndrome after stent implantation in symptomatic intracranial atherosclerotic stenosis.

Background: Hyperperfusion syndrome (HPS) is a serious complication after stent implantation in symptomatic intracranial atherosclerotic stenosis (ICAS). This study aims to explore the predictive value of preprocedural computed tomography perfusion (CTP) for HPS after intracranial stenting.

Methods: In this retrospective case-control study we collected data from consecutive patients from June 2012 to September 2019 who underwent stent implantation due to severe symptomatic ICAS.

Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.

The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING.

Endovascular treatment versus standard medical treatment for basilar artery occlusion: a meta-analysis of randomized controlled trials.

Objective: Acute ischemic stroke caused by basilar artery occlusion (BAO) is devastating, but the optimal treatment for patients with BAO remains controversial. In this study, the authors aimed to investigate the safety and efficacy of endovascular treatment (ET) versus standard medical treatment (SMT) in patients with BAO.

Methods: The PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs).

Association of periprocedural perfusion non-improvement with recurrent stroke after endovascular treatment for Intracranial Atherosclerotic Stenosis.

Background: Predictors of recurrent stroke after endovascular treatment for symptomatic intracranial atherosclerotic stenosis (ICAS) remain uncertain.

Objectives: Among baseline characteristics, lesion features, and cerebral perfusion changes, we try to explore which factors are associated with the risk of recurrent stroke in symptomatic ICAS after endovascular treatment.

Design: Consecutive patients with symptomatic ICAS of 70-99% receiving endovascular treatment were enrolled.

Reconceptualizing the clinicopathological features, locoregional therapy and prognostic factors of occult breast cancer in the era of molecular subtyping.

To evaluate the clinical features, molecular subtypes, therapeutic strategies, and prognostic factors of occult breast cancer (OBC). Patients with T0-3/N1-3/M0 breast cancer diagnosed in 2010-2018 ( = 114,303, including 691 with OBC) were retrieved from the Surveillance, Epidemiology, and End-Results (SEER) database. The endpoints were overall survival (OS) and breast cancer-specific survival (BCSS).