Cinobufacini enhances the therapeutic response of 5-Fluorouracil against gastric cancer by targeting cancer stem cells via AKT/GSK-3ß/ß-catenin signaling axis.

BACKGROUND: Gastric cancer stem cells (GCSCs) play crucial role in the development, recurrence, and resistance of gastric cancer (GC). Cinobufacini, a traditional Chinese medicine, offers significant advantages in improving tumor therapy. However, pre-clinical investigation into the antitumor effect and mechanism of Cinobufacini on GC is still lacking. Additionally, it has not been reported whether Cinobufacini is related to cancer stem cells (CSCs). METHODS: The CCK-8, clone formation, EdU staining, transwell and wound healing experiments were performed to assess the cell toxicity of Cinobufacini and demonstrate the preventive effects of Cinobufacini on proliferation, invasion, and migration of GC cells. Elucidating the underlying mechanism of Cinobufacini in GC based on the transcriptome sequencing. Flow cytometry assays, sphere formation assays, subcutaneous xenograft model in nude mice, and immunofluorescent staining have been used to investigate whether the anti-GC effect of Cinobufacini is associated with GCSCs and enhancing therapeutic response to 5-Fluorouracil (5-FU). RESULTS: Cinobufacini exerts minimal impact on normal human gastric epithelium cell GES-1, while significantly suppressing the proliferation, invasion, and migration of GC cell lines. Additionally, Cinobufacini attenuates the stemness of GCSCs by disrupting the AKT/GSK-3ß/ß-catenin signaling cascade. Moreover, Cinobufacin enhances the anti-tumor effects of 5-FU against GCSCs by reducing in vitro sphere formation and inhibiting subcutaneous graft tumor growth in vivo. CONCLUSIONS: Cinobufacini enhances the therapeutic response of 5-FU against GC by targeting CSCs via AKT/GSK-3ß/ß-catenin signaling axis. Our findings offer a crucial insight into the molecular mechanism of Cinobufacini's anticancer activity in GC.

Aptamer-mediated therapeutic strategies provide a potential approach for cancer.

The treatment of tumors still faces considerable challenges. While conventional treatments such as surgery, chemotherapy, and radiation therapy provide some curative effects, their side effects and limitations highlight the importance of finding more precise treatment strategies. Aptamers have become an important target molecule in the field of drug delivery systems due to their good affinity and targeting, and they have gradually become an important link from basic research to clinical application. In this paper, we discussed the latest progress of aptamer-mediated nanodrugs, as well as aptamer-mediated photodynamic therapy, photothermal therapy, and immunotherapy strategies for tumor treatment, and explored the possibility of aptamer-mediated therapy for accurate tumor treatment. The purpose of this review is to provide novel insights for treating tumors with aptamer-mediated therapies by summarizing these innovative strategies, thereby ultimately enhancing the therapeutic efficacy for cancer patients.

Association between weight-adjusted waist index and non-alcoholic fatty liver disease: a population-based study.

BACKGROUND: Obesity is the most important driver of non-alcoholic fatty liver disease (NAFLD); nevertheless, the relationship of weight-adjusted waist index (WWI), a new obesity index, with NAFLD is unclear. METHODS: This retrospective study used data from the NAGALA project from 1994 to 2016. WWI values were calculated using waist circumference (WC) and weight measurements of the participants. Three stepwise adjusted logistic regression models were developed to assess the relationship of WWI with NAFLD in the whole population and in both sexes. Additionally, we also conducted a series of exploratory analysis to test the potential impact of body mass index (BMI), age, smoking status and exercise habits on the association of WWI with NAFLD. Receiver operating characteristic (ROC) curves were used to estimate cut-off points for identifying NAFLD in the entire population and in both sexes. RESULTS: The current study included a population of 11,805 individuals who participated in health screenings, including 6,451 men and 5,354 women. After adjusting for all non-collinear variables in the multivariable logistic regression model, we found a significant positive correlation of WWI with NAFLD. For each unit increase in WWI, the risk of NAFLD increased by 72% in the entire population, by 84% in men, and by 63% in women. Furthermore, subgroup analyses revealed no significant discrepancies in the correlation of WWI with NAFLD across individuals with varying ages, exercise habits, and smoking status (all P-interaction > 0.05), except for different BMI groups (P-interaction < 0.05). Specifically, compared to the overweight/obese group, the relationship of WWI with NAFLD was significantly stronger in the non-obese group, especially in non-obese men. Finally, based on the results of ROC analysis, we determined that the WWI cut-off point used to identify NAFLD was 9.7675 in men and 9.9987 in women. CONCLUSIONS: This study is the first to establish a positive correlation between WWI and NAFLD. Moreover, assessing the influence of WWI on NAFLD in individuals without obesity may yield more valuable insights compared to those who are overweight or obese.

Advances in the research of exosomes in renal cell carcinoma: from mechanisms to applications.

Renal cell carcinoma (RCC) is one of the most malignant urological tumors. Currently, there is a lack of molecular markers for early diagnosis of RCC. The 5-year survival rate for early-stage RCC is generally favorable; however, the prognosis takes a significant downturn when the tumor progresses to distant metastasis. Therefore, the identification of molecular markers for RCC is crucial in enhancing early diagnosis rates. Exosomes are a type of extracellular vesicle (EV) typically ranging in size from 30 nm to 150 nm, which contain RNA, DNA, proteins, lipids, etc. They can impact neighboring receptor cells through the autocrine or paracrine pathway, influence cellular communication, and regulate the local immune cells, consequently shaping the tumor immune microenvironment and closely associating with tumor development. The clinical application of exosomes as tumor markers and therapeutic targets has ignited significant interest within the research community. This review aims to provide a comprehensive summary of the advancements in exosome research within the context of RCC.

Advances and challenges in the treatment of lung cancer.

Lung cancer accounts for a relatively high proportion of malignant tumors. As the most prevalent type of lung cancer, non-small cell lung cancer (NSCLC) is characterized by high morbidity and mortality. Presently, the arsenal of treatment strategies encompasses surgical resection, chemotherapy, targeted therapy and radiotherapy. However, despite these options, the prognosis remains distressingly poor with a low 5-year survival rate. Therefore, it is urgent to pursue a paradigm shift in treatment methodologies. In recent years, the advent of sophisticated biotechnologies and interdisciplinary integration has provided innovative approaches for the treatment of lung cancer. This article reviews the cutting-edge developments in the nano drug delivery system, molecular targeted treatment system, photothermal treatment strategy, and immunotherapy for lung cancer. Overall, by systematically summarizing and critically analyzing the latest progress and current challenges in these treatment strategies of lung cancer, we aim to provide a theoretical basis for the development of novel drugs for lung cancer treatment, and thus improve the therapeutic outcomes for lung cancer patients.

Cancer immunotherapies: advances and bottlenecks.

Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.

Advances and Prospects in the Treatment of Pancreatic Cancer.

Pancreatic cancer is a highly malignant and incurable disease, characterized by its aggressive nature and high fatality rate. The most common type is pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis and high mortality rate. Current treatments for pancreatic cancer mainly encompass surgery, chemotherapy, radiotherapy, targeted therapy, and combination regimens. However, despite efforts to improve prognosis, and the 5-year survival rate for pancreatic cancer remains very low. Therefore, it's urgent to explore novel therapeutic approaches. With the rapid development of therapeutic strategies in recent years, new ideas have been provided for treating pancreatic cancer. This review expositions the advancements in nano drug delivery system, molecular targeted drugs, and photo-thermal treatment combined with nanotechnology for pancreatic cancer. It comprehensively analyzes the prospects of combined drug delivery strategies for treating pancreatic cancer, aiming at a deeper understanding of the existing drugs and therapeutic approaches, promoting the development of new therapeutic drugs, and attempting to enhance the therapeutic effect for patients with this disease.

Multiparametric Magnetic Resonance Imaging-based Prostate Specific Antigen Density and PI-RADSv2 score help identify Apical Prostate Cancer.

Objective: To investigate the potential roles of preoperative multiparametric magnetic resonance imaging (mpMRI) in identifying aggressive apical prostate cancer (APCa), thereby helping to facilitate patient counseling and surgical planning. Patients and Methods: We performed a retrospective analysis of 662 patients who underwent radical prostatectomy (RP) between January 2010 to October 2019. All patients underwent a preoperative biopsy and mpMRI of the prostate. APCa was defined as any malignant lesions in the prostatic apex. Clinical, pathological and mpMRI variables were retrieved. Univariate, multivariate, and receiver operating characteristic (ROC) analyses were performed. Results: A total of 214 (32.3%) patients had APCa. Patients presenting APCa were more likely to harbor adverse clinicopathological features (all p < 0.05). On univariable analysis, serum prostate-specific antigen (PSA) (p < 0.001), mpMRI-based PSA density (PSAD) (p < 0.001), Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) score (p < 0.001), number of positive cores (p < 0.001), percentage of positive cores (p < 0.001), max core involvement (p < 0.001) and biopsy GG (p = 0.001) were significant predictors of APCa. On multivariable analysis, mpMRI-based PSAD ≥ 0.27 ng/ml/cm3 (odds ratio [OR]: 2.251, p = 0.003), PI-RADSv2 score > 4 (OR: 1.611, p = 0.023) and percentage of positive cores (OR: 2.333, p = 0.041) were independently predictive of APCa during RP. The AUC values of mpMRI-based PSAD and PI-RADSv2 score were 0.646 (95% Confidence Intervals [CI]: 0.608-0.682) and 0.612 (95% CI: 0.568-0.656), respectively. Conclusion: Preoperative mpMRI-based PSAD and PI-RADSv2 score help identify the presence of APCa and may be useful for surgical decision-making during RP.

Effectiveness and safety of implementing an enhanced patient comfort programme for elective neurosurgical patients: a randomised controlled trial protocol.

INTRODUCTION: Patient comfort is an important quality indicator of healthcare. According to Kolcaba's comfort theory, enhanced comfort is achieved by meeting the needs in four contexts: physical, psychospiritual, sociocultural and environmental. An enhanced patient comfort (EPC) programme based on this theory has been designed for elective neurosurgical patients. This study aims to assess its feasibility, effectiveness and safety. METHODS AND ANALYSIS: The EPC programme patients will be evaluated in a single institutional randomised controlled trial. A total of 110 patients admitted for elective neurosurgery (including craniotomy, endoscopic trans-sphenoidal surgery and spine surgery) will be randomised in a 1:1 ratio to two groups. Patients in the EPC group are managed under the newly developed EPC programme, which aims to enhance patient experience and includes care coordination since admission (such as appointment of a care support coordinator, personalised setting, and cultural and spiritual support), preoperative management (such as lifestyle intervention, potential psychological and sleep intervention, and prerehabilitation), intraoperative and anaesthetic management (such as nurse coaching, music playing, and pre-emptive warming), postoperative management (such as early extubation, early diet advancement, mood and sleep management, and early ambulation) and optimised discharge planning; while those in the control group receive conventional perioperative care. The primary outcome is patient satisfaction and comfort measured by the Chinese Surgical Inpatient Satisfaction and Comfort Questionnaire. The secondary outcomes include postoperative morbidity and mortality, postoperative pain score, postoperative nausea and vomiting, functional recovery status (Karnofsky performance status and Quality of Recovery-15 score), mental status (anxiety and depression), nutritional status, health-related quality of life, hospital length of stay, reoperation and readmission rates, overall cost and patient experience. ETHICS AND DISSEMINATION: Ethical approval to conduct the study has been obtained from Institutional Review Board of Xi'an International Medical Center (No. 202028). The results will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Chinese clinical trial registry ChiCTR2000039983.

Cytoskeleton regulator RNA expression on cancer-associated fibroblasts is associated with prognosis and immunotherapy response in bladder cancer.

Background: Dysregulation of long noncoding RNAs (lncRNAs) has been reported to be associated with multiple tumors where they act as tumor suppressors or accelerators. The lncRNA CYTOR was identified as an oncogene involved in many cancers, such as gastric cancer, colorectal cancer, hepatocellular carcinoma, and renal cell carcinoma. However, the role of CYTOR in bladder cancer (BCa) has rarely been reported. Methods: Using cancer datasets from The Cancer Genome Atlas (TCGA) program, we analyzed the association between CYTOR expression and prognostic value, oncogenic pathways, antitumor immunity and immunotherapy response in BCa. The influence of CYTOR on the immune infiltration pattern in the urothelial carcinoma microenvironment was further verified in our dataset. Single-cell analysis revealed the role of CYTOR in the tumor microenvironment (TME) of BCa. Finally, we evaluated the expression of CYTOR in BCa in the Peking University First Hospital (PKU-BCa) dataset and its correlation with the malignant phenotype of BCa in vitro and in vivo. Results: The results indicated that CYTOR was highly expressed in multiple cancer samples, including BCa, and increased CYTOR expression contributed to poor overall survival (OS). Additionally, elevated CYTOR expression was significantly correlated with clinicopathological features of BCa, such as female sex, advanced TNM stage, high histological grade and non-papillary subtype. Functional characterization revealed that CYTOR may be involved in immune-related pathways and the epithelial mesenchymal transformation (EMT) process. Moreover, CYTOR had a significant association with infiltrating immune cells, including M2 macrophages and regulatory T cells (Tregs). CYTOR facilitates the crosstalk between cancer-associated fibroblasts (CAFs) and macrophages, and mediates M2 polarization of macrophages. Correlation analysis revealed a positive correlation between CYTOR expression and programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1)/expression and other targets for specific immunotherapy in BCa, which are recognized to predict the efficacy of immunotherapy. Conclusions: These results suggest that CYTOR serves as a potential biomarker for predicting survival outcome, TME cell infiltration characteristics and immunotherapy response in BCa.

Advances in aptamer-mediated targeted delivery system for cancer treatment.

Aptamers with high affinity and specificity for certain targets have rapidly become a novel class of targeted ligands applicated in drug delivery. Based on the excellent characteristics of aptamers, different aptamer-mediated drug delivery systems have been developed, including aptamer-drug conjugate (ApDC), aptamer-siRNA, and aptamer-functionalized nanoparticle systems for the effective treatment of cancer, which can reduce potential toxicity and improve therapeutic efficacy. In this review, we summarize the recent progress of aptamer-mediated delivery systems in cancer therapy, and discuss the application prospects and existing problems of innovative approaches based on aptamer therapy. Overall, this review aims to better understand the current aptamer-based targeted delivery applications through in-depth analysis to improve efficacy and develop new therapeutic methods which can ultimately improve treatment outcomes for cancer patients.

Determination of Whether Apex or Non-Apex Prostate Cancer Is the Best Candidate for the Use of Prostate-Specific Antigen Density to Predict Pathological Grade Group Upgrading and Upstaging after Radical Prostatectomy.

Objective: Previous studies have demonstrated that prostate-specific antigen density (PSAD) may aid in predicting Gleason grade group (GG) upgrading and pathological upstaging in patients with prostate cancer (PCa). However, the differences and associations between patients with apex prostate cancer (APCa) and non-apex prostate cancer (NAPCa) have not been described. The aim of this study was to explore the different roles of PSAD in predicting GG upgrading and pathological upstaging between APCa and NAPCa. Patients and Methods: Five hundred and thirty-five patients who underwent prostate biopsy followed by radical prostatectomy (RP) were enrolled. All patients were diagnosed with PCa and classified as either APCa or NAPCa. Clinical and pathological variables were collected. Univariate, multivariate, and receiver operating characteristic (ROC) analyses were performed. Results: Of the entire cohort, 245 patients (45.8%) had GG upgrading. Multivariate analysis revealed that only PSAD (odds ratio [OR]: 4.149, p < 0.001) was an independent, significant predictor of upgrading. A total of 262 patients (49.0%) had pathological upstaging. Both PSAD (OR: 4.750, p < 0.001) and percentage of positive cores (OR: 5.108, p = 0.002) were independently significant predictors of upstaging. Of the 374 patients with NAPCa, 168 (44.9%) displayed GG upgrading. Multivariate analysis also showed PSAD (OR: 8.176, p < 0.001) was an independent predictor of upgrading. Upstaging occurred in 159 (42.5%) patients with NAPCa, and PSAD (OR: 4.973, p < 0.001) and percentage of positive cores (OR: 3.994, p = 0.034) were independently predictive of pathological upstaging. Conversely, of the 161 patients with APCa, 77 (47.8%) were identified with GG upgrading, and 103 (64.0%) patients with pathological upstaging. Multivariate analysis demonstrated that there were no significant predictors, including PSAD, for predicting GG upgrading (p = 0.462) and pathological upstaging (p = 0.100). Conclusions: PSAD may aid in the prediction of GG upgrading and pathological upstaging in patients with PCa. However, this may only be practical in patients with NAPCa but not with APCa. Additional biopsy cores taken from the prostatic apex region may help improve the accuracy of PSAD in predicting GG upgrading and pathological upstaging after RP.

Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation.

OBJECTIVE: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy. METHODS: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3∼AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed. RESULTS: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3∼AE displayed highly potent cytotoxicity to cancer cells with IC50 at 0.1 nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3∼AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-ß in athymic mice. CONCLUSION: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.

Initial characterization of immune microenvironment in pheochromocytoma and paraganglioma.

Due to fewer adverse events, faster onset of action, and longer durable responses compared to chemotherapy, immunotherapy has been widely used to treat advanced solid tumors. Moreover, immunotherapy can improve the autoimmune status, thus allowing patients to benefit from the treatment in the long term. The immune microenvironment status is closely associated with the response to chemotherapies. Here, we analyzed the characteristics of the immune microenvironment in pheochromocytoma and paraganglioma (PPGL). Immunohistochemistry showed that PD-L1 is sparely expressed in PPGL with low positive rates and low expression levels, an expression pattern, that is, not correlated with tumor malignancy. Moreover, the level of intratumoral CD4+ and CD8+ lymphocyte infiltration in PPGL is low, suggesting that the immune microenvironment in PPGL may be in "immune desertification" or "immune rejection" states in which CD4+ and CD8+ lymphocyte infiltration is prevented, rendering immunotherapy less effective. In sum, our results indicate that PPGL is a microsatellite-stable tumor with low tumor mutational burden (TMB) levels, weak neoantigen production, and poor tumor antigenicity, hinting at a poor response of PPGL to chemotherapies.

Neurosurgical enhanced recovery after surgery ERAS for geriatric patients undergoing elective craniotomy: A review.

Population aging is an unprecedented, multifactorial, and global process that poses significant challenges to healthcare systems. Enhanced recovery after surgery (ERAS) protocols aim to optimize perioperative care. The first neurosurgical ERAS protocol for elective craniotomy has contributed to a shortened postoperative hospital stay, accelerated functional recovery, improved patient satisfaction, and reduced medical care cost in adult patients aged 18 to 65 years compared with conventional perioperative care. However, ERAS protocols for geriatric patients over 65 years of age undergoing cranial surgery are lacking. In this paper, we propose a novel ERAS protocol for such patients by reviewing and summarizing the key elements of successful ERAS protocols/guidelines and optimal perioperative care for geriatric patients described in the literature, as well as our experience in applying the first neurosurgical ERAS protocol for a quality improvement initiative. This proposal aimed to establish an applicable protocol for geriatric patients undergoing elective craniotomy, with evidence addressing its feasibility, safety, and potential efficacy. This multimodal, multidisciplinary, and evidence-based ERAS protocol includes preoperative, intraoperative, and postoperative assessment and management as well as outcome measures. The implementation of the current protocol may hold promise in reducing perioperative morbidity, enhancing functional recovery, improving postoperative outcomes in geriatric patients scheduled for elective craniotomy, and serving as a stepping stone to promote further research into the advancement of geriatric patient care.