Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T‐cell–mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p‐AKT/p‐ERK/p‐MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol‐treated mice. The expression of GzmB/IFN‐γ/T‐bet in the CD8+ T‐cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol‐treated surgical specimens, the expression of p‐ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T‐cell population was significantly increased in propranolol‐treated subjects. Together, these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p‐AKT/p‐ERK/p‐MEK in mouse tumor models, while inhibiting the expression of p‐ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward.

BackgroundHydronephrosis is a common finding in patients with bladder cancer. The aim of the study was to appraise the prognostic value of preoperative hydronephrosis in bladder cancer patients undergoing radical cystectomy.MethodsWe conducted a literature search using PubMed and Embase databases in Aug 2018. Summary hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed-effect or random-effects models. The primary endpoint was overall survival (OS). Secondary endpoints were cancer-specific survival (CSS) and recurrence-free survival (RFS).ResultsOverall, 13 studies published between 2008 and 2018 including 4,820 patients were selected for the meta-analysis. The age of bladder cancer patients ranged from 27 to 90.4 years, and the overall proportion of males was 72.5%. Preoperative hydronephrosis was reported in 27.4% of patients. The pooled HR was statistically significant for OS (HR, 1.36; 95% CI [1.20–1.55]) and CSS (HR, 1.64; 95% CI [1.33–2.02]), with no heterogeneity among the enrolled studies. Patients with bilateral hydronephrosis showed a poorer CSS compared to those with no hydronephrosis (HR 5.43, 95% CI [3.14–9.40]). However, there was no difference in CSS between no hydronephrosis and unilateral hydronephrosis groups (HR 1.35, 95% CI [0.84–2.14]). Despite a tendency towards poorer RFS (HR, 1.27; 95% CI [0.96–1.96]), the results demonstrated no significant association between presence of preoperative hydronephrosis and RFS after radical cystectomy.ConclusionThis meta-analysis indicates that preoperative hydronephrosis is significantly associated with poorer OS and CSS after radical cystectomy for patients with bladder cancer. Preoperative hydronephrosis has a stronger effect on CSS in patients with bilateral hydronephrosis. The presence of preoperative hydronephrosis not only predicts prognosis, but may also help to identify patients who benefit the most from neoadjuvant chemotherapy.

Background and aims: Vasoactive intestinal polypeptide type-I receptor (VIPR1) overexpression has been reported in numerous types of malignancies and utilized to develop novel target therapeutics and radiolabeled VIP analogue-based tumor imaging technology, but its role in liver carcinogenesis has not been explored. In the current study, we investigated the role of the VIP/VIPR1 signaling in controlling hepatocellular carcinoma (HCC) progression. Approach and results: By analyzing clinical samples, we found the expression level of VIPR1 was downregulated in human HCC tissues, which was correlated with advanced clinical stages, tumor growth, recurrence, and poor outcomes of HCC clinically. In vitro and in vivo studies revealed that activation of VIPR1 by VIP markedly inhibited HCC growth and metastasis. Intriguingly, transcriptome sequencing analyses revealed that activation of VIPR1 by VIP regulated arginine biosynthesis. Mechanistical studies in cultured HCC cells demonstrated that VIP treatment partially restored the expression of arginine anabolic key enzyme argininosuccinate synthase (ASS1), and to some extent, inhibited de novo pyrimidine synthetic pathway by downregulating the activation of CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). VIP treatment upregulated ASS1 and subsequently suppressed CAD phosphorylation in an mTOR/p70S6K signaling dependent manner. Clinically, we found human HCC samples were associated with downregulation of ASS1 but upregulation of CAD phosphorylation, and that VIPR1 levels positively correlated with ASS1 levels and serum levels of urea, the end product of the urea cycle and arginine metabolism in HCC. Conclusions: Loss of VIPR1 expression in HCC facilitates CAD phosphorylation and tumor progression, and restoration of VIPR1 and treatment with the VIPR1 agonist may be a promising approach for HCC treatment.

Background: Tumor-infiltrating lymphocytes (TILs) and postoperative chemotherapeutics interact in the tumor micro-environment. This interaction has not been well investigated in gastric cancer. Materials & methods: A total of 129 patients were divided into high or low TILs based on the median number of positive CD3+ and FoxP3+ T cells, which was assessed by immunocytochemistry. Results: Cox regression analysis showed that the stage III disease with shorter overall survival was significant. The analysis showed that high numbers of CD3+ or FoxP3+ T cells have better clinical outcomes in FOLFOX-treated patients. Conclusion: High CD3+ and FoxP3+ T-cell infiltration was associated with better clinical outcomes in patients with gastric cancer treated with FOLFOX, suggesting TILs incorporated into algorithms to improve the therapeutic efficacy of optimal chemotherapy.

Background Coronary artery disease (CAD) is a multifactorial cardiovascular disease that causes high mortality worldwide. Cuproptosis is a newly discovered method of programmed cell death, but it is unclear whether it is involved in the development of CAD. Methods GSE180081 was downloaded from the GEO database and genes that were differentially expressed in controls and patients with CAD were identified. These were clustered according to the cuproptosis gene set, to identify differentially expressed cuproptosis related genes. The intersection of the two sets of differentially expressed genes was used to identify genes relevant to the diagnosis of CAD using LASSO regression. A diagnostic model was created using the selected genes and logistic regression. Enriched immune genes were identified, the associated ceRNA network was characterized, and drugs that may target the identified genes were searched for. Results We identified 818 differentially expressed genes that were common to the CAD and cuproptosis gene sets, which principally represented the cell-substrate junction and the positive regulation of leukemia. Furthermore, HIST1H4E, IL6ST, RN7SKP45, LST1, and SNORD50B were found be potentially useful for the diagnosis of CAD using the diagnostic model. These genes were found to be closely associated with immune modification. Conclusion We have constructed a diagnostic prediction model based on a cuproptosis gene set using whole-blood transcriptome data. Using this, we have identified HIST1H4E, IL6ST, and LST1 as potential biomarkers of the risk of CAD. These findings provide a novel approach to the prediction, prevention, and individualized treatment of CAD.