The role of TERT C228T and KDM6A alterations and TME in NMIBC treated with BCG.

We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette-Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment.

Recent breakthroughs in innovative elements, multidimensional enhancements, derived technologies, and novel applications of PROTACs.

Proteolysis Targeting Chimera (PROTAC) is an emerging and evolving technology based on targeted protein degradation (TPD). Small molecule PROTACs have shown great efficacy in degrading disease-specific proteins in preclinical and clinical studies, but also showed various limitations. In recent years, new technologies and advances in TPD have provided additional optimized strategies based on conventional PROTACs that can overcome the shortcomings of conventional PROTACs in terms of undruggable targets, bioavailability, tissue-specificity, spatiotemporal control, and degradation scope. In addition, some designs of special targeting chimeras and applications based on multidisciplinary science have shed light on novel therapeutic modalities and drug design. However, each improvement has its own advantages, disadvantages and application conditions. In this review, we summarize the exploration of PROTAC elements, depict a landscape of improvements and derived concepts of PROTACs, and expect to provide perspectives for technological innovations, combinations and applications in future targeting chimera design.

Longxuetongluo Capsule alleviate ischemia/reperfusion induced cardiomyocyte apoptosis through modulating oxidative stress and mitochondrial dysfunction.

BACKGROUND: Chinese dragon's blood, the red resin of Dracaena cochinchinensis (Lour.) S. C. Chen., is widely used to treat cardiovascular and cerebrovascular diseases in China. Longxuetongluo Capsule (LTC) is a total phenolic compound extracted from Chinese dragon's blood, currently used in treating ischemic stroke. Myocardial injury can be aggravated after reperfusion of ischemic myocardium, which is called myocardial ischemia-reperfusion injury (MIRI), and the mechanism of MIRI is complex. However, the exact effect and mechanism of LTC on MIRI are still unclear. We explore the effect of LTC on alleviating MIRI based on mitochondrial dysfunction and oxidative stress. AIM OF THE STUDY: To explore the cardioprotective mechanism of LTC against MIRI. MATERIALS AND METHODS: A rat MIRI model was constructed through ligation of the left anterior descending coronary artery, and LTC was given continuously for 28 days before surgery. The H9c2 cardiomyocyte injury model was induced by oxygen-glucose deprivation/reperfusion (OGD/R), and LTC was given 24 h before OGD. Myocardial ischemia areas were detected with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cardiac histopathological changes were detected with hematoxylin-eosin (HE) staining. And biochemical indexes were detected with serum biochemical kit. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining and flow cytometry were used to detect apoptosis. Fluorescent probes were used to observe reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), Ca2+and other indexes. MitoTracker staining and immunofluorescence were used to observe the morphology of mitochondria and translocation of dynamin-related protein 1 (Drp1). Finally, immunohistochemistry and Western blotting were used to examine the expression of proteins related to apoptosis, mitochondrial fission and fusion and oxidative stress. RESULTS: LTC could ameliorate cardiac pathological changes, decrease myocardial infarct area and the content or level of relevant serum cardiac enzymes, indicating that LTC could alleviate MIRI. Meanwhile, LTC could inhibit cardiomyocyte apoptosis via regulating apoptosis-related protein expression, and it could restore mitochondrial morphology, maintain ΔΨm, inhibit mitochondrial ROS generation and Ca2+ accumulation, increase the expression of mitochondrial fusion protein 2 (Mfn2), decrease the level of phosphorylation dynamin-related protein 1 (p-Drp1), and regulate ATP synthesis, thereby significantly ameliorating mitochondrial dysfunction. Moreover, LTC significantly reduced the expression of NADPH oxidase 2 (NOX2), NADPH oxidase 4 (NOX4) and neutrophil cytosolic factor 2 (NOXA2/p67phox), and reduced ROS production. CONCLUSION: The study demonstrated that LTC could inhibit MIRI induced cardiomyocyte apoptosis by inhibiting ROS generation and mitochondrial dysfunction, and these fundings suggested that LTC can be used to alleviate MIRI, which provides a potential therapeutic approach for future treatment of MIRI.

Design, synthesis and biological evaluation of dual inhibitors targeting AR/AR-Vs and PARP1 in castration resistant prostate cancer therapy.

The combination of androgen signaling inhibitors and PARP inhibitors has shown promising results in clinical trials for the treatment of castration-resistant prostate cancer (CRPC). Multi-target inhibitors can inhibit tumors through different pathways, addressing the limitations of traditional single target inhibitors. We designed and synthesized dual inhibitors targeting AR/AR-Vs and PARP1 using a pharmacophore hybridization strategy. The most potent compound, II-3, inhibits AR/AR-Vs signaling and induces DNA damage by inhibiting PARP1. The IC50 values of II-3 in the castration-resistant prostate cancer cell lines 22RV1 and C4-2 are 4.38 ± 0.56 µM, and 3.44 ± 0.63 µM, respectively. II-3 not only suppresses the proliferation and migration of 22RV1 and C4-2 cells, but also promotes their apoptosis. Intraperitoneal injection of II-3 effectively inhibits tumor growth in 22RV1 xenograft nude mice without evident drug-induced toxicity. Overall, a series of novel dual inhibitors targeting AR/AR-Vs and PARP1 were designed and synthesized, and meanwhile the in vivo and in vitro effects were comprehensively explored, which provided a potential new therapeutic strategy for CRPC.

A clinical evaluation of robotic-assisted radical prostatectomy (RARP) in located prostate cancer: A systematic review and network meta-analysis.

Prostate cancer (PCa) is a prevalent malignant tumor affecting the male reproductive system and there are mainly three widely accepted PCa surgery types in current clinical treatment: open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP) and robot-assisted radical prostatectomy (RARP). Here, we aimed to evaluate the clinical effect of RARP for PCa patients compared with ORP and LRP based on the context of PCa encompass two dimensions: oncological outcomes (biochemical recurrence (BCR) and positive surgical margin (PSM)) and functional outcomes (urinary continence and recovery of erectile function) in this network meta-analysis (NMA). PubMed, Embase and Cochrane databases were systematically searched in January 7, 2024. 4 randomized controlled trials (RCTs) and 72 non-RCTs were included. RARP displayed significant positive effect on lower BCR and better recovery of erectile function but no significant differences existed among three surgery types for PSM and urinary continence.

Sex-specific modulating role of social support in the associations between oxidative stress, inflammation, and telomere length in older adults.

Telomere length, a biomarker of human aging, is related to adverse health outcomes. Growing evidence indicates that oxidative stress and inflammation contributes to telomere shortening, whereas social support may protect from telomere shortening. Despite sex differences in telomere length and social support, little is known about whether there are sex differences in the relationship between oxidative stress/inflammation and telomere length, and sex-specific moderating roles of social support in older adults. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, this study assessed whether the associations between oxidative stress/inflammation and telomere length vary with sex and explored social support as a moderator in these associations among 2289 older adults. Oxidative stress was measured based on serum Gamma-glutamyl transferase (GGT), and inflammation was measured based on C-reactive protein (CRP). After adjusting for the covariates, GGT was significantly associated with telomere length in females only (ß = - 0.037, 95% CI = - 0.070, - 0.005), while CRP was associated with telomere length in males only (ß = - 0.019, 95% CI = - 0.035, - 0.002). Moreover, high social support mitigated the negative association between GGT and telomere length, which was more evident in females. Furthermore, social support moderated the association between CRP and telomere length in males aged 70 and above. Our findings indicated that biological mechanisms related to telomere length may vary with sex, while social support plays a sex-specific moderating role.

Traditional Chinese medicine and plant-derived natural products in regulating triglyceride metabolism: Mechanisms and therapeutic potential.

The incidence of cardiometabolic disease is increasing globally, with a trend toward younger age of onset. Among these, atherosclerotic cardiovascular disease is a leading cause of mortality worldwide. Despite the efficacy of traditional lipid-lowering drugs, such as statins, in reducing low-density lipoprotein cholesterol levels, a significant residual risk of cardiovascular events remains, which is closely related to unmet triglyceride (TG) targets. The clinical application of current TG-lowering Western medicines has certain limitations, necessitating alternative or complementary therapeutic strategies. Traditional Chinese medicine (TCM) and plant-derived natural products, known for their safety owing to their natural origins and diverse biological activities, offer promising avenues for TG regulation with potentially fewer side effects. This review systematically summarises the mechanisms of TG metabolism and subsequently reviews the regulatory effects of TCM and plant-derived natural products on TG metabolism, including the inhibition of TG synthesis (via endogenous and exogenous pathways), promotion of TG catabolism, regulation of fatty acid absorption and transport, enhancement of lipophagy, modulation of the gut microbiota, and other mechanisms. In conclusion, through a comprehensive analysis of recent studies, this review consolidates the multifaceted regulatory roles of TCM and plant-derived natural products in TG metabolism and elucidates their potential as safer, multi-target therapeutic agents in managing hypertriglyceridemia and mitigating cardiovascular risk, thereby providing a basis for new drug development.

Combining lymph node ratio to develop prognostic models for postoperative gastric neuroendocrine neoplasm patients.

BACKGROUND: Lymph node ratio (LNR) was demonstrated to play a crucial role in the prognosis of many tumors. However, research concerning the prognostic value of LNR in postoperative gastric neuroendocrine neoplasm (NEN) patients was limited. AIM: To explore the prognostic value of LNR in postoperative gastric NEN patients and to combine LNR to develop prognostic models. METHODS: A total of 286 patients from the Surveillance, Epidemiology, and End Results database were divided into the training set and validation set at a ratio of 8:2. 92 patients from the First Affiliated Hospital of Soochow University in China were designated as a test set. Cox regression analysis was used to explore the relationship between LNR and disease-specific survival (DSS) of gastric NEN patients. Random survival forest (RSF) algorithm and Cox proportional hazards (CoxPH) analysis were applied to develop models to predict DSS respectively, and compared with the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging. RESULTS: Multivariate analyses indicated that LNR was an independent prognostic factor for postoperative gastric NEN patients and a higher LNR was accompanied by a higher risk of death. The RSF model exhibited the best performance in predicting DSS, with the C-index in the test set being 0.769 [95% confidence interval (CI): 0.691-0.846] outperforming the CoxPH model (0.744, 95%CI: 0.665-0.822) and the 8th edition AJCC TNM staging (0.723, 95%CI: 0.613-0.833). The calibration curves and decision curve analysis (DCA) demonstrated the RSF model had good calibration and clinical benefits. Furthermore, the RSF model could perform risk stratification and individual prognosis prediction effectively. CONCLUSION: A higher LNR indicated a lower DSS in postoperative gastric NEN patients. The RSF model outperformed the CoxPH model and the 8th edition AJCC TNM staging in the test set, showing potential in clinical practice.

Short-term sedimentary evidence for increasing diatoms in Arctic fjords in a warming world.

Arctic fjords are hotspots of marine carbon burial, with diatoms playing an essential role in the biological carbon pump. Under the background of global warming, the proportion of diatoms in total phytoplankton communities has been declining in many high-latitude fjords due to increased turbidity and oligotrophication resulting from glacier melting. However, due to the habitat heterogeneity among Svalbard fjords, diatom responses to glacier melting are also expected to be complex, which will further lead to changes in the biological carbon pumping and carbon sequestration. To address the complexity, three short sediment cores were collected from three contrasting fjords in Svalbard (Krossfjorden, Kongsfjorden, Gronfjorden), recording the history of fjord changes in recent decades during significant glacier melting. The amino acid molecular indicators in cores K4 and KF1 suggested similar organic matter degradation states between these two sites. In contrast to the turbid Kongsfjorden and Gronfjorden, preserved fucoxanthin in Krossfjorden indicated a continuous increase in diatoms since the mid-1980s, corresponding to a 59 % increase in biological carbon pumping, as quantified by the δ13C of sedimentary organic carbon. The increasing biological carbon pumping in Krossfjorden is further attributed to its hard rock types in the glacier basin, compared to Kongsfjorden and Gronfjorden, which are instead covered by soft rocks, as confirmed by a one-dimensional model. Given the distribution of rock types among basins in Svalbard, we extrapolate our findings and propose that approximately one-fifth of Svalbard's fjords, especially those with hard rock basins and persistent marine-terminated glaciers, still have the potential for an increase in diatom fractions and efficient biological carbon pumping. Our findings reveal the complexity of fjord phytoplankton responses and biological carbon pumping to increasing glacier melting, and underscore the necessity of modifying Arctic marine carbon feedback to climate change based on results from fjords underlain by hard rocks.

X-Paste improves wound healing in diabetes via NF-E2-related factor/HO-1 signaling pathway.

BACKGROUND: Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality. AIM: To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice. METHODS: Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP's main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP's treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2) knockdown elucidated Andro's molecular mechanisms. RESULTS: XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation, with Nrf2 knockdown reducing Andro's proliferative and endothelial protective effects. CONCLUSION: XP significantly promotes wound healing in STZ-induced diabetic models. As XP's key component, Andro activates the Nrf2/HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.

Effects of low-dose methotrexate with MMI in patients with Graves' disease: results of a randomized clinical trial.

CONTEXT: Supplemental methotrexate (MTX) may affect the clinical course of Graves' disease (GD). OBJECTIVE: Evaluate efficacy of add-on MTX on medical treatment in GD. DESIGN: Prospective, open-label, randomized supplementation controlled trial. SETTING: Academic endocrine outpatient clinic. PATIENTS: One hundred and fifty-three untreated hyperthyroid patients with GD. INTERVENTION: Patients received MTX 10 mg/d with methimazole (MMI) or MMI only. MTX and MMI were discontinued at months 12-18 in euthyroid patients. MAIN OUTCOME MEASURES: Discontinuation rate at months 18 in each group. RESULTS: In the MTX with MMI group, the discontinuation rate was higher than the MMI group at months 15-18 (50.0 vs. 33.3%, P=0.043, 95% CI 1.020 to 3.922; and 55.6 vs 38.9%, P=0.045, 95%CI 1.011 to 3.815, respectively). The decrease in TRAb levels in the MTX with MMI group was significant from baseline to months 6 compared to the MMI alone group [MTX+MMI 67.22% (43.12-80.32), MMI 54.85% (33.18-73.76), P= 0.039) and became more significant from months 9 [MTX+MMI 77.79% (62.27-88.18), MMI 69.55% (50.50-83.22), P= 0.035] to months 18 (P < 0.01 in 15-18 months). A statistically significant difference between the levels of TRAb in the MTX with MMI group and the MMI group at 9-18 months. There were no significant differences in the levels of FT3, FT4 and TSH between two groups. No serious drug-related adverse events were observed in both groups(P=0.771). CONCLUSIONS: Supplemental MTX with MMI resulted in higher discontinuation rate and improvement in decreased TRAb levels to homeostatic levels faster than methimazole treatment alone at months 12-18.

Diagnostic Accuracy and Safety of Nonsurgical Biopsy for Diagnosing Pulmonary Ground-Glass Opacities: A Systematic Review and Meta-Analysis.

INTRODUCTION: Previous meta-analyses have explored the diagnostic accuracy and safety of computed tomography-guided percutaneous lung biopsy of ground-glass opacities (GGOs). However, no research investigated the role of nonsurgical biopsies (including transbronchial approaches). Additionally, studies reporting the diagnostic accuracy of GGOs with different characteristics are scarce, with no quantitative assessment published to date. We performed a systematic review to explore the diagnostic accuracy and safety of nonsurgical biopsy for diagnosing GGOs, especially those with higher ground-glass components and smaller nodule sizes. METHODS: A thorough literature search of four databases was performed to compile studies evaluating both or either of the diagnostic accuracy and complications of nonsurgical biopsy for GGOs. A bivariate random-effects model and random-effect model were utilized for data synthesis. The methodological quality of the studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: Nineteen eligible studies with a total of 1,379 biopsy-sampled lesions were analyzed, of which 1,124 were confirmed to be malignant. Nonsurgical biopsy reported a pooled sensitivity of 0.89, a specificity of 0.99, and a negative predictive value (NPV) of 60.3%. The overall sensitivity, specificity, and NPV of nonsurgical biopsy for diagnosing GGOs according to GGO component were 0.90, 0.99, and 77.2% in pure GGOs; 0.87, 0.99, and 67.2% in GG-predominant lesions; and 0.89, 1.00, and 44.1% in solid-predominant lesions, respectively. Additionally, the diagnostic sensitivity was better in lesions ≥20 mm than in small lesions (0.95 vs. 0.88). Factors that contributed to higher sensitivity were the use of a coaxial needle system and CT fluoroscopy but not the needle gauge. The summary sensitivity of core needle biopsy (CNB) was not significantly higher than fine needle aspiration (FNA) (0.92 vs. 0.84; p = 0.42); however, we found an increased incidence of hemorrhage in CNB compared with FNA (60.9 vs. 14.2%; p = 0.012). CONCLUSION: Nonsurgical biopsy for diagnosing GGOs shows high sensitivity and specificity with an acceptably low risk of complications. However, negative biopsy results are unreliable in excluding malignancy, necessitating resampling or subsequent follow-up. The applicability of our study is limited due to significant heterogeneity, indirect comparisons, and the paucity of data on bronchoscopic approaches, restricting the generalizability of our findings to patients requiring transbronchial biopsies.

Eruptive xanthomas in a patient with severe hypertriglyceridemia: A case report.

BACKGROUND: Xanthomatosis, a metabolic disorder causing yellow growths (xanthomas), poses challenges in lipid metabolism. This case study introduces the first documented instance within China's Yi population, emphasizing the need to explore dietary habits and treatment strategies tailored to this specific community. CASE SUMMARY: Xanthomatosis is a metabolic disorder where lipid metabolism goes awry, resulting in the development of yellowish growths called xanthomas. A male patient, 47 years of age, from China's Yi population, who is obese, visited our dermatology clinic complaining of widespread, non-painful rashes that have been present for two weeks. The patient works as a chef and has a diet that frequently includes oily and greasy foods. This case represents the initial documentation of xanthomatosis within the Yi population in China, offering a theoretical foundation for understanding dietary patterns and treatment options specific to the Yi community. CONCLUSION: The first report of xanthomatosis in the Yi population in China lays a theoretical foundation for understanding Yi dietary patterns and treatment.

Serum beta2-microglobulin acts as a biomarker for severity and prognosis in glioma patients: a preliminary clinical study.

BACKGROUND: Gliomas are the deadliest malignant tumors of the adult central nervous system. We previously discovered that beta2-microglobulin (B2M) is abnormally upregulated in glioma tissues and that it exerts a range of oncogenic effects. Besides its tissue presence, serum B2M levels serve as biomarkers for various diseases. This study aimed to explore whether serum B2M levels can be used in the diagnosis and prognosis of gliomas. METHODS: Medical records from 246 glioma patients were retrospectively analyzed. The relationship between preoperative serum B2M levels and clinicopathological features was examined. Kaplan-Meier analysis, alongside uni- and multivariate Cox regression, assessed the association between B2M levels, systemic inflammatory markers, and glioma patient prognosis. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic significance of these biomarkers specifically for glioblastoma (GBM). RESULTS: Patients with malignant gliomas exhibited elevated preoperative serum B2M levels. Glioma patients with high serum B2M levels experienced shorter survival times. Multivariate Cox analysis determined the relationship between B2M levels (hazard ratio = 1.92, 95% confidence interval: 1.05-3.50, P = 0.034) and the overall survival of glioma patients. B2M demonstrated superior discriminatory power in distinguishing between GBM and non-GBM compared to inflammation indicators. Moreover, postoperative serum B2M levels were lower than preoperative levels in the majority of glioma patients. CONCLUSIONS: High preoperative serum B2M levels correlated with malignant glioma and a poor prognosis. Serum B2M shows promise as a novel biomarker for predicting patient prognosis and reflecting the therapeutic response.

The Role of Beta2-Microglobulin in Central Nervous System Disease.

Central nervous system (CNS) disorders represent the leading cause of disability and the second leading cause of death worldwide, and impose a substantial economic burden on society. In recent years, emerging evidence has found that beta2 -microglobulin (B2M), a subunit of major histocompatibility complex class I (MHC-I) molecules, plays a crucial role in the development and progression in certain CNS diseases. On the one hand, intracellular B2M was abnormally upregulated in brain tumors and regulated tumor microenvironments and progression. On the other hand, soluble B2M was also elevated and involved in pathological stages in CNS diseases. Targeted B2M therapy has shown promising outcomes in specific CNS diseases. In this review, we provide a comprehensive summary and discussion of recent advances in understanding the pathological processes involving B2M in CNS diseases (e.g., Alzheimer's disease, aging, stroke, HIV-related dementia, glioma, and primary central nervous system lymphoma).

Nickel-Catalyzed Cross-Coupling Reaction of Aryl Bromides/Nitriles with Imidazolium Salts Involving Inert C-N Bond Cleavage.

We herein present a nickel-catalyzed cross-coupling reaction of aryl halides and nitriles with imidazolium salts. A series of 2-arylated imidazoles could be obtained in moderate to good yields through inert C-N bond cleavage. The imidazolium salt in this reaction acts as both a coupling partner and N-heterocyclic carbene (NHC) ligand precursor. Mechanistic studies reveal that consecutive steps of migratory insertion of the NHC into the aryl C-Ni bond and ß-C elimination might be involved in the proposed reaction mechanism.