Targeting cellular senescence as a therapeutic vulnerability in gastric cancer.

AIMS: Cellular senescence (CS) represents an intracellular defense mechanism responding to stress signals and can be leveraged as a "vulnerability" in cancer treatment. This study aims to construct a CS atlas for gastric cancer (GC) and uncover potential therapeutics for GC patients. MATERIALS AND METHODS: 38 senescence-associated regulators with prognostic significance in GC were obtained from the CellAge database to construct Gastric cancer-specific Senescence Score (GSS). Using eXtreme Sum algorism, GSS-based drug repositioning was conducted to identify drugs that could antagonize GSS in CMap database. In vitro experiments were conducted to test the effect of combination of palbociclib and exisulind in eliminating GC cells. KEY FINDINGS: Patients with high GSS exhibited CS-related features, such as CS markers upregulation, adverse clinical outcomes and hypomethylation status. scRNA-seq data showed malignant cells with high GSS exhibited enhanced senescence state and more immunosuppressive signals such as PVR-CD96 compared with malignant cells with low GSS. In addition, the GSS-High cancer associated fibroblasts might secrete cytokines and chemokines such as IL-6, CXCL1, CXCL12, and CCL2 to from an immunosuppressive microenvironment, and GSS could serve as an indicator for immunotherapy resistance. Exisulind exhibited the greatest potential to reverse GSS. In vitro experiments demonstrated that exisulind could induce apoptosis and suppress the proliferation of palbociclib-induced senescent GC cells. SIGNIFICANCE: Overall, GSS offers a framework for better understanding of correlation between senescence and GC, which might provide new insights into the development of novel therapeutics in GC.

Comprehensive Analysis of ANLN in Human Tumors: A Prognostic Biomarker Associated with Cancer Immunity.

Background: Anillin (ANLN), a ubiquitously expressed actin-binding protein, plays a critical tumor-promoting role in cell growth, migration, and cytokinesis. Numerous studies have suggested that ANLN is upregulated in many cancer types, as well as significantly associated with patient prognosis and malignant cancer characteristics. Herein, we performed an integrated pan-cancer analysis of ANLN and highlighted its underlying mechanism, which may benefit further exploration of the potential therapeutic options for cancer. Methods: ANLN expression data were extracted from online databases, including TCGA, GTEx, and CCLE databases. The TIMER database was used to study the association between ANLN expression with immune checkpoint genes and immunocyte infiltration. The ScanNeo pipeline was adopted for neoantigen discovery. KEGG analysis and the STRING tool were used to elucidate the potential mechanism of ANLN in cancer development. Results: ANLN is abnormally overexpressed in almost all cancer tissues compared with normal tissues. The high-ANLN expression level was positively associated with various malignant characteristics, suggesting its potential role in the immune microenvironment and poor prognosis. In addition, ANLN expression was correlated with the number of neoantigens and different phosphorylation pattern in various cancer types, revealing a functional role of genetic mutation accumulation and high phosphorylation in ANLN-mediated oncogenesis. Moreover, we found that ANLN was an important regulatory factor participating in many signaling events, especially the cell cycle and nucleocytoplasmic transport pathways. Conclusions: ANLN expression is generally overexpressed in various types of cancers, and it may have an important influence on tumor progression and development. ANLN expression is significantly associated with the immune checkpoint biomarkers and tumor immunity. Together, these findings suggest that ANLN may be a predictive marker for patient prognosis across cancers.

MRI radiomic features of peritumoral edema may predict the recurrence sites of glioblastoma multiforme.

Background and purpose: As one of the most aggressive malignant tumor in the central nervous system, the main cause of poor outcome of glioblastoma (GBM) is recurrence, a non-invasive method which can predict the area of recurrence pre-operation is necessary.To investigate whether there is radiological heterogeneity within peritumoral edema and identify the reproducible radiomic features predictive of the sites of recurrence of glioblastoma(GBM), which may be of value to optimize patients' management. Materials and methods: The clinical information and MR images (contrast-enhanced T1 weighted and FLAIR sequences) of 22 patients who have been histologically proven glioblastoma, were retrospectively evaluated. Kaplan-Meier methods was used for survival analysis. Oedematous regions were manually segmented by an expert into recurrence region, non-recurrence region. A set of 94 radiomic features were obtained from each region using the function of analyzing MR image of 3D slicer. Paired t test was performed to identify the features existing significant difference. Subsequently, the data of two patients from TCGA database was used to evaluate whether these features have clinical value. Results: Ten features with significant differences between the recurrence and non-recurrence subregions were identified and verified on two individual patients from the TCGA database with pathologically confirmed diagnosis of GBM. Conclusions: Our results suggested that heterogeneity does exist in peritumoral edema, indicating that the radiomic features of peritumoral edema from routine MR images can be utilized to predict the sites of GBM recurrence. Our findings may further guide the surgical treatment strategy for GBM.

Pan-Cancer Landscape of NEIL3 in Tumor Microenvironment: A Promising Predictor for Chemotherapy and Immunotherapy.

With the aim of enhancing the understanding of NEIL3 in prognosis prediction and therapy administration, we conducted a pan-cancer landscape analysis on NEIL3. The mutation characteristics, survival patterns, and immune features of NEIL3 across cancers were analyzed. Western blotting, qPCR, and immunohistochemistry were conducted to validate the bioinformatics results. The correlation between NEIL3 and chemotherapeutic drugs, as well as immunotherapies, was estimated. NEIL3 was identified as an oncogene with prognostic value in predicting clinical outcomes in multiple cancers. Combined with the neoantigen, tumor mutational burden (TMB), and microsatellite instability (MSI) results, a strong relationship between NEIL3 and the TME was observed. NEIL3 was demonstrated to be closely associated with multiple immune parameters, including infiltrating immunocytes and pro-inflammatory chemokines, which was verified by experiments. More importantly, patients with a higher expression of NEIL3 were revealed to be more sensitive to chemotherapeutic regimens and immune checkpoint inhibitors in selected cancers, implying that NEIL3 may be an indicator for therapeutic administration. Our study indicated NEIL3 has a strong association with the immune microenvironment and phenotypic changes in certain types of cancers, which facilitated the improved understanding of NEIL3 across cancers and highlighted the potential for clinical application of NEIL3 in precision medical stratification.

Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma.

Accumulating evidence shows a close association between various types of bile acids (BAs) and hepatocellular carcinoma (HCC), and they have been revealed to affect tumor immune response and progression mainly by regulating Farnesoid X receptor (FXR). Nevertheless, the roles of Norcholic acid(NorCA) in HCC progression remain unknown yet. In this study, herein we demonstrate that NorCA can promote HCC cell proliferation, migration and invasion through negatively regulating FXR. Additionally, NorCA can increase PD-L1 level on the surfaces of HCC cells and their exosomes, and NorCA-induced exosomes dramatically dampen the function of CD4+T cells, thereby inducing an immunosuppressive microenvironment. Meanwhile, a negative correlation between PD-L1 and FXR expression in human HCC specimens was identified, and HCC patients with FXRlowPD-L1high expression exhibit a rather dismal survival outcome. Importantly, FXR agonist (GW4064) can synergize with anti-PD-1 antibody (Ab) to inhibit HCC growth in tumor-bearing models. Taken together, NorCA can promote HCC progression and immune invasion by inhibiting FXR signaling, implying a superiority of the combination of FXR agonist and anti-PD-1 Ab to the monotherapy of immune checkpoint inhibitor in combating HCC. However, more well-designed animal experiments and clinical trials are warranted to further confirm our findings in future due to the limitations in our study.

Prognostic and immunological role of CD36: A pan-cancer analysis.

CD36 plays a critical role in lipid metabolism, which is closely associated with human immunity. However, the role of CD36 in cancer remains unclear. We performed a pan-cancer analysis to elucidate the potential role of CD36 in cancer by investigating its prognostic value and current predictors for the efficacy of immune checkpoint inhibitors (ICIs) in multiple cancer types. CD36 expression in cancer cell lines, tumor tissue, and their adjacent normal tissues displayed heterogeneity among different cancers. Immunohistochemistry was used to detect CD36 expression and confirmed the results. CD36 expression significantly affects prognosis in the six cancer types. High CD36 expression was marginally associated with poorer prognosis in four of them and improved prognosis in the remaining two types. CD36 expression was significantly correlated with the 6 immune infiltrates in most cancer types. In addition, CD36 gene expression was positively correlated with Stromal score, Immune score, and ESTIMATE score. A total of 47 immune checkpoint genes were collected and their relationship with CD36 expression was analyzed. CD36 expression was significantly associated with multiple stimulatory and inhibitory checkpoint molecules with a disease-specific pattern. As to the genes reported to positively relate to the efficacy of ICIs, CD36 expression was positively correlated with most of them but negatively associated with a small proportion of cancer type-specific patterns. Concerning the genes negatively related to the efficacy of ICIs, CD36 expression was positively correlated with NRP1 and TNFSF15 in multiple cancers. CD36 expression was negatively correlated with tumor neoantigen burden in most cancer types. However, CD36 expression was negatively correlated with tumor mutation burden in most cancer types. The correlation between CD36 expression and the four methyltransferases was also significant in multiple cancers, but also with a cancer type-specific pattern. In summary, the current study found CD36 expression and its prognostic value in multiple cancer types. In addition, the expression of CD36 was significantly associated with current predictors for the efficacy of ICIs. The practical application value of CD36 is disease specific.

Safety and feasibility of single-incision radical vulvectomy: a novel approach for the treatment of vulvar cancer.

BACKGROUND: In the process of decreasing the morbidity of wound-related complications after vulvectomy and IL for treating vulvar malignancy, we performed a novel surgical procedure-single-incision radical vulvectomy (SIRV). Here, we share our initial experience and report its safety and feasibility. METHODS: Patients with advanced local vulvar tumors were sequentially enrolled in this prospective cohort study to undergo SIRV. While performing SIRV, routine radical vulvectomies were performed first. Subsequently, the flaps of the bridge area between the vulvectomy incisions and femoral triangles were separated and the lymph nodes underneath were removed. Anterior working spaces (AWS) before the femoral triangle were then made. The saphenous vein was carefully identified and retained, while the superficial and deep inguinal lymph nodes were removed from the medial to the lateral sides. After careful hemostasis, the wounds were sutured. Patient demographics, clinical data, pathologic data, operation time, node count, and complications were recorded. RESULTS: Ten patients underwent SIRV for vulvar cancer. Average hospital stay was 11.70±3.16 (range, 9-13) days. The average number of harvested lymph nodes was 7.59±3.62 (range, 3-15) and 15.14±3.63 (range, 11-20) for per side or both sides of the groin. Blood loss was ≤35 mL. Three patients developed inguinal lymphoceles and underwent needle aspirations. Two patients had impaired wound healing and achieved healing after dressing change. No other postoperative complications were noted during follow-up. CONCLUSIONS: Compared with conventional open inguinal lymphadenectomy (COIL) and video endoscopic inguinal lymphadenectomy (VEIL), SIRV is a more minimally invasive procedure. Our short-term observations showed that SIRV is safe and feasible and has good future application prospects for vulvar cancer. However, definitive conclusions cannot be made. Therefore, long-term oncologic outcomes and large-scale clinical trials are warranted.

Comparison of emergency cholecystectomy and delayed cholecystectomy after percutaneous transhepatic gallbladder drainage in patients with acute cholecystitis: a systematic review and meta-analysis.

Laparoscopic cholecystectomy and percutaneous transhepatic gallbladder drainage (PTGBD) are common treatments for patients with acute cholecystitis. However, the safety and efficacy of emergency laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC) after PTGBD in patients with acute cholecystitis remain unclear. The PubMed, EMBASE, and Cochrane Library databases were searched through October 2019. The quality of the included nonrandomized studies was assessed using the Methodological Index for Nonrandomized Studies (MINORS). The meta-analysis was performed using STATA version 14.2. A random-effects model was used to calculate the outcomes. A total of fifteen studies involving 1780 patients with acute cholecystitis were included in the meta-analysis. DLC after PTGBD was associated with a shorter operative time (SMD - 0.51; 95% CI - 0.89 to - 0.13; P = 0.008), a lower conversion rate (RR 0.43; 95% CI 0.26 to 0.69; P = 0.001), less intraoperative blood loss (SMD - 0.59; 95% CI - 0.96 to - 0.22; P = 0.002) and longer time of total hospital stay compared to ELC (SMD 0.91; 95% CI 0.57-1.24; P < 0.001). There was no difference in the postoperative complications (RR 0.68; 95% CI 0.48-0.97; P = 0.035), biliary leakage (RR 0.65; 95% CI 0.34-1.22; P = 0.175) or mortality (RR 1.04; 95% CI 0.39-2.80; P = 0.933). Compared to ELC, DLC after PTGBD had the advantages of a shorter operative time, a lower conversion rate and less intraoperative blood loss.

Nomograms for Predicting the Overall and Cancer-Specific Survival of Patients with High-Grade Glioma: A Surveillance, Epidemiology, and End Results Study.

AIM: To predict the overall survival (OS) and the cancer-specific survival (CSS) of patients with high-grade glioma (HGG) using nomograms and the surveillance, epidemiology, and end results (SEER) database (2000-2013). MATERIAL AND METHODS: A total of 3706 patients with high-grade glioma were identified by the SEER database (2000-2013). Based on the relevant information of these patients, we divided the primary cohort into a training cohort (n=3336) and a validation cohort (n=370). The nomograms were constructed by the training cohort and corroborated by the validation cohort. RESULTS: According to the multivariate analysis of the training cohort, the nomograms of OS and CSS indicated that patient age at diagnosis, laterality, radiation, and the extent of resection are significantly correlated with the survival rate. The c-indexes of the nomograms of OS and CSS of the training cohort are 0.682 [95% confidence interval (CI): 0.671-0.693] and 0.678 (95%CI: 0.666- 0.690), respectively. The calibration curve plots of 1- and 3-year OS and CSS showed that the nomogram predictions are consistent with the observed outcomes for both the training and validation cohorts. CONCLUSION: Based on the data obtained, we established a scoring model to predict the OS and the CSS of patients with HGG. All calibration curves showed high consistency between the predicted and actual survival.

Risk of skin cancers in thiopurines-treated and thiopurines-untreated patients with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: The thiopurines are effective in the management of patients with inflammatory bowel disease (IBD), but the association between thiopurines use and the risk of skin cancer (including nonmelanoma skin cancer [NMSC] and melanoma skin cancer) has already been sufficiently reported. However, the results of these studies are inconsistent, and thus, the objective of our analysis was to explore whether thiopurines can lead to an excess risk of skin cancer in IBD patients. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies that evaluated the risk of skin cancer in IBD patients treated with thiopurines. A random effects meta-analysis was conducted to calculate the pooled incidence rate ratios as well as risk ratios (RRs). Subgroup analysis was performed to explore the potential source of heterogeneity. RESULTS: Thirteen studies comprising 149 198 participants were included. The result suggested that thiopurines significantly increased the risk of overall skin cancer in IBD patients (random effects: RR = 1.80, 95% confidence interval [CI] 1.14-2.87, P = 0.013), among which NMSC showed an excess risk associated with thiopurines use (random effects: RR = 1.88, 95% CI 1.48-2.38, P < 0.001) while no increased risk was observed with respect to melanoma skin cancer (random effects: RR = 1.22, 95% CI 0.90-1.65, P = 0.206). Subgroup analysis regarding sample size and geographic distribution in skin cancer and follow-up duration in NMSC reached statistical significance, while other subgroups showed no significance. CONCLUSION: Exposition of thiopurines in patients with IBD is associated with a higher risk of skin cancer. Routine skin screening and daily skin protective practice are recommended for these patients.

The prognostic role of pretreatment thrombocytosis in gastric cancer: A systematic review and meta-analysis.

BACKGROUND: The association between platelet count and the prognosis of patients with gastric cancer has already been reported by numerous studies. As the reports are inconsistent, we conducted this meta-analysis to evaluate the prognostic significance of platelet count in patients with gastric cancer. METHODS: A comprehensive search was performed in PubMed, Embase, and the Cochrane Library to identify relevant studies, which evaluated the prognostic impact of pretreatment platelet count in patients with gastric cancer. Data was pooled using a random effect model to calculate hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Around 10 studies were included, comprising 8166 patients in total. The result showed that patients with thrombocytosis had significant worse overall survival (HR 1.57, 95% CI 1.36-1.81, P < .001) than those with normal platelet count, and were associated with advanced clinical stage (OR, 1.57; 95% CI, 1.15-2.13; P = .004), deeper tumor invasion (OR,3.49; 95% CI, 2.48-4.91; P < .001), and higher risk of recurrence (OR, 2.28; 95% CI, 1.55-3.35; P < .001). CONCLUSION: Pretreatment thrombocytosis is a potential effective predictor of overall survival (OS) for patients with gastric cancer and is correlated with higher risks of recurrence, serosal invasion, and advanced stage.

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-tumour Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: The association between anti-tumour necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumour necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. RESULTS: Twelve studies comprising 285,811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumour necrosis factor alpha agents exposed and anti-tumour necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR] = 1.43, 95% CI, 0.91-2.25; P = 0.116; random effects: risk ratio [RR] = 0.83, 95% CI, 0.47-1.48; P = 0.534). However, monotherapy of anti-tumour necrosis factor alpha agents [random effects: IRR = 1.65, 95% CI, 1.16-2.35; P = 0.006; random effects: RR = 1.00, 95% CI, 0.39-2.59; P = 0.996] or combination therapy [random effects: IRR = 3.36, 95% CI, 2.23-5.05; P < 0.001; random effects: RR = 1.90, 95% CI, 0.66-5.44; P = 0.233] can significantly increase the risk of lymphoma. CONCLUSIONS: Exposition of anti-tumour necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumour necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease.

Decreased CD8+CD28+/CD8+CD28- T cell ratio can sensitively predict poor outcome for patients with complicated Crohn disease.

Crohn disease (CD) with complications such as penetrating, stricturing, and perianal disease is called complicated CD. The aim of this study is to test the efficiency with which the CD8CD28/CD8CD28 cell balance can predict a subsequent active stage in patients with newly diagnosed complicated CD.Seventeen patients with complicated CD and 48 CD patients with no complications were enrolled. Blood CD8 T cells were tested from all of the 65 newly diagnosed CD patients upon enrollment. The potential risk factors were compared between the 2 groups. A 30-week follow-up was performed, and the efficiency of the CD8 cell balance at predicting active CD was analyzed using receiver-operating characteristic curves. The cumulative remission lasting rates (CRLRs) were analyzed using the Kaplan-Meier method.Compared with the control CD group, patients with complicated CD were predominantly male and younger in age; they also had lower body mass indices (BMIs), higher Crohn disease activity indices (CDAIs), higher immunosuppressant and steroid prescription rates, and significantly higher surgical rates. The CD8CD28/CD8CD28 balance was associated with BMI, CDAI, steroids, and surgery. The CD8CD28/CD8CD28 ratios were significantly lower at week 0 and on the 6th, 22nd, and 30th week during follow-up with a shorter lasting time of remission for the complicated CD patients. The CD8CD28/CD8CD28 ratio could accurately predict the active stage for the patients with complicated CD, and the highest sensitivity (89.2%) and specificity (85.3%) were found when the ratio was 1.03. Treatment with steroids and surgery, along with a significantly lower CD8CD28/CD8CD28 ratio and lower CRLRs, was closely related to a worse outcome for the patients with complicated CD.Patients requiring steroids and surgery experience more severe disease activity and thus a disequilibrated immunological balance, which could be the main reason for a decreased CD8CD28/CD8CD28 ratio. This ratio can sensitively predict the active stage for patients with complicated CD, and more care should be taken when this ratio is <1.03.

CD8+CD28+/CD8+CD28- T cell equilibrium can predict the active stage for patients with inflammatory bowel disease.

BACKGROUND/AIM: The balance of blood CD8+CD28+/CD8+CD28- T cells has been verified to be vital for patients with ulcerative colitis (UC), but their role in inflammatory bowel disease (IBD) remains unknown. This investigation aimed to evaluate the efficiency of the balance in predicting the active stage in IBD patients. METHODS: Fifty-three IBD subjects, including 31 UC and 22 Crohn's disease (CD) patients, were enrolled, and their peripheral blood CD8+CD28+ and CD8+CD28- T cell levels were tested using flow cytometry. The risk factors related to prognosis were compared between UC and CD patients. A 1-year follow-up was performed for all the IBD patients, and the CD8+ T cells and their ratio were compared at the 3rd, 6th, 9th, and 12th months during follow-up. The sensitivity and specificity of the CD8+ T cell level and balance were analyzed through receiver operator characteristic (ROC) curves. The cumulative remission lasting rates (CRLRs) under the different factors were analyzed using the Kaplan-Meier method. RESULTS: Higher prescription rates of immunosuppressants, steroids, probiotics, and biological agents (BAs) were found in CD subjects in comparison to UC subjects (P=0.005, 0.024, 0.034, and 0.001), as was a higher active rate during follow-up (95.5% of CD patients vs 67.7% of UC patients, P=0.035). The CD8+CD28+ T cell level and the CD8+CD28+/CD8+CD28- T cell ratio were significantly higher in UC patients than in CD patients, but the reverse was true for CD8+CD28- T cells during follow-up at the 9th and 12th month (all P<0.05). The diagnostic models of the initial CD8+CD28+ and CD8+CD28- T cell numbers and the CD8+CD28+/CD8+CD28- T cell ratio in predicting the active stage were found to be significant, with areas under the curves (AUCs) of 0.883, 0.098, and 0.913 for UC subjects (with 95% CI: 0.709-0.940, 0.009-0.188, and 0.842-1.003; P=0.001, 0.00, and 0.000) and 0.812, 0.078, and 0.898 for CD subjects (with 95% CI: 0.683-0.957, 0.003-0.158, and 0.837-0.998; P=0.003, 0.00, and 0.000). The cut-off values showed that when the ratios were 1.30 for UC and 1.22 for CD patients, the best sensitivity and specificity were observed, with 91.6% and 89.0% for UC and 88.5% and 85.1% for CD, respectively. The CRLRs were significantly higher in female, non-BA-treated, non-surgical IBD subjects when compared to male, BA-treated, surgical subjects (P=0.031, 0.000, and 0.000). The number of CD8+CD28+ and CD8+CD28- T cells and the CD8+CD28+/CD8+CD28- T cell ratio were correlated with BA treatment and surgery (all P<0.05). CONCLUSION: The CD8+CD28+/CD8+CD28- T cell balance, expected to be a novel immunologic marker, presented a satisfactory efficiency with high sensitivity and specificity in predicting the active stage in UC and CD patients, and the balance was closely related to the use of BAs and surgery.