Ethanol inhibits pancreatic acinar cell autophagy through upregulation of ATG4B, mediating pathological responses of alcoholic pancreatitis.

Excessive alcohol intake is a major risk factor for pancreatitis, sensitizing the exocrine pancreas to stressors by mechanisms that remain obscure. Impaired autophagy drives nonalcoholic pancreatitis, but the effects of ethanol (EtOH) and alcoholic pancreatitis on autophagy are poorly understood. Here, we find that ethanol reduces autophagosome formation in pancreatic acinar cells, both in a mouse model of alcoholic pancreatitis induced by a combination of EtOH diet and cerulein (a CCK ortholog) and in EtOH+CCK-treated acinar cells (ex vivo model). Ethanol treatments decreased pancreatic level of LC3-II, a key mediator of autophagosome formation. This was caused by ethanol-induced upregulation of ATG4B, a cysteine protease that, cell dependently, regulates the balance between cytosolic LC3-I and membrane-bound LC3-II. We show that ATG4B negatively regulates LC3-II in acinar cells subjected to EtOH treatments. Ethanol raised ATG4B level by inhibiting its degradation, enhanced ATG4B enzymatic activity, and strengthened its interaction with LC3-II. We also found an increase in ATG4B and impaired autophagy in a dissimilar, nonsecretagogue model of alcoholic pancreatitis induced by EtOH plus palmitoleic acid. Adenoviral ATG4B overexpression in acinar cells greatly reduced LC3-II and inhibited autophagy. Furthermore, it aggravated trypsinogen activation and necrosis, mimicking key responses of ex vivo alcoholic pancreatitis. Conversely, shRNA Atg4B knockdown enhanced autophagosome formation and alleviated ethanol-induced acinar cell damage. The results reveal a novel mechanism, whereby ethanol inhibits autophagosome formation and thus sensitizes pancreatitis, and a key role of ATG4B in ethanol's effects on autophagy. Enhancing pancreatic autophagy, particularly by downregulating ATG4B, could be beneficial in mitigating the severity of alcoholic pancreatitis.NEW & NOTEWORTHY Ethanol sensitizes mice and humans to pancreatitis, but the underlying mechanisms remain obscure. Autophagy is important for maintaining pancreatic acinar cell homeostasis, and its impairment drives pancreatitis. This study reveals a novel mechanism, whereby ethanol inhibits autophagosome formation through upregulating ATG4B, a key cysteine protease. ATG4B upregulation inhibits autophagy in acinar cells and aggravates pathological responses of experimental alcoholic pancreatitis. Enhancing pancreatic autophagy, particularly by down-regulating ATG4B, could be beneficial for treatment of alcoholic pancreatitis.

Identification of novel susceptibility factors related to CP/CPPS-like symptoms: Evidence from a multicenter case-control study.

BACKGROUND: We aimed to systematically identify novel susceptible factors related to the occurrence and development of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)-like symptoms that were not limited to lifestyles or dietary habits in Chinese population. METHODS: We recruited participants from three centers (Shanghai [northeast], Hefei [east], and Lanzhou [northwest]) from August 2020 to June 2021. Demographics, lifestyles, dietary habits, past medical history, and national institutes of health-chronic prostatitis symptom index (NIH-CPSI) were collected from the individuals via optimized questionnaires. Logistic regression analysis and multivariate adjustment models were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) to assess the association between these variables and CP/CPPS-like symptoms. RESULTS: A total of 1851 participants were enrolled in this study (764 cases and 1087 controls). Age distributions differed between groups (median, range: 32, 18-74 vs. 29, 18-70, p < 0.001). After adjustment, physicochemical occupational hazards were identified significantly related to CP/CPPS-like symptom occurrence and development (ORoccurrence : 1.389, 95% CI: 1.031-1.870, p < 0.001; ORdevelopment : 2.222, 95% CI: 1.464-3.372, p < 0.001); besides, greater than or equal to four ejaculations per week significantly increased the likelihood of CP/CPPS-like symptoms compared with one ejaculation per week (ORoccurrence : 3.051, 95% CI: 1.598-5.827, p = 0.001). For these patients, who were easily felt gastrointestinal discomfort caused by spicy food intake, they had a higher incidence to affect with CP/CPPS-like symptoms (ORoccurrence : 2.258, 95% CI: 1.858-2.745, p < 0.001). In addition, history of drug allergy and genitourinary infections were identified as independent susceptible factors for the occurrence of CP/CPPS-like symptoms (ORoccurrence : 1.689, 95% CI: 1.007-2.834, p = 0.047; ORoccurrence : 3.442, 95% CI: 2.202-5.382, p < 0.001, respectively), while the history of rheumatic immune diseases was found tightly associated with the development of CP/CPPS-like symptoms (ORdevelopment : 2.002, 95% CI: 1.008-4.058, p = 0.048). CONCLUSION: Infection/inflammatory/immune-related disorders, novel dietary habits, and lifestyles associated with the susceptibility of CP/CPPS-like symptoms' occurrence and development are identified. Altering these irregular conditions serves as potential strategies for the treatment of patients with CP/CPPS-like symptoms.

Infiltration of inflammatory factors induced penile damage in chronic prostatitis.

The present study aimed to investigate the mechanism of penile damages in experimental autoimmune prostatitis (EAP) rat models to reveal the potential pathological mechanism of the relationship between CP and penile damages. Sprague-Dawley (SD) rats were administered with different concentrations of prostate tissue homogenate supernatant (PTHS) by multipoint subcutaneous injection to establish EAP models. IHC staining was done to assess the expression of inflammatory cytokines in prostate tissues and the corpus cavernosum of penis. Masson and Tunel staining was conducted to observe the fibrosis and apoptosis in the corpus cavernosum. Finally, the functional changes of corpus cavernosum were assessed by WB and IHC staining. The results revealed that EAP rats with different prostatitis severity were successfully established by PTHS. The expression of IL-1ß, IL-6 and TNF-α in prostate tissues increased with the concentration of PTHS. The results of Masson and Tunel staining indicated fibrosis and apoptosis gradually aggravated in corpus cavernosum among different subgroups. The function of cavernosum impaired by prostatitis from WB and IHC results and positively with the severity. In conclusion, there existed the infiltration of inflammatory factors and impaired function in the corpus cavernosum of EAP rats' penis and positively correlated with the severity of prostatitis.

MLC1 Overexpression Inhibits Tumor Progression through PI3K/AKT Signal Pathway in Prostate Cancer.

Prostate cancer (PC) is a prevalent malignancy in males, characterized by high morbidity and mortality. Despite MLC1 being established as a key mediator in tumor progression, its role in PC remains unexplored. This study aims to validate MLC1's anti-tumor effects and uncover potential mechanisms. MLC1's clinical significance is assessed using data from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. MLC1 expression is significantly reduced in PC samples compared with the adjacent normal tissues. MLC1 expression correlates negatively with tumor metastasis and positively with the survival of patients with PC. In vitro, up-regulating MLC1 effectively inhibits tumor progression by curtailing proliferation, infestation, and migration through the deactivation of the PI3K/AKT signaling pathway. Conversely, down-regulating MLC1 promotes PC progression, a phenomenon alleviated by the PI3K/AKT inhibitor, Gefitinib. Furthermore, the anti-tumor function of MLC1 is corroborated by a reduction in tumor volume compared with the negative control in vivo. This study confirms the anti-tumor effects of MLC1 via in vitro and in vivo experiments, demonstrating its potential mechanism of inhibiting the PI3K/AKT signaling pathway.

Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases.

Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) and cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles and an unselective ß-adrenergic receptor blocker (propranolol). The two components (i.e., fibrin and alginate) can respond to two triggers (thrombin and Ca2+, respectively) in postoperative bleeding to gelate, shaping into an interpenetrating network (IPN) featuring high strength. The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function and hamper cytotoxic T cell exhaustion. The reprogrammed TME significantly suppress locally residual and distant tumors, induce strong immune memory effects and thus inhibit lung metastasis. Thus, targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.

Prognostic value of preoperative combined neutrophil, monocyte, and lymphocyte scores in patients with renal cell carcinoma undergoing laparoscopic nephrectomy: A retrospective study.

BACKGROUND: In a multi-institutional clinical study, we assessed the prognostic significance of a novel indicator preoperative peripheral blood immune (PBIS) scores that combined ratios of preoperative lymphocyte, monocyte, and neutrophil of renal cell carcinoma (RCC) patients undergoing laparoscopic nephrectomy. METHODS: Between January 2014 and December 2019, 438 patients with RCC were retrospectively analyzed in three centers. We used X-tile software to obtain the optimum cut-off values for neutrophils, monocytes, and lymphocytes to classify the patients. To assess the relationship between PBIS score and overall survival (OS), and cancer-specific survival (CSS) in patients with RCC by Kaplan-Meier survival curves and Cox regression analyses. In addition, predictive OS and CSS nomograms were constructed. The discriminative ability of nomogram and predictive performance accuracy were verified with consistency index (C-index), calibration curves, receiver operating curve (ROC) curves, decision curve analysis (DCA) curves, and time-dependent ROC curves. RESULTS: The optimum cutoff values for monocytes, lymphocytes, and neutrophils were 0.46, 1.01, and 4.50, respectively. We divided patients into four subgroups according to PBIS scores, which were significantly associated with M-stage (p = 0.008), T-stage (p < 0.001), N-stage (p = 0.006), and AJCC stage (p < 0.001). Multivariate Cox regression analysis revealed that RCC patients with lower PBIS scores showed a worse postoperative prognosis and served as an independent predictor of OS (p = 0.002) and CSS (p < 0.001). Ultimately, the nomograms based on PBIS scores demonstrated excellent predictive performance for OS (C-index: 0.770) and CSS (C-index: 0.828) through the analysis of calibration curves, ROC curves, DCA curves, and time-dependent ROC curves. CONCLUSION: PBIS score served as novel and effective predictor to accurately predict OS and CSS in patients with RCC receiving laparoscopic nephrectomy.

Endogenous Zinc-Ion-Triggered In Situ Gelation Enables Zn Capture to Reprogram Benign Hyperplastic Prostate Microenvironment and Shrink Prostate.

Benign prostatic hyperplasia (BPH) as the leading cause of urination disorder is still a refractory disease, and there have no satisfied drugs or treatment protocols yet. With identifying excessive Zn2+ , inflammation, and oxidative stress as the etiology of aberrant hyperplasia, an injectable sodium alginate (SA) and glycyrrhizic acid (GA)-interconnected hydrogels (SAGA) featuring Zn2+ -triggered in situ gelation are developed to load lonidamine for reprogramming prostate microenvironment and treating BPH. Herein, SAGA hydrogels can crosslink with Zn2+ in BPH via coordination chelation and switch free Zn2+ to bound ones, consequently alleviating Zn2+ -arisen inflammation and glycolysis. Beyond capturing Zn2+ , GA with intrinsic immunoregulatory property can also alleviate local inflammation and scavenge reactive oxygen species (ROS). Intriguingly, Zn2+ chelation-bridged interconnection in SAGA enhances its mechanical property and regulates the degradation rate to enable continuous lonidamine release, favoring hyperplastic acini apoptosis and further inhibiting glycolysis. These multiple actions cooperatively reprogram BPH microenvironment to alleviate characteristic symptoms of BPH and shrink prostate. RNA sequencing reveals that chemotaxis, glycolysis, and tumor necrosis factor (TNF) inflammation-related pathways associated with M1-like phenotype polarization are discerned as the action rationales of such endogenous Zn2+ -triggered in situ hydrogels, providing a candidate avenue to treat BPH.

LncRNA SNHG3 enhances BMI1 mRNA stability by binding and regulating c-MYC: Implications for the carcinogenic role of SNHG3 in bladder cancer.

The transformation of nonmuscle-invasive bladder cancer (BLCa) to muscle-invasive type and distant metastasis are the two major threats to patients after surgery. Thus, it is important to identify the key genes of BLCa cell invasion and metastasis. Long noncoding RNA (lncRNA) is a potential clinical tool for cancer diagnosis and treatment. Herein, we verified that lncRNA SNHG3 is upregulated in human BLCa specimens and is proportional to poor clinical prognosis via a combination of bioinformatic analyses and wet bench experiments. Then, we constructed SNHG3 knockdown and overexpression cell models via lentiviral packaging and CRISPR-Cas9 technique. Fluorescence in situ hybridization assay showed that SNHG3 is distributed in both the nucleus and cytoplasm of BLCa cell lines. In vitro assays including CCK-8, EdU, colony formation, wound healing, transwell, and tube formation demonstrated that SNHG3 knockdown and overexpression potently inhibited and enhanced BLCa cell proliferation, migration, invasion, and angiogenesis. In addition, IVIS imaging revealed that SNHG3 knockdown could significantly inhibit M-NSG mice xenograft tumor growth. Next, RNA sequencing, bioinformatics analyses and western blots indicated that SNHG3 could promote c-MYC expression. RNA immunoprecipitation, actinomycin D assay and western blot assays suggested that SNHG3 could also bind c-MYC protein which subsequently facilitate the stabilization of BMI1 mRNA, thus enhancing BMI1 protein level. However, SNHG3 knockdown had a slightly weaker inhibitory effect on BMI1 expression than c-MYC knockdown. Further, in vitro assays demonstrated that BMI1 knockdown could suppress the SNHG3 activation-induced tumor promoting effect in BLCa cells. Overall, this study has provided new insights into the potential implication of lncRNA SNHG3 in the pathogenesis of BLCa. Importantly, SNHG3/c-MYC/BMI1 axis may be a novel target for regulating tumor growth and metastasis in BLCa patients.

Cuproptosis-related LINC01711 promotes the progression of kidney renal clear cell carcinoma.

This study utilized The Cancer Genome Atlas (TCGA) database to identify cuproptosis-related long non-coding RNAs (CRlncRNAs) in patients with kidney renal clear cell carcinoma (KIRC) which was further applied to construct risk signatures. All KIRC patients were divided into the training and the validation sets at a ratio of 7:3. Lasso regression analysis identified two prognosis-associated CRlncRNAs (LINC01204 and LINC01711), and prognostic risk signatures were constructed in both the training and the validation sets. Kaplan-Meier survival curves showed that patients with high-risk scores had significantly shorter overall survival (OS) than those with low-risk scores both in both the training and the validation sets. The area under the curve (AUC) of the prognostic nomogram generated based on age, grade, stage and risk signature to predict the 1-, 3- and 5-year OS were 0.84, 0.81 and 0.77, respectively, and the calibration curves also showed the high accuracy of the nomogram. In addition, we constructed the LINC01204/LINC01711-miRNA-mRNA ceRNA network graph. Finally, we experimentally investigated the function of LINC01711 by knocking down LINC01711 and revealed that knockdown of LINC01711 inhibited the proliferation, migration and invasion of KIRC cells. Hence, in this study, we developed a signature of prognostic risk-associated CRlncRNAs that could accurately predict the prognosis of KIRC patients and constructed a related ceRNA network to shed light on the mechanistic study of KIRC. LINC01711 might serve as a potential biomarker for the early diagnosis and prognosis of KIRC patients.

The relationship between ethylene oxide levels in hemoglobin and the prevalence of kidney stones in US adults: an exposure-response analysis from NHANES 2013-2016.

Exposure to ethylene oxide may cause a number of diseases. The purpose of this study was to investigate whether there is an association between hemoglobin ethylene oxide (HbEO) and the risk of developing kidney stones in US adults. We analyzed 3348 patients from the National Health and Nutrition Survey (NHANES) 2013-2016 and conducted a cross-sectional study. Dose-response analysis curves of restricted cubic spline function, multiple logistic regression, and subgroup analysis were used to investigate the association between HbEO and the risk of kidney stones. Logistic regression models were used to analyze the correlation between HbEO and kidney stones. Among the 3348 participants, 3016 people self-reported having a kidney stone. After adjusting for age, sex, race, marital status, education level, diabetes, vigorous recreational activity, moderate recreational activity, body mass index, blood urea nitrogen, creatinine, eGFR, and uric acid, we found a positive association between HbEO and the risk of kidney stones. We divided patients into four groups based on quartiles of HbEO levels and performed multifactorial logistic regression after adjusting for confounders, which showed that the incidence of kidney stones increased with increasing HbEO concentrations compared with Q1 (Q2, OR = 0.922, 95% CI, 0. 657-1.295, P = 0.639; Q3, OR = 1.004, 95% CI, 0.713-1.414, P = 0.983; Q4, OR = 1.535, 95% CI, 1.114-2.114, P = 0.009). High levels of HbEO were positively correlated with the risk of kidney stone development and could be used as an indicator of kidney stone prevention.

Association between sarcopenia and kidney stones in United States adult population between 2011 and 2018.

Purpose: To investigate the relationship between kidney stones and sarcopenia in United States adult population between 2011 and 2018. Materials and methods: We conducted a cross-section study based on the National Health and Nutrition Examination Survey (NHANES) including 39,156 individuals. Sarcopenia was assessed by the sarcopenia index. Association between kidney stones and sarcopenia verified by multiple logistic regression analysis and dose-response curves analysis using restricted cubic spline (RCS) regression. Meanwhile, propensity score matching (PSM) was performed to exclude the effect of confounding variables. Results: There were 9,472 participants in the study by our accurate enrollment screening process. The odds of kidney stones decreased significantly with the increase of sarcopenia index. Logistic regression analysis showed that sarcopenia expressed significant differences in the participants which suffered kidney stone before PSM (p < 0.001). In model 4, adjusting all relevant covariates shown that adjusted odds ratio (aOR) of the 95% confidence intervals for kidney stones in all participants, age <39 years and age ≥40 years, were, respectively, 1.286 (1.006-1,643), 1.697 (1.065-2.702), and 0.965 (0.700-1.330) for sarcopenia, and p values were 0.044, 0.026, and 0.827. After performing PSM, the aOR of the 95% in modal 4 for kidney stones in all participants and age <40 year were 2.365 (1.598-3.500) and 6.793 (2.619-17.6180), respectively (p < 0.01), and especially the aOR in participants (age ≥40) was 1.771(1.138-2.757) with p value being 0.011. Conclusion: Sarcopenia was positively related to the potential risk of kidney stones in the United States adult population.

Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions.

Patients with castration-resistant prostate cancer (CRPC) often develop drug resistance after treatment with enzalutamide. The goal of our study was to identify the key genes related to enzalutamide resistance in CRPC and to provide new gene targets for future research on improving the efficacy of enzalutamide. Differential expression genes (DEGs) associated with enzalutamide were obtained from the GSE151083 and GSE150807 datasets. We used R software, the DAVID database, protein-protein interaction networks, the Cytoscape program, and Gene Set Cancer Analysis for data analysis. The effect of RAD51 knockdown on prostate cancer (PCa) cell lines was demonstrated using Cell Counting Kit-8, clone formation, and transwell migration experiments. Six hub genes with prognostic values were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which were significantly associated with immune cell infiltration in PCa. High RAD51, BLM, EXO1, and RFC2 expression was associated with androgen receptor signaling pathway activation. Except for APOE, high expression of hub genes showed a significant negative correlation with the IC50 of Navitoclax and NPK76-II-72-1. RAD51 knockdown inhibited the proliferation and migration of PC3 and DU145 cell lines and promoted apoptosis. Additionally, 22Rv1 cell proliferation was more significantly inhibited with RAD51 knockdown than without RAD51 knockdown under enzalutamide treatment. Overall, six key genes associated with enzalutamide resistance were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which are potential therapeutic targets for enzalutamide-resistant PCa in the future.

Prognostic value of total body muscle-fat ratio in patients with kidney stone disease: A US population-based study.

Purpose: To examine the relationship between the muscle-fat ratio (MFR) and kidney stone disease (KSD) in the adult population of the United States between 2011 and 2018, and whether it can be used as a predictor of KSD prognosis. Materials and methods: We conducted a cross-sectional study analysing 9326 patients from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. We analyzed all participants by sex, age, race, level of education, marital status, household income-to-poverty ratio, hypertension, diabetes, vigorous physical activity, moderate physical activity, blood urea nitrogen, creatinine, uric acid, cotinine, and MFR. Dose-response curves with a restricted cubic spline function, univariate and multifactorial logistic regression were used for the analysis of the correlation between MFR and KSD. Finally, we created predictive models based on age, race, hypertension, diabetes mellitus, cotinine and MFR. The prediction model was evaluated using calibration curves, receiver operating characteristic curves and clinical decision curves from the training and test sets. Results: Of the 9326 participants, 8582 (92%) self-reported that they did not have KSD and 744 (8%) self-reported that they had KSD. Univariate and multifactorial logistic regression showed that MFR was negatively associated with the prevalence of KSD (odds ratio [OR]: 0.770, 95% CI: 0.703-0.843; OR: 0.815, 95% CI: 0.738-0.897). Similarly, the risk of developing KSD decreased with increasing MFR as shown by the dose curves in the restricted cubic bar graphs. Furthermore, there is some accuracy (AUC = 0.652) and clinical applicability to the model we constructed based on the results of multifactorial logistic regression. Conclusion: The MFR is protective factor against the developing KSD in adults in the USA.

M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription.

Lymphatic metastasis is recognized as the leading manner of metastasis in bladder cancer (BLCa), but hematogenous metastasis accounts for a majority of cancer-associated deaths. The past two decades have witnessed tremendous attention in long non-coding RNAs (lncRNAs), which are a new hope for the development of targeted drug therapy for metastatic cancers; however, the underlying mechanism of lncRNAs involved in BLCa hematogenous metastasis remains to be elucidated. Here, we identified BLCa-associated transcript 3 (BLACAT3), a lncRNA, which was aberrantly upregulated in BLCa and corelated with poor prognosis of patients with muscle-invasive bladder cancer. Methodologically, m6A epitranscriptomic microarray, RNA sequencing and mass spectrometry (MS) were used to screen the key molecules of the regulatory axis. Functional assays, animal models and clinical samples were used to explore the roles of BLACAT3 in BLCa in vitro and in vivo. Mechanistically, m6A modification contributes to BLACAT3 upregulation by stabilizing RNA structure. BLACAT3 recruits YBX3 to shuttle into the nucleus, synergistically enhances NCF2 transcription, and promotes BLCa angiogenesis and hematogenous metastasis by activating downstream NF-κB signaling. Our findings will develop prognosis prediction tools for BLCa patients and discover novel therapeutic biological targets for metastatic BLCa.

Advances in nanobiotechnology-propelled multidrug resistance circumvention of cancer.

Multidrug resistance (MDR) is one of the main reasons for the failure of tumor chemotherapy and has a negative influence on the therapeutic effect. MDR is primarily attributable to two mechanisms: the activation of efflux pumps for drugs, which can transport intracellular drug molecules from cells, and other mechanisms not related to efflux pumps, e.g., apoptosis prevention, strengthened DNA repair, and strong oxidation resistance. Nanodrug-delivery systems have recently attracted much attention, showing some unparalleled advantages such as drug targeting and reduced drug efflux, drug toxicity and side effects in reversing MDR. Notably, in drug-delivery platforms based on nanotechnology, multiple therapeutic strategies are integrated into one system, which can compensate for the limitations of individual strategies. In this review, the mechanisms of tumor MDR as well as common vectors and nanocarrier-combined therapy strategies to reverse MDR were summarized to promote the understanding of the latest progress in improving the efficiency of chemotherapy and synergistic strategies. In particular, the adoption of nanotechnology has been highlighted and the principles underlying this phenomenon have been elucidated, which may provide guidance for the development of more effective anticancer strategies.

Association between multiple meteorological variables and seasonal influenza A and B virus transmission in Macau.

Few studies have evaluated the influence of meteorological variables on different influenza types in subtropical regions. This study aimed to explore the association between meteorological variables and the onset of influenza A (Flu-A) and B (Flu-B) in Macau. Daily influenza case data in Macau were collected from Kiang Wu Hospital from 1 January, 2014 to 31 December, 2018. Daily meteorological data were obtained from the Macau Meteorological Service. The distributed lag non-linear model (DLNM) was used to estimate the effects of meteorological variables on seasonal influenza outbreaks. Regarding mean air temperature (temp), the peaks of the cumulative relative risks (RRs) of Flu-A and Flu-B were both at 4.0 °C and 28.0 °C. Regarding the diurnal temperature range (DTR), the peaks of the cumulative RR of Flu-A were at 1.0 °C and 5.0 °C, while the cumulative RR of Flu-B increased as the DTR decreased. The association between influenza risks and relative humidity (RH) showed a U-shape curve. The risk of influenza increased when the RH was below 50% or above 90%. The risk of both types of influenza increased significantly when the sunshine duration (SD) was below 3.5 h. Taking the median value as the reference, a significant cold effect was observed over 16-24 days lag for Flu-A. Lag effects were found for both types of influenza in low-DTR, and humid and short SD conditions. This study revealed complex non-linear association between meteorological variables and the different influenza types in Macau.

Constructing a heparin-modified penile decellularized scaffold to improve re-endothelialization in organizational reconstruction.

Background: Due to the unique anatomy and complex function of the penis, the reconstruction of penile defect is fraught with great challenges. The current standard methods are limited by numerous complications and insufficient donor sites. While functional vascularized penile tissue engineering offers a novel way to address this problem, revascularization remains the primary concern. Methods: In this study, a penile scaffold with associated modifications was constructed. The performance of decellularized penile scaffolds (DPSs) was improved by conjugation with heparin (HEP) and reseeding with human umbilical vein endothelial cells (HUVECs). There were three groups according to the modifications, including native DPSs, HEP-DPSs, HEP-HUVECs-DPSs. After perfusing with 1% Triton X-100/0.1% ammonium hydroxide solution, the cellular components were removed. Subsequently, the covalent binding of heparin in the DPSs was performed with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide, followed by reseeding with HUVECs. Scaffolds were implanted into the backs of rats and the implanted tissues were harvested at 1, 2, 3, and 4 weeks. Then hematoxylin and eosin (H&E) staining and immunofluorescence assays were performed to assess the degree of angiogenesis. Results: The native DPSs retained the extracellular matrix and heparinized modification. The H&E results indicated that more HUVECs covered the inner surface of tubular structures in the HEP-DPSs group compared to the native DPSs group. The number of vessels in the HEP-HUVECs-DPSs was significantly increased compared to the control scaffolds at all time points. Conclusions: These results suggested that, compared to the native DPS, heparin-conjugated scaffolds provided a superior environment for the growth of HUVECs and the modified methods provided a perspective for overcoming the obstacles in tissue engineering of transplantable penile tissues and the establishment of a functional vasculature.

Noncoding-RNA mediated high expression of zinc finger protein 268 suppresses clear cell renal cell carcinoma progression by promoting apoptosis and regulating immune cell infiltration.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant kidney tumors with a poor prognosis. Accumulating evidence proves that zinc finger protein 268 (ZNF268) is associated with tumor progression, but the detailed regulatory functions of ZNF268 in ccRCC require further exploration. Thus, here we aim to characterize the role of ZNF268 in ccRCC. The clinical significance of ZNF268 was evaluated using The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Subsequently, tumor-infiltrating immune cells, as well as upstream noncoding RNAs (ncRNAs) related to the tumor-suppressing function of ZNF268, were identified by in silico analyses. The expression of ZNF268 was significantly decreased in ccRCC samples compared with adjacent normal tissues. In addition, ZNF268 expression was negatively correlated with tumor progression and positively correlated with overall and disease-specific survival. TCGA and GTEx databases proved the potential tumor-suppressing function, which was measured both in vitro and in vivo after ZNF268 over-expression. Overexpression of ZNF268 effectively inhibited the proliferation, migration, invasion and promotied apoptosis of the Caki-1. The level of ZNF268 was positively related to the immune cell infiltration in the tumor. Moreover, we determined that the AC093157.1/miR-27a-3p axis can potentially regulate ZNF268 function in ccRCC. Our work describes a novel ncRNA-mediated ZNF268 function in ccRCC. ZNF268 acts as a tumor suppressor, and it is associated with apoptosis and immune cell infiltration in ccRCC.

Identification of prognostic factors for predicting survival of patients with malignant adrenal tumors: A population-based study.

Background: This study aimed to identify the prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in patients with malignant adrenal tumors and establish a predictive nomogram for patient survival. Methods: The clinical characteristics of patients diagnosed with malignant adrenal tumors between 1988 and 2015 were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. As the external validation set, we included 110 real-world patients from our medical centers. Univariate and multivariate Cox regressions were implemented to determine the prognostic factors of patients. The results from Cox regression were applied to establish the nomogram. Results: A total of 2,206 eligible patients were included in our study. Patients were randomly assigned to the training set (1,544; 70%) and the validation set (662; 30%). It was determined that gender, age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy were prognostic factors that affected patient survival. The OS prediction nomogram contained all the risk factors, while gender was excluded in the CSS prediction nomogram. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) indicated that the nomogram had a better predictive performance than SEER stage. Moreover, the clinical impact curve (CIC) showed that the nomograms functioned as effective predictive models in clinical application. The C-index of nomogram for OS and CSS prediction was 0.773 (95% confidence interval [CI]: 0.761-0.785) and 0.689 (95% CI: 0.675-0.703) in the training set. The calibration curves exhibited significant agreement between the nomogram and actual observation. Additionally, the results from the external validation set also presented that established nomograms functioned well in predicting the survival of patients with malignant adrenal tumors. Conclusions: The following clinical variables were identified as prognostic factors: age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy. The nomogram for patients with malignant adrenal tumors contained the accurate predictive performance of OS and CSS, contributing to optimizing individualized clinical treatments.

Double-Tetrahedral DNA Probe Functionalized Ag Nanorod Biointerface for Effective Capture, Highly Sensitive Detection, and Nondestructive Release of Circulating Tumor Cells.

Circulating tumor cells (CTCs) are indicative of tumorigenesis, metastasis, and recurrence; however, it is still a great challenge to efficiently analyze the extremely rare CTCs in peripheral blood. Herein, a novel nanobiointerface integrating high affinities of arrayed silver nanorods (Ag NRs) and double-tetrahedral DNA (DTDN) probes by a clever strategy is proposed for the efficient capture, highly sensitive detection, and nondestructive release of CTCs. Under the optimal conditions, the DTDN-probe-functionalized Ag NRs nanobiointerface can capture 90.2% of SGC-7901 cells in PBS, and the capture efficiency is 2.8 times and 50 times those of a DTDN-probe-functionalized Ag film and unfunctionalized Ag NRs, respectively, benefiting from the nanorough interface of the Ag NRs array and multivalent recognition of the DTDN probe. In addition, 93.4% of cells was released via Zn2+-assisted DNAzyme cleavage, and the viability of the postreleased CTCs is about 98.0%. The potential practicality of the nanobiointerface for testing CTCs in blood was further characterized by spiking SGC-7901 cells in leukocytes collected from human blood, and the results show that 83.8% capture efficiency, 91.2% release efficiency, and single-cell detection limit were achieved, which indicates that the nanobiointerface has great potential in clinical applications for reliable CTC analyses.