Acidification alleviates the inhibition of hyposaline stress on physiological performance of tropical seagrass Thalassia hemprichii.

Since the Industrial Revolution, increasing atmospheric CO2 concentrations have had a substantial negative impact influence on coastal ecosystems because of direct effects including ocean acidification and indirect effects such as extreme rainfall events. Using a two-factor crossover indoor simulation experiment, this study examined the combined effects of acidification and hyposaline stress on Thalassia hemprichii. Seawater acidification increased the photosynthetic pigment content of T. hemprichii leaves and promoted seagrass growth rate. Hyposaline stress slowed down seagrass growth and had an impact on the osmotic potential and osmoregulatory substance content of seagrass leaves. Acidification and salinity reduction had significant interaction effects on the photosynthesis rate, photosynthetic pigment content, chlorophyll fluorescence parameters, and osmotic potential of T. hemprichii, but not on the growth rate. Overall, these findings have shown that the hyposaline stress inhibitory effect on the T. hemprichii physiological performance and growth may be reduced by acidification.

A new perspective on prostate cancer treatment: the interplay between cellular senescence and treatment resistance.

The emergence of resistance to prostate cancer (PCa) treatment, particularly to androgen deprivation therapy (ADT), has posed a significant challenge in the field of PCa management. Among the therapeutic options for PCa, radiotherapy, chemotherapy, and hormone therapy are commonly used modalities. However, these therapeutic approaches, while inducing apoptosis in tumor cells, may also trigger stress-induced premature senescence (SIPS). Cellular senescence, an entropy-driven transition from an ordered to a disordered state, ultimately leading to cell growth arrest, exhibits a dual role in PCa treatment. On one hand, senescent tumor cells may withdraw from the cell cycle, thereby reducing tumor growth rate and exerting a positive effect on treatment. On the other hand, senescent tumor cells may secrete a plethora of cytokines, growth factors and proteases that can affect neighboring tumor cells, thereby exerting a negative impact on treatment. This review explores how radiotherapy, chemotherapy, and hormone therapy trigger SIPS and the nuanced impact of senescent tumor cells on PCa treatment. Additionally, we aim to identify novel therapeutic strategies to overcome resistance in PCa treatment, thereby enhancing patient outcomes.

Enhanced cellular therapy: revolutionizing adoptive cellular therapy.

Enhanced cellular therapy has emerged as a novel concept following the basis of cellular therapy. This treatment modality applied drugs or biotechnology to directly enhance or genetically modify cells to enhance the efficacy of adoptive cellular therapy (ACT). Drugs or biotechnology that enhance the killing ability of immune cells include immune checkpoint inhibitors (ICIs) / antibody drugs, small molecule inhibitors, immunomodulatory factors, proteolysis targeting chimera (PROTAC), oncolytic virus (OV), etc. Firstly, overcoming the inhibitory tumor microenvironment (TME) can enhance the efficacy of ACT, which can be achieved by blocking the immune checkpoint. Secondly, cytokines or cytokine receptors can be expressed by genetic engineering or added directly to adoptive cells to enhance the migration and infiltration of adoptive cells to tumor cells. Moreover, multi-antigen chimeric antigen receptors (CARs) can be designed to enhance the specific recognition of tumor cell-related antigens, and OVs can also stimulate antigen release. In addition to inserting suicide genes into adoptive cells, PROTAC technology can be used as a safety switch or degradation agent of immunosuppressive factors to enhance the safety and efficacy of adoptive cells. This article comprehensively summarizes the mechanism, current situation, and clinical application of enhanced cellular therapy, describing potential improvements to adoptive cellular therapy.

Knowledge mapping of application of image-guided surgery in prostate cancer: a bibliometric analysis (2013-2023).

BACKGROUND: Image-guided surgery (IGS) refers to surgery navigated by medical imaging technology, helping doctors better clarify tumor boundaries, identify metastatic lymph nodes and preserve surrounding healthy tissue function. Recent studies have provided expectable momentum of the application of IGS in prostate cancer (PCa). The authors aim to comprehensively construct a bibliometric analysis of the application of IGS in PCa. METHOD: The authors searched publications related to application of IGS in PCa from 2013 to 2023 on the web of science core collection (WoSCC) databases. VOSviewer, CiteSpace, and R package 'bibliometrix' were used for bibliometric analysis. RESULTS: Two thousand three eighty-nine articles from 75 countries and 2883 institutions led by the United States were included. The number of publications related to the application of IGS in PCa kept high in the last decade. Johns Hopkins University is the top research institutions. Journal of Nuclear Medicine has the highest popularity as the selection of journal and co-cited journal. Pomper Martin G. had published the most paper. Ali Afshar-Oromieh was co-cited most frequently. The clinical efficacy of PSMA-PET/CT in PCa diagnosis and treatment are main topics in this research field, with emerging focuses on the use of fluorescence imaging guidance technology in PCa. 'PSMA' and 'PET/CT' are the main keywords as long-term research hotspots. CONCLUSION: This study is the first bibliometric analysis of researches on application of IGS in PCa with three recognized bibliometric software, providing an objective description and comprehensive guidance for the future relevant investigations.

SLAMF3 promotes Th17 differentiation and is reversed by iguratimod through JAK1/STAT3 pathway in primary Sjögren's syndrome.

OBJECTIVE: The signaling lymphocytic activation molecule family of receptors (SLAMF) is involved in the activation of T cells and plays important roles in the pathogenesis of autoimmune diseases. The purpose of this study is to observe the expression of SLAMF3 on CD4 + T cells and its effect on the differentiation of T helper 17 (Th17) in primary Sjögren's syndrome (pSS). Furthermore, we found iguratimod (IGU) could effectively reverse the aberrant Th17 differentiation through JAK1/STAT3 signaling. METHODS: Peripheral blood mononuclear cells from 40 pSS and 40 healthy control subjects were enrolled for analysis of expression of SLAMF3 on CD4 + T and Th17 cells by flow cytometry. Serum IL-17 and SLAMF3 were detected by ELISA assay. Labial biopsies from 20 pSS patients and 20 non-pSS controls were performed immunohistochemical for staining expression of CD4, IL-17, and SLAMF3. Under the priming conditions with anti-CD3/CD28 or CD3/SLAMF3 antibodies on CD4 + T cells extracted from pSS and controls, the proportion of Th17 cells in CD4 + T cells and the amount of soluble IL-17A were assessed by flow cytometry and ELISA. Furthermore, RNA sequencing was performed for the transcriptomics study. Additionally, RNA level of RORγt and IL-17A and the protein level of RORγt, p-JAK1 and p-STAT3, were detected by real-time PCR and western blot. RESULTS: The expression levels of SLAMF3 on CD4 + T and Th17 cells in the peripheral blood and salivary glands in pSS patients were significantly elevated than that in control groups. The serum IL-17A and SLAMF3 in pSS patients were much higher compared with the control group. Although co-stimulation of CD3/SLAMF3 could promote CD4 + T cells differentiate into Th17 cells both in pSS and controls, the CD4 + T cells from pSS have a more sensitive response in Th17 differentiation with the SLAMF3 stimulation. Transcriptomics results showed the CD3/SLAMF3 stimulation caused the activation of Th17 signaling and JAK1/STAT3 pathway. Quantitative PCR and western blotting confirmed the IGU (iguratimod), which is a safe clinical drug in treatment of autoimmune diseases, effectively reversed the increased Th17 proportion, the expression levels of RORγt, pJAK1, and pSTAT3 caused by CD3/SLAMF3 stimulation. CONCLUSION: SLAMF3 upregulates Th17 cell differentiation of CD4 + T cells and IL-17A secretion through enriching RORγt and activating the transcriptomics participating in the pathogenesis of primary Sjögren's syndrome. IGU could inhibit the process through this therapeutic target in pSS.

The effect of different timing of blood transfusion on oncological outcomes of patients undergoing radical cystectomy for bladder cancer: a systematic review and meta-analysis.

Highlights: This meta-analysis and systematic review aim to analyze the association between BT and oncological outcomes of patients undergoing RC for bladder cancer, and tries to find out whether the timing of blood transfusion could also have an effect on this relationship. A total of 20 retrospective studies from online databases and other sources are identified and enrolled in this study. The results show that BT administration during RC operation or perioperative period is significantly associated with worse oncological outcomes including ACM, CSM and DR. Background: Bladder cancer is one of the most common urological malignancies. Radical cystectomy (RC) remains the main treatment for localized muscle-invasive bladder cancer (MIBC) or high-grade non-muscle-invasive bladder cancer (NMIBC). In the process of RC, the administration of blood transfusion (BT) is sometimes needed, however, it may cause transfusion-related complications or lead to worse oncological outcomes. This meta-analysis and systematic review aims to give a comprehensive insight into the association between BT and oncological outcomes of patients undergoing RC, and tries to find out whether the timing of blood transfusion could also have an impact on this association. Methods: This systematic review and meta-analysis were carried out according to the PRISMA 2020 reporting guideline. We have searched four bibliographic databases including PubMed (Medline), EMBASE, Cochrane Library, and Web of Science with no language limitation. Studies investigating the association between BT and oncological outcomes of patients undergoing RC are identified and included in this research from inception through March 20, 2023. This research calculates the pooled hazard ratios (pHR) and 95% confidence intervals (95% CI) of all-cause mortality (ACM), cancer-specific mortality (CSM) and disease recurrence (DR) using Random Effects models or Fixed Effects models. Subgroup analyses stratified by parameters such as timing of transfusion are also conducted. This meta-analysis was registered with PROSPERO, CRD42022381656. Results: A total of 20 retrospective studies from online databases and other sources are identified and enrolled in this study. Results show that blood transfusion significantly increased the risks for ACM (HR = 1.33, 95% CI: 1.23-1.44), CSM (HR = 1.25, 95% CI: 1.15 - 1.35) and DR (HR = 1.26, 95% CI: 1.15 - 1.38). However, when stratified by the timing of BT, we find that only intraoperative and perioperative transfusion significantly increased in risks for worse prognosis, while postoperative transfusion raised none of the risks of ACM (HR = 1.26, 95% CI: 0.92-1.73), CSM (HR = 1.08, 95% CI: 0.93-1.26) nor DR (HR = 1.08, 95% CI: 0.90-1.29) significantly. Conclusion: BT administration during RC operation or perioperative period is significantly associated with worse oncological outcomes including ACM, CSM and DR. Clinicians should consider carefully when deciding to administrate BT to patients undergoing RC and carry out according to current guidelines.

Pan-cancer analysis reveals the prognostic and immunologic roles of cereblon and its significance for PROTAC design.

Background: Cereblon (CRBN) has emerged as a vital E3 ubiquitin ligase for Proteolysis-targeting chimera (PROTAC) design. However, few studies focus on the physiological mechanism of CRBN, and more studies are needed to explore the influence of CRBN on tumorigenesis. This pan-cancer analysis aims to explore the prognostic and immunologic roles of CRBN, and provide new insight for CRBN into cancer treatment and PROTAC design. Methods: The TCGA database, TIMER 2.0 database, and TISIDB database were used to analyze the role of CRBN in pan-cancer. Multiple bioinformatic methods (ssGSEA, Kaplan-Meier, univariate cox regression, ESTIMATE, CIBERSORT) were applied to investigate the CRBN expression status, gene activity, prognostic values, and its correlation with immune scores, immune infiltration, immune-related functions, HALLMARKs functions, and response to immunotherapy in pan-cancer. Results: In most cancer types, the expression and activity of CRBN in tumor groups were lower compared with normal groups. Upregulated CRBN expression may indicate a better prognosis for cancer patients. The Immune score, stromal score, and tumor purity varied greatly among different cancer types. GSEA analysis showed that high CRBN expression was correlated with the downregulation of tumor-promoting signaling pathways. The level of CRBN was associated with Tumor mutation burden (TMB), Microsatellite instability (MSI), objective response rate (ORR), and immune cell infiltration in a few cancer types. Conclusion: Pan-cancer analysis reveals the potential role of CRBN as a prognostic biomarker and versatile immunologic roles in different cancer types. Upregulated expression of CRBN may be beneficial to CRBN-related immunotherapy and PROTAC design.

Hyperthermia intravesical chemotherapy acts as a promising alternative to bacillus Calmette-Guérin instillation in non-muscle-invasive bladder cancer: a network meta-analysis.

Introduction: With the shortage of bacillus Calmette-Guérin (BCG) vaccine, it is important to find an alternative to BCG instillation, which is the most commonly used adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC) patients after transurethral resection of bladder tumor treatment (TURBt) to delay tumor recurrence. Hyperthermia intravesical chemotherapy (HIVEC) with mitomycin C (MMC) is a potential treatment choice. We aim to compare HIVEC with BCG instillation for the preventive efficacy of bladder tumor recurrence and progression. Methods: A network meta-analysis (NMA) was taken with MMC instillation and TURBt as the attached comparators. Randomized controlled trials (RCTs) with NIMBC patients after TURBt were included. Articles with pure BCG unresponsive patients and combined therapies were excluded. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42023390363). Results: It was found that HIVEC had a non-significant 22% relative reduction in bladder tumor recurrence compared with BCG instillation [HIVEC vs. BCG: HR 0.78, 95% credible interval (CrI) 0.55-1.08] and a nonsignificant higher risk of bladder tumor progression (BCG vs. HIVEC: HR 0.77, 95% CrI 0.22-3.03). Discussion: HIVEC is a potential alternative to BCG, and it is expected to be the standard therapy for NMIBC patients after TURBt during the global shortage of BCG. Systematic Review Registration: PROSPERO identifier, CRD42023390363.

Integrated bioinformatic analysis and cell line experiments reveal the significant role of the novel immune checkpoint TIGIT in kidney renal clear cell carcinoma.

Background: T cell immunoglobulin and ITIM domain (TIGIT) is a widely concerned immune checkpoint, which plays an essential role in immunosuppression and immune evasion. However, the role of TIGIT in normal organ tissues and renal clear cell carcinoma is unclear. We aim to identify the critical role of TIGIT in renal clear cell carcinoma and find potential targeted TIGIT drugs. Materials and methods: Data retrieved from the GTEX database and TCGA database was used to investigate the expression of TIGIT in normal whole-body tissues and abnormal pan-cancer, then the transcriptome atlas of patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database were applied to distinguish the TIGIT related features, including differential expression status, prognostic value, immune infiltration, co-expression, and drug response of sunitinib an anti-PD1/CTLA4 immunotherapy in KIRC. Furthermore, we constructed a gene-drug network to discover a potential drug targeting TIGIT and verified it by performing molecular docking. Finally, we conducted real-time polymerase chain reaction (PCR) and assays for Transwell migration and CCK-8 to explore the potential roles of TIGIT. Results: TIGIT showed a moderate expression in normal kidney tissues and was confirmed as an essential prognostic factor that was significantly higher expressed in KIRC tissues, and high expression of TIGIT is associated with poor OS, PFS, and DSS in KIRC. Also, the expression of TIGIT was closely associated with the pathological characteristics of the tumor, high expression of TIGIT in KIRC was observed with several critical functions or pathways such as apoptosis, BCR signaling, TCR signaling et al. Moreover, the expression of TIGIT showed a strong positive correlation with infiltration of CD8+ T cells and Tregs and a positive correlation with the drug sensitivity of sunitinib simultaneously. Further Tide ips score analysis and submap analysis reveal that patients with high TIGIT expression significantly show a better response to anti-PD1 immunotherapy. Following this, we discovered Selumetinib and PD0325901 as potential drugs targeting TIGIT and verified the interaction between these two drugs and TIGIT protein by molecular docking. Finally, we verified the essential role of TIGIT in the proliferation and migration functions by using KIRC cell lines. Conclusions: TIGIT plays an essential role in tumorigenesis and progression in KIRC. High expression of TIGIT results in poor survival of KIRC and high drug sensitivity to sunitinib. Besides, Selumetinib and PD0325901 may be potential drugs targeting TIGIT, and combined therapy of anti-TIGIT and other treatments show great potential in treating KIRC.

The growth toxicity and neurotoxicity mechanism of waterborne TBOEP to nematodes: Insights from transcriptomic and metabolomic profiles.

Tris(2-butoxy) ethyl phosphate (TBOEP) is a typical organophosphorus flame retardant (OPFR), which has been detected in natural water bodies and drinking water and has reached a certain concentration. As a new type of organic pollutant, the environmental health risk of TBOEP needs to be assessed urgently. Here, Caenorhabditis elegans were exposed to 0, 50, 500, and 5000 ng/L TBOEP in water for 72 h. The results showed that TBOEP exposure caused concentration-dependent inhibition to the growth of nematodes, while exposure to 5000 ng/L TBOEP significantly inhibited the locomotor behavior of nematodes. Transcriptomic and metabolomic analysis showed that the disturbances in neurotransmitter transmission and amino acid, carbohydrate, and lipid metabolism were the reason for the neurotoxicity and growth toxicity of TBOEP to nematodes. These results provide basic data and a theoretical basis for evaluating the environmental health risks of organophosphorus flame retardants.

A Novel Predictive Model of Pathological Lymph Node Metastasis Constructed with Preoperative Independent Predictors in Patients with Renal Cell Carcinoma.

Introduction: Renal cell carcinoma (RCC) is one of the most common urinary tumors. The risk of metastasis for patients with RCC is about 1/3, among which 30−40% have lymph node metastasis, and the existence of lymph node metastasis will greatly reduce the survival rate of patients. However, the necessity of lymph node dissection is still controversial at present. Therefore, a new predictive model is urgently needed to judge the risk of lymph node metastasis and guide clinical decision making before operation. Method: We retrospectively collected the data of 189 patients who underwent retroperitoneal lymph node dissection or enlarged lymph node resection due to suspected lymph node metastasis or enlarged lymph nodes found during an operation in Tongji Hospital from January 2016 to October 2021. Univariate and multivariate logistic regression and least absolute shrinkage and selection operator (lasso) regression analyses were used to identify preoperative predictors of pathological lymph node positivity. A nomogram was established to predict the probability of lymph node metastasis in patients with RCC before surgery according to the above independent predictors, and its efficacy was evaluated with a calibration curve and a DCA analysis. Result: Among the 189 patients, 54 (28.60%) were pN1 patients, and 135 (71.40%) were pN0 patients. Three independent impact factors were, finally, identified, which were the following: age (OR = 0.3769, 95% CI = 0.1864−0.7622, p < 0.01), lymph node size according to pre-operative imaging (10−20 mm: OR = 15.0040, 95% CI = 1.5666−143.7000, p < 0.05; >20 mm: OR = 4.4013, 95% CI = 1.4892−7.3134, p < 0.01) and clinical T stage (cT1−2 vs. cT3−4) (OR = 3.1641, 95% CI = 1.0336−9.6860, p < 0.05). The calibration curve and DCA (Decision Curve Analysis) showed the nomogram of this predictive model had good fitting. Conclusions: Low age, large lymph node size in pre-operative imaging and high clinical T stage can be used as independent predictive factors of pathological lymph node metastasis in patients with RCC. Our predictive nomogram using these factors exhibited excellent discrimination and calibration.

The association between human papillomavirus and bladder cancer: Evidence from meta-analysis and two-sample mendelian randomization.

INTRODUCTION: Bladder cancer (BCa) is the 10th most common type of cancer worldwide, and human papillomavirus (HPV) is the most common sexually transmitted infection. However, the relationship between HPV infection and the risk of BCa is still controversial and inconclusive. METHODS: This systematic review and meta-analysis were conducted following the PRISMA 2020 reporting guideline. This study searched four bibliographic databases with no language limitation. The databases included PubMed (Medline), EMBASE, Cochrane Library, and Web of Science. Studies evaluating the interaction between HPV infection and the risk of BCa from inception through May 21, 2022, were identified and used in this study. This study estimated the overall and type-specific HPV prevalence and 95% confidence intervals (95% CI) using Random Effects models and Fixed Effects models. In addition, this study also calculated the pooled odds ratio and pooled risk ratio with 95% CI to assess the effect of HPV infection on the risk and prognosis of bladder cancer. Two-sample mendelian randomization (MR) study using genetic variants associated with HPV E7 protein as instrumental variables were also conducted. RESULTS: This study retrieved 80 articles from the four bibliographic databases. Of the total, 27 were case-control studies, and 53 were cross-sectional studies. The results showed that the prevalence of HPV was 16% (95% CI: 11%-21%) among the BCa patients, most of which were HPV-16 (5.99% [95% CI: 3.03%-9.69%]) and HPV-18 (3.68% [95% CI: 1.72%-6.16%]) subtypes. However, the study found that the prevalence varied by region, detection method, BCa histological type, and sample source. A significantly increased risk of BCa was shown for the positivity of overall HPV (odds ratio [OR], 3.35 [95% CI: 1.75-6.43]), which was also influenced by study region, detection method, histological type, and sample source. In addition, the study found that HPV infection was significantly associated with the progression of BCa (RR, 1.73 [95% CI: 1.39-2.15]). The two-sample MR analysis found that both HPV 16 and 18 E7 protein exposure increased the risk of BCa (HPV 16 E7 protein: IVW OR per unit increase in protein level = 1.0004 [95% CI: 1.0002-1.0006]; p = 0.0011; HPV 18 E7 protein: IVW OR per unit increase in protein level = 1.0003 [95% CI: 1.0001-1.0005]; p = 0.0089). CONCLUSION: In conclusion, HPV may play a role in bladder carcinogenesis and contribute to a worse prognosis for patients with BCa. Therefore, it is necessary for people, especially men, to get vaccinated for HPV vaccination to prevent bladder cancer.

Future in precise surgery: Fluorescence-guided surgery using EVs derived fluorescence contrast agent.

Surgery is the only cure for many solid tumors, but positive resection margins, damage to vital nerves, vessels and organs during surgery, and the range and extent of lymph node dissection are significant concerns which hinder the development of surgery. The emergence of fluorescence-guided surgery (FGS) means a farewell to the era when surgeons relied only on visual and tactile feedback, and it gives surgeons another eye to distinguish tumors from normal tissues for precise resection and helps to find a balance between complete tumor lesions removal and maximal organ function conservation. However, the existing synthetic fluorescence contrast agent has flaws in safety, specificity and biocompatibility to various extents. Extracellular vesicles (EVs) are a group of heterogeneous types of cell-derived membranous structures present in all biological fluids. EVs, especially engineered targeting EVs, play an increasingly important role in drug delivery because of their good biocompatibility, validated safety and targeting ability. Nevertheless, few studies have employed EVs loaded with fluorophores to construct fluorescence contrast agents and used them in FGS. Here, we systematically reviewed the current state of knowledge regarding FGS, fundamental characteristics of EVs, and the development of engineered targeting EVs, and put forward a novel strategy and procedures to produce EVs-based fluorescence contrast agent used in fluorescence-guided surgery.

Tertiary lymphoid structure patterns aid in identification of tumor microenvironment infiltration and selection of therapeutic agents in bladder cancer.

Background: Tertiary lymphoid structures (TLSs) are emerging as a potential predictor of prognosis and response to immunotherapy in some solid tumors. However, the comprehensive role of TLSs in bladder cancer remains unclear. Methods: Eighteen bladder cancer (BCa) datasets were downloaded from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArratyExpress and IMvigor210. Based on 39 validated TLS signature genes (TSGs), we evaluated the TLS patterns in all patients, and correlated the TLS patterns with prognosis and tumor microenvironment (TME) cell-infiltrating characteristics. The cox regression model and principal component analysis (PCA) algorithms were used to construct the TLS score, which helps to quantify the TLS pattern in individuals. Results: The landscape of 39 validated TSGs in BCa was assessed first. Five distinct TLS patterns and four gene clusters were determined. TLS cluster C2 and gene cluster A were thought to be characterized by mature TLSs and showed better prognosis and higher immune cells infiltration than other clusters. The TLS score was discovered to be tightly correlated with the infiltration level of immune cells, and could predict the maturation status of TLSs to some extent. We found TLS score was an excellent predictor for prognosis in patients with BCa independent of tumor mutation burden (TMB), and low TLS score was related to better prognosis than high TLS score. Besides, low TLS score was correlated with a better response to immune checkpoint blockade (ICB) immunotherapy and commonly used chemotherapy drugs. Conclusions: Our work demonstrated the characteristics of TLSs in BCa. By using the TLS score, we could evaluate the TLS pattern in individuals. Better understanding of TLS pattern and the usage of TLS score could help instruct clinical strategy and precision medicine for BCa.

Regulation effect of miR-7 on intervening colorectal cancer rats with HP infection through Akt/GSK-3ß/ß-catenin pathway.

This experiment aimed to analysis of the intervention effects of modulating miR-7 on rats with colorectal cancer complicated with HP infection and the effects on (serine/threonine kinase) Akt / (glycogen synthase kinase 3 ß） GSK-3 ß/ （ ß- ß - Catenin) ß- Influence of the catenin pathway. For this purpose, forty special pathogen-free (SPF) - grade rats of both sexes were randomly divided into 10 control, 10 colorectal cancer and HP infection model groups, 10 up-regulated miR-7, and 10 down-regulated miR-7 groups. Observational analysis of rat colon tissues was performed using the HE staining method. Detection of inflammatory factors [TNF- α、 IL-8, IL-6], detection of miR-7 expression, detection of Akt, GSK-3 using Western blot ß、ß- Catenin protein expression. Results showed that forty special pathogen-free (SPF) - grade rats of both sexes were randomly divided into 10 control, 10 colorectal cancer and HP infection model groups, 10 up-regulated miR-7, and 10 down-regulated miR-7 groups. Observational analysis of rat colon tissues was performed using the HE staining method. Detection of inflammatory factors [TNF- α、 IL-8, IL-6], detection of miR-7 expression, detection of Akt, GSK-3 using Western blot ß、ß- Catenin protein expression. It was concluded that modulation of miR-7 in rats with colorectal cancer and HP infection enables regulation of the Akt / GSK-3 ß/ß- Catenin pathway to improve serum inflammation condition and alleviate HP infection in rats, which played a better role in intervention.

A Four-Cell-Senescence-Regulator-Gene Prognostic Index Verified by Genome-Wide CRISPR Can Depict the Tumor Microenvironment and Guide Clinical Treatment of Bladder Cancer.

Bladder cancer (BCa) is the 10th most commonly diagnosed cancer worldwide, and cellular senescence is defined as a state of permanent cell cycle arrest and considered to play important roles in the development and progression of tumor. However, the comprehensive effect of senescence in BCa has not ever been systematically evaluated. Using the genome-wide CRISPR screening data acquired from DepMap (Cancer Dependency Map), senescence genes from the CellAge database, and gene expression data from The Cancer Genome Atlas (TCGA), we screened out 12 senescence genes which might play critical roles in BCa. A four-cell-senescence-regulator-gene prognostic index was constructed using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression model. The transcriptomic data and clinical information of BCa patients were downloaded from TCGA and Gene Expression Omnibus (GEO). We randomly divided the patients in TCGA cohort into training and testing cohorts and calculated the risk score according to the expression of the four senescence genes. The validity of this risk score was validated in the testing cohort (TCGA) and validation cohort (GSE13507). The Kaplan-Meier curves revealed a significant difference in the survival outcome between the high- and low-risk score groups. A nomogram including the risk score and other clinical factors (age, gender, stage, and grade) was established with better predictive capacity of OS in 1, 3, and 5 years. Besides, we found that patients in the high-risk group had higher tumor mutation burden (TMB); lower immune, stroma, and ESTIMATE scores; higher tumor purity; aberrant immune functions; and lower expression of immune checkpoints. We also performed gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to investigate the interaction between risk score and hallmark pathways and found that a high risk score was connected with activation of senescence-related pathways. Furthermore, we found that a high risk score was related to better response to immunotherapy and chemotherapy. In conclusion, we identified a four-cell-senescence-regulator-gene prognostic index in BCa and investigated its relationship with TMB, the immune landscape of tumor microenvironment (TME), and response to immunotherapy and chemotherapy, and we also established a nomogram to predict the prognosis of patients with BCa.

Standard therapies: solutions for improving therapeutic effects of immune checkpoint inhibitors on colorectal cancer.

Immunotherapy using immune checkpoint inhibitors has opened a new era for cancer management. In colorectal cancer, patients with a phenotype of deficient mismatch repair or high microsatellite instability benefit from immunotherapy. However, the response of rest cases to immunotherapy alone is still poor. Nevertheless, preclinical data have revealed that either ionizing irradiation or chemotherapy can improve the tumoral immune milieu, because these approaches can induce immunogenic cell death among cancer cells. In this regard, combination use of standard therapy plus immunotherapy should be feasible. In this review, we will introduce the specific roles of standard therapies, including radiotherapy, chemotherapy, antiangiogenic and anti-EGFR therapy, in improving therapeutic effect of immune checkpoint inhibitors on colorectal cancer.

[Group 2 innate lymphoid cells (ILC2) relieves pathogenesis of rheumatoid arthritis by secreting IL-13].

Objective To study the changes of group 2 innate lymphoid cells (ILC2) in rheumatoid arthritis (RA) and its possible mechanism. Methods The 28 joint disease activity score (DAS28) and peripheral blood samples were collected from RA patients. Erythrocyto sedimentation rate (ESR) and C-reactive protein (CRP) were measured by an automatic erythrocyte sedimentation device and immune transmission turbidimetry, respectively. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACCP) were assessed by immunoturbidimetry and chemiluminescence assay, respectively. Flow cytometry was used to detect the proportion of ILC2 in the patients with RA. The correlations between ILC2 and the above disease indexes were analyzed by Spearman correlation analysis. RA patients were divided into two groups: low disease activity (DAS28<3.2) group and high disease activity (DAS28≥3.2) group. The expression of interleukin-13 (IL-13) in ILC2 of RA patients was detected by flow cytometry, and the differences of ILC2 expression were compared in RA patients with different disease activity of IL-13. Results Compared with healthy people, the proportion and absolute number of ILC2 in the peripheral blood of RA patients increased. ILC2 was negatively correlated with ESR, CRP and DAS28. IL-13 secreted by ILC2 in RA patients with high disease activity was significantly lower than that in the ones with low disease activity. Conclusion ILC2 inhibits RA disease activity by secreting IL-13.

Scoulerine promotes cell viability reduction and apoptosis by activating ROS-dependent endoplasmic reticulum stress in colorectal cancer cells.

Scoulerine, an isoquinoline alkaloid isolated from Corydalis plants, has been reported to possess potent anti-proliferative and pro-apoptotic function in cancer cells. However, the effects and underlying mechanisms of scoulerine on colorectal cancer (CRC) progression remain elusive. CCK-8 and LDH assays were used to evaluate cell viability. Apoptosis was assessed by flow cytometry analysis, caspase-3/7 activity assay, and Western blot analysis of Bax, Bcl-2 and cytochrome c (Cyt C) expression. Oxidative stress level was examined by measuring reactive oxygen species (ROS) and glutathione (GSH) contents and superoxide dismutase (SOD) activity. Endoplasmic reticulum (ER) stress activation was detected by Western blot analysis of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) expression. Results showed that scoulerine dose-dependently suppressed CRC cell viability. Scoulerine induced apoptosis and increased caspase-3/7 activity in CRC cells. Bax and cytosolic Cyt C expression was enhanced while Bcl-2 and mitochondrial Cyt C expression was reduced in scoulerine-treated CRC cells. Additionally, scoulerine induced oxidative damage in CRC cells by increasing ROS generation and reducing GSH content and SOD activity. Scoulerine activated ER stress, as evidenced by the increased GRP78 and CHOP expression in CRC cells. Interestingly, blocking ROS production by ROS scavenger N-acetyl-cysteine (NAC) attenuated scoulerine-induced ER stress. Inhibition of ER stress by 4-phenyl butyric acid (4-PBA) abolished scoulerine-induced ROS generation in CRC cells. Blockage of ROS and ER stress attenuated scoulerine-induced cell viability reduction and apoptosis in CRC cells. In conclusion, scoulerine promoted cell viability reduction and apoptosis by activating ROS-dependent ER stress in CRC cells.

Mesenchymal Stem Cell-Derived Exosomes: Biological Function and Their Therapeutic Potential in Radiation Damage.

Radiation-induced damage is a common occurrence in cancer patients who undergo radiotherapy. In this setting, radiation-induced damage can be refractory because the regeneration responses of injured tissues or organs are not well stimulated. Mesenchymal stem cells have become ideal candidates for managing radiation-induced damage. Moreover, accumulating evidence suggests that exosomes derived from mesenchymal stem cells have a similar effect on repairing tissue damage mainly because these exosomes carry various bioactive substances, such as miRNAs, proteins and lipids, which can affect immunomodulation, angiogenesis, and cell survival and proliferation. Although the mechanisms by which mesenchymal stem cell-derived exosomes repair radiation damage have not been fully elucidated, we intend to translate their biological features into a radiation damage model and aim to provide new insight into the management of radiation damage.