Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy.

Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity; however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression, and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.

Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.

Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.

Nomogram to predict cause-specific mortality of patients with rectal adenocarcinoma undergoing surgery: a competing risk analysis.

BACKGROUND: Rectal adenocarcinoma is one of major public health problems, severely threatening people's health and life. Cox proportional hazard models have been applied in previous studies widely to analyze survival data. However, such models ignore competing risks and treat them as censored, resulting in excessive statistical errors. Therefore, a competing-risk model was applied with the aim of decreasing risk of bias and thereby obtaining more-accurate results and establishing a competing-risk nomogram for better guiding clinical practice. METHODS: A total of 22,879 rectal adenocarcinoma cases who underwent primary-site surgical resection were collected from the SEER (Surveillance, Epidemiology, and End Results) database. Death due to rectal adenocarcinoma (DRA) and death due to other causes (DOC) were two competing endpoint events in the competing-risk regression analysis. The cumulative incidence function for DRA and DOC at each time point was calculated. Gray's test was applied in the univariate analysis and Gray's proportional subdistribution hazard model was adopted in the multivariable analysis to recognize significant differences among groups and obtain significant factors that could affect patients' prognosis. Next, A competing-risk nomogram was established predicting the cause-specific outcome of rectal adenocarcinoma cases. Finally, we plotted calibration curve and calculated concordance indexes (c-index) to evaluate the model performance. RESULTS: 22,879 patients were included finally. The results showed that age, race, marital status, chemotherapy, AJCC stage, tumor size, and number of metastasis lymph nodes were significant prognostic factors for postoperative rectal adenocarcinoma patients. We further successfully constructed a competing-risk nomogram to predict the 1-year, 3-year, and 5-year cause-specific mortality of rectal adenocarcinoma patients. The calibration curve and C-index indicated that the competing-risk nomogram model had satisfactory prognostic ability. CONCLUSION: Competing-risk analysis could help us obtain more-accurate results for rectal adenocarcinoma patients who had undergone surgery, which could definitely help clinicians obtain accurate prediction of the prognosis of patients and make better clinical decisions.

6-Gingerol suppresses tumor cell metastasis by increasing YAPser127 phosphorylation in renal cell carcinoma.

According to the World Health Organization, the incidence and mortality rates of renal cell carcinoma (RCC) are rapidly increasing worldwide. Serious side effects caused by immune therapy and resistance to targeted drug therapy are urgent clinical problems facing kidney treatment. There is increasing global interest in developing natural products with a reduced number of side effects as adjunctive therapeutic options for RCC. Ginger is a spice and herbal remedy used worldwide, and 6-gingerol is a major pharmacologically active ingredient in ginger. In our study, we found that 6-gingerol suppressed RCC cell migration and metastasis in vitro and in vivo. Moreover, reduction in MMP2, Slug, and Vimentin protein levels was observed following 6-gingerol treatment of 786-O and ACHN cells. Furthermore, we revealed the mechanisms underlying the ability of 6-gingerol to inhibit RCC cell migration and metastasis. 6-Gingerol increased yes-associated protein (YAP)ser127 phosphorylation and reduced YAP levels in cell nuclei. We also used a series of loss-of-function and gain-of-function experiments to support our results. Western blot results showed that MMP2, Slug, and Vimentin protein expression was downregulated in YAP-silenced cells and upregulated in YAP-overexpressing cells. Transwell data demonstrated that YAP suppressed RCC migration ability. Immunofluorescence images showed that 6-gingerol decreased YAP levels, leading to disordered F-actin and a reduction in cell lamellipodia. Overall, our results indicated that 6-gingerol is a potential antimetastatic compound for use in kidney therapy.

Incidence trends and survival prediction of urothelial cancer of the bladder: a population-based study.

BACKGROUND: The aim of this study is to determine the incidence trends of urothelial cancer of the bladder (UCB) and to develop a nomogram for predicting the cancer-specific survival (CSS) of postsurgery UCB at a population-based level based on the SEER database. METHODS: The age-adjusted incidence of UCB diagnosed from 1975 to 2016 was extracted, and its annual percentage change was calculated and joinpoint regression analysis was performed. A nomogram was constructed for predicting the CSS in individual cases based on independent predictors. The predictive performance of the nomogram was evaluated using the consistency index (C-index), net reclassification index (NRI), integrated discrimination improvement (IDI), a calibration plot and the receiver operating characteristics (ROC) curve. RESULTS: The incidence of UCB showed a trend of first increasing and then decreasing from 1975 to 2016. However, the overall incidence increased over that time period. The age at diagnosis, ethnic group, insurance status, marital status, differentiated grade, AJCC stage, regional lymph nodes removed status, chemotherapy status, and tumor size were independent prognostic factors for postsurgery UCB. The nomogram constructed based on these independent factors performed well, with a C-index of 0.823 and a close fit to the calibration curve. Its prediction ability for CSS of postsurgery UCB is better than that of the existing AJCC system, with NRI and IDI values greater than 0 and ROC curves exhibiting good performance for 3, 5, and 8 years of follow-up. CONCLUSIONS: The nomogram constructed in this study might be suitable for clinical use in improving the clinical predictive accuracy of the long-term survival for postsurgery UCB.

PSA nadir and time to PSA nadir during initial androgen deprivation therapy as prognostic factors in metastatic castration-resistance prostate cancer patients treated with docetaxel.

Prostate-specific antigen nadir (nPSA) and time to nPSA (TTN) have been proved to be associated with the prognosis of prostate cancer. In this study, we explored the prognosis effect of nPSA and TTN during initial androgen deprivation therapy (ADT) in patients with metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel-based chemotherapy. The data of 153 mCRPC patients received docetaxel followed by ADT were retrospectively reviewed. Multivariate Cox regression analysis demonstrated that TTN (overall survival (OS): Hazard ratio [HR] 0.096, 95% confidence interval [CI] 0.045-0.206, p < .001; progression-free survival (PFS): HR 0.128, 95% CI 0.078-0.211, p < .001) and nPSA (OS: HR 2.849, 95% CI 1.318-6.157, p = .008; PFS: HR 1.573, 95% CI 1.008-2.454, p = .046) acted as independent predictors of chemotherapy prognosis. Kaplan-Meier analysis showed that patients with nPSA ≥ 0.2 ng/ml or TTN < 6.5 months had shorter OS and PFS. These results suggest that TTN and nPSA during ADT can affect the prognosis of docetaxel-based chemotherapy prognosis post-castration resistance in patients with mCRPC, and higher nPSA and shorter TTN lead to poor chemotherapy prognosis. What is more, TTN has a greater impact during ADT on the prognosis of chemotherapy than nPSA.

Decreased glucose bioavailability and elevated aspartate metabolism in prostate cancer cells undergoing epithelial-mesenchymal transition.

Prostate cancer (PCa) is a common malignancy with a high tendency for metastasis. Epithelial-mesenchymal transition (EMT) plays a crucial role in PCa metastasis. Metabolic reprogramming offers metabolic advantages for cancer development and could result in the discovery of novel targets for cancer therapy. However, the metabolic features of PCa cells undergoing EMT remain unclear. We used metabolome and transcriptome analyses and found that PCa cells undergoing EMT showed impaired glucose utilization. In vitro studies demonstrated that PCa cells undergoing EMT were less addicted to glucose than epithelial-like PCa cells. However, cells that underwent EMT had higher levels of aspartate and its downstream metabolites, indicative of upregulated aspartate metabolism. As aspartate is a contributor for EMT and metastasis in human cancer cells, we conclude that this metabolic reprogramming may play a vital role in EMT and PCa progression.

G Protein γ subunit 7 loss contributes to progression of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common urinary neoplasm, looking for useful candidates to establish scientific foundation for the therapy of ccRCC is urgent. We downloaded genomic profiles of GSE781, GSE6244, GSE53757, and GSE66271 from the Gene Expression Omnibus (GEO) database. GEO2R was used to analyze the derivative genes, while hub genes were screened by protein-protein interactions and cytoscape. Further, overall survival, gene methylation, gene mutation, and gene expression were all analyzed using bioinformatics tools. Colony formation and cell-cycle assay were used to detect the biological function of GNG7 in vitro. We found that GNG7 was downregulated in ccRCC tissues and negatively associated with overall survival in ccRCC patients. We also found that promoter methylation and frequent gene mutation were responsible for GNG7 gene suppression. GNG7 low expression was related to upregulation of enhancer of zeste homolog 2 and downregulation of disabled homolog 2-interacting protein. Further, Gene Set Enrichment Analysis results showed that mTOR1, E2F, G2M, and MYC pathways were all significantly altered in response to GNG7 low expression. In vitro, A498 and 786-O cells in which GNG7 expression was silenced, exhibited a lower G1 phase when compared to the negative control cells. Taken together, our findings suggest that GNG7 is a tumor suppressor gene in ccRCC progression and represents a novel candidate for ccRCC treatment.

Curcumin Inhibits Vasculogenic Mimicry Via Regulating ETS-1 in Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (RCC) poses a huge challenge once it has become resistant to targeted therapy. Vasculogenic mimicry (VM) is a novel blood supply system formed by tumor cells that can circumvent molecular targeted therapies. As one of the herbal remedies, curcumin has been demonstrated to play antineoplastic effects in many different types of human cancers; however, its function and mechanism of targeting VM in RCC remains unknown. OBJECTIVE: Here, in the work, we explored the role of curcumin and its molecular mechanism in the regulation of VM formation in RCC. METHODS: RNA-sequencing analysis, immunoblotting, and immunohistochemistry were used to detect E Twenty Six-1(ETS-1), vascular endothelial Cadherin (VE-Cadherin), and matrix metallopeptidase 9 (MMP9) expressions in RCC cells and tissues. RNA sequencing was used to screen the differential expressed genes. Plasmid transfections were used to transiently knock down or overexpress ETS-1. VM formation was determined by tube formation assay and animal experiments. CD31-PAS double staining was used to label the VM channels in patients and xenograft samples. RESULTS: Our results demonstrated that VM was positively correlated with RCC grades and stages using clinical patient samples. Curcumin inhibited VM formation in dose and time-dependent manner in vitro. Using RNA-sequencing analysis, we discovered ETS-1 as a potential transcriptional factor regulating VM formation. Knocking down or overexpression of ETS-1 decreased or increased the VM formation, respectively and regulated the expression of VE-Cadherin and MMP9. Curcumin could inhibit VM formation by suppressing ETS-1, VE-Cadherin, and MMP9 expression both in vitro and in vivo. CONCLUSION: Our finding might indicate that curcumin could inhibit VM by regulating ETS-1, VE-Cadherin, and MMP9 expression in RCC cell lines. Curcumin could be considered as a potential anti-cancer compound by inhibiting VM in RCC progression.

CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression.

Prostate cancer (PCa) is one of the most common malignancy in men. However, the molecular mechanism of its pathogenesis has not yet been elucidated. In this study, we demonstrated that CYLD, a novel deubiquitinating enzyme, impeded PCa development and progression via tumor suppression. First, we found that CYLD was downregulated in PCa tissues, and its expression was inversely correlated with pathological grade and clinical stage. Moreover, we discovered that CYLD inhibited tumor cell proliferation and enhanced the sensitivity to cell ferroptosis in PCa in vitro and in vivo, respectively. Mechanistically, we demonstrated that CYLD suppressed the ubiquitination of YAP protein, then promoted ACSL4 and TFRC mRNA transcription. Then, we demonstrated that CYLD could enhance the sensitivity of PCa xenografts to ferroptosis in vivo. Furthermore, we discovered for the first time that there was a positive correlation between CYLD expression and ACSL4 or TFRC expression in human PCa specimens. The results of this study suggested that CYLD acted as a tumor suppressor gene in PCa and promoted cell ferroptosis through Hippo/YAP signaling.

CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity.

DNA replication is a vulnerable cellular process, and its deregulation leads to genomic instability. Here, we demonstrate that chromobox protein homolog 3 (CBX3) binds replication protein A 32-kDa subunit (RPA2) and regulates RPA2 retention at stalled replication forks. CBX3 is recruited to stalled replication forks by RPA2 and inhibits ring finger and WD repeat domain 3 (RFWD3)-facilitated replication restart. Phosphorylation of CBX3 at serine-95 by casein kinase 2 (CK2) kinase augments cadherin 1 (CDH1)-mediated CBX3 degradation and RPA2 dynamics at stalled replication forks, which permits replication fork restart. Increased expression of CBX3 due to gene amplification or CK2 inhibitor treatment sensitizes prostate cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors while inducing replication stress and DNA damage. Our work reveals CBX3 as a key regulator of RPA2 function and DNA replication, suggesting that CBX3 could serve as an indicator for targeted therapy of cancer using PARP inhibitors.

MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation.

CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.

Application of Carbon Nanofiber-Modified Concrete in Industrial Building Design.

In order to explore the influence law and action mechanism of carbon nanofibers on the basic mechanical properties of concrete, the author proposes the mechanical properties and microscopic mechanism of carbon nanofiber-modified concrete. Concrete was prepared with different dosages of carbon nanofibers, and the compressive strength, flexural strength, and splitting strength of carbon nanofiber-modified concrete were tested, and the modification mechanism was explored. Experimental results show that an appropriate amount of carbon nanofibers can improve the mechanical properties of concrete. When the dosage is 0.3%, the mechanical properties of carbon nanofiber-modified concrete are the best, and its compressive strength, flexural strength, and split tensile strength are increased by 9.2%, 13.2%, and 17.5%, respectively, compared with plain concrete. Carbon nanofibers can form a three-dimensional network structure inside the concrete, which can improve the microscopic morphology of the concrete, enhance the toughness and integrity of the concrete, fill the pore defects inside the concrete, refine the pore size distribution, and consume part of the fracture failure energy when the concrete is damaged.

Effect of Early External Ventricular Drainage on Perihemorrhagic Edema and Functional Outcome in Patients with Intraventricular Hemorrhage.

OBJECTIVE: External ventricular drainage (EVD) is the most common neurosurgical procedure that allows drainage of cerebrospinal fluid and intraventricular blood. A specific time threshold for insertion of an EVD catheter in patients with spontaneous intracerebral hemorrhage and intraventricular hemorrhage has not been established. This study aimed to evaluate the association of early EVD with functional outcome in patients with intracerebral hemorrhage and intraventricular hemorrhage. METHODS: Propensity score matching was used to account for baseline imbalances. Modified Rankin Scale score at 3 and 6 months, mortality rates at 3 and 6 months, postoperative complications, time course of edema evolution, and peak perihemorrhagic edema (PHE) were compared in patients who received early EVD versus routine EVD. RESULTS: The rate of favorable outcome at 3 months was higher in the early EVD group compared with the routine EVD group. There were no differences between groups in modified Rankin Scale score at 6 months or mortality rates at 3 and 6 months. Absolute peak PHE and relative PHE volumes were significantly less in the early EVD group compared with the routine EVD group. The incidence of postoperative infections was lower in the early EVD group compared with the routine EVD group. CONCLUSIONS: Early EVD was associated with improved functional outcome at 3 months, reduced PHE, and lower rate of infection in intracerebral hemorrhage and intraventricular hemorrhage. However, survival at 3 and 6 months and functional outcome at 6 months were not improved.

Knocking down AR promotes osteoblasts to recruit prostate cancer cells by altering exosomal circ-DHPS/miR-214-3p/CCL5 pathway.

ABSTRACT: Tumor-derived exosomes have been shown to play a key role in organ-specific metastasis, and the androgen receptor regulates prostate cancer (PCa) progression. It is unclear whether the androgen receptor regulates the recruitment of prostate cancer cells to the bone microenvironment, even bone metastases, through exosomes. Here, we found that exosomes isolated from PCa cells after knocking down androgen receptor (AR) or enzalutamide treatment can facilitate the migration of prostate cancer cells to osteoblasts. In addition, AR silencing or treatment with the AR antagonist enzalutamide may increase the expression of circular RNA-deoxyhypusine synthase (circ-DHPS) in PCa cells, which can be transported to osteoblasts by exosomes. Circ-DHPS acts as a competitive endogenous RNA (ceRNA) against endogenous miR-214-3p to promote C-C chemokine ligand 5 (CCL5) levels in osteoblasts. Increasing the level of CCL5 in osteoblasts could recruit more PCa cells into the bone microenvironment. Thus, blocking the circ-DHPS/miR-214-3p/CCL5 signal may decrease exosome-mediated migration of prostate cancer cells to osteoblasts.

TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks.

53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains poorly understood. Here, we demonstrate that TRABID deubiquitinase binds to 53BP1 at endogenous level and regulates 53BP1 retention at DSB sites. TRABID deubiquitinates K29-linked polyubiquitination of 53BP1 mediated by E3 ubiquitin ligase SPOP and prevents 53BP1 dissociation from DSBs, consequently inducing HR defects and chromosomal instability. Prostate cancer cells with TRABID overexpression exhibit a high sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work shows that TRABID facilitates NHEJ repair over HR during DNA repair by inducing prolonged 53BP1 retention at DSB sites, suggesting that TRABID overexpression may predict HR deficiency and the potential therapeutic use of PARP inhibitors in prostate cancer.

FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner.

Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy. SIGNIFICANCE: FPR2 is a sex-dependent mediator of macrophage function in pancreatic cancer and can be targeted to reprogram macrophages and stimulate antitumor immunity in females.

Multimodal recurrence scoring system for prediction of clear cell renal cell carcinoma outcome: a discovery and validation study.

BACKGROUND: Improved markers for predicting recurrence are needed to stratify patients with localised (stage I-III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel assay integrating three modalities-clinical, genomic, and histopathological-to improve the predictive accuracy for localised renal cell carcinoma recurrence. METHODS: In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI). FINDINGS: The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825-0·876 vs 0·608-0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio [HR] 4·57, 95% CI 2·49-8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19-6·59; p<0·0001). INTERPRETATION: Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy. FUNDING: National Natural Science Foundation of China, and National Key Research and Development Program of China.

Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy.

Capsaicin (CAP), extracted from Capsicum fruits, has been reported to exhibit antitumor effects in various lines of cancer cells. However, the mechanism underlying its antitumor efficiency is not fully understood. Autophagy is a fundamental self-degradation process of cells that maintains homeostasis and plays a controversial role in tumor initiation and progression. The EMT is defined as a system regulating cells transformed from an epithelial-like phenotype into a mesenchymal phenotype by several internal and external factors, following the metastatic performance of the cells developed. The present study aimed to investigate the potential role of autophagy in CAP-induced antitumor effects in renal cell carcinoma (RCC) 786-O and CAKI-1 cell lines. The results revealed that CAP remarkably inhibited the migration and invasion of RCC cells in vitro and metastasis in vivo. Moreover, we found that the CAP treatment increased the formation of autophagolysosome vacuoles and LC3 yellow and red fluorescent puncta in RCC cells and upregulated the expression of LC3, suggesting that autophagy was induced by CAP in 786-O and CAKI-1 cell lines. Our further results demonstrated that CAP-induced autophagy was mediated by the AMPK/mTOR pathway. In conclusion, our study provides new knowledge of the potential relationship between autophagy and metastasis inhibition induced by CAP, which might be a promising therapeutic strategy in RCC.

Deubiquitinase OTUD5 modulates mTORC1 signaling to promote bladder cancer progression.

The mechanistic (formally "mammalian") target of rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer progression. In bladder cancer, recent discoveries showing the cancer-promoting role of mTOR complex 1 have attracted wide attention. However, the regulation of mTOR signaling in bladder cancer is complicated and the underlying mechanism remains elusive. Here, we report that the deubiquitinating enzyme, ovarian tumor domain-containing protein 5 (OTUD5), can activate the mTOR signaling pathway, promote cancer progression, and show its oncogenic potential in bladder cancer. In our study, we found that OTUD5 deubiquitinated a RING-type E3 ligase, RNF186, and stabilized its function. In addition, the stabilization of RNF186 further led to the degradation of sestrin2, which is an inhibitor of the mTOR signaling pathway. Together, we provide novel insights into the pathogenesis of bladder cancer and first prove that OTUD5 can promote bladder cancer progression through the OTUD5-RNF186-sestrin2-mTOR axis, which may be exploited in the future for the diagnosis and treatment of this malignancy.