Temporal and spatial variations of terrestrial water storage in the northeastern Tibetan Plateau retrieved by GNSS observations.

The variation of solid Earth's hydrologic loading could cause the elastic vertical deformation of the crust, and the Global Navigation Satellite System (GNSS) could effectively monitor the vertical displacement of surface loads. However, the widely used Green's function method does not work well in areas where GNSS sites are sparse. Here, the vertical displacement time series of GNSS stations and the Slepian basis function method have been applied to convert displacement signals into spatial spectrum signals. The elastic mass load theory is used to study the changes in terrestrial water storage on the Northeastern Tibetan Plateau (NETP). The temporal and spatial characteristics of seasonal water changes are well-represented by the GNSS, the Gravity Recovery and Climate Experiment (GRACE), and the Global Land Data Assimilation System (GLDAS). Several data points suggest that the change in water storage shows a gradual increase from the northeast to the southwest. The greatest annual amplitude of water storage retrieved by GNSS is ∼159 mm, which is greater than the ∼47 mm and ∼44 mm obtained by GRACE and GLDAS. These results demonstrate that GNSS is capable of capturing small-scale hydrological changes in this region, whereas GRACE and GLDAS data tend to underestimate seasonal variations in water storage. We also used GNSS to describe the hydrological drought conditions in NETP, showing that GNSS could be used as an independent method to characterize hydrological drought events. The findings suggest it could observe water storage with high spatial and temporal resolution and aid in comprehending regional hydrological trends with a sparse GNSS station network.

The prognostic impact of tumor location in non-muscle-invasive bladder cancer patients undergoing transurethral resection: insights from a cohort study utilizing chinese multicenter and SEER registries.

OBJECTIVE: Most bladder cancers are non-muscle invasive bladder cancer (NMIBC), and transurethral resection of bladder tumors (TURBT) is the standard treatment. However, postoperative recurrence remains a significant challenge, and the influence of bladder tumor location on prognosis is still unclear. This study aims to investigate how tumor location affects the prognosis of NMIBC patients undergoing TURBT and to identify the optimal surgical approach. METHODS: A multicenter study was conducted, which included Chinese NMIBC data from 15 hospitals (1996-2019) and data from 17 registries of the Surveillance, Epidemiology, and End Results database (SEER) (2000-2020). Patients initially diagnosed with NMIBC and undergoing TURBT or partial cystectomy were analyzed, with cases lost to follow-up or with missing data excluded. The study investigated the overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) among patients with different tumor locations. Kaplan-Meier, Cox regression, and propensity score matching methods were employed to explore the association between tumor location and prognosis. Stratified populations were analyzed to minimize bias. RESULTS: This study included 118,477 NMIBC patients and highlighted tumor location as a crucial factor impacting post-TURBT prognosis. Both anterior wall and dome tumors independently predicted adverse outcomes in two cohorts. For anterior wall tumors, the Chinese cohort showed hazard ratios (HR) for OS of 4.35 (P < 0.0001); RFS of 2.21 (P < 0.0001); SEER cohort OS HR of 1.10 (P = 0.0001); DSS HR of 1.13 (P = 0.0183). Dome tumors displayed similar trends (Chinese NMIBC cohort OS HR of 7.91 (P < 0.0001); RFS HR of 2.12 (P < 0.0001); SEER OS HR of 1.05 (P = 0.0087); DSS HR of 1.14 (P = 0.0006)). Partial cystectomy significantly improved the survival of dome tumor patients compared to standard TURBT treatment (P < 0.01). CONCLUSION: This study reveals the significant impact of tumor location in NMIBC patients on the outcomes of TURBT treatment, with tumors in the anterior wall and bladder dome showing poor post-TURBT prognosis. Compared to TURBT treatment, partial cystectomy improves the prognosis for bladder dome tumors. This study provides guidance for personalized treatment and prognosis management for NMIBC patients.

Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression.

Clear cell renal cell carcinoma (ccRCC) is a complex disease with remarkable immune and metabolic heterogeneity. Here we perform genomic, transcriptomic, proteomic, metabolomic and spatial transcriptomic and metabolomic analyses on 100 patients with ccRCC from the Tongji Hospital RCC (TJ-RCC) cohort. Our analysis identifies four ccRCC subtypes including De-clear cell differentiated (DCCD)-ccRCC, a subtype with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, reduced metabolic activity, enhanced nutrient uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD is associated with worse outcomes and higher recurrence rate, suggesting that it cannot be cured by nephrectomy alone. Our study also suggests a treatment strategy based on subtype-specific immune cell infiltration that could guide the clinical management of ccRCC.

A "safety cap" for improving hospital sanitation and reducing potential disease transmission.

BACKGROUND: During endotracheal intubation, extubation, tracheotomy, and tracheotomy tube replacement, the splashed airway secretions of patients will increase the risk of transmission of SARS-CoV-2 and many other potential viral and bacterial diseases, such as influenza virus, adenovirus, respiratory syncytial virus, rhinovirus, Middle East respiratory coronavirus syndrome (MERS-CoV), Streptococcus pneumoniae, and Mycobacterium tuberculosis. Therefore, it is necessary to establish a barrier between patients and medical workers to reduce the risk of operators' infection with potentially pathogenic microorganisms. METHODS: We designed a "safety cap" that can be connected to the opening of an endotracheal tube or tracheotomy tube to reduce the diffusion area of respiratory secretions during the process of endotracheal intubation, extubation and tracheotomy tube replace, so as to reduce the infection risk of medical workers. RESULTS: Through a series of hydrodynamic simulation analysis and experiments, we demonstrated that the use of "safety cap" can substantially limit the spatter of airway secretions, so as to improve the hospital sanitation. CONCLUSION: The "safety cap" can effectively limit the dissemination of patients' respiratory secretions, thus reducing the risk of potential diseases transmission and may have certain application prospects.

Targeting inhibition of prognosis-related lipid metabolism genes including CYP19A1 enhances immunotherapeutic response in colon cancer.

BACKGROUND: Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore, this study aimed to develop a lipid metabolism-related prognostic risk score (LMrisk) to provide new biomarkers and combination therapy strategies for colon cancer immunotherapy. METHODS: Differentially expressed lipid metabolism-related genes (LMGs) including cytochrome P450 (CYP) 19A1 were screened to construct LMrisk in TCGA colon cancer cohort. The LMrisk was then validated in three GEO datasets. The differences of immune cell infiltration and immunotherapy response between LMrisk subgroups were investigated via bioinformatic analysis. These results were comfirmed by in vitro coculture of colon cancer cells with peripheral blood mononuclear cells, human colon cancer tissue microarray analysis, multiplex immunofluorescence staining and mouse xenograft models of colon cancer. RESULTS: Six LMGs including CYP19A1, ALOXE3, FABP4, LRP2, SLCO1A2 and PPARGC1A were selected to establish the LMrisk. The LMrisk was positively correlated with the abundance of macrophages, carcinoma-associated fibroblasts (CAFs), endothelial cells and the levels of biomarkers for immunotherapeutic response including programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden and microsatellite instability, but negatively correlated with CD8+ T cell infiltration levels. CYP19A1 protein expression was an independent prognostic factor, and positively correlated with PD-L1 expression in human colon cancer tissues. Multiplex immunofluorescence analyses revealed that CYP19A1 protein expression was negatively correlated with CD8+ T cell infiltration, but positively correlated with the levels of tumor-associated macrophages, CAFs and endothelial cells. Importantly, CYP19A1 inhibition downregulated PD-L1, IL-6 and TGF-ß levels through GPR30-AKT signaling, thereby enhancing CD8+ T cell-mediated antitumor immune response in vitro co-culture studies. CYP19A1 inhibition by letrozole or siRNA strengthened the anti-tumor immune response of CD8+ T cells, induced normalization of tumor blood vessels, and enhanced the efficacy of anti-PD-1 therapy in orthotopic and subcutaneous mouse colon cancer models. CONCLUSION: A risk model based on lipid metabolism-related genes may predict prognosis and immunotherapeutic response in colon cancer. CYP19A1-catalyzed estrogen biosynthesis promotes vascular abnormality and inhibits CD8+ T cell function through the upregulation of PD-L1, IL-6 and TGF-ß via GPR30-AKT signaling. CYP19A1 inhibition combined with PD-1 blockade represents a promising therapeutic strategy for colon cancer immunotherapy.

Spatial interpolation of regional PM2.5 concentrations in China during COVID-19 incorporating multivariate data.

During specific periods when the PM2.5 variation pattern is unusual, such as during the coronavirus disease 2019 (COVID-19) outbreak, epidemic PM2.5 regional interpolation models have been relatively little investigated, and little consideration has been given to the residuals of optimized models and changes in model interpolation accuracy for the PM2.5 concentration under the influence of epidemic phenomena. Therefore, this paper mainly introduces four interpolation methods (kriging, empirical Bayesian kriging, tensor spline function and complete regular spline function), constructs geographically weighted regression (GWR) models of the PM2.5 concentration in Chinese regions for the periods from January-June 2019 and January-June 2020 by considering multiple factors, and optimizes the GWR regression residuals using these four interpolation methods, thus achieving the purpose of enhancing the model accuracy. The PM2.5 concentrations in many regions of China showed a downward trend during the same period before and after the COVID-19 outbreak. Atmospheric pollutants, meteorological factors, elevation, zenith wet delay (ZWD), normalized difference vegetation index (NDVI) and population maintained a certain relationship with the PM2.5 concentration in terms of linear spatial relationships, which could explain why the PM2.5 concentration changed to a certain extent. By evaluating the model accuracy from two perspectives, i.e., the overall interpolation effect and the validation set interpolation effect, the results showed that all four interpolation methods could improve the numerical accuracy of GWR to different degrees, among which the tensor spline function and the fully regular spline function achieved the most stable effect on the correction of GWR residuals, followed by kriging and empirical Bayesian kriging.

Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment.

Single-cell sequencing technologies have noteworthily improved our understanding of the genetic map and molecular characteristics of bladder cancer (BC). Here we identify CD39 as a potential therapeutic target for BC via single-cell transcriptome analysis. In a subcutaneous tumor model and orthotopic bladder cancer model, inhibition of CD39 (CD39i) by sodium polyoxotungstate is able to limit the growth of BC and improve the overall survival of tumor-bearing mice. Via single cell RNA sequencing, we find that CD39i increase the intratumor NK cells, conventional type 1 dendritic cells (cDC1) and CD8 + T cells and decrease the Treg abundance. The antitumor effect and reprogramming of the tumor microenvironment are blockaded in both the NK cells depletion model and the cDC1-deficient Batf3-/- model. In addition, a significant synergistic effect is observed between CD39i and cisplatin, but the CD39i + anti-PD-L1 (or anti-PD1) strategy does not show any synergistic effects in the BC model. Our results confirm that CD39 is a potential target for the immune therapy of BC.

CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non-Small Cell Lung Cancer.

SIGNIFICANCE: The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non-small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882.

Spatio-temporal monitoring of marsh vegetation phenology and its response to hydro-meteorological factors using CCDC algorithm with optical and SAR images: In case of Honghe National Nature Reserve, China.

Vegetation phenology is a sensitive indicator which can comprehensively reflect the response of wetland vegetation to external environment changes. However, the time-series monitoring wetland vegetation phenological changes and clarifying its response to hydrology and meteorology still face great challenges. To fill these research gaps, this paper proposed a novel time-series approach for monitoring phenological change of marsh vegetation in Honghe National Nature Reserve (HNNR), Northeast China, using continuous change detection and classification (CCDC) algorithm and Landsat and Sentinel-1 SAR images from 1985 to 2021. We evaluated the spatio-temporal response relationship of phenological characteristics to hydro-meteorological factors by combining CCDC algorithm with partial least squares regression (PLSR). Finally, this study further explored the intra-annual loss and restoration of marsh vegetation in response to hydro-meteorological factors using the transfer entropy (TE) and CCDC-MLSR model constructed by CCDC and Multiple Linear Stepwise Regression (MLSR) algorithms. We found that the bimodal trajectory of phenology reflects two growth processes of marsh vegetation in one year, and high-frequency and high-amplitude loss occurred in shallow-water and deep-water marsh vegetation from April to October, resulting in the loss area within the year was significantly greater than the recovery area. We confirmed that the CCDC algorithm could track the evolution trajectory of time-series phenology of marsh vegetation. We further revealed that precipitation, temperature and frequency of water-level changes are the main driving factors for the spatio-temporal phenological evolution of different marsh vegetation. This study verified the effect of alternative changes of hydrology and climate on loss and recovery of marsh vegetation in each growth stage. The results of this study provide a scientific basis for wetland protection, ecological restoration, and sustainable development.

TIMP1 Indicates Poor Prognosis of Renal Cell Carcinoma and Accelerates Tumorigenesis via EMT Signaling Pathway.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. The mortality of advanced RCC remains high despite advances in systemic therapy of RCC. Considering the misdiagnosis of early-stage RCC, the identification of effective biomarkers is of great importance. Tissue inhibitor matrix metalloproteinase 1 (TIMP1), which belongs to TIMP gene family, is a natural inhibitor of the matrix metalloproteinases (MMPs). In this study, we found TIMP1 was significantly up-regulated in cell lines and RCC tissues. Kaplan-Meier analysis revealed that high expression of TIMP1 indicated a poor prognosis. Multivariate analysis further indicated that TIMP1 overexpression was an independent prognostic factor of RCC patients. Furthermore, knockdown of TIMP1 in vitro suppressed the proliferation, migration, and invasion of RCC cells, while upregulating TIMP1 accelerated the proliferation, migration, and invasion of RCC cells. In addition, we also found that TIMP1 prompted the progression of RCC via epithelial-to-mesenchymal transition (EMT) signaling pathway. In conclusion, the present results suggested that TIMP1 indicated poor prognosis of renal cell carcinoma and could serve as a potential diagnostic and prognostic biomarker for RCC.

Induction of resistance of Podosphaera xanthii (hull-less pumpkin powdery mildew) to triazole fungicides and its resistance mechanism.

The aim of this study was to uncover the molecular mechanism through which fungicide resistance develops in Podosphaera xanthii, a fungi that causes powdery mildew in hull-less pumpkin. Treatments of inoculated P. xanthii were carried out on leaves of hull-less pumpkin and subsequently treated with kinds of triazole fungicide for seven generations. Resistant strains of P. xanthii thus obtained were evaluated for their resistance levels. The resistance levels of the fungi to four fungicides of were high except that of the propiconazole-resistant strain, which showed moderate resistance. The F7 generations of five resistant strains thus obtained were cultured continuously for five generations without fungicide induction, and their resistance level were found to be relatively stable. The DNA of the sensitive strain and the five kinds of resistant strains were extracted by the sodium dodecyl sulfate (SDS) method and its internal transcribed spacer (ITS) region was amplified by using ITS1/ITS4 primer and specific primer F/R and they were sequenced respectively. The DNA sequence comparison of resistant and sensitive strains showed that the base pairs of tebuconazole-resistant strains and flusilazole-resistant strains were mutated, with mutation rates of 4.8% and 1.6%, respectively. The base pairs of the other three resistant strains did not change.

Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages.

BACKGROUND: Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity. METHODS: A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson's trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1ß) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student's t-test for two-group comparisons, and one-way ANOVA followed by Student-Newman-Keul test for multiple-group comparisons. RESULTS: We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1ß greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1ß through downregulation of PPARα-CYP4X1 axis. CONCLUSIONS: Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1ß in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity.

Identify Key Determinants of Contraceptive Use for Sexually Active Young People: A Hybrid Ensemble of Machine Learning Methods.

Sexually active young people face an increasing public health burden of unintended pregnancies and sexually transmitted diseases due to improper contraception. However, environmental and social factors related to young people's contraception remain unclear. To identify the key factors, we applied ensemble machine learning methods to the data of 12,280 heterosexual Chinese college students who reported sexual intercourse experience in the National College Student Survey on Sexual and Reproductive Health in 2020 (NCSS-SRH 2020). In the order of variable importance, convenient access to contraceptives, certain attitudes towards sex, sexual health knowledge level, being an only-child, and purchasing a bachelor's or master's degree were positively associated with a high frequency of contraceptive use. In contrast, smoking, free access to contraceptives, a specific attitude towards marriage, and negotiation with a sexual partner were negatively associated with a higher frequency of contraceptive use. Our analysis provides insights into young people's contraceptive use under a typically conservative culture of sexuality. Compared to previous studies, we thoroughly investigated internal and external factors that might impact young people's decision on contraception while having sex. Under a conservative culture of sexuality, the effects of the external factors on young people's contraception may outweigh those of the internal factors.

Ingestion of GNSS-Derived ZTD and PWV for Spatial Interpolation of PM2.5 Concentration in Central and Southern China.

With the increasing application of global navigation satellite system (GNSS) technology in the field of meteorology, satellite-derived zenith tropospheric delay (ZTD) and precipitable water vapor (PWV) data have been used to explore the spatial coverage pattern of PM2.5 concentrations. In this study, the PM2.5 concentration data obtained from 340 PM2.5 ground stations in south-central China were used to analyze the variation patterns of PM2.5 in south-central China at different time periods, and six PM2.5 interpolation models were developed in the region. The spatial and temporal PM2.5 variation patterns in central and southern China were analyzed from the perspectives of time series variations and spatial distribution characteristics, and six types of interpolation models were established in central and southern China. (1) Through correlation analysis, and exploratory regression and geographical detector methods, the correlation analysis of PM2.5-related variables showed that the GNSS-derived PWV and ZTD were negatively correlated with PM2.5, and that their significances and contributions to the spatial analysis were good. (2) Three types of suitable variable combinations were selected for modeling through a collinearity diagnosis, and six types of models (geographically weighted regression (GWR), geographically weighted regression kriging (GWRK), geographically weighted regression-empirical bayesian kriging (GWR-EBK), multiscale geographically weighted regression (MGWR), multiscale geographically weighted regression kriging (MGWRK), and multiscale geographically weighted regression-empirical bayesian kriging (MGWR-EBK)) were constructed. The overall R2 of the GWR-EBK model construction was the best (annual: 0.962, winter: 0.966, spring: 0.926, summer: 0.873, and autumn: 0.908), and the interpolation accuracy of the GWR-EBK model constructed by inputting ZTD was the best overall, with an average RMSE of 3.22 µg/m3 recorded, while the GWR-EBK model constructed by inputting PWV had the highest interpolation accuracy in winter, with an RMSE of 4.5 µg/m3 recorded; these values were 2.17% and 4.26% higher than the RMSE values of the other two types of models (ZTD and temperature) in winter, respectively. (3) The introduction of the empirical Bayesian kriging method to interpolate the residuals of the models (GWR and MGWR) and to then correct the original interpolation results of the models was the most effective, and the accuracy improvement percentage was better than that of the ordinary kriging method. The average improvement ratios of the GWRK and GWR-EBK models compared with that of the GWR model were 5.04% and 14.74%, respectively, and the average improvement ratios of the MGWRK and MGWR-EBK models compared with that of the MGWR model were 2.79% and 12.66%, respectively. (4) Elevation intervals and provinces were classified, and the influence of the elevation and the spatial distribution of the plane on the accuracy of the PM2.5 regional model was discussed. The experiments showed that the accuracy of the constructed regional model decreased as the elevation increased. The accuracies of the models in representing Henan, Hubei and Hunan provinces were lower than those of the models in representing Guangdong and Guangxi provinces.

SARS-CoV-2 Causes Acute Kidney Injury by Directly Infecting Renal Tubules.

Acute kidney injury (AKI) is one of the most prevalent complications among hospitalized coronavirus disease 2019 (COVID-19) patients. Here, we aim to investigate the causes, risk factors, and outcomes of AKI in COVID-19 patients. We found that angiotensin-converting enzyme II (ACE2) and transmembrane protease serine 2 (TMPRSS2) were mainly expressed by different cell types in the human kidney. However, in autopsy kidney samples, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein was detected in ACE2+ or TMPRSS2+ renal tubular cells, whereas the RNAscope® Assay targeting the SARS-CoV-2 Spike gene was positive mainly in the distal tubular cells and seldom in the proximal tubular cells. In addition, the TMPRSS2 and kidney injury marker protein levels were significantly higher in the SARS-CoV-2-infected renal distal tubular cells, indicating that SARS-CoV-2-mediated AKI mainly occurred in the renal distal tubular cells. Subsequently, a cohort analysis of 722 patients with COVID-19 demonstrated that AKI was significantly related to more serious disease stages and poor prognosis of COVID-19 patients. The progressive increase of blood urea nitrogen (BUN) level during the course of COVID-19 suggests that the patient's condition is aggravated. These results will greatly increase the current understanding of SARS-CoV-2 infection.

Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1.

BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration-resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. METHODS: We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. RESULTS: We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta-analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1-knockout (Ces-/- ) mice verified the important role of endogenous Ces1 in PCa. CONCLUSIONS: Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa.

Integrative Analysis of Methylation and Copy Number Variations of Prostate Adenocarcinoma Based on Weighted Gene Co-expression Network Analysis.

Prostate adenocarcinoma (PRAD) is the most pervasive carcinoma diagnosed in men with over 170,000 new cases every year in the United States and is the second leading cause of death from cancer in men despite its indolent clinical course. Prostate-specific antigen testing, which is the most commonly used non-invasive diagnostic method for PRAD, has improved early detection rates in the past decade, but its effectiveness for monitoring disease progression and predicting prognosis is controversial. To identify novel biomarkers for these purposes, we carried out weighted gene co-expression network analysis of the top 10,000 variant genes in PRAD from The Cancer Genome Atlas in order to identify gene modules associated with clinical outcomes. Methylation and copy number variation analysis were performed to screen aberrantly expressed genes, and the Kaplan-Meier survival and gene set enrichment analyses were conducted to evaluate the prognostic value and potential mechanisms of the identified genes. Cyclin E2 (CCNE2), rhophilin Rho GTPase-binding protein (RHPN1), enhancer of zeste homolog 2 (EZH2), tonsoku-like DNA repair protein (TONSL), epoxide hydrolase 2 (EPHX2), fibromodulin (FMOD), and solute carrier family 7 member (SLC7A4) were identified as potential prognostic indicators and possible therapeutic targets as well. These findings can improve diagnosis and disease monitoring to achieve better clinical outcomes in PRAD.

SLC39A8/Zinc Suppresses the Progression of Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most frequent and lethal subtype, which has high risk of metastasis or recurrence, accounting for 75-83% of renal cell carcinoma (RCC). Zrt- and Irt-like proteins (ZIP) family members (SLC39A1-14) function to pass zinc into the cytoplasm for many critical biological processes when cellular zinc is depleted. However, the functional analysis of individual ZIP family genes in ccRCC is not clarified. This study aimed to investigate whether ZIP family genes are related to the clinicopathological features and survival of ccRCC patients, and to identify the function of key gene of ZIP family in ccRCC in vitro. Through bioinformatics analysis of tumor databases, SLC39A8 was identified as a key gene of ZIP family in ccRCC, which could be used as an effective indicator for diagnosing ccRCC and judging its prognosis. With the progression of tumor, the expression of SLC39A8 decreased progressively. The prognosis of patients with low expression of SLC39A8 is significantly worse. Furthermore, we found that overexpression of SLC39A8 or treatment with low concentration of zinc chloride could effectively inhibit the proliferation, migration and invasion of ccRCC cells. Moreover, the inhibition effect of SLC39A8 overexpression could be enhanced by low concentration zinc supplement. Therefore, this study provides a novel understanding for the role of SLC39A8/zinc in the regulation of ccRCC progression. These findings provide a new direction and target for progressive ccRCC drug development and combination therapy strategies.

ACSS3 represses prostate cancer progression through downregulating lipid droplet-associated protein PLIN3.

Current endocrine therapy for prostate cancer (PCa) mainly inhibits androgen/androgen receptor (AR) signaling. However, due to increased intratumoural androgen synthesis and AR variation, PCa progresses to castration-resistant prostate cancer (CRPC), which ultimately becomes resistant to endocrine therapy. A search for new therapeutic perspectives is urgently needed. Methods: By screening lipid metabolism-related gene sets and bioinformatics analysis in prostate cancer database, we identified the key lipid metabolism-related genes in PCa. Bisulfite genomic Sequence Polymerase Chain Reaction (PCR) (BSP) and Methylation-Specific Polymerase Chain Reaction (PCR) (MSP) were preformed to detect the promoter methylation of ACSS3. Gene expression was analyzed by qRT-PCR, Western blotting, IHC and co-IP. The function of ACSS3 in PCa was measured by CCK-8, Transwell assays. LC/MS, Oil Red O assays and TG and cholesterol measurement assays were to detect the levels of TG and cholesterol in cells. Resistance to Enzalutamide in C4-2 ENZR cells was examined in a xenograft tumorigenesis model in vivo. Results: We found that acyl-CoA synthetase short chain family member 3 (ACSS3) was downregulated and predicted a poor prognosis in PCa. Loss of ACSS3 expression was due to gene promoter methylation. Restoration of ACSS3 expression in PCa cells significantly reduced LD deposits, thus promoting apoptosis by increasing endoplasmic reticulum (ER) stress, and decreasing de novo intratumoral androgen synthesis, inhibiting CRPC progression and reversing Enzalutamide resistance. Mechanistic investigations demonstrated that ACSS3 reduced LD deposits by regulating the stability of the LD coat protein perilipin 3 (PLIN3). Conclusions: Our study demonstrated that ACSS3 represses prostate cancer progression through downregulating lipid droplet-associated protein PLIN3.

Clinical Characteristics of Patients with Severe and Critical COVID-19 in Wuhan: A Single-Center, Retrospective Study.

INTRODUCTION: This retrospective, single-center study was performed to systemically describe the characteristics and outcomes of patients with severe and critical coronavirus disease 2019 (COVID-19) in Wuhan, analyze the risk factors, and propose suggestions for clinical diagnosis and treatment to guide the subsequent clinical practice. METHODS: A total of 753 consecutive patients with COVID-19 admitted to the West Campus of Wuhan Union Hospital from January 22, 2020 to May 7, 2020 were enrolled in this study. Demographic, clinical, laboratory, and outcome data were extracted from the electronic medical records of Wuhan Union Hospital and were exhaustively analyzed using R (version 3.6.1). RESULTS: A total of 493 severe and 228 critical cases out of 753 COVID-19 cases were considered in this study. Among the critical cases, the death rate was 79.4%, and age was a risk factor for death. Compared to the severe disease group, the critical disease group had higher white blood cell (WBC) and neutrophil counts and a decreased lymphocyte count at admission. Compared to early death cases (death within 1 week after admission), a more prolonged course of the disease was associated with a higher risk of hypoproteinemia, liver injury, thrombocytopenia, anemia, disseminated intravascular coagulation (DIC), coagulation disorders, acute kidney injury (AKI), and infection. Higher creatine kinase (CK) and lactate dehydrogenase (LDH) levels were related to early death events, but univariate and multivariate analyses confirmed only LDH as an independent predictor of early death. Notably, anticoagulation therapy was associated with an improved prognosis of critical cases in this cohort. CONCLUSION: Our results showed large differences between patients with severe and critical COVID-19. During the course of COVID-19 in the critical disease group, the incidence of hypoproteinemia, anemia, thrombocytopenia, and coagulation disorders increased significantly, which highlighted the importance of medical care in the first week after admission. LDH could act as an independent predictor of early death in critical cases, and anticoagulation therapy was correlated with an improved prognosis of patients with critical COVID-19.