Global burden of bladder cancer attributable to smoking in 204 countries and territories, 1990-2019.

Bladder cancer (BCa) poses a significant medical burden worldwide. However, the epidemiological pattern of the global smoking-induced BCa burden is unclear. Our analysis of the 2019 Global Burden of Disease (GBD) database showed a significant increase in the number of BCa cases worldwide from 1990 to 2019, with a clear upward trend in both age-standardized prevalence and incidence. In contrast, age-standardized rates of mortality (ASMR) and disability-adjusted life-years (ASDR) showed a downward trend, despite an increase in the absolute number of death and disability-adjusted life years. The burden of BCa caused by smoking is greater in males, middle-aged and older adults, and people in countries with high-middle socio-demographic indices (SDI). The study highlights the continuing global health challenge posed by smoking-related BCa. Targeted health policies and interventions are critical, especially in areas with high smoking rates and low socioeconomic status.

Network pharmacology and experimental validation to explore the role and potential mechanism of Liuwei Dihuang Decoction in prostate cancer.

OBJECTIVE: To evaluate the anti-tumor effector of Liuwei Dihuang Decoction (LWDHD) in prostate cancer (PCa) and explore the potential mechanism using experimental validation, network pharmacology, bioinformatics analysis, and molecular docking. METHODS: CCK test, Clone formation assay and wound-healing assays were used to determine the effect of LWDHD on prostate cancer growth and metastasis. The active ingredients and targets of LWDHD were obtained from the TCMSP database, and the relevant targets were selected by GeneCards, OMIM and DisGeNET databases for PCa. The cross-targets of drugs and disease were imported into the STRING database to construct protein interactions. The network was also visualized using Cytoscape software and core targets are screened using the Network Analyzer plug-in. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed using R software. TCGA database was used to analyze the correlation of bioinformatics genes. AutoDock vina was used to predict the molecular docking and binding ability of active ingredients to key targets. Through WB and q-PCR experiments, the above gene targets were detected to verify the effect of LWDHD on PCa. RESULTS: CCK and scratch tests confirmed that LWDHD could inhibit the proliferation, invasion and migration of prostate cancer cells. Clone formation experiments showed that LWDHD inhibited the long-term proliferative capacity of PC3 cells. LWDHD and PCa had a total of 99 common targets, establishing a "drug-ingredient-common target" network. Through GO and KEGG enrichment analysis, PI3K/AKT, MAPK, TP53 pathway, MYC, TNF pathway and other signaling pathways were found. Bioinformatics analysis showed that MYC gene was highly expressed and CCND1 and MAPK1 were low expressed in prostate cancer tissues. In addition, TP53, AKT1, MYC, TNF and CCND1 were positively correlated with MAPK1, among which AKT1 and CCND1 were most closely correlated with MAPK1. Molecular docking results showed that quercetin, kaempferol, ß-sitosterol and other main active ingredients of LWDHD treatment for PCa were combined with core proteins MAPK1 and AKT1 well. WB and q-PCR results showed that LWDHD inhibited the expression of PI3K and AKT in PC3 cells. CONCLUSION: The mechanism of LWDHD therapy for PCa is a multi-target and multi-pathway complex process, which may be related to the biological processes mediated by MAPK1 and AKT1 pathways, such as cell proliferation and inhibition of metastasis, and the regulation of signaling pathways. The PI3K/AKT signaling pathway may be a central pathway of LWDHD to inhibit prostate cancer proliferation.

Bisphenol S enhances the cell proliferation ability of prostate cancer cells by regulating the expression of SDS.

Recent times have witnessed an increase in both incidence and mortality rates of prostate cancer. While some individuals with localized or metastatic cancer may progress slowly with a lower mortality risk, those with intermediate or high-risk cancer often face a higher likelihood of death, despite treatment. Bisphenol A (BPA) has been linked to various cancers, including prostate and breast cancer, yet the relationship between bisphenol S (BPS) and human health remains underexplored. In our study, we employed ssGSEA analysis to evaluate the BPS-associated score in a prostate cancer cohort. Additionally, differential expression analysis identified BPS-related genes within the same group. Through COX and LASSO regression analyses, we developed and validated a BPS-related risk model using ROC curve and survival analyses. A nomogram, integrating clinical characteristics with this risk model, was established for improved predictive accuracy, further substantiated by calibration curve validation. Molecular docking analysis suggested potential binding between SDS and BPS. We also conducted cell proliferation assays on C4-2 and LNCaP prostate cancer cells, revealing increased cell growth at a BPS concentration of 10-7 M, as evidenced by CCK8 and EdU assays. In summary, our findings shed light on the BPS-prostate cancer linkage, identifying BPS-associated genes, establishing a validated risk model, exploring SDS-BPS binding potential, and assessing BPS's effect on prostate cancer cell growth. These insights underscore the need for further investigation into BPS and its impact on human diseases.

PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking.

BACKGROUND: Bladder cancer is very common worldwide. PIGT is a subunit of the glycosylphosphatidylinositol transamidase which involves in tumorigenesis and invasiveness. m6A modification of mRNA has been linked to cell proliferation, tumor progression and other biological events. However, how PIGT is regulated and what is the function of PIGT in bladder cancer remains to be elucidated. METHODS: PIGT was silenced or overexpressed to study its role in regulating bladder cancer. Cell proliferation and invasion were examined with the Cell Counting Kit-8, colony formation and Transwell assay, respectively. Cellular oxygen consumption rates or extracellular acidification rates were detected by a XF24 Analyzer. Quantitative RT-PCR and immunoblots were performed to detect mRNA and protein levels. RESULTS: PIGT was overexpressed in bladder cancer. Silencing PIGT inhibited cell proliferation, oxidative phosphorylation, and glycolysis. Overexpressing PIGT promoted cell proliferation, oxidative phosphorylation, glycolysis in vitro and tumor metastasis in vivo by activating glucose transporter 1 (GLUT1). PIGT also promoted GLUT1 glycosylation and membrane trafficking. Wilms' tumor 1-associated protein (WTAP) mediated PIGT m6A modification, and m6A reader, insulin-like growth factor 2 mRNA-binding protein (IGF2BP2), binds to the methylated PIGT to promote the stability of PIGT, leading to up-regulation of PIGT. CONCLUSION: WTAP mediates PIGT m6A modification to increase the stability of PIGT via the IGF2BP2, which enhances cell proliferation, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking.

CHKB-AS1 enhances proliferation and resistance to NVP-BEZ235 of renal cancer cells via regulating the phosphorylation of MAP4 and PI3K/AKT/mTOR signaling.

Targeted therapy is pivotal in renal carcinoma treatment, and the dual-inhibitor NVP-BEZ235 has emerged as a promising candidate in preliminary studies. Its effectiveness against renal carcinoma and the mechanisms underlying potential resistance, however, warrant further exploration. This study aims to elucidate these aspects, enhancing our understanding of NVP-BEZ235's future clinical utility. To investigate resistance mechanisms, renal cancer cell lines were exposed to progressively increasing concentrations of NVP-BEZ235, leading to the development of stable resistance. These resistant cells underwent extensive RNA-sequencing analysis. We implemented gene interference techniques using plasmid vectors and lentivirus and conducted regular IC50 assessments. To pinpoint the role of LncRNAs, we utilized FISH and immunofluorescence staining assays, supplemented by RNA pull-down and RIP assays to delineate interactions between LncRNA and its RNA-binding protein (RBP). Further, Western blotting and qRT-PCR were employed to examine alterations in signaling pathways, with an animal model providing additional validation. Our results show a marked increase in the IC50 of NVP-BEZ235 in resistant cell lines compared to their parental counterparts. A significant revelation was the role of LncRNA-CHKB-AS1 in mediating drug resistance. We observed dysregulated expression of CHKB-AS1 in both clinical samples of clear cell renal cell carcinoma (ccRCC) and cell lines. In vivo experiments further substantiated our findings, showing that CHKB-AS1 overexpression significantly enhanced tumor growth and resistance to NVP-BEZ235 in a subcutaneous tumorigenesis model, as evidenced by increased tumor volume and weight, whereas CHKB-AS1 knockdown led to a marked reduction in these parameters. Critically, CHKB-AS1 was identified to interact with MAP4, a key regulator in the phosphorylation of the PI3k/Akt/mTOR pathway. This interaction contributes to a diminished antitumor effect of NVP-BEZ235, highlighting the intricate mechanism through which CHKB-AS1 modulates drug resistance pathways, potentially impacting therapeutic strategies against renal carcinoma.

PPARG is a potential target of Tanshinone IIA in prostate cancer treatment: a combination study of molecular docking and dynamic simulation based on transcriptomic bioinformatics.

Tanshinone IIA is a lipophilic organic compound from the root of Danshen (Salvia miltiorrhiza) and is one of the most well-known Tanshinone molecules by pharmacologists. In recent years, in addition to effects of anti-cardiovascular and neurological diseases, Tanshinone IIA has also shown some degrees of anti-prostate cancer potential. Although they do have some studies focusing on the molecular mechanism of Tanshinone IIA's anti-prostate cancer effects, a further understanding on the transcriptomic and structural level is still lacking. In this study, transcriptomic sequencing technology and computer technology were employed to illustrate the effects of Tanshinone IIA on prostate cancer through bioinformatic analysis and molecular dynamics simulation, and PPARG was considered to be one of the targets for Tanshinone IIA according to docking scoring and dynamic calculation. Our study provides a novel direction to further understand the mechanism of the effects of Tanshinone IIA on prostate cancer, and further molecular biological studies need to be carried on to further investigate the molecular mechanism of Tanshinone IIA's anti-prostate cancer effect through PPARG.

The stratification and prognostic importance of molecular and immune landscapes in clear cell renal cell carcinoma.

The aim of our research is to explore the various characteristics and genetic profiles of clear cell renal cell carcinoma (ccRCC) in order to discover possible predictors of prognosis and targets for treatment. By utilizing ssGSEA scores, we categorized patients with ccRCC into groups based on their phenotype, distinguishing between low and high. This categorization revealed significant variations in the expression of crucial immune checkpoint genes and Human Leukocyte Antigen (HLA) genes, suggesting the presence of a potential immune evasion tactic in different subtypes of ccRCC. A predictive model was built using genes that are expressed differently and linked to cell death, showing strong effectiveness in categorizing patient risk. Furthermore, we discovered a noteworthy correlation among risk scores, infiltration of immune cells, the expression of genes related to immune checkpoint inhibitors, and diverse clinical features. This indicates that our scoring system for risk could function as a comprehensive gauge of the severity of the disease. The examination of the mutational terrain further highlighted the predominance of particular genetic changes, including VHL and PBRM1 missense mutations. Finally, we have discovered the function of DKK1 in facilitating cell death in ccRCC, presenting an additional possibility for therapeutic intervention. The results of our study suggest the possibility of incorporating molecular information into clinical prediction, which could lead to personalized treatment approaches in ccRCC.

An online questionnaire survey on the sexual function of Chinese male adults in the COVID-19 pandemic with loosened controls.

The coronavirus disease 2019 (COVID-19) may have a negative impact on the sexual health of male adults. An online questionnaire survey was conducted among male adults from February 04, 2023 to March 15, 2023 to analyze the impact of COVID-19 on the sexual health of male adults in China. Participants provided about their medical, social, lifestyle, and family situations information through questionnaires including the Brief Sexual Function Inventory (BSFI). Sexual function problems were defined based on predetermined cutoff values of the BSFI domain scores. A total of 1,250 male adults were included with median age as 32 years. According to the analysis of statistical results, sexual drive and erections firm enough to have sexual intercourse were reported to be present only a few days or less last month among 14.8 % and 11.1 % of COVID-19 survivors, respectively. Compared with uninfected persons, COVID-19 survivors had significantly lower scores on all BSFI domains and an increased risk of problems with sexual drive and erectile. In multivariate models of COVID-19 survivors, age ≥30 years, rural resident, lower education level, manual worker, lower income, and shorter duration from recovery to survey date were significantly associated with poorer overall sexual function. In this study, COVID-19 survivors was reported to have significantly poorer sexual function than uninfected persons. The COVID-19 may have had a significant impact on the sexual health of Chinese male adults. We need to focus on sexual dysfunction in COVID-19 survivors, and proactively provide effective interventions.

Relationships between position of patellar ridge high point and morphology of resected surface for patellar resurfacing in total knee arthroplasty.

Background: Reproducing the native patellar ridge high point while maximizing osseous coverage is important for the success of patellar replacement, but it cannot always be achieved simultaneously. This study aimed to thoroughly investigate the relationships and their influencing factors between the positions of the high point of patellar ridge (HPPR) and the morphology of the patellar resected surface. Methods: Four hundred seventy-three patients (265 men, 208 women) aged 18 to 50 years with knee injuries before arthroscopy were retrospectively collected for this cross-sectional study. Computed tomography (CT) and magnetic resonance imaging (MRI) were used to construct 3D computer models of the patella and patellar cartilage. The morphometric characteristics of the patellar cut after virtual resection and the HPPR position relative to the patellar cut centre were measured and analyzed. Results: The medial displacements of the HPPR were positively correlated with Wiberg's classification and index (all P<0.001). The mean values of HPPR's medial displacements were 0.15 of the medial width of patellar cut, and 93.2% of all patella ranged from 0 to 0.3. When the implant's apex were placed at 0.15 of the medial width of patellar cut medialized, the proportion of implant placement errors within 1 mm of the native high point was 12% more in female patella (P=0.01), and 7% more in all patella (P=0.03) than 3 mm medialized. Conclusions: Wiberg's system can roughly predicted the medial-lateral position of the HPPR. The HPPR was mainly medially located at the 0.15 of the medial patellar width approximately, and 15% medialized of the implant's apex can better reproduce the native patellar high point than 3 mm medialized. The current results provide basic data for patellar implant selection, preoperative planning, and implant design to reproduce the native patellar high point better while maximizing osseous coverage for patellar resurfacing.

Long non-coding RNA X-Inactive Specific Transcript (XIST) interacting with USF2 promotes osteogenic differentiation of periodontal ligament stem cells through regulation of WDR72 transcription.

BACKGROUND: Periodontal ligament stem cells (PDLSCs) are the most potential cells in periodontal tissue regeneration and bone tissue regeneration. Our prior work had revealed that WD repeat-containing protein 72 (WDR72) was crucial for osteogenic differentiation of PDLSCs. Here, we further elucidated its underlying mechanism in PDLSC osteogenic differentiation. METHODS: Human PDLSCs, isolated and identified by flow cytometry, were prepared for osteogenic differentiation induction. Levels of WDR72, long non-coding RNA X-Inactive Specific Transcript (XIST), upstream stimulatory factor 2 (USF2), and osteogenic marker genes (Runx2, Osteocalcin, and Collagen I) in human PDLSCs and clinical specimens were detected by RT-qPCR. Protein expressions of WDR72, Runx2, Osteocalcin, and Colla1 were tested by Western blot. The interactions among the molecules were verified by RIP, RNA pull-down, ChIP, and luciferase reporter assays. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) and alizarin red staining (ARS). RESULTS: WDR72 was decreased in periodontal tissues of periodontitis patients, and overexpression reversed TNF-α-mediated suppressive effects on PDLSC osteogenic differentiation. Mechanically, XIST recruited the enrichment of USF2 to the WDR72 promoter region, thereby positively regulating WDR72. WDR72 silencing overturned XIST-mediated biological effects in PDLSCs. CONCLUSION: WDR72, regulated by the XIST/USF2 axis, enhances osteogenic differentiation of PDLSCs, implying a novel strategy for alleviating periodontitis.

Super-enhancer-associated SNHG15 cooperating with FOSL1 contributes to bladder cancer progression through the WNT pathway.

Small nucleolar RNA host gene 15 (SNHG15) plays an oncogenic role in many cancers. However, the role of SNHG15 in bladder cancer (BLCA) remains unclear. In this study, the regulation of SNHG15 on the activities of BLCA cells (T24 and RT112) was investigated. In detail, super-enhancers (SEs), differentially expressed genes, and functional enrichment were detected by bioinformatic analyses. Mutant cell lines lacking SNHG15-SEs were established using CRISPR-Cas9. Relative gene expression was detected by quantitative polymerase chain reaction (qPCR), western blot, in situ hybridization, and immunohistochemistry assays. Cell senescence, apoptosis, viability, and proliferation were measured. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter gene assays were conducted to analyze the interactions between genes. A novel super-enhancer of SNHG15 (SNHG15-SEs) was discovered in several BLCA datasets. The deletion of SNHG15-SEs resulted in a significant downregulation of SNHG15. Mechanistically, the core active region of SNHG15-SEs recruited the transcription factor FOSL1 to facilitate the SNHG15 transcription, thereby inducing the proliferation and metastasis of BLCA cells. Deletion of SNHG15-SEs inhibited the growth and metastasis of T24 and RT112 cells by inactivating the WNT/CTNNB1 pathway activation. Overexpression of FOSL1 in SNHG15-SEs restored the cell proliferation and metastasis. Next, a xenograft mouse model showed that SNHG15-SEs deletion inhibited the proliferation and metastasis of BLCA cells in vivo. Collectively, our data indicate that SNHG15-SEs recruit FOSL1 to promote the expression of SNHG15 which interacts with CTNNB1 in the nucleus to activate the transcription of ADAM12, leading to the malignance of BLCA cells.

Unethical pro-supervisor behavior and employees' family satisfaction: The roles of workplace ostracism and work-home segmentation preference.

The present study proposes a moderated mediation model that examines how and when unethical pro-supervisor behavior is related to employees' family satisfaction. The two-wave study design consisted of 207 full-time employees in China. The study results indicate that unethical pro-supervisor behavior is negatively related to family satisfaction, and that workplace ostracism mediates the influence of unethical pro-supervisor behavior on family satisfaction. In addition, the relationship between workplace ostracism and family satisfaction as well as the indirect influence of unethical pro-supervisor behavior on family satisfaction through workplace ostracism, are moderated by employees' work-home segmentation preference. The study findings not only enrich the literature on unethical pro-supervisor behavior, but also have important practical implications for organizational managers.

A novel traffic optimization method using GRU based deep neural network for the IoV system.

At present, China is moving towards the direction of "Industry 4.0". The development of the automobile industry, especially intelligent automobiles, is in full swing, which brings great convenience to people's life and travel. However, at the same time, urban traffic pressure is also increasingly prominent, and the situation of traffic congestion and traffic safety is not optimistic. In this context, the Internet of Vehicles (also known as "IoV") opens up a new way to relieve urban traffic pressure. Therefore, in order to further optimize the road network traffic conditions in the IoV environment, this research focuses on the traffic flow prediction algorithm on the basis of deep learning to enhance traffic efficiency and safety. First, the study investigates the short-time traffic flow prediction by combining the characteristics of the IoV environment. To address the issues that existing algorithms cannot automatically extract data features and the model expression capability is weak, the study chooses to build a deep neural network using GRU model in deep learning for short-time traffic flow prediction, thereby improving the prediction accuracy of algorithm. Secondly, a fine-grained traffic flow statistics approach suitable for the IoV situation is suggested in accordance with the deep learning model that was built. The algorithm sends the vehicle characteristic data obtained through GRU model training into the fine-grained traffic flow statistics algorithm, so as to realize the statistics of traffic information of various types of vehicles. The advantage of this algorithm is that it can well count the traffic flow of multiple lanes, so as to better predict the current traffic status and achieve traffic optimization. Finally, the IoV environment is constructed to confirm the effectiveness of the prediction model. The prediction results prove that the new algorithm has good performance in traffic flow statistics in different scenarios.

Identification of the novel therapeutic targets and biomarkers associated of prostate cancer with cancer-associated fibroblasts (CAFs).

Globally, prostate cancer remains a leading cause of mortality and morbidity despite advances in treatment. Research on prostate cancer has primarily focused on the malignant epithelium, but the tumor microenvironment has recently been recognized as an important factor in the progression of prostate cancer. Cancer-associated fibroblasts (CAFs) play an important role in prostate cancer progression among multiple cell types in the tumor microenvironment. In order to develop new treatments and identify predictive and prognostic biomarkers for CAFs, further research is needed to understand the mechanism of action of prostate cancer and CAF. In this work, we performed the single-cell RNA sequence analysis to obtain the biomarkers for CAFs, and ten genes were finally regarded as the marker genes for CAFs. Based on the ssGSEA algorithm, the prostate cancer cohort was divided into low- and high-CAFs groups. Further analysis revealed that the CAFs-score is associated with many immune-related cells and immune-related pathways. In addition, between the low- and high-CAFs tissues, a total of 127 hub genes were discovered, which is specific in CAFs. After constructing the prognostic prediction model, SLPI, VSIG2, CENPF, SLC7A1, SMC4, and ITPR2 were finally regarded as the key genes in the prognosis of patients with prostate cancer. Each patient was assigned with the risk score as follows: SLPI* 0.000584811158157081 + VSIG2 * -0.01190627068889 + CENPF * -0.317826812875334 + SLC7A1 * -0.0410213995358753 + SMC4 * 0.202544454923637 + ITPR2 * -0.0824652047622673 + TOP2A * 0.140312081524807 + OR51E2 * -0.00136602095885459. The GSVA revealed the biological features of CAFs, many cancer-related pathways, such as the adipocytokine signaling pathway, ERBB signaling pathway, GnRH signaling pathway, insulin signaling pathway, mTOR signaling pathway and PPAR signaling pathway are closely associated with CAFs. As a result of these observations, similar transcriptomics may be involved in the transition from normal fibroblasts to CAFs in adjacent tissues. As one of the biomarkers for CAFs, CENPF can promote the proliferation ability of prostate cancer cells. The overexpress of CENPF could promote the proliferation ability of prostate cancer cells. In conclusion, we discuss the potential prognostic and therapeutic value of CAF-dependent pathways in prostate cancer.

TLimmuno2: predicting MHC class II antigen immunogenicity through transfer learning.

Major histocompatibility complex (MHC) class II molecules play a pivotal role in antigen presentation and CD4+ T cell response. Accurate prediction of the immunogenicity of MHC class II-associated antigens is critical for vaccine design and cancer immunotherapies. However, current computational methods are limited by insufficient training data and algorithmic constraints, and the rules that govern which peptides are truly recognized by existing T cell receptors remain poorly understood. Here, we build a transfer learning-based, long short-term memory model named 'TLimmuno2' to predict whether epitope-MHC class II complex can elicit T cell response. Through leveraging binding affinity data, TLimmuno2 shows superior performance compared with existing models on independent validation datasets. TLimmuno2 can find real immunogenic neoantigen in real-world cancer immunotherapy data. The identification of significant MHC class II neoantigen-mediated immunoediting signal in the cancer genome atlas pan-cancer dataset further suggests the robustness of TLimmuno2 in identifying really immunogenic neoantigens that are undergoing negative selection during cancer evolution. Overall, TLimmuno2 is a powerful tool for the immunogenicity prediction of MHC class II presented epitopes and could promote the development of personalized immunotherapies.

Molecular Targets of Shenqi Dihuang, A Traditional Chinese Herbal Medicine, and Its Potential Role in Renal Cell Carcinoma Therapy.

Chinese herbal medicine (CHM), which includes herbal slices and proprietary products, is widely used in China. Shenqi Dihuang (SQDH) is a traditional Chinese medicine (TCM) formula with ingredients that affect tumor growth. Despite recent advances in prognosis, patients with renal cell carcinoma (RCC) cannot currently receive curative treatment. The present study aimed to explore the potential target genes closely associated with SQDH. The gene expression data for SQDH and RCC were obtained from the TCMSP and TCGA databases. The SQDH-based prognostic prediction model reveals a strong correlation between RCC and SQDH. In addition, the immune cell infiltration analysis indicated that SQDH might be associated with the immune response of RCC patients. Based on this, we successfully built the prognostic prediction model using SQDH-related genes. The results demonstrated that CCND1 and NR3C2 are closely associated with the prognosis of RCC patients. Finally, the pathways enrichment analysis revealed that response to oxidative stress, cyclin binding, programmed cell death, and immune response are the most enriched pathways in CCND1. Furthermore, transcription regulator activity, regulation of cell population proliferation, and cyclin binding are closely associated with the NR3C2.

NF-κB represses retinoic acid receptor-mediated GPRC5A transactivation in lung epithelial cells to promote neoplasia.

Chronic inflammation is associated with lung tumorigenesis, in which NF-κB-mediated epigenetic regulation plays a critical role. Lung tumor suppressor G protein-coupled receptor, family C, member 5A (GPRC5A), is repressed in most non-small cell lung cancer (NSCLC); however, the mechanisms remain unclear. Here, we show that NF-κB acts as a transcriptional repressor in suppression of GPRC5A. NF-κB induced GPRC5A repression both in vitro and in vivo. Intriguingly, transactivation of NF-κB downstream targets was not required, but the transactivation domain of RelA/p65 was required for GPRC5A repression. NF-κB did not bind to any potential cis-element in the GPRC5A promoter. Instead, p65 was complexed with retinoic acid receptor α/ß (RARα/ß) and recruited to the RA response element site at the GPRC5A promoter, resulting in disrupted RNA polymerase II complexing and suppressed transcription. Notably, phosphorylation on serine 276 of p65 was required for interaction with RARα/ß and repression of GPRC5A. Moreover, NF-κB-mediated epigenetic repression was through suppression of acetylated histone H3K9 (H3K9ac), but not DNA methylation of the CpG islands, at the GPRC5A promoter. Consistently, a histone deacetylase inhibitor, but not DNA methylation inhibitor, restored GPRC5A expression in NSCLC cells. Thus, NF-κB induces transcriptional repression of GPRC5A via a complex with RARα/ß and mediates epigenetic repression via suppression of H3K9ac.

Extraperitoneal tissue retraction technique: An effective assistant of extraperitoneal pure single-port robotic-assisted radical prostatectomy with the da Vinci Si surgical system.

Objective: The limitations of tissue retraction and the amount of surgical working space have a great impact on extraperitoneal single-port robotic-assisted radical prostatectomy (sp-RARP) with the multiport robotic surgical system. We used an extraperitoneal tissue retraction technique to achieve tissue exposure and working space expansion. This study evaluated the safety, feasibility, and efficacy of the extraperitoneal tissue retraction technique in extraperitoneal pure sp-RARP with the da Vinci Si surgical system. Methods: Data from 42 patients were analyzed retrospectively from December 2018 to February 2020. The extraperitoneal tissue retraction technique was not used in 20 patients (group I) and was used in 22 patients (group II). Preoperative, intraoperative, and postoperative data were collected. The oncological and functional data during late follow-up were recorded. Results: All patients successfully underwent extraperitoneal pure sp-RARP. No patients required conversion to a multiport surgery or placement of additional assistant ports. The two groups were similar regarding baseline features. The median operation time in group I was significantly longer than that in group II (P < 0.001). The estimated blood loss volume in group I was significantly higher than that in group II (P < 0.001). There were no serious complications in either group. There were four cases of peritoneal tears in group I and none in group II (P = 0.043). The surgical margin and lymph nodes were negative in both groups. The oncological and functional outcomes were similar between the two groups 6 months after the procedure. Conclusions: The extraperitoneal tissue retraction technique is safe and feasible. The technique promotes tissue exposure and expands the surgical working space, which is important for achieving extraperitoneal pure sp-RARP with the da Vinci Si surgical system, especially for beginners. The short-term oncological and functional outcomes were within acceptable ranges. The long-term effects of this technique need further evaluation.

Identifying tumor antigens and immune subtypes of renal cell carcinoma for immunotherapy development.

Renal cell carcinoma (RCC) is one of the leading causes of death in men. Messenger ribonucleic acid (mRNA) vaccines may be an attractive means to achieve satisfactory results. Cancer immunotherapy is a promising cancer treatment strategy. However, immunotherapy is not widely used in renal cell carcinoma, as only a few patients show a positive response. The present study aimed to identify potential antigens associated with renal cell carcinoma to develop an anti-renal cell carcinoma mRNA vaccine. Moreover, the immune subtypes of renal cell carcinoma cells were determined. The Cancer Genome Atlas (TCGA) analysis revealed gene expression profiles and clinical information. Antigen-presenting cells infiltrated the immune system using Tumor Immune Estimation Resource (TIMER) tool (http://timer.cistrome.org/). GDSC (Genomics of Drug Sensitivity in Cancer) database were used to estimate drug sensitivity. The 13 immune-related genes discovery could be targets for immunotherapy in renal cell carcinoma patients, as they were associated with a better prognosis and a higher level of antigen-presenting cells. These immune subtypes have significant relationships with immunological checkpoints, immunogenic cell death regulators, and RCC prognostic variables. Furthermore, DBH-AS1 was identified as a potential antigen for developing an mRNA vaccine. The CCK8 assay demonstrated that the proliferative capacity of 786-O and Caki-1 cells overexpressing DBH-AS1 was higher than in the control group. In addition, transwell assay revealed that 786-O and Caki-1 cells overexpressing DBH-AS1 showed higher invasion capacity compared with control. This study provides a theoretical basis for the development of mRNA vaccines. Our findings suggest that DBH-AS1 could be potential antigens for developing RCC mRNA vaccines.

Medium Activity Prevents Periprosthetic Bone Mass Loss in the Medial Metaphyseal Region of the Tibia after Posterior-Stabilized TKA: A 5-Year Follow-up Study of 110 Knees.

OBJECTIVE: The bone mass around the prosthesis plays an important role in the stability of the prosthesis. This study aimed to assess the effect of postoperative activity on bone mineral density (BMD) in the proximal tibia 5 years after total knee arthroplasty (TKA). To provide a scientific guidance for postoperative functional exercise. METHODS: 110 patients underwent unilateral primary TKA were divided into three groups based on the University of California Los Angeles (UCLA) activity scale: low activity group (LA group, UCLA = 4, 5); medium activity group (MA group, UCLA = 6, 7); and high activity group (HA group, UCLA = 8, 9). The primary observation was a comparison of the BMD and BMD change percentage (ΔBMD (%)) in the periprosthetic tibia among the LA, MA and HA groups at 1 year, 3 years and 5 years. The secondary observations were radiographic evaluation (prosthetic stability, periprosthetic fractures, aseptic loosening and periprosthetic joint infection) and clinical evaluation (Knee Society Score (KSS), visual analogue score scores and range of motion (ROM)). A one-way ANOVA was used to compare the clinical scores and BMD among the three groups. RESULTS: The BMD of medial region decreased by 10.80%, 12.64%, 13.61% at 1, 3, and 5 years respectively; these were 5.72%, 6.26%, 7.83% in lateral region and 1.42%, 1.78%, 3.28% in diaphyseal region. For medial metaphyseal region, the BMD of the MA group was significantly greater than that of the LA and HA groups at 1 and 3 years (108.9 ± 5.2 vs. 106.1 ± 6.69 vs. 105.4 ± 5.2 and 108.5 ± 6.0 vs. 101.2 ± 6.76 vs. 103.0 ± 6.8, P < 0.01 and P < 0.001), and the BMD changes (ΔBMD (%)) in the MA group were significantly smaller than those in the LA and HA groups (8.75 ± 5.36 vs. 11.92 ± 5.49 vs. 12.70 ± 5.21 and 9.11 ± 5.11 vs. 16.04 ± 4.79 vs. 14.82 ± 4.26, P < 0.01 and P < 0.001). Regarding secondary observations, all of the prostheses were assessed as stable, without periprosthetic fractures, aseptic loosening and periprosthetic joint infection. Regarding KSS scores, there was no significant difference among the three groups. However, the VAS and ROM of the HA group were better than those of the MA and LA groups (1.65 ± 0.79 vs. 2.63 ± 0.77 vs. 3.00 ± 1.17, p < 0.001, and 111.90 ± 9.17 vs. 110.20 ± 6.78 vs. 102.90 ± 8.48, P < 0.001). CONCLUSION: Medium activity prevented periprosthetic bone loss in the medial metaphyseal region of the tibia after posterior-stabilized TKA, and moderate-intensity exercise is recommended for patients after TKA to reduce periprosthetic bone loss.