Therapy Research Articles

Immunotherapy for MSI-H colorectal cancer with isolated peritoneal metastases.

187 Background: NCCN guidelines recommend immunotherapy for MSI-H colon cancer (CC) with isolated peritoneal metastases (iPM); however, limited data support its benefit. This study aimed to evaluate the impact of immunotherapy in this population. Methods: Patients diagnosed with MSI-H CC with iPM from 2016-2019 were selected from the NCDB. Patients who received immunotherapy were compared to those who did not. Overall survival was assessed using Kaplan-Meier analysis and multivariate Cox proportional hazard regression. The trend of immunotherapy utilization from 2016-2020 was analyzed using the Cochran-Armitage test. Results: We analyzed a cohort of 444 patients, with 161 (36%) receiving immunotherapy. Patients in the immunotherapy group were, on average, younger (63 vs. 71 years; P<0.001), with balanced gender distribution between groups. Among those who received immunotherapy, 70% were treated as a first-line agent, and 30% after chemotherapy. Immunotherapy was more commonly administered in the adjuvant setting (66%) compared to neoadjuvant (7%) or without surgery (27%). Immunotherapy was associated with significantly longer median survival (33.6 vs. 14.9 months; P<0.001). In multivariate analysis, immunotherapy was associated with improved overall survival, whether given as a first-line agent (HR 0.54, 95% CI 0.39-0.74; P<0.001) or second-line after chemotherapy (HR 0.59, 95% CI 0.37-0.94; P=0.03). Additionally, primary tumor resection (HR 0.44, 95% CI 0.32-0.60; P<0.001), but not metastatectomy (HR 0.96, 95% CI 0.71-1.29; P=0.8), was associated with prolonged survival. Patients who received both immunotherapy and primary tumor resection (n=118) had a median survival of 43.8 months. From 2016 to 2020, the utilization of immunotherapy in this cohort increased from 29% to 37% (χ^2=0.23, P=0.63). Conclusions: Utilization of immunotherapy remains low in MSI-H CRC with iPM and did not change significantly during the study period. Immunotherapy is associated with improved overall survival and should be considered for appropriate candidates. The combination of primary tumor resection and immunotherapy yielded the best overall survival.

Intelligent Drug Delivery: Pioneering Stimuli-Responsive Systems to Revolutionize Disease Management- An In-depth Exploration.

In recent years, there has been an escalating interest in stimuli-responsive drug delivery systems (SRDDS) due to their ability to revolutionize the delivery of therapeutics. SRDDSs offer a multitude of benefits in comparison to conventional drug delivery systems (DDS), including spatiotemporal control of drug release, targeted delivery, and improved therapeutic efficacy. The development of various classes of stimuli-responsive DDS, such as pH-responsive, temperature-responsive, photo-responsive, redox responsive systems, has been propelled by advances in materials science, nanotechnology, and biotechnology. These systems exploit specific environmental or physiological cues to trigger drug release in a precisely controlled manner, making them highly promising for the treatment of various diseases. In this review article, an in-depth exploration of the principles, mechanisms, and applications of SRDDS in the context of diverse pathologies such as cancer, arthritis, Alzheimer's disease, atherosclerosis and tissue engineering has been provided. Furthermore, this article delves into the discussion of recent patents, market overview and the progress of research in clinical trials. Overall, this article underscores the transformative potential of SRDDS in enabling personalized, precise, and effective drug delivery for the treatment of the above-mentioned diseases.

KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the first KDIGO guideline on this subject. Its scope includes nomenclature, diagnosis, prognosis, and prevalence; kidney manifestations; chronic kidney disease (CKD) management and progression, kidney failure, and kidney replacement therapy; therapies to delay progression of kidney disease; polycystic liver disease; intracranial aneurysms and other extrarenal manifestations; lifestyle and psychosocial aspects; pregnancy and reproductive issues; pediatric issues; and approaches to the management of people with ADPKD. The guideline has been developed with patient partners, clinicians, and researchers around the world, with the goal to generate a useful resource for healthcare providers and patients by providing actionable recommendations. The development of this guideline followed an explicit process of evidence review and appraisal, based on a rigorous, formal systematic literature review. The strength of recommendations follows the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The guideline also provides practice points serving to direct clinical care or activities relating to areas for which a systematic review was not conducted. Limitations of the evidence are discussed. Research recommendations to address gaps in knowledge, and implications for policy and payment, are provided. The guideline targets a broad audience of healthcare providers, people living with ADPKD, and stakeholders involved in the various aspects of ADPKD care.

Video conferencing algorithms for enhanced access to mental healthcare services in cloud-powered telepsychiatry

Exploring the video conferencing algorithms for cloud-powered telepsychiatry to improve mental healthcare access. The goal is to evaluate and optimise these algorithms' latency, bandwidth utilisation, packet loss, and jitter across worldwide locations. To provide a smooth and high-quality virtual consultation between patients and mental health providers. Using performance data to identify areas for development, the effort aims to lower technological hurdles and increase telepsychiatry session dependability. Findings will help create strong, efficient algorithms that can handle different network situations, increasing patient outcomes and extending mental healthcare services. In the 1st instance latent analysis in a sample of 5 cities, the average latency (ms) is 45, the peak latency is 120, the off-peak latency is 30, and the packet loss is 0.5. In another instance, bandwidth utilisation in a sample of 5 sessions ranged from 30 to 120 minutes, with data supplied in MB - 150-600 and received in MB - 160-620, with average bandwidth (Mbps) - 5-15 and maximum bandwidth: 10-20.

Clinical characteristics and treatment outcomes for metastatic early-onset small bowel adenocarcinoma treated with first-line chemotherapy.

796 Background: Small bowel adenocarcinoma (SBA) is an aggressive rare cancer with its incidence on the rise. Although early-onset SBA (EO-SBA: diagnosed at < 50 years old) accounts for approximately 10% of all SBA, characteristics and survival outcomes of advanced EO-SBA remains under-evaluated. This study aims to evaluate clinical features and treatment outcomes of patients with advanced EO-SBA receiving first-line chemotherapy. Methods: We retrospectively analyzed the clinical data of patients who received fluoropyrimidine plus oxaliplatin as first-line treatment for recurrent or metastatic SBA at our hospital between January 2012 and July 2024 Patients were divided into two groups: those who were diagnosed at age of < 50 years old (EO-SBA) and those who were diagnosed at age of ≥50 years old (late-onset SBA, LO-SBA). Clinicopathological characteristics and treatment outcomes (objective response rate [ORR], progression-free survival [PFS], overall survival [OS], and adverse events [AEs]) were compared between two groups. Survival outcomes were estimated using the Kaplan–Meier method and compared by the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were calculated by univariable and multivariable Cox regression analyses. Results: A total of 69 patients (EO-SBA 18, LO-SBA 51) were included in this study. Compared to the LO-SBA group, the EO-SBA group were more likely to have non-duodenum tumor (89% vs. 49%, p = 0.002), lesser number of metastatic sites (≤2, 100% vs.78%, p = 0.007), and prior resection of primary tumor (83% vs 49%, p = 0.008). The EO-SBA group had longer PFS compared to the LO-SBA group (median PFS: HR = 0.32 [95% CI 0.12 - 0.85] p = 0.022). The EO-SBA group had a trend of longer OS compared to the LO-SBA group (median OS: HR = 0.39 [95%CI 0.15 - 1.01] p = 0.053). Age group was not identified as an independent prognostic factor for OS (HR = 0.63 [95% CI: 0.21 - 1.85], p = 0.40) and PFS (HR = 0.47 [95% CI: 0.16 - 1.37], p = 0.17) by multivariable analyses adjusted for previously reported prognostic factors (performance status, liver metastasis, primary site, histological classification, prior resection of primary tumor, and carcinoembryonic antigen [CEA] elevation). Among patients with measurable lesions (EO-SBA 9, LO-SBA 41), the EO-SBA group showed a numerically higher ORR compared with the LO-SBA group (63% vs 29%, p = 0.07). There were no significant differences of AE frequencies between two groups except for anemia (grade 3/4. EO-SBA 0% vs LO-SBA 22%, p < 0.001). Conclusions: Our study indicates the difference of clinical characteristics between two age groups in patients with advanced SBA. EO-SBA was not identified as independent prognostic factor for OS and PFS in patients treated with first-line chemotherapy.

Giardia duodenalis flavohemoglobin is a target of 5-nitroheterocycle and benzimidazole compounds acting as enzymatic inhibitors or subversive substrates.

Giardia duodenalis causes giardiasis in humans, companion, livestock and wild animals. Control of infection involves drugs as benzimidazoles (e.g., albendazole, ABZ) and 5-nitroheterocyclics [5-NHs: metronidazole (MTZ), furazolidone (FZD), nitazoxanide (NTZ)] as first-line agents. During infection, Giardia is exposed to immune and pro-oxidant host responses involving nitric oxide (NO). In Giardia, NO is detoxified by a flavohemoglobin (gFlHb), a heme-containing enzyme which is absent in mammals. gFlHb has NO dioxygenase and NADH oxidase activities converting NO into nitrate and producing a superoxide anion (O2•-) that causes oxidative stress and parasite death. The modulation of gFlHb activities may provide novel approaches for treatment of giardiasis. We investigated the capacity of selected benzimidazole-2-carbamates (BZCs: ABZ, oxibendazole, nocodazole), non-BZCs (thiabendazole), an ehtylphenylcarbamate (LQM-996) and 5-NHs (MTZ, NTZ, FZD and some derivatives) to bind to recombinant gFlHb at the heme group, modifying NADH consumption activity and/or inducing ROS production. Of these, BZCs and NTZ bind to heme and increased O2•- production (i.e. caused enzyme subversion), whereas MTZ binds to heme but inhibited NADH consumption. LQM-996 decreased NADH consumption and two out of four NTZ derivatives altered NADH oxidase activity. In silico docking and molecular dynamics studies suggested the interaction of distinct drug moieties in ABZ and NTZ with gFlHb sites involved in NADH and NO catalysis. These findings provide new insights on gFlHb as a novel target of BZCs, MTZ and NTZ, and provides a useful platform to assess the compounds binding capacity to gFlHb prior to experimental and clinical trials in giardiasis.

A Multicenter Evaluation of the Impact of Therapies on Deep Learning-based Electrocardiographic Hypertrophic Cardiomyopathy Markers

Artificial intelligence-enhanced electrocardiography (AI-ECG) can identify hypertrophic cardiomyopathy (HCM) on 12-lead ECGs and offers a novel way to monitor treatment response. Although the surgical or percutaneous reduction of the interventricular septum (SRT) represented initial HCM therapies, mavacamten offers an oral alternative. We aimed to assess the use of AI-ECG as a strategy to evaluate biologic responses to SRT and mavacamten. We applied an AI-ECG model for HCM detection to electrocardiography images from patients who underwent SRT across 3 sites: Yale New Haven Health System (YNHHS), Cleveland Clinic Foundation (CCF), and Atlantic Health System (AHS) and to electrocardiography images from patients receiving mavacamten at YNHHS. A total of 70 patients underwent SRT at YNHHS, 100 at CCF, and 145 at AHS. At YNHHS, there was no significant change in the AI-ECG HCM score before versus after SRT (before SRT: median 0.55 [interquartile range 0.24 to 0.77] vs after SRT: 0.59 [0.40 to 0.75]). The AI-ECG HCM scores also did not improve after SRT at CCF (0.61 [0.32 to 0.79] vs 0.69 [0.52 to 0.79]) and AHS (0.52 [0.35 to 0.69] vs 0.61 [0.49 to 0.70]). Of the 36 YNHHS patients on mavacamten therapy, the median AI-ECG score before starting mavacamten was 0.41 (0.22 to 0.77), which decreased significantly to 0.28 (0.11 to 0.50, p <0.001 by Wilcoxon signed-rank test) at the end of a median follow-up period of 237 days. In conclusion, we observed a lack of improvement in AI-based HCM score with SRT, in contrast to a significant decrease with mavacamten. Our approach suggests the potential role of AI-ECG for serial point-of-care monitoring of pathophysiologic improvement after medical therapy in HCM using ECG images.

Perioperative and long-term outcomes of bilateral cardiac sympathetic denervation via video-assisted thoracoscopic surgery in patients with refractory ventricular arrhythmias.

Bilateral cardiac sympathetic denervation (CSD) performed via video-assisted thoracoscopic (VAT) surgery shows potential in managing ventricular tachycardia (VT), thereby reducing arrhythmic burden. In this setting, the scarcity of studies addressing both perioperative and long-term outcomes creates a substantial gap in the optimal management of patients with multiple comorbidities and limited treatment options. This observational study aimed to assess the medical comorbidities, as well as the short- and long-term outcomes of patients who underwent CSD for VT refractory to catheter ablation and medical therapy at a referral tertiary teaching hospital. We retrospectively analyzed data of all patients with VT who underwent bilateral CSD-VAT surgery at a single center. Unadjusted Kaplan-Meier survival curves were generated to analyze the survival rates at 1-year and 2-years following the procedure. Ten consecutive patients were unrolled between August 2014 and March 2024. Bilateral CSD-VAT surgery was successfully performed in all patients. Pre-operative ejection fraction was 33% (26-41). Two patients (22%) suffered cardiogenic shock and 1 vasoplegia. Half (50%) of the patients necessitated inotrope/vasopressor support and 1 an intra-aortic balloon pump. Median hospital stay was 12 (9-19) days. Three (33%) patients required postoperative ICU admission. All patients were alive upon hospital discharge. Neither major surgical complications nor complications typically associated with VAT-CSD (e.g., Horner's syndrome) were observed. The 1-year survival was 80% while the survival at 24months was 60%. CSD-VAT is a feasible rescue treatment in patients with refractory VT and is associated with limited intra- and postoperative complications alongside an acceptable long-term survival rate.

The effect of tonsillectomy on clinical manifestations in Familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most prevalent genetic autoinflammatory disease worldwide. There are several novel advancements in pathophysiology, genetic testing, diagnosis, comorbidities, disease-related damage, and treatment strategies. This study aimed to assess the effect of tonsillectomy on FMF disease severity and activity. This prospective randomized cohort study was conducted on 43 patients diagnosed with FMF and chronic tonsillitis, who were divided randomly into two groups: Group I, a case group including 23 patients subjected to tonsillectomy and medical treatment using colchicine; Group II, a control group consisting of 20 cases receiving only colchicine. The monthly frequency of the attacks and average duration of the three symptoms, such as fever, abdominal/chest pain, and musculoskeletal pain in days, were evaluated and recorded. A highly significant reduction in the monthly frequency of attacks, duration of fever, abdominal/chest pain, and musculoskeletal pain was observed three months after management in both study groups (p<0.00001 for all). Evaluation of the values of both groups revealed a significant increase in the degree of change for the duration of fever, abdominal/chest pain in Group I relative to Group II (p=0.0003 and 0.006 respectively) and a significant increase in the degree of change for musculoskeletal pain in Group II relative to Group I (p=0.007). Survival analysis showed a nonsignificant difference between the two groups regarding the resolution of fever, abdominal/chest pain, and musculoskeletal pain at 12, 18, and 24 months (p=0.26, 0.08, and 0.42, respectively) CONCLUSION: Tonsillectomy operation combined with colchicine resulted in a greater but nonsignificant decrease in the monthly frequency of the FMF attacks and a significant greater decrease in the duration of fever and abdominal/chest pain compared with the use of colchicine alone. Further research is recommended to confirm these results on a larger scale.

Effects of Exercise Training on the Bone Marrow Immune Microenvironment and Minimal Residual Disease in Multiple Myeloma Patients Following First-Line Treatment.

The purpose of the study was to investigate the effects of exercise training on the bone marrow immune microenvironment and on minimal residual disease of multiple myeloma patients who completed first-line induction treatment. Eight multiple myeloma patients underwent 5 months of exercise training along with standard medical treatment. Eight age- and sex-matched patients who received medical treatment only, served as controls. Before and after the intervention, white blood cells, red blood cells, and platelets, as well as the percentages of neutrophils, lymphocytes, monocytes, eosinophils, and basophils, were measured in the peripheral blood. Abnormal plasma cells, normal plasma cells, B cells, T cells, NK/NKT cells, monocytes, neutrophils, eosinophils, basophils, mast cells, myeloid progenitors, erythroid progenitors, and erythroblasts were assessed in the bone marrow. Exercise training increased the percentage of blood monocytes (mean difference 3.5% ± 2.6%; p = 0.006), while no change was detected in the control group. In the bone marrow, the CD27+ T cell subset increased (mean difference 18.2% ± 21.9%; p = 0.043) and the ratio of CD27-/CD27+ T lymphocytes decreased (pre: 1.06 ± 0.59; post: 0.76 ± 0.47; p = 0.049) in the exercise group, but remained unaltered in the control group. In conclusion, the study provides evidence that 5 months of exercise training can induce an increase in the percentage of activated T lymphocytes, as shown by the higher expression of the costimulatory CD27 marker. It also suggests that exercise-induced changes in the bone marrow microenvironment may be beneficial in the control of clonal cell proliferation.

Assessing impact of postoperative outcomes and quality of life on decisional regret after resection of pancreatic ductal adenocarcinoma.

699 Background: Surgery is potentially curative for patients with localized pancreatic ductal adenocarcinoma (PDAC). Given the high rate of complications, decline in quality of life (QoL) postoperatively, and high rates of recurrence, clear preoperative communication and expectation setting is critical. This study investigates clinical outcomes that affect postoperative decisional regret (DR) in patients with PDAC. Methods: This mixed-methods study investigates the impact of clinical outcomes and QoL on the degree of DR in patients with PDAC who have undergone curative-intent resection at least 6 months prior to study recruitment. Patients completed validated surveys assessing DR and QoL by the European Organization for Research and Treatment of Cancer (EORTC). Groups are stratified by presence or absence of DR, assessed by the Decisional Regret Scale (DRS). Characteristics and survey scores were compared by chi-square, independent t-test, and median test. Narrative responses were thematically analyzed. Given significant findings, results of this interim analysis are reported below. Results: 45 patients met inclusion criteria and completed all questionnaires. 19 (42.2%) patients expressed regret about their decision to pursue curative-intent surgery, with 5 patients expressing moderate to severe regret (DRS ≥ 25). There was no significant difference in median postoperative timing of survey completion between groups (56 months in DR group vs 34 months, P=0.465). Baseline characteristics, medical treatments, and operative approaches were similar. Both groups had similar recurrence rates at time of survey completion. While 30 and 90 day readmission rates were similar, a greater proportion of the DR group had 30 day complications (42.1% vs 15.4%, P=0.045). Those expressing regret reported poorer physical functional status (mean score 79.30 ± 18.84 vs 92.31 ± 10.27, P=0.011) and greater impact on social activities (mean score 67.54 ± 33.55 vs 84.67 ± 19.19, P=0.038). Thematic analysis of narrative responses revealed that a majority of patients expressed a strong desire to have a greater focus on potential QoL changes during preoperative discussions. Conclusions: Patients expressing postoperative DR experienced more 30 day complications, and still report lasting effects on their current physical status and social activities. This emphasizes the importance of thorough preoperative counseling on surgical risks and potential changes in postoperative QoL so that patients may make the best informed decision.

Survival of radioiodine treated hyperthyroid cats that are euthyroid and hypothyroid after treatment, and effect of levothyroxine supplementation on survival time of cats with iatrogenic hypothyroidism.

Hyperthyroid cats that are azotemic and hypothyroid after surgical or medical treatment have poor outcomes, and supplementation with levothyroxine (LT4) improves survival. However, the effect of LT4 supplementation on survival of nonazotemic, hypothyroid radioiodine (RI)-treated hyperthyroid cats is unknown. Radioiodine treated hyperthyroid cats with iatrogenic hypothyroidism or azotemia have shorter survival times than euthyroid, nonazotemic cats and supplementation of LT4 improves survival times of hypothyroid cats. One hundred seventeen RI treated hyperthyroid cats. Prospective cohort study. Radioiodine treated cats were screened for azotemia and iatrogenic hypothyroidism using TSH stimulation test; LT4 supplementation was offered to all hypothyroid cats with decision to treat based on owner preference. The log rank test was used to compare survival times between groups, and the Mann-Whitney U test was used to compare age and renal variables. Data are presented as median [range]. Euthyroid azotemic cats (934 [759-2035] days) and nonsupplemented hypothyroid cats (azotemic and nonazotemic combined, 1232 [238-2363] days) had shorter survival times than euthyroid nonazotemic cats (1616 [663-3369] days, P = .003 and P = .002, respectively). Levothyroxine supplemented hypothyroid nonazotemic cats had longer survival times than nonsupplemented hypothyroid nonazotemic cats (1037 [300-2401] days vs 768 [34-1014] days; P = .027). Levothyroxine supplementation was not associated with prolonged survival times in hypothyroid azotemic cats vs nonsupplemented hypothyroid azotemic cats (771 [718-1558] days vs 152 [82-1852] days, respectively, P = .991). Levothyroxine supplementation in nonazotemic cats with iatrogenic hypothyroidism (diagnosed based on TSH stimulation test results) improved survival times, although randomized controlled trials are needed.

Patient-derived xenograft model in cancer: establishment and applications.

The patient-derived xenograft (PDX) model is a crucial in vivo model extensively employed in cancer research that has been shown to maintain the genomic characteristics and pathological structure of patients across various subtypes, metastatic, and diverse treatment histories. Various treatment strategies utilized in PDX models can offer valuable insights into the mechanisms of tumor progression, drug resistance, and the development of novel therapies. This review provides a comprehensive overview of the establishment and applications of PDX models. We present an overview of the history and current status of PDX models, elucidate the diverse construction methodologies employed for different tumors, and conduct a comparative analysis to highlight the distinct advantages and limitations of this model in relation to other in vivo models. The applications are elucidated in the domain of comprehending the mechanisms underlying tumor development and cancer therapy, which highlights broad applications in the fields of chemotherapy, targeted therapy, delivery systems, combination therapy, antibody-drug conjugates and radiotherapy. Furthermore, the combination of the PDX model with multiomics and single-cell analyses for cancer research has also been emphasized. The application of the PDX model in clinical treatment and personalized medicine is additionally emphasized.

Downregulation of LncRNA CCAT1 Enhances Chemosensitivity in Cisplatin-Resistant Gastric Cancer Cells.

Chemotherapy is an effective treatment for gastric cancer. However, many patients develop resistance to chemotherapeutic agents during clinical treatment. LncRNA CCAT1 has recently been shown to influence cellular resistance to specific chemotherapeutic drugs, but its role in gastric cancer remains underexplored. This study aims to investigate the role of LncRNA CCAT1 in cisplatin resistance in gastric cancer cells and its potential underlying mechanisms. Gastric cancer cell lines with acquired resistance were established. The expression of CCAT1 was assessed in both cisplatin-sensitive and cisplatin-resistant AGS cell lines. CCAT1 expression was knocked down in AGS/DDP cells, and the changes in IC50 values were measured using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in gastric cancer cells was evaluated by flow cytometry. Additionally, Western blotting was employed to measure the expression levels of PI3K/AKT/mTORsignaling pathway proteins and apoptosis-related proteins in both interference and control groups. RT-qPCR results indicated that CCAT1 expression was significantly elevated in cisplatin-resistant gastric cancer cells compared to non-resistant cells. Similarly, CCK-8 assay results demonstrated that knocking down CCAT1 in resistant cells increased their sensitivity to cisplatin treatment. Flow cytometry and Western blot results further confirmed that silencing CCAT1 promoted apoptosis in these cells. Additionally, the expression of PI3K/AKT/mTORsignaling pathway proteins was higher in resistant cells compared to their sensitive counterparts, and silencing CCAT1 in AGS/DDP cells resulted in reduced expression of these proteins. In conclusion, the above studies demonstrated that LncRNA CCAT1 induced cisplatin resistance in gastric cancer cells.

Study progress of etiologic mechanisms of chronic prostatitis/chronic pelvic pain syndrome.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) represents a prevalent condition within the male genitourinary system. CP/CPPS occurs in men of varying ages, with an increasing recurrence rate associated with advancing age. The pathogenesis of CP/CPPS remains unclear, and clinical treatment typically focuses on symptom management with limited efficacy, resulting in significant economic and psychological burdens for patients. Research has increasingly identified several factors potentially associated with the development of CP/CPPS, including lifestyle, psychosocial influences, neuroendocrine elements, and other variables. This paper reviews recent studies on the risk factors and etiological mechanisms of CP/CPPS to enhance understanding of its mechanisms, providing a reference framework for future basic research and clinical diagnosis and treatment.

Real-time mechanism-based interventions for daily alcohol challenges: Protocol for ecological momentary assessment and intervention.

Advancing evidence-based, tailored interventions for substance use disorders (SUDs) requires understanding temporal directionality while upholding ecological validity. Previous studies identified loneliness and craving as pivotal factors associated with alcohol consumption, yet the precise directionality of these relationships remains ambiguous. This study aims to establish a smartphone-based real-life intervention platform that integrates momentary assessment and intervention into everyday life. The platform will explore the temporal directionality of contextual influences on alcohol use among individuals experiencing loneliness and craving. We will target 180 individuals aged 18 to 70 in Germany who report loneliness, alcohol cravings, and meet risk or binge drinking criteria (over 14 standard drinks per week or five drinks in a single day for males, and over seven drinks per week or four drinks in a single day for females). Using a Within-Person-Encouragement-Design and Just-In-Time-Adaptive-Interventions, we will manipulate the contexts of loneliness and alcohol craving with cognitive reappraisal and physical activity interventions against a control condition (working memory task). Recruitment started in June 2024, with data collection and processing expected by June 2027. Our real-life intervention platform endeavors to serve as a robust tool for discerning the directionality of the effects from time series data in everyday life influences on alcohol use for the future study. Ultimately, it will pave the way for low-threshold prevention, clinical treatment, and therapy to target diverse contexts of everyday life in SUD. German Clinical Trials Register DRKS00033133.

Exploring the Therapeutic Potential of Lupeol: A Review of Its Mechanisms, Clinical Applications, and Advances in Bioavailability Enhancement.

Lupeol, a naturally occurring triterpenoid, has garnered significant attention for its diverse range of biological activities and potential therapeutic applications. This comprehensive review delves into the various aspects of lupeol, including its sources, extraction methods, chemical characteristics, pharmacokinetics, safety evaluation, mechanisms of action, and applications in disease treatment. We highlight the compound's unique carbon skeleton and its role in inflammation regulation, antioxidant activity, and broad-spectrum antimicrobial effects. The review also underscores lupeol's potential in cancer therapy, cardiovascular protection, metabolic disease management, and wound healing. Furthermore, we discuss the challenges and future perspectives of lupeol's clinical application, emphasizing the need for further research to improve its bioavailability and explore its full therapeutic potential. The review concludes by recognizing the significance of lupeol in drug development and healthcare, with expectations for future breakthroughs in medical applications.

Design, synthesis, and evaluation of novel benzofuran and pyrazole-based derivatives as dual AChE/BuChE inhibitors with antioxidant properties for Alzheimer's disease management.

As a complicated neurodegenerative disorder with several clinical hallmarks, Alzheimer's disease (AD) requires multi-target treatment medicines to address multiple elements of disease progression. In this study, we reported two novel series of compounds: benzofuran-based donepezil analogs (9a-i) and their pyrazole-based counterparts (11a-i) as potential dual inhibitors of AChE and BuChE with additional antioxidant properties, aiming to address multiple pathological aspects of AD simultaneously. The design strategy employed bioisosteric replacement, substituting donepezil's indanone motif with a benzofuran ring in series (9a-i) to maintain crucial hydrogen bonding interactions with the Phe295 residue in the enzyme's active site. Subsequently, the benzofuran ring underwent cleavage, yielding pyrazole-tethered hydroxyphenyl derivatives (11a-i). The biological evaluation revealed that benzofuran-based derivative 9g exhibited exceptional efficacy against both AChE and BuChE, with IC50 values of 0.39 and 0.51μg/ml, respectively, although it lacked antioxidant activity. Compound 11f demonstrated dual inhibition of AChE (IC50=1.24μg/ml) and BuChE (IC50=1.85μg/ml) while also displaying strong DPPH free radical scavenging activity (IC50=3.15μg/ml). In vivo toxicity studies on compound 11f revealed a favorable safety profile, with no signs of toxicity or adverse events in acute oral toxicity tests in male Wistar rats. Chronic administration of 11f resulted in negligible differences in blood profiles, hepatic enzymes, urea, creatinine, and albumin levels compared to the control group. Histopathological examination of hepatic and kidney tissues from treated rats showed normal histology without damage. In silico molecular docking analysis was performed to rationalize the design approaches and support the experimental findings. This study provides valuable insights into the development of multi-target compounds for potential Alzheimer's disease treatment.

The Renoprotective and Anti-Inflammatory Effects of Human Urine-Derived Stem Cells on Acute Kidney Injury Animals.

Acute Kidney Injury (AKI) is defined as a sudden loss of kidney function, which is often caused by drugs, toxins, and infections. The large spectrum of AKI implies diverse pathophysiological mechanisms. In many cases, AKI can be lethal, and kidney replacement therapy is frequently needed. However, current treatments are not satisfying. Developing novel therapies for AKI is essential. Adult stem cells possess regenerative ability and play an important role in medical research and disease treatment. In this study, we isolated and characterized a distinct human urine-derived stem cell, which expressed both proximal tubular cell and mesenchymal stem cell genes as well as certain unique genes. It was found that these cells exhibited robust protective effects on tubular cells and anti- inflammatory effects on macrophages in vitro. In an ischemia-reperfusion-induced acute kidney injury NOD-SCID mouse model, transplantation of USCs significantly protected the kidney morphology and functions in vivo. In summary, our results highlighted the effectiveness of USCs in protecting from PTC injury and impeding macrophage polarization, as well as the secretion of pro-inflammatory interleukins, suggesting the potential of USCs as a novel cell therapy in AKI.

Fruquintinib combined with PD-1 inhibitors and chemotherapy in the first-line treatment of HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma (FDZL-FIX): A single-arm, open-label phase 2 study.

461 Background: For unresectable locally advanced or metastatic HER2-negative gastric cancer (GC), the combination of chemotherapy with immunotherapy, specifically PD-1 inhibitors, has emerged as a new standard of care in first-line treatment of advanced GC, but the patients’ outcomes remain poor. Early clinical studies investigating the combination of immunotherapy with anti-angiogenic drugs have demonstrated favorable efficacy. Therefore, it is worth exploring whether the addition of fruquintinib, a potent VEGFR-1,2,3 inhibitor, to the combination of PD-1 inhibitor and chemotherapy can further enhance the survival benefits for patients with unresectable locally advanced or metastatic HER2-negative GC. Methods: This is an open-label, single-center clinical study. The enrolled patients were all no less than 18 years old with HER2 negative locally advanced unresectable or metastatic gastric or gastrooesophageal junction adenocarcinoma, without any systemic anticancer treatment for advanced disease. Eligible patients received 6 cycles of combined first line treatment with fuquinitinib (4mg daily, d1-14, q3w, oral) combined with PD-1 inhibitor (sintilimab 200mg or nivolumab 360mg intravenously q3w) and chemotherapy (XELOX or SOX) regimen. The following maintenance treatment was fuquinitinib combined with PD-1 inhibitor and S-1/capecitabine until disease progression or intolerable toxicity. The primary endpoint was progress free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. Results: At the cutoff date on Sep 18, 2024, a total of 27 patients were enrolled and received at least one dose of treatment. 23 patients had received the response evaluation, with an ORR of 60.9% (14/23; 95%CI 38.5-80.3) and DCR of 100% (23/23 95%CI 85.2-100.0). In the intention to treatment (ITT) population, the median PFS was 9.79 months (95% CI 5.29-NA). Safety profile indicated that 22.2% (6/27) experienced grade≥3 adverse events. The most common grade ≥ 3 adverse reactions mainly include neutropenia (7.4%, 2/27) and thrombocytopenia (7.4%%, 2/27). Conclusions: The combination of fruquintinib and chemotherapy with PD-1 blockade in the first-line treatment for unresectable locally advanced or metastatic HER2-negative GC had shown promising efficacy and acceptable safety profile. Enrollment in the trials is still ongoing. Clinical trial information: NCT06158919 .