An androgen receptor-based signature to predict prognosis and identification of ORC1 as a therapeutical target for prostate adenocarcinoma.

Background: Aberrant activation of androgen receptor (AR) signaling plays a crucial role in the progression of prostate adenocarcinoma (PRAD) and contributes significantly to the development of enzalutamide resistance. In this study, we aimed to identify a novel AR-driven signature that can predict prognosis and endows potentially reveal novel therapeutic targets for PRAD. Methods: The Seurat package was used to preprocess the single-cell RNA sequencing (scRNA-seq). Differentially expressed genes were visualized using limma and pheamap packages. LASSO and multi-variate Cox regression models were established using glmnet package. The package "Consensus Cluster Plus" was utilized to perform the consensus clustering analysis. The biological roles of origin recognition complex subunit 1 (ORC1) in PRAD were determined by gain- and loss-of-function studies in vitro and in vivo. Result: We characterized the scRNA-seq data from GSE99795 and identified 10 AR-associated genes (ARGs). The ARGs model was trained and validated in internal and external cohorts. The ARGs were identified as an independent hazard factor in PRAD and correlated with clinical risk characteristics. In addition, the ARGs were found to be correlated with somatic tumor mutation burden (TMB) levels. Two groups that have distinct prognostic and molecular features were identified through consensus clustering analysis. ORC1 was identified as a critical target among these ARGs, and it ORC1 promoted proliferation and stem-like properties of PRAD cells. Chromatin immunoprecipitation (ChIP)-qPCR assay confirmed that AR could directly bind the promoter of ORC1. Activated AR/ORC1 axis contributed to enzalutamide resistance, and targeting ORC1 rendered PRAD cells more susceptible to enzalutamide. Conclusions: This study defines an AR-driven signature that AR activates ORC1 expressions to promote PRAD progression and enzalutamide resistance, which may provide novel targets for PRAD treatment.

SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10.

BACKGROUND: ARHGAP10 is a tumor-suppressor gene related to ovarian cancer (OC) progression; however, its specific mechanism is unclear. AIMS: To investigate the effect of ARHGAP10 on OC cell migration, invasion, and glycolysis. METHODS AND RESULTS: Quantitative real-time PCR (qRT-PCR) quantified mRNA and protein expressions of AKT, p-AKT, HK2, and SMAD4 were tested by Western blot. EdU, Wound healing, and Transwell assay were utilized to evaluate OC cell proliferation, migration, and invasion. We used a Seahorse XF24 Extracellular Flux Analyzer to monitor cellular oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Chromatin immunoprecipitation (ChIP) was used to analyze the transcriptional regulation of ARHGAP10 by SMAD4. ARHGAP10 expression in OC tissues was detected by immunohistochemistry. Our results showed that ARHGAP10 expression was negatively related to lactate levels in human OC tissues. ARHGAP10 overexpression can inhibit the migration, proliferation, and invasion of OC cells, and this function can be blocked by 2-Deoxy-D-glucose. Moreover, we found that ARHGAP10 expression can be rescued with the AKT inhibitor LY294002. CONCLUSIONS: This study revealed that the antitumor effects of ARHGAP10 in vivo and in vitro possibly suppress oncogenic glycolysis through the PI3K/AKT/HK2-regulated glycolysis metabolism pathway.

Serum Galectin-3 Predicts Mortality in Venoarterial Extracorporeal Membrane Oxygenation Patients.

Objective: We investigated the potential use of galectin-3 (Gal-3) as a prognostic indicator for patients with cardiogenic shock and developed a predictive mortality model for venoarterial extracorporeal membrane oxygenation (VA-ECMO). Methods: We prospectively studied patients (survivors and nonsurvivors) who received VA-ECMO for cardiogenic shock from 2019 to 2021. We recorded baseline data, Gal-3, and B-type natriuretic peptide (BNP) before ECMO and 24-72 h after ECMO. We used multivariable logistic regression to analyze significant risk factors and construct a VA-ECMO death prediction model. Receiver operating characteristic (ROC) curves were plotted to assess the predictive efficacy of the model. Results: We enrolled 73 patients with cardiogenic shock who received VA-ECMO support; 38 (52.05%) died in hospital. The median age was 57 years (interquartile range (IQR): 48-67 years); the median duration of ECMO therapy was 5.8 days (IQR: 4.62-7.57 days); and the median intensive care unit stay was 19.04 days (IQR: 13.92-26.15 days). Compared with the nonsurvivors, survivors had lower acute physiology and chronic health evaluation (APACHE) II scores (p < 0.001), increased left ventricular ejection fraction (p < 0.05), lower Gal-3 levels at 24 and 72 h (both p = 0.001), lower BNP levels at 24 and 72 h (both p = 0.001), and higher platelet counts (p = 0.009). Further multivariable analysis showed that APACHE II score, BNP-T72, and Gal-3-T72 were independent risk factors for death in VA-ECMO patients. Gal-3 and BNP were positively correlated (p < 0.05) and decreased significantly during ECMO treatment. The areas under the ROC curve (AUC) for APACHE II score, Gal-3-T72, and BNP-T72 were 0.687, 0.799, and 0.723, respectively. We constructed a combined prediction model with an AUC of 0.884 (p < 0.01). Conclusion: Gal-3 may serve as a prognostic indicator for patients receiving VA-ECMO for cardiogenic shock. The combined early warning score is a simple and effective tool for predicting mortality in VA-ECMO patients.

Association of inactivated COVID-19 vaccination with maternal coagulation function in early pregnancy.

Reports of rare but severe thrombotic events after receiving some COVID-19 vaccines brought concerns for the possibility of vaccine-induced coagulation abnormality. However, no study has reported the impacts of COVID-19 vaccination on coagulation function in pregnant women. We aimed to explore whether vaccination with inactivated COVID-19 vaccines before pregnancy was associated with coagulation changes in pregnant women. We conducted a retrospective cohort study in a tertiary-care hospital in Shanghai, China. A total of 5166 pregnant women were included, of whom 2721 (52.7%) completed vaccination before conception. Compared with unvaccinated women, the mean serum levels of prothrombin time (PT) and fibrinogen (FIB) were lower in vaccinated women by 0.09 (ß = -0.09, 95% confidence interval [CI], -0.13, -0.05) mg/L and 0.11 (ß = -0.11, 95% CI, -0.15, -0.07) mg/L, and the mean D-Dimer (D-D) levels were higher by 0.12 (ß = 0.12, 95% CI, 0.09, 0.15) mg/L. However, no significant association was observed between COVID-19 vaccination and serum levels of activated partial thromboplastin time (APTT), fibrinogen degradation product (FDP) or thrombin time (TT). Our findings suggested that inactivated COVID-19 vaccination before conception resulted in a small change in maternal coagulation function, but this might not have clinical significance.

p16INK4A flow cytometry of exfoliated cervical cells: Its role in quantitative pathology and clinical diagnosis of squamous intraepithelial lesions.

BACKGROUND: P16INK4A is a surrogate signature compensating for the specificity and/or sensitivity deficiencies of the human papillomavirus (HPV) DNA and Papanicolaou smear (Pap) co-test for detecting high-grade cervical squamous intraepithelial lesions or worse (HSIL+). However, traditional p16INK4A immunostaining is labour intensive and skill demanding, and subjective biases cannot be avoided. Herein, we created a high-throughput, quantitative diagnostic device, p16INK4A flow cytometry (FCM) and assessed its performances in cervical cancer screening and prevention. METHODS: P16INK4A FCM was built upon a novel antibody clone and a series of positive and negative (p16INK4A -knockout) standards. Since 2018, 24 100-women (HPV-positive/-negative, Pap-normal/-abnormal) have been enrolled nationwide for two-tier validation work. In cross-sectional studies, age- and viral genotype-dependent expression of p16INK4A was investigated, and optimal diagnostic parameter cut-offs (using colposcopy and biopsy as a gold standard) were obtained. In cohort studies, the 2-year prognostic values of p16INK4A were investigated with other risk factors by multivariate regression analyses in three cervicopathological conditions: HPV-positive Pap-normal, Pap-abnormal biopsy-negative and biopsy-confirmed LSIL. RESULTS: P16INK4A FCM detected a minimal ratio of 0.01% positive cells. The p16INK4A -positive ratio was 13.9 ± 1.8% among HPV-negative NILM women and peaked at the ages of 40-49 years; after HPV infection, the ratio increased to 15.1 ± 1.6%, varying with the carcinogenesis of the viral genotype. Further increments were found in women with neoplastic lesions (HPV-negative: 17.7 ± 5.0-21.4 ± 7.2%; HPV-positive: 18.0 ± 5.2-20.0 ± 9.9%). Extremely low expression of p16INK4A was observed in women with HSILs. As the HPV-combined double-cut-off-ratio criterion was adopted, a Youden's index of 0.78 was obtained, which was significantly higher than that (0.72) of the HPV and Pap co-test. The p16INK4A -abnormal situation was an independent HSIL+ risk factor for 2-year outcomes in all three cervicopathological conditions investigated (hazard ratios: 4.3-7.2). CONCLUSIONS: FCM-based p16INK4A quantification offers a better choice for conveniently and precisely monitoring the occurrence of HSIL+ and directing risk-stratification-based interventions.

Mitonuclear Interactions and the Origin of Macaque Societies.

In most eukaryotes, aerobic respiration requires interactions between autosomally encoded genes (Ninteract genes) and mitochondrial DNA, RNA, and protein. In species where females are philopatric, contrasting distributions of genetic variation in mitochondrial and nuclear genomes create variation in mitonuclear interactions that may be subject to natural selection. To test this expectation, we turned to a group with extreme female philopatry: the macaque monkeys. We examined four genomic data sets from (1) wild caught and (2) captive populations of rhesus macaque, which is the most widely distributed nonhuman primate, and (3) the stump-tailed macaque and (4) a subspecies of longtail macaque, both of whose mitochondrial DNA is introgressed from a highly diverged ancestor. We identified atypically long runs of homozygosity, low polymorphism, high differentiation, and/or rapid protein evolution associated with Ninteract genes compared with non-Ninteract genes. These metrics suggest a subset of Ninteract genes were independently subject to atypically pervasive natural selection in multiple species. These findings suggest that natural selection on mitonuclear interactions could have influenced several aspects of macaque societies including species diversity, ecological breadth, female-biased adult sex ratio and demography, sexual dimorphism, and mitonuclear phylogenomics.

Herpesvirus entry mediator regulates the transduction of Tregs via STAT5/Foxp3 signaling pathway in ovarian cancer cells.

The ratio of regulatory T cells (Treg) in peripheral blood of cancer patients has a closely correlation to the occurrence and development of ovarian cancer. In this study, our aim to explore the expression of herpesvirus entry mediator (HVEM) in ovarian cancer and its correlation with Tregs. The expression of HVEM in peripheral blood of ovarian cancer patients was detected by ELISA, and the ratio of CD4+ CD25 + Foxp3 positive Tregs cells was detected by flow cytometry. Ovarian cancer cell lines with high- and low-HVEM expression were constructed. CD4+ cells were co-cultured with ovarian cancer (OC) cells, and the expressions of IL-2 and TGF-ß1 in the supernatant of cells were detected by ELISA, and western blot was used to detect the expressions of STAT5, p-STAT5, and Foxp3. The results indicated that the number of Treg cells in the peripheral blood of OC patients increased, and the expression of HVEM increased, the two have a certain correlation. At the same time, the overexpression of HVEM promoted the expression of cytokines IL-2 and TGF- ß1, promoted the activation of STAT5 and the expression of Foxp3, leading to an increase in the positive rate of Treg, while the HVEM gene silence group was just the opposite. Our results showed that the expression of HVEM in OC cells has a positive regulation effect on Tregs through the STAT5/Foxp3 signaling pathway. To provide experimental basis and related mechanism for the clinical treatment of ovarian cancer.

m6A-related long noncoding RNAs predict prognosis and indicate therapeutic response in endometrial carcinoma.

BACKGROUND: N6-methyladenosine (m6A) has been identified as the most common, abundant, and conserved internal transcriptional modification. Long noncoding RNAs (lncRNAs) are noncoding RNAs consisting of more than 200 nucleotides, and the expression of various lncRNAs may affect cancer prognosis. The impact of m6A-associated lncRNAs on uterine corpus endometrial carcinoma (UCEC) prognosis is unknown. METHODS: In this study, UCEC prognosis-related m6A lncRNAs were screened, bioinformatics analysis was performed, and experimental validation was conducted. Endometrial carcinoma (EC) and normal tissue samples were obtained from The Cancer Genome Atlas. The prognosis-related m6A lncRNAs screened by the least absolute shrinkage and selection operator method were used for multivariate Cox proportional risk regression modeling. Principal component analysis and Gene Ontology, immune function difference, and drug sensitivity analyses of the prognostic models were performed. Prognostic analysis was conducted for m6A-associated lncRNAs. The immune infiltration relationship of m6A-associated lncRNAs in EC was identified using the ssGSEA immune infiltration algorithm. A competing endogenouse RNA network was constructed using the LncACTdb database. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) assays were used to validate the differences in m6A-related lncRNA expression in normal and EC cells. RESULTS: CDKN2B-AS1 and MIR924HG were found to be risk factors for EC. RAB11B-AS1 was a protective factor in EC patients. MIR924HG expression was upregulated in KLE and RL95-2 endometrial cancer cell lines. Prognostic models involved RAB11B-AS1, LINC01812, HM13-IT1, TPM1-AS, SLC16A1-AS1, LINC01936, and CDKN2B-AS1. The high-risk group was more sensitive to five compounds (ABT.263, ABT.888, AP.24534, ATRA, and AZD.0530) than the low-risk group. CONCLUSION: These findings contribute to understanding of the function of m6A-related lncRNAs in UCEC and provide promising therapeutic strategies for UCEC.

Anterior Gradient 2 is a Significant Prognostic Biomarker in Bone Metastasis of Breast Cancer.

Background: The study aimed to detect DEGs associated with BRCA bone metastasis, filter prognosis biomarkers, and explore possible pathways. Methods: GSE175692 dataset was used to detect DEGs between BRCA bone metastatic cases and non-bone metastatic cases, followed by the construction of a PPI network among DEGs. The main module among the PPI network was then determined and pathway analysis on genes within the module was performed. Through performing Cox regression, Kaplan-Meier, nomogram, and ROC curve analyses using GSE175692 and GSE124647 datasets at the same time, the most significant prognostic biomarker was gradually filtered. Finally, important pathways associated with prognostic biomarkers were explored by GSEA analysis. Results: The 74 DEGs were detected between bone metastasis and non-bone metastasis groups. A total of 15 nodes were included in the main module among the whole PPI network and they mainly correlated with the IL-17 signaling pathway. We then performed Cox analysis on 15 genes using two datasets and only enrolled the genes with p < 0.05 in Cox analysis into the further analyses. Kaplan-Meier analyses using two datasets showed that the common biomarker AGR2 expression was related to the survival time of BRCA metastatic cases. Further, the nomogram determined the greatest contribution of AGR2 on the survival probability and the ROC curve revealed its optimal prognostic performance. More importantly, high expression of AGR2 prolonged the survival time of BRCA bone metastatic patients. These results all suggested the importance of AGR2 in metastatic BRCA. Finally, we performed the GSEA analysis and found that AGR2 was negatively related to IL-17 and NF-kß signaling pathways. Conclusion: AGR2 was finally determined as the most important prognostic biomarker in BRCA bone metastasis, and it may play a vital role in cancer progression by regulating IL-17 and NF-kB signaling pathways.

The Relationship between Serum CXCL8 and ET-1 Expression Levels and Sepsis Complicated with Heart Failure.

Objective: The objective is to investigate the relationship between sepsis complicated with heart failure and the expression levels of CXC chemokine ligand 8 (CXCL8) and endothelin-1 (ET-1). Methods: A total of 128 sepsis patients accepted by the Ganzhou People's Hospital from March 2019 to December 2021 were collected as observation objects, and they were separated into a simple sepsis group (86 cases) and a complicated heart failure group (42 cases) according to whether they were accompanied by heart failure or not. General data such as Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation II (APACHE II) were collected; the expression levels of serum CXCL8 and ET-1 were detected by enzyme-linked immunosorbent assay (ELISA); the cardiac function parameters such as left ventricular ejection fraction (LVEF), stroke volume (SV), cardiac output (CO), and cardiac index (CI) were measured by color Doppler ultrasound; the correlation between serum CXCL8 and ET-1 expression levels with clinical data and cardiac function parameters in patients with sepsis complicated with heart failure was analyzed by the Pearson correlation; and the influencing factors of sepsis complicated with heart failure were analyzed by the logistic regression analysis. Results: The serum CXCL8 and ET-1 expression levels, SOFA score, and APACHE II score in the complicated heart failure group were higher than those in the simple sepsis group (P < 0.05), and LVEF, SV, CO, and CI in the complicated heart failure group were lower than those in the simple sepsis group (P < 0.05). Serum CXCL8 was positively correlated with ET-1 in patients with sepsis complicated with heart failure (r = 0.531, P < 0.05), and the two were positively correlated with SOFA score and APACHE II score (P < 0.05) and were negatively correlated with LVEF, SV, CO, and CI (P < 0.05). CXCL8 and ET-1 were independent risk factors for sepsis complicated with heart failure (P < 0.05). Conclusion: The expression levels of serum CXCL8 and ET-1 in sepsis patients with heart failure are significantly increased, and both are risk factors for heart failure in sepsis patients.

Ferroptosis-Related lncRNA for the Establishment of Novel Prognostic Signature and Therapeutic Response Prediction to Endometrial Carcinoma.

Background: Ferroptosis is a recently described form of intentional cellular damage that is iron-dependent and separate from apoptosis, cellular necrosis, and autophagy. It has been demonstrated to be adequately regulated by long noncoding RNAs (lncRNAs) in various cancers. However, the predictive profile of ferroptosis-related lncRNAs (FRLs) in endometrial carcinoma (EC) is unknown. Herein, FRLs associated with uterine corpus endometrial carcinoma (UCEC) prognosis were screened to predict treatment response in EC. Methods: Samples of EC and adjacent normal tissues were obtained from The Cancer Genome Atlas (TCGA) dataset repository. Limma and survival packages in R software were used to screen FRLs associated with the prognosis of EC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) chord and circle plots of FRLs were also plotted. Next, FRLs screened by the least absolute shrinkage and selection operator (LASSO) method were applied to construct and validate a multivariate Cox proportional risk regression model. Nomogram plots were created to forecast the outcome of UCEC patients, and gene set enrichment analysis (GSEA), principal component analysis (PCA), and immunoassays were performed on the prognostic models. Finally, limma, ggpubr, pRRophetic, and ggplot2 programs were used for drug sensitivity analysis of the prognostic models. Results: A signature based on nine FRLs (CFAP58-DT, LINC00443, EMSLR, HYI-AS1, ADIRF-AS1, LINC02474, CDKN2B-AS1, LINC01629, and LINC00942) was constructed. The developed FRL prognostic model effectively discriminated UCEC patients into low-risk and high-risk groups. Immunological checkpoints CD80 and CD40 were strongly expressed in the high-risk group. In addition, the nine FRLs were all more expressed in the high-risk group compared to the low-risk group. Conclusion: These findings significantly contribute to the understanding of the function of FRLs in UCEC and provide promising therapeutic strategies for UCEC.

Removal of Chromium (VI) by a Magnetic Nanoscale Zerovalent Iron-Assisted Chicken Manure-Derived Biochar: Adsorption Behavior and Synergetic Mechanism.

Using chicken manure as raw material to prepare activated carbon as a dispersant, a novel biochar-loaded nano-zerovalent iron composite (nZVI@CMBC) was developed and applied to remove hexavalent chromium, i.e., Cr(VI), in wastewater. The dispersion of nano-zerovalent iron (nZVI) particles on the surface of chicken manure-derived biochar (CMBC) successfully inhibited the aggregation of magnetic iron particles and effectively reduced the size of nZVI particles. The results demonstrated that under acidic conditions, the removal efficiency of Cr(VI) by the nZVI@CMBC composite could reach 124.12 mg g-1. The pseudosecond-order kinetic model had a good agreement with the adsorption kinetics of the nZVI@CMBC composite, implying that the adsorption of Cr(VI) is based on the multi-layer chemical adsorption. Therefore, this study provides a new clue and strategy for removing Cr(VI) in wastewater.

Signal transducer and activator of transcription family is a prognostic marker associated with immune infiltration in endometrial cancer.

BACKGROUND: Signal transducer and activator of transcription (STAT) is a unique protein family that binds to DNA and plays a vital role in regulating major physiological cellular processes. Seven STAT genes have been identified in the human genome. Several studies suggest STAT family members to be involved in cancer development, progression, and metastasis. However, the predictive relationship between STAT family expression and immune cell infiltration in endometrial cancer remains unknown. METHODS: We explored STAT family expression and prognosis in endometrial cancer using various databases. The STRING, GeneMANIA, and DAVID databases, along with GO and KEGG analyses, were used to construct a protein interaction network of related genes. Finally, the TIMER database and ssGSEA immune infiltration algorithm were used to investigate the correlation of STAT family expression with the immune infiltration level in uterine corpus endometrial carcinoma (UCEC). RESULTS: Our study showed that different STAT family members are differentially expressed in UCEC. STAT1 and STAT2 expression increased at various stages of UCEC, and STAT5A, STAT5B, and STAT6 levels were decreased. STAT3 and STAT4 expression was not significantly different between UCEC and normal tissues. High STAT1 expression may be a prognostic disadvantage of UCEC, and high STAT6 expression may improve UCEC patient prognosis. The STAT family-associated genes were significantly enriched in signal transduction, protein binding, DNA binding, and ATP binding upon GO analysis. Related genes in the KEGG analysis were mainly enriched in pathways in cancer, viral carcinogenesis, chemokine signaling pathway, JAK/STAT signaling pathway, and regulation of the actin cytoskeleton. In terms of immune infiltration, STAT1 and STAT2 were positively correlated with B, CD8+ T, CD4+ T, and dendritic cells, and neutrophils (p < 0.05). All STAT family members were positively correlated with neutrophils and dendritic cells (p < 0.05). STAT1 and STAT2 showed similar correlations with all immune cell types, whereas STAT1 and STAT6 showed opposite correlations. CONCLUSION: These findings suggest that the STAT family is a prognostic marker, and the immune infiltration level, a therapeutic target, for endometrial cancer.

CMTM5 inhibits the development of prostate cancer via the EGFR/PI3K/AKT signaling pathway.

Prostate cancer (PCa) endangers the life and health of older men. Most PCa cases develop into castration­resistant PCa (CRPC) within 2 years. At present, the molecular mechanisms of the occurrence and development of PCa and its transformation to CRPC remain unknown. The present study aimed to investigate the role of CKLF­like Marvel transmembrane domain containing family member 5 (CMTM5) in PCa and its molecular mechanism in vitro. PCa tissues and paired adjacent normal prostate tissues from 70 patients were collected to examine the expression levels of CMTM5 and EGFR via immunohistochemistry, reverse transcription­quantitative PCR and western blotting. Then, CMTM5­overexpressing DU145 cells were constructed, and CMTM5 expression in these transfected cells and vector control cells was examined via western blotting. Cell Counting Kit­8 and plate clone formation assays were used to evaluate the proliferation and colony number of CMTM5­overexpressing cells and vector control cells. Then, cell migration and invasion were assessed using wound healing assay, Transwell assay and immunofluorescence analysis with DAPI staining. The effect of CMTM5 on apoptosis and its underlying molecular mechanism were examined using western blotting and flow cytometry. The results demonstrated that CMTM5 expression in PCa tissues and cell lines was significantly downregulated, while EFGR expression was significantly upregulated. The proportion of high CMTM5 expression in PCa tissues was significantly lower compared with that in normal prostate tissues. By contrast, the proportion of high EGFR expression in PCa tissues was significantly increased compared with that in normal prostate tissues. Moreover, CMTM5 overexpression significantly inhibited cell proliferation, migration and invasion, and promoted cell apoptosis compared with vector control cells in vitro. Furthermore, the regulation of PCa by CMTM5 was associated with the downregulation of PI3K/AKT and its downstream Bcl­2 expression, as well as the upregulation of Bax expression. In conclusion, CMTM5 may be an effective tumor suppressor gene for PCa, especially for castration­resistant PCa, by downregulating EGFR and PI3K/AKT signaling pathway components.

Long-term outcomes of radiofrequency ablation vs. partial nephrectomy for cT1 renal cancer: A meta-analysis and systematic review.

Background: Partial nephrectomy (PN) is one of the most preferred nephron-sparing treatments for clinical T1 (cT1) renal cancer, while radiofrequency ablation (RFA) is usually used for patients who are poor surgical candidates. The long-term oncologic outcome of RFA vs. PN for cT1 renal cancer remains undetermined. This meta-analysis aims to compare the treatment efficacy and safety of RFA and PN for patients with cT1 renal cancer with long-term follow-up of at least 5 years. Method: This meta-analysis was performed following the PRISMA reporting guidelines. Literature studies that had data on the comparison of the efficacy or safety of RFA vs. PN in treating cT1 renal cancer were searched in databases including PubMed, Embase, Web of Science, and the Cochrane Library from 1 January2000 to 1 May 2022. Only long-term studies with a median or mean follow-up of at least 5 years were included. The following measures of effect were pooled: odds ratio (OR) for recurrence and major complications; hazard ratio (HR) for progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Additional analyses, including sensitivity analysis, subgroup analysis, and publication bias analysis, were also performed. Results: A total of seven studies with 1,635 patients were finally included. The treatment efficacy of RFA was not different with PN in terms of cancer recurrence (OR = 1.22, 95% CI, 0.45-3.28), PFS (HR = 1.26, 95% CI, 0.75-2.11), and CSS (HR = 1.27, 95% CI, 0.41-3.95) as well as major complications (OR = 1.31, 95% CI, 0.55-3.14) (P > 0.05 for all). RFA was a potential significant risk factor for OS (HR = 1.76, 95% CI, 1.32-2.34, P < 0.001). No significant heterogeneity and publication bias were observed. Conclusion: This is the first meta-analysis that focuses on the long-term oncological outcomes of cT1 renal cancer, and the results suggest that RFA has comparable therapeutic efficacy with PN. RFA is a nephron-sparing technique with favorable oncologic efficacy and safety and a good treatment alternative for cT1 renal cancer.

Mitonuclear interactions and introgression genomics of macaque monkeys (Macaca) highlight the influence of behaviour on genome evolution.

In most macaques, females are philopatric and males migrate from their natal ranges, which results in pronounced divergence of mitochondrial genomes within and among species. We therefore predicted that some nuclear genes would have to acquire compensatory mutations to preserve compatibility with diverged interaction partners from the mitochondria. We additionally expected that these sex-differences would have distinctive effects on gene flow in the X and autosomes. Using new genomic data from 29 individuals from eight species of Southeast Asian macaque, we identified evidence of natural selection associated with mitonuclear interactions, including extreme outliers of interspecies differentiation and metrics of positive selection, low intraspecies polymorphism and atypically long runs of homozygosity associated with nuclear-encoded genes that interact with mitochondria-encoded genes. In one individual with introgressed mitochondria, we detected a small but significant enrichment of autosomal introgression blocks from the source species of her mitochondria that contained genes which interact with mitochondria-encoded loci. Our analyses also demonstrate that sex-specific demography sculpts genetic exchange across multiple species boundaries. These findings show that behaviour can have profound but indirect effects on genome evolution by influencing how interacting components of different genomic compartments (mitochondria, the autosomes and the sex chromosomes) move through time and space.

Lanatoside C inhibits human cervical cancer cell proliferation and induces cell apoptosis by a reduction of the JAK2/STAT6/SOCS2 signaling pathway.

Cervical cancer is one of the leading causes of cancer-associated mortality in gynecological diseases and ranks third among female cancers worldwide. Although early detection and vaccination have reduced incidence rates, cancer recurrence and metastasis lead to high mortality due to the lack of effective medicines. The present study aimed to identify novel drug candidates to treat cervical cancer. In the present study, lanatoside C, an FDA-approved cardiac glycoside used for the treatment of heart failure, was demonstrated to have anti-proliferative and cytotoxic effects on cervical cancer cells, with abrogation of cell migration in a dose-dependent manner. Lanatoside C also triggered cell apoptosis by enhancing reactive oxygen species production and reducing the mitochondrial membrane potential, which induced cell cycle arrest at the S and G2/M phases. Furthermore, lanatoside C inhibited the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 6 (STAT6), while inducing the expression of suppressor of cytokine signaling 2, a negative regulator of JAK2-STAT6 signaling. Taken together, the results of the present study suggest that lanatoside C suppresses cell proliferation and induces cell apoptosis by inhibiting JAK2-STAT6 signaling, indicating that lanatoside C is a promising agent for the treatment of cervical cancer.

The risk factors for acute respiratory distress syndrome in patients with severe acute pancreatitis: A retrospective analysis.

ABSTRACT: Acute respiratory distress syndrome (ARDS) is very common in patients with severe acute pancreatitis (SAP), the early interventions are essential to the prognosis of SAP patients. We aimed to evaluate the risk factors for ARDS in SAP patients, to provide insights into the management of SAP.SAP patients treated in our hospital from June 1, 2018 to May 31, 2020 were included. The characteristics and lab test results were collected and compared, and we conducted the logistic regression analyses were conducted to identify the potential risk factors for ARDS in patients with SAP.A total of 281 SAP patients were included finally, the incidence of ARDS in patients with SAP was 30.60%. There were significant differences on the respiratory rate, heart rate, APACHE II and Ranson score between 2 groups (all P < .05). And there were significant differences on the polymorphonuclear, procalcitonin, C-reactive protein, serum creatinine, albumin and PO2/FiO2 between 2 groups (all P < .05), and no significant differences on the K+, Na+, Ca+, white blood cell, neutrophils, urine and blood amylase, trypsin, lipase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, triglyceride, total cholesterol, total bilirubin, fasting blood glucose, and pH were found (all P > .05). Respiratory rate >30/min (odds ratio [OR]: 2.405, 95% confidence interval[CI]: 1.163-4.642), APACHE II score >11 (OR: 1.639, 95% CI: 1.078-2.454), Ranson score >5 (OR: 1.473, 95% CI: 1.145-2.359), polymorphonuclear >14 × 109/L (OR: 1.316, 95% CI: 1.073-2.328), C-reactive protein >150 mg/L (OR: 1.127, 95% CI: 1.002-1.534), albumin ≤30 g/L (OR: 1.113, 95% CI: 1.005-1.489) were the independent risk factors for ARDS in patients with SAP (all P < .05).The incidence of ARDS in SAP patients is relatively high, and it is necessary to carry out targeted early prevention and treatment for the above risk factors.

HVEM/HIF-1α promoted proliferation and inhibited apoptosis of ovarian cancer cells under hypoxic microenvironment conditions.

BACKGROUND: Our previous studies showed the expression of herpes virus entry mediator (HVEM) is high in ovarian cancer samples and correlated to the patient clinic pathological features. As we all know, the hypoxic environment is the main feature of tumor. In this work, we explored the role of HVEM in hypoxic ovarian cancer cells and its effects on HIF-1α, a transcription factor responding to hypoxia. METHODS: The expression of HVEM, HIF-1α and apoptosis-related genes was detected by qRT-PCR and western blot. The proliferation and apoptosis of the ovarian cancer cells were determined with the Cell Counting Kit-8 assay and AnnexinV-FITC/PI-stained flow cytometry assay, respectively. RESULTS: The expression of HVEM was positively correlated to that of HIF-1α. The expression of HVEM and HIF-1α under hypoxic conditions was higher than that under normoxic conditions, which suggested that the level of HVEM and HIF-1α correlates with prolonged periods of hypoxia in ovarian cancer. The overexpression of HVEM promoted cell proliferation and inhibited cell apoptosis under hypoxic condition. HVEM overexpression elevated the expression of HIF-1α and Bcl-2 (anti-apoptotic protein), and reduced the expression of Bax (pro-apoptotic protein). In addition, overexpression of HVEM activated the AKT/mTOR signaling. Moreover, knockdown of HVEM had the completely opposite effects. CONCLUSION: These data indicated that HVEM signaling might promote HIF-1α activity via AKT/mTOR signaling pathway and thus to regulate tumor growth in ovarian cancer under the hypoxic conditions. Furthermore, these findings indicate that this molecular mechanism could represent a therapeutic target for ovarian cancer.

Alteration of (Frequency-Dependent) Fitness in Time-Shift Experiments Reveals Cryptic Coevolution and Uncoordinated Stasis in a Virtual Jurassic Park.

Among the major unresolved questions in ecosystem evolution are whether coevolving multispecies communities are dominated more by biotic or by abiotic factors, and whether evolutionary stasis affects performance as well as ecological profile; these issues remain difficult to address experimentally. Digital evolution, a computer-based instantiation of Darwinian evolution in which short self-replicating computer programs compete, mutate, and evolve, is an excellent platform for investigating such topics in a rigorous experimental manner. We evolved model communities with ecological interdependence among community members, which were subjected to two principal types of mass extinction: a pulse extinction that killed randomly, and a selective press extinction involving an alteration of the abiotic environment to which the communities had to adapt. These treatments were applied at two different strengths (Strong and Weak), along with unperturbed Control experiments. We performed several kinds of competition experiments using simplified versions of these communities to see whether long-term stability that was implied previously by ecological and phylogenetic metrics was also reflected in performance, namely, whether fitness was static over long periods of time. Results from Control and Weak treatment communities revealed almost completely transitive evolution, while Strong treatment communities showed higher incidences of temporal intransitivity, with pre-treatment ecotypes often able to displace some of their post-recovery successors. However, pre-treatment carryovers more often had lower fitness in mixed communities than in their own fully native conditions. Replacement and invasion experiments pitting single ecotypes against pre-treatment reference communities showed that many of the invading ecotypes could measurably alter the fitnesses of one or more residents, usually with depressive effects, and that the strength of these effects increased over time even in the most stable communities. However, invaders taken from Strong treatment communities often had little or no effect on resident performance. While we detected periods of time when the fitness of a particular evolving ecotype remained static, this stasis was not permanent and never affected an entire community at once. Our results lend support to the fitness-deterioration interpretation of the Red Queen hypothesis, and highlight community context dependence in determining fitness, the shaping of communities by both biotic factors and abiotic forcing, and the illusory nature of evolutionary stasis. Our results also demonstrate the potential of digital evolution studies to illuminate many aspects of evolution in interacting multispecies communities.