GABA transporter 1 is a promising drug target for CUL4B mutation-associated epilepsy.

Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene result in syndromic X-linked intellectual disability (XLID). In addition to intellectual disability, patients with CUL4B mutations exhibit epilepsy.

Discovery of a Selective and Orally Bioavailable RET Degrader with Effectiveness in Various Mutations.

The rearranged during transfection (RET) mutation such as the G810C mutation has significantly restricted the clinical application of selective RET inhibitors in the treatment of RET-driven cancers. This study designed and evaluated RET proteolysis targeting chimeras (PROTACs) based on selpercatinib (LOXO-292), identifying as a potent and selective RET PROTAC. effectively inhibited the proliferation of BaF3 cells with various RET mutations, showing IC values of 2.

SOX13 as a potential prognostic biomarker linked to immune infiltration and ferroptosis inhibits the proliferation, migration, and metastasis of thyroid cancer cells.

Background: SOX13 is a transcription factor belonging to the SOX family. SOX proteins are critical regulators of multiple cancer progression, and some are known to control carcinogenesis. Nevertheless, the functional and clinical significance of SOX13 in human thyroid cancer (THCA) remain largely unelucidated.

Discovery of novel KSP-targeting PROTACs with potent antitumor effects in vitro and in vivo.

Kinesin spindle protein (KSP) plays a crucial role during mitosis, making it an attractive target for cancer treatment. Herein, we report the design, synthesis, and evaluation of the first series of KSP degraders by using the utilization of the proteolysis-targeting chimera (PROTAC) technology. Compound 21 was identified as a potent KSP degrader with a DC (concentration causing 50 % of protein degradation) value of 114.

Isoalantolactone/hydroxamic acid hybrids as potent dual STAT3/HDAC inhibitors and self-assembled nanoparticles for cancer therapy.

Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis.

Metal ions-anchored bacterial outer membrane vesicles for enhanced ferroptosis induction and immune stimulation in targeted antitumor therapy.

The activation of ferroptosis presents a versatile strategy for enhancing the antitumor immune responses in cancer therapy. However, developing ferroptosis inducers that combine high biocompatibility and therapeutic efficiency remains challenging. In this study, we propose a novel approach using biological nanoparticles derived from outer membrane vesicles (OMVs) of Escherichia coli for tumor treatment, aiming to activate ferroptosis and stimulate the immune responses.

Structure and anti-inflammatory activity of neo-clerodane diterpenoids from Scutellaria barbata.

Herein, 13 previously undescribed neo-clerodane diterpenoids (1-13) and 27 known analogs (14-40) were isolated from the aerial parts of Scutellaria barbata. Absolute configurations of undescribed compounds were assigned based on single-crystal X-ray diffraction analysis and comparison of experimental and circular dichroism. All isolates were evaluated for the inhibition of nitric oxide generation induced by lipopolysaccharide in RAW 264.

Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1).

Glioblastoma multiforme (GBM) is one of the most lethal malignant tumors in the human brain, with only a few chemotherapeutic drugs available after surgery. Nitrovin (difurazone) is widely used as an antibacterial growth promoter in livestock. Here, we reported that nitrovin might be a potential anticancer lead.

Synthesis and anticancer activity of novel histone deacetylase inhibitors that inhibit autophagy and induce apoptosis.

The combination of histone deacetylase (HDAC) and autophagy inhibitor has been considered as a novel cancer therapeutic strategy. To find novel HDAC inhibitors that can inhibit autophagy, several new series of oxazole- and thiazole-based HDAC inhibitors were designed and synthesized by replacing the phenyl cap in SAHA with 5-phenyloxazoles and 5-phenylthiazoles. The representative oxazole derivative, compound 21, showed better enzymatic inhibitory activity than SAHA (vorinostat).

Alteration of gut microbiota in high-fat diet-induced obese mice using carnosic acid from rosemary.

(rosemary) is widely used as a food ingredient. Rosemary extract (containing 40% carnosic acid) exhibited potent antiobesity activity. However, the relationship between carnosic acid (CA) and changes in the gut microbiota of high-fat diet (HFD)-induced obese mice has not been fully investigated.

Using Case Costing to Evaluate the Potential Impact of a Reintegration Unit on an Acute-Care Hospital's Capacity and Resources.

The Ontario Ministry of Health funded a reintegration unit to transition hospitalized patients who no longer required acute care to alternate level of care (ALC), such as long-term care. In its first year, 102 (3.5%) patients of the hospital's waiting-for-ALC population were transferred, with 37.

The effects of hypoxia on mitochondrial function and metabolism in gastric cancer cells.

Background: A number of studies have found that metabolic disorders are the characteristic manifestations of tumor cells. However, the effects of hypoxic environment on mitochondrial function and glucose metabolism of tumor cells were still unclear. The study wanted to explore the regulatory mechanism of hypoxic environment on mitochondrial function and metabolism in gastric cancer cells.

Inhibitory effect of roburic acid in combination with docetaxel on human prostate cancer cells.

Roburic acid (ROB) is a naturally occurred tetracyclic triterpenoid, and the anticancer activity of this compound has not been reported. Docetaxel (DOC) is the first-line chemotherapeutic agent for advanced stage prostate cancer but toxic side effects and drug resistance limit its clinical success. In this study, the potential synergistic anticancer effect and the underlying mechanisms of ROB in combination with DOC on prostate cancer were investigated.

[Imaging study of soft tissue swelling after anterior cervical corpectomy].

Objective: To study the changes of anterior soft tissue swelling after anterior cervical subtotal corpectomy, titanium mesh fusion and internal fixation.

Methods: From November 2015 to July 2018, 151 patients with cervical spondylotic myelopathy were treated with anterior single corpectomy, titanium mesh fusion and internal fixation, including 109 males and 42 females, aged 44 to 81 (59.77±8.

White Blood Cell Counts to High-Density Lipoprotein Cholesterol Ratio, as a Novel Predictor of Long-Term Adverse Outcomes in Patients After Percutaneous Coronary Intervention: A Retrospective Cohort Study.

White blood cell (WBC) counts and high-density lipoprotein cholesterol (HDL-C) are widely available in clinical practice. However, the predictive value for cardiovascular disease (CVD) is uncertain. In the present study, we firstly assessed the prognostic value of WBC to HDL-C ratio (WHR) in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI).

Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer.

Lactate has been observed to fuel TCA cycle and is associated with cancer progression in human lung cancer, the leading cause of cancer deaths worldwide, but the effect of lactate on lung cancer metabolism is rarely reported. In this study, disordered metabolism in non-small cell lung cancer was demonstrated by increased G6PD and SDHA protein levels immunofluorescence, and up-regulated lactate dehydrogenase was found to be associated with poor prognosis. Then flow cytometry and Seahorse XFe analyzer were utilized to detect the effect of lactate on glycolysis and mitochondrial function in non-small cell lung cancer cells.

Bidirectional interaction of nobiletin and gut microbiota in mice fed with a high-fat diet.

Nobiletin is abundant in citrus peels and demonstrates good anti-obesity bioactivity. However, its anti-obesity mechanisms still remain unclear. This study aims to explore the bidirectional interaction between nobiletin and gut microbiota in mice fed with a high-fat diet.

Synthesis and structure-activity relationships of 5-phenyloxazole-2-carboxylic acid derivatives as novel inhibitors of tubulin polymerization.

A series of 5-phenyloxazole-2-carboxylic acid derivatives were synthesized, and their structure-activity relationships (SARs) were studied. N,5-diphenyloxazole-2-carboxamides 6, 7, and 9, which mimicked ABT751, showed improved cytotoxicity compared with ABT751. Compound 9 exhibited the highest antiproliferative activities against Hela A549, and HepG2 cancer cell lines, with IC values of 0.

Effects of atorvastatin in combination with celecoxib and tipifarnib on proliferation and apoptosis in pancreatic cancer sphere-forming cells.

Cancer stem cell (CSC) plays an important role in pancreatic cancer pathogenesis and treatment failure. CSCs are characterized by their ability to form tumor spheres in serum-free medium and expression of CSC related markers. In the present study, we investigated the effect atorvastatin, celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells.

A Novel ABC Score Predicts Mortality in Non-ST-Segment Elevation Acute Coronary Syndrome Patients Who underwent Percutaneous Coronary Intervention.

Objective:  In the present study, we aimed to establish a novel score to predict long-term mortality of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients who underwent percutaneous coronary intervention (PCI).

Methods:  A total of 2,174 NSTE-ACS patients from the CORFCHD-ZZ study were enrolled as the derivation cohort. The validation cohort including 1,808 NSTE-ACS patients were from the CORFCHD-PCI study.

Transcatheter mitral valve implantation using a novel system: preclinical results.

Background: This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system (Mi-thos valve) composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis.

Methods: The valve was implanted in 26 sheep using a transapical approach for short- and long-term evaluation. The technical feasibility, safety, durability, and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography, multisliced computed tomography, histological analysis, and electron microscopy.

Asymmetric Construction of Cyclobutanes via Direct Vinylogous Michael Addition/Cyclization of β,γ-Unsaturated Amides.

The construction of cyclobutanes has attracted much attention because of its unique four-membered ring skeleton. Herein, we report the highly enantioselective direct vinylogous Michael reaction of β,γ-unsaturated pyrazole amides and nitroolefin using a squaramide catalyst. Cyclobutane derivatives were obtained by subsequent cyclization in good yields (up to 85%) with excellent enantioselectivities (up to 99% ee).