Discovery of Highly Selective and Potent Macrocyclic JAK2 Inhibitors for the Treatment of MPNs.

The development of selective JAK2 inhibitors represents a promising therapeutic strategy for MPNs. Building upon the foundation of our first-generation JAK2 inhibitor, we employed macrocyclization-driven structural optimization to address its off-target limitations. This strategy yielded a novel class of macrocyclic JAK2 inhibitors, with compound emerging as a standout candidate through systematic SAR studies.

Dietary sugar intervention: A promising approach for cancer therapy.

Cancer constitutes a significant global health challenge, with altered metabolism being a hallmark feature of cancer cells. Diet can directly modulate systemic metabolite levels, thereby exerting both direct and indirect influences on tumor progression. The primary mechanisms include: (1) directly altering signaling pathways related to tumor cell proliferation or apoptosis, (2) indirectly affecting tumor progression by modulating nutrient availability or immune cell function in the tumor microenvironment, and (3) influencing tumor development through changes in gut microbiota composition or metabolic activity.

Thyroid function and viability after larynx-trachea-thyroid allotransplantation: a case series.

Introduction: Larynx-trachea-thyroid allotransplantation is a multi-organ cluster transplant that involves both solid organs and the thyroid gland. Thyroid dysfunction is frequently reported after an organ transplant. However, there are few reports neither about the thyroid function after laryngeal allotransplantation nor about the feasibility of thyroid allotransplantation.

Discovery of Novel KuE PSMA PET Tracers through Structure Fine-Tuning and Direct Photocatalyzed F-Deoxyfluorination.

Prostate-specific membrane antigen (PSMA) PET imaging has been recognized as an effective modality for early and accurate prostate cancer (PCa) diagnosis. While the F-labeled PSMA tracer was initially approved for clinical use, the structure-activity relationship (SAR) has been underexplored due to limited accessibility of the tracers. Herein, we designed and synthesized a group of PSMA PET tracers through structure-based meticulous optimization for potential interactions at the amphipathic S1 site.

Discovery of degrader for FLT3, GSPT1 and IKZF1/3 proteins merging PROTAC and molecular glue targeting FLT3-ITD mutant acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase expressed in hematopoietic progenitor cells and in most AML cell lines. Pharmacological inhibition of FLT3 enzymatic function is now a well-established strategy for the treatment of patients with these malignancies. Herein, we report the discovery and characterization of a FLT3 degrader A2.

Design, synthesis, and evaluation of 1,3,4-oxadiazole-based EGFR inhibitors.

The epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family, serves as a validated and significant therapeutic target in various cancers. EGFR inhibitors have substantially improved the treatment outcomes for patients with EGFR-positive tumors. The EGFR mutation has emerged as a leading cause of clinically acquired resistance to both first- and second-generation EGFR inhibitors.

AdipoRon attenuates steatosis, inflammation and fibrosis in murine diet-induced NASH via inhibiting ER stress.

Aim: The rising global prevalence of obesity has accelerated the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), with nonalcoholic steatohepatitis (NASH) representing its progressive and life-threatening phenotype. Despite its clinical urgency, no pharmacotherapy is currently approved for NASH. AdipoRon, an orally active adiponectin receptor agonist, exhibits dual regulatory effects on glucose/lipid homeostasis alongside anti-inflammatory and antioxidant properties.

Challenges and opportunities for the diverse substrates of SPOP E3 ubiquitin ligase in cancer.

The Speckle-type POZ protein (SPOP), a substrate adaptor of the cullin-RING E3 ligase complex, mediates both the degradation and non-degradative ubiquitination of substrates, which are crucial for regulating various biological functions and cellular processes. Dysregulation of SPOP-mediated ubiquitination has been implicated in several cancers. Emerging evidence suggests that SPOP functions as a double-edged sword: acting as a tumor suppressor in prostate cancer (PCa), hepatocellular carcinoma (HCC), and colorectal cancer (CRC), while potentially serving as an oncoprotein in kidney cancer (KC).

Irradiation-induced increase in nuclear p62 levels contributes to chromosomal fragmentation and chromothripsis.

Chromosomal instability (CIN) is a hallmark of cancer, closely associated with tumor evolution, metastasis, immune evasion, and resistance to treatment. CIN is driven by persistent chromosome missegregation, resulting in abnormal chromosomal copy numbers and promoting tumor progression through mitotic errors, faulty chromosome segregation, and the formation of micronuclei or chromosome bridges. Previous studies have demonstrated that p62 localizes to micronuclei, where it interacts with mitochondria, enhancing reactive oxygen species-mediated cysteine oxidation and promoting p62 homo-oligomerization.

Synthesis of polysubstituted cyclobutanes through a photoredox strain-release/[3,3]-rearrangement cascade.

Small saturated carbocycles, such as cyclobutanes, with elevated three-dimensionality and rich C centers are privileged scaffolds in naturally occurring molecules and drug discovery. It remains highly desirable and challenging to develop modular and straightforward strategies to craft densely substituted cyclobutanes. Herein, a photoredox-catalyzed radical strain-release/[3,3]-rearrangement cascade (SRRC) strategy for efficient synthesis of polysubstituted cyclobutanes is disclosed.

Incidence, prevalence, and burden of type 2 diabetes in China: Trend and projection from 1990 to 2050.

Background: The epidemiological pattern and disease burden of type 2 diabetes have been shifting in China over the past decades. This analysis described the epidemiological transition of type 2 diabetes in the past three decades and projected the trend in the future three decades in China.

Methods: Age-, sex-, and year-specific incidence, prevalence, death, and disability-adjusted life years (DALYs) for people with 15 years or older and diabetes or high fasting glucose in China and related countries from 1990 to 2021 were obtained from the Global Burden of Disease.

Laparoscopic hepatectomy and near-infrared fluorescence based on the concept of "biliary territory" in the treatment of hepatolithiasis: a propensity score-matched study with videos.

Background: Hepatolithiasis, a common condition in East Asia, often requires surgical treatment. The aim of this study was to evaluate the safety and efficacy of near-infrared fluorescence (NIF)-guided laparoscopic hepatectomy (LH) using the 'biliary territory' concept for hepatolithiasis.

Methods: This retrospective study included 97 patients who had undergone LH for hepatolithiasis between June 2018 and November 2022.

Vision transformer-based model can optimize curative-intent treatment for patients with recurrent hepatocellular carcinoma.

The treatment selection for recurrent hepatocellular carcinoma (rHCC) within Milan criteria after hepatectomy remains challenging. Here, we present HEROVision, a Vision Transformer-based model designed for personalized prognosis prediction and treatment optimization between thermal ablation (TA) and surgical resection (SR). HEROVision is trained on initial HCC cohorts (8492 images; 772 patients) and independently tested on rHCC cohorts (9163 images; 833 patients) from five centers.

Pan-cancer analysis of GJB5 as a novel prognostic and immunological biomarker.

Gap junction protein B5 (GJB5, also known as Connexin 31.1) has recently been reported to be downregulated in several cancer types, where it functions primarily as a tumor suppressor in cancers such as melanoma and non-small cell lung cancer (NSCLC). However, there no reports describing its prognostic and immunological roles in pan-cancer.

Indocyanine green fluorescence imaging (ICG-FI) in difficult laparoscopic hepatectomy for hepatocellular carcinoma: a retrospective propensity score-matched analysis.

Background: Indocyanine green fluorescence imaging (ICG-FI) is increasingly used in laparoscopic hepatectomy (LH). However, its efficacy in enhancing both short- and long-term outcomes in difficult LH for hepatocellular carcinoma (HCC) compared with traditional white light (WL) LH remains unclear.

Methods: This retrospective cohort study analyzed 573 patients who underwent LH between April 2018 and April 2023, stratified by the use of ICG-FI or WL.

CLIC1 and IFITM2 expression in brain tissue correlates with cognitive impairment via immune dysregulation in sepsis and Alzheimer's disease.

Background: Sepsis, a life-threatening condition driven by dysregulated host responses to infection, is associated with long-term cognitive impairments resembling Alzheimer's disease (AD). However, the molecular mechanisms linking sepsis-induced cognitive dysfunction and AD remain unclear. We hypothesized that shared genetic pathways underlie cognitive deficits in both conditions.

Crystal Structure of an Aldo-keto Reductase MGG_00097 from Magnaporthe grisea.

The enzyme MGG_00097 from rice blast fungus (Magnaporthe grisea) is a NADPH-dependent oxidoreductase, involved in synthesizing glycerol from dihydroxyacetone phosphate and dihydroxyacetone. The 35.5-kDa monomer belongs to the aldo-keto reductase superfamily, characterized by a highly conserved catalytic tetrad.

The crystal structure of an uncharacterized domain of P113 from Plasmodium falciparum.

The surface protein P113 serves as a membrane-anchored protein that tethers the Plasmodium falciparum RH5 complex, including its associated partners CyRPA and RIPR, to the parasite surface. This anchoring mechanism ensures the proper localization and stabilization of RH5, facilitating its critical interaction with the host erythrocyte receptor basigin during erythrocyte invasion. Here, the helical-rich domain of P113 (residues 311-679) from a Plasmodium species was expressed, purified and crystallized to elucidate its structural and functional characteristics.

GLP-1RAs attenuated obesity and reversed leptin resistance partly activating the microbiome-derived inosine/A2A pathway.

Extensive evidence has demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can ameliorate obesity. Our previous studies revealed that (Ex-4)-Fc, a long-acting GLP-1RA we developed, depends on the leptin pathway to treat obesity. However, the mechanisms linking (Ex-4)-Fc and leptin resistance remain largely unclear.

Preoperative SII Can Predict Postoperative Recurrence and Serious Complications in Patients with Hepatolithiasis.

Purpose: The occurrence and progression of hepatolithiasis are related to inflammatory reactions and immune proteins. This study aims to evaluate the relationship between systemic immune index (SII) in recurrence-free survival (RFS), as well as the incidence of severe postoperative complications in hepatolithiasis patients.

Patients And Methods: We retrospectively analyzed 177 patients with hepatolithiasis.

Advanced RPL19-TRAP-seq method reveals mechanism of action of bioactive compounds.

Natural products play a crucial role in new drug development, but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action. In this study, we developed a new RPL19-TRAP-seq method, combining CRISPR/Cas9 and TRAP technologies, to investigate these mechanisms. We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP, selecting RPL19 for its high enrichment.

Design and Synthesis of Novel Deazapurine DNMT 1 Inhibitors with Efficacy in DLBCL.

The application of drugs to regulate abnormal epigenetic changes has become an important means of tumor treatment. In this study, we employed computer-aided design methods to develop a novel deazapurine compound targeting DNA methyltransferase 1 (DNMT1). Through screening for enzyme activity, selectivity, and cellular efficacy, we optimized three structural skeletons, ultimately yielding compound exhibiting an IC of 2.

p62/SQSTM1 in cancer: phenomena, mechanisms, and regulation in DNA damage repair.

The multidomain protein cargo adaptor p62, also known as sequestosome 1, serves as a shuttling factor and adaptor for the degradation of substrates via the proteasome and autophagy pathways. Regarding its structure, p62 is composed of several functional domains, including the N-terminal Phox1 and Bem1p domains, a ZZ-type zinc finger domain, a LIM protein-binding domain that contains the tumor necrosis factor receptor-associated factor 6 (TRAF6) binding region, two nuclear localization signals (NLS 1/2), a nuclear export signal (NES), the LC3-interacting region (LIR), a Kelch-like ECH-associated protein 1 (KEAP1)-interacting region, and a ubiquitin-associated (UBA) domain. Recent studies have highlighted the critical role of p62 in the development and progression of various malignancies.

Insights into Extrachromosomal DNA in Cancer: Biogenesis, Methodologies, Functions, and Therapeutic Potential.

Originating from, but independent of, linear chromosomes, extrachromosomal DNA (ecDNA) exists in a more active state of transcription and autonomous replication. It plays a crucial role in the development of malignancies and therapy resistance. Since its discovery in eukaryotic cells more than half a century ago, the biological characteristics and functions of ecDNA have remained unclear due to limitations in detection methods.

StatGel: An Innovative hydrogel carrying STAT3-targeted small molecule inhibitor for the treatment of abdominal adhesions.

Adhesions in the abdominal cavity are among the most common complications post abdominal surgery, resulting from excessive fibrous tissue proliferation and collagen synthesis due to various factors. To date, physical barrier materials have been approved for preventing adhesions, though their effectiveness remains unsatisfactory. One of the important causes of abdominal adhesions is the excessive proliferation of fibrotic cells, and our previous research indicated that STAT3 is a promising therapeutic target for anti-fibrosis.