GTSE1 promotes tumor growth and metastasis by attenuating of KLF4 expression in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial-mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.

Kidney ventrally rotation technique in retroperitoneal robot-assisted partial nephrectomy for posterior hilar tumor: technical feasibility and preliminary results.

PURPOSE: The retroperitoneal robotic assisted partial nephrectomy (RAPN) is suitable for tumors locating on the posterior side of the kidney. However, the posterior hilar tumor poses an additional surgical challenge due to the special location and poor tumor exposure. We developed a novel kidney ventrally rotation technique to overcome this difficulty during retroperitoneal RAPN and evaluated its efficacy in a retrospective case-control comparative study. METHODS: From March 2016 to April 2019, a total of 39 patients with posterior renal hilar tumor underwent retroperitoneal RAPN. The kidney ventrally rotation technique, which improved the tumor exposure by opening the peritoneum and rotating the kidney ventrally, was applied in 24 cases, and the conventional RAPN was performed in the other 15 cases (control group). Perioperative data was analyzed to evaluate the efficacy of the kidney ventrally rotation technique. RESULTS: In kidney rotation group, the 24 patients underwent RAPN successfully without converting to open surgery or radical nephrectomy. The warm ischemia time was 17.4 ± 6.6 min, which was significantly shorter than 24.5 ± 8.3 min in control group. The mean operation time (80 ± 24 min) and estimated blood loss (104 ± 65 ml) were not different from the control group. No sever complications occurred, and no positive surgical margin was found in all the malignant cases. After 14 months follow-up, no recurrence or metastasis occurred in all cases. CONCLUSION: Kidney ventrally rotation technique is safe and feasible for improving the exposure of posterior renal hilar tumor during retroperitoneal RAPN. It could be regarded as an efficient option for the management of posterior hilar tumor.

Retraction Note: Antisense oligonucleotides targeting midkine induced apoptosis and increased chemosensitivity in hepatocellular carcinoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Robot-assisted laparoscopic antegrade versus open inguinal lymphadenectomy: a retrospective controlled study.

BACKGROUND: To investigate the surgical methods and clinical results of robot-assisted laparoscopic antegrade inguinal lymphadenectomy. METHODS: A retrospective study was performed on clinical data from 19 patients with penile cancer admitted from March 2013 to October 2017. Among them, nine patients underwent robot-assisted laparoscopic antegrade inguinal lymphadenectomy (robot-assisted group) and 10 patients underwent open inguinal lymphadenectomy (open group). In the robot-assisted group, preoperative preparation, patient position, robot placement, design of operating channel and establishment of operating space are described. Key surgical procedures and techniques are also summarized. In addition, the number of lymph nodes removed, postoperative complications and follow-up in both groups were statistically analyzed. RESULTS: For the 9 patients in the robot-assisted group, surgery was successfully accomplished at 17 sides without intraoperative conversion to open surgery. The surgery time for each side was 45~90 min using laparoscope with an average of 68.5 ± 13.69 min/side. The intraoperative blood loss was estimated to be < 10 ml/side, and the number of removed lymph nodes was not significantly different from that of the open group (12 ± 4.2/side vs.11 ± 5.8/side, P = 0.84). There were no postoperative complications such as skin necrosis, delayed wound healing and cellulitis in the robot-assisted group. Skin-related complications occurred in 9 (45%) of the 20 sides in the open group. During a median follow-up of 25 months in robot-assisted group and 52.5 mouths in open group, was not significantly different there were no statistical differences in recurrence-free survival between the groups (75% vs 60%, p = 0.536). CONCLUSION: Robot-assisted laparoscopic antegrade inguinal lymphadenectomy achieved the desired surgical outcomes with fewer intraoperative and postoperative complications. The robotic arms of the surgical system were placed between the lower limbs of each patient. There was no need to re-position the robotic arms during bilateral inguinal lymphadenectomy. This simplified the procedure and reduced the use of trocars. If necessary, pelvic lymphadenectomy could be performed simultaneously using the original trocar position.

Eukaryotic translation initiation factor 5A2 (eIF5A2) regulates chemoresistance in colorectal cancer through epithelial mesenchymal transition.

BACKGROUND: Chemoresistance is a major obstacle to successful chemotherapy for colorectal cancer. Eukaryotic translation initiation factor 5A2 (eIF5A2), one of the two isoforms in the eIF5A family, has been reported to be a new oncogene in many types of human cancer. In the present study, we aimed to investigate whether eIF5A2 was involved in the chemoresistance to doxorubicin in colorectal cancer. METHODS: Cell viability was measured by CCK-8 assay with or without doxorubicin treatment. Protein expression was detected by western blot. Tumor cells were transfected with eIF5A2 siRNA or plasmid encoding eIF5A2 to down- or up regulate the expression of eIF5A2. RESULTS: We found that eIF5A2-negtive colon cancer cells (HCT116 and HT29) were more sensitive to doxorubicin compare with the eIF5A2-positive cells (LOVO and SW480). Downregulation of eIF5A2 in LOVO and SW480 cells enhanced the chemosensitivity to doxorubicin. On the contrary, overexpression of eIF5A2 reduced doxorubicin sensitivity in colon cancer cells. In addition, eIF5A2 knockdown increased the protein level of E-cadherin and reduced vimentin expression in LOVO and SW480 cells. Meanwhile, upregulation of eIF5A2 potentiated epithelial mesenchymal transition (EMT) in colon cancer cells. Moreover, blockade of EMT with Twist siRNA abolished eIF5A2-regulated chemoresistance in colon cancer cells. CONCLUSION: Our present study demonstrated that eIF5A2 promoted the chemoresistance to doxorubicin via regulation of EMT in colon cancer cells. Therefore, eIF5A2 inhibition may be a new potential strategy for the reversal of drug resistance in colorectal cancer therapy.

Phospholipid Scramblase 1 Interacts with Midkine and Regulates Hepatic Cancer Cell Proliferation and Migration.

BACKGROUND: Mounting evidence indicates that nuclear targeting by growth factors plays an indispensable role on their biological activities. Midkine (MK) is a multifunctional growth factor and has been discovered to play important roles in carcinogenesis. MK has been reported to localize to the nucleus and nucleolus of HepG2 cells and is involved in cell proliferation and apoptosis. METHODS: The interaction was reconfirmed by in vitro pull down and in vivo coimmunoprecipitation (Co-IP), also by the colocalization in the HepG2 cells. The proliferation and migration was determined by MTT and trans-well assay. RESULTS: PLSCR1 was identified as a novel MK-interacting protein. Notably, PLSCR1 interacted with MK in the cell nucleus and regulated hepatic carcinoma cell proliferation and migration. CONCLUSIONS: This study suggests that PLSCR1 positively regulates hepatic carcinoma cell proliferation and migration through interacting with MK, thus deepening our understanding on the regulation of midkine during hepatic carcinoma growth and metastasis.

Genome re-sequencing suggested a weedy rice origin from domesticated indica-japonica hybridization: a case study from southern China.

MAIN CONCLUSION: Whole-genome re-sequencing of weedy rice from southern China reveals that weedy rice can originate from hybridization of domesticated indica and japonica rice. Weedy rice (Oryza sativa f. spontanea Rosh.), which harbors phenotypes of both wild and domesticated rice, has become one of the most notorious weeds in rice fields worldwide. While its formation is poorly understood, massive amounts of rice genomic data may provide new insights into this issue. In this study, we determined genomes of three weedy rice samples from the lower Yangtze region, China, and investigated their phylogenetics, population structure and chromosomal admixture patterns. The phylogenetic tree and principle component analysis based on 46,005 SNPs with 126 other Oryza accessions suggested that the three weedy rice accessions were intermediate between japonica and indica rice. An ancestry inference study further demonstrated that weedy rice had two dominant genomic components (temperate japonica and indica). This strongly suggests that weedy rice originated from indica-japonica hybridization. Furthermore, 22,443 novel fixed single nucleotide polymorphisms were detected in the weedy genomes and could have been generated after indica-japonica hybridization for environmental adaptation.

Effect of naringenin on brain insulin signaling and cognitive functions in ICV-STZ induced dementia model of rats.

Recent evidence indicates that severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease pathology. It has been reported that naringenin (NAR), derived from citrus aurantium, exhibits antioxidant potential and protects the brain against neurodegeneration. The current study was designed to further investigate the protective effect of the NAR on neurodegeneration in a rat model of AD induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ), and to determine whether this neuroprotective effect was associated with brain insulin signaling. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with NAR (25, 50 mg, 100 mg/kg, respectively) for 3 weeks. The ICV-STZ injected rats did not have elevated blood glucose levels. 21 days following ICV-STZ injection, rats treated with NAR had better learning and memory performance in the Morris water maze test compared with rats treated with saline. We demonstrated that NAR increased the mRNA expression of INS and INSR in cerebral cortex and hippocampus. In addition, NAR reversed ICV-STZ induced Tau hyper-phosphorylation in both hippocampus and cerebral cortex through downregulation of glycogen synthase kinase-3ß (GSK-3ß) activity, a key kinase in the insulin signaling. Brain levels of Abeta, which were elevated in ICV-STZ rats, were significantly reduced in NAR-treated rats via upregulation of insulin degrading enzyme. These effects were mediated by increased insulin and insulin receptors expression in the brain, suggesting that insulin sensitizer agents might have therapeutic efficacy in early AD.

Enhanced Herbicide Metabolism and Target Site Mutation Enabled the Multiple Resistance to Cyhalofop-butyl, Florpyrauxifen-benzyl, and Penoxsulam in Echinochloa crus-galli.

This study investigated the multiple herbicide resistance (MHR) mechanism of one Echinochloa crus-galli population that was resistant to florpyrauxifen-benzyl (FPB), cyhalofop-butyl (CHB), and penoxsulam (PEX). This population carried an Ala-122-Asn mutation in the acetolactate synthase (ALS) gene but no mutation in acetyl-CoA carboxylase (ACCase) and transport inhibitor response1 (TIR1) genes. The metabolism rate of PEX was 2-fold higher, and the production of florpyrauxifen-acid and cyhalofop-acid was lower in the resistant population. Malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) could reverse the resistance, suggesting that cytochrome P450 (CYP450) and glutathione S-transferase (GST) contribute to the enhanced metabolism. According to RNA-seq and qRT-PCR validation, two CYP450 genes (CYP71C42 and CYP71D55), one GST gene (GSTT2), two glycosyltransferase genes (rhamnosyltransferase 1 and IAAGLU), and two ABC transporter genes (ABCG1 and ABCG25) were induced by CHB, FPB, and PEX in the resistant population. This study revealed that the target mutant and enhanced metabolism were involved in the MHR mechanism in E. crus-galli.

Comparative metabolomics and transcriptomics provide new insights into florpyrauxifen-benzyl resistance in Echinochloa glabrescens.

Echinochloa glabrescens Munro ex Hook. f. is a weed of the genus Echinocloa (Echinocloa spp.) that occurs frequently in paddy fields, causing serious harm to rice production. Florpyrauxifen-benzyl (FPB) is a foliar-applied herbicide used to control Echinocloa spp. in paddy fields. However, in recent years, with the widespread use of FPB in rice production, FPB-resistant barnyard grasses have been reported. Here, we identified an FPB-resistant E. glabrescens population with a resistance index (RI) of 10.65 and conducted a comparative analysis using untargeted metabolomics and transcriptomics to investigate the differences between an FPB-resistant E. glabrescens population and a susceptible E. glabrescens population after treatment with the recommended field dose of FPB. Our results showed that the FPB-resistant E. glabrescens had 115 differentially accumulated metabolites (DAMs; 65 up-regulated and 50 down-regulated) and 6397 differentially expressed genes (DEGs; 65 up-regulated and 50 down-regulated) compared to the susceptible E. glabrescens. The analysis of DAMs and DEGs revealed that DAMs were significantly enriched in Glutathione metabolism, Arginine and proline metabolism, and Zeatin biosynthesis pathways, while DEGs were mainly enriched in carbon fixation in photosynthetic organisms, photosynthesis, cyanoamino acid metabolism and glutathione metabolism, etc. The glutathione metabolism pathway was found to be significantly enriched for both DEGs and DAMs. Within this pathway, the metabolites (spermine) and genes (GSTU8, GSTU18, GSTF1) may play a pivotal role in the resistance mechanism of FPB-resistant E. glabrescens. Furthermore, we demonstrated the presence of GST-mediated metabolic resistance in an FPB-resistant E. glabrescens population by using NBD-Cl. Overall, our study provides new insights into the underlying mechanisms of E. glabrescens resistance to FPB through a comparative analysis of untargeted metabolomics and transcriptomics. Additionally, we identified the GST-mediated metabolic resistance in an FPB-resistant E. glabrescens population, and screened for three candidate genes (GSTU8, GSTU18, GSTF1), which has significant implications for improving the weed management efficacy of FPB in rice production and guiding judicious herbicide usage.

Clinical significance, molecular characterization, and immune microenvironment analysis of coagulation-related genes in clear cell renal cell carcinoma.

Background: Numerous studies have revealed a tight connection between tumor development and the coagulation system. However, the effects of coagulation on the prognosis and tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) remain poorly understood. Methods: We employed the consensus clustering method to characterize distinct molecular subtypes associated with coagulation patterns. Subsequently, we examined variations in the overall survival (OS), genomic profiles, and TME characteristics between these subtypes. To develop a prognostic coagulation-related risk score (CRRS) model, we utilized the least absolute shrinkage and selection operator Cox regression and stepwise multivariate Cox regression analyses. We also created a nomogram to aid in the clinical application of the risk score, evaluating the relationships between the CRRS and the immune microenvironment, responsiveness to immunotherapy, and targeted treatment. The clinical significance of PLAUR and its biological function in ccRCC were also further analyzed. Results: There were significant differences in clinical features, prognostic stratification, genomic variation, and TME characteristics between the two coagulation-related subtypes. We established and validated a CRRS using six coagulation-related genes that can be employed as an effective indicator of risk stratification and prognosis estimation for ccRCC patients. Significant variations in survival outcomes were observed between the high- and low-risk groups. The nomogram was proficient in predicting the 1-, 3-, and 5-year OS. Additionally, the CRRS emerged as a novel tool for evaluating the clinical effectiveness of immunotherapy and targeted treatments in ccRCC. Moreover, we confirmed upregulated PLAUR expression in ccRCC samples that was significantly correlated with poor patient prognosis. PLAUR knockdown notably inhibited ccRCC cell proliferation and migration. Conclusion: Our data suggested that CRRS may be employed as a reliable predictive biomarker that can provide therapeutic benefits for immunotherapy and targeted therapy in ccRCC.

Hepatitis B virus X (HBx) play an anti-apoptosis role in hepatic progenitor cells by activating Wnt/ß-catenin pathway.

Increasing evidence has shown that normal stem cells may act as cancer-initiating cells and contribute to the development and progression of cancer. HBx has a close relationship with hepatocellular carcinoma, however, the role of HBx in hepatic progenitor cells (HPCs) is poorly understood. In this study, we sought to determine the role of HBx in regulating HPCs apoptosis and the underlying molecular mechanism(s) using HPCs derived from mouse fetal liver. The apoptotic ratio of HPCs infected with adenovirus-expressing HBx (Ad-HBx) was examined using flow cytometry. Results showed that the Ad-HBx treatment led to substantially decreased apoptotic ratio of HPCs, as confirmed by the Hoechst 33342 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). Possible alterations of relative proteins were examined using Western blot and real-time PCR assays. The HBx expression in HPCs increased the expression levels of Bcl2 and Mcl1 while decreasing the expression levels of Bax and cleaved caspase-9 and -3. In addition, the mRNA and protein expression levels of ß-catenin were both increased. The ß-catenin protein were mainly accumulated in cytoplasm and tended to transfer into cell nucleus after Ad-HBx treatment. The over-expression of ß-catenin decreased the apoptotic ratio of HPCs and inhibited the expression of cleaved caspase-9 and -3 while blocking ß-catenin expression resulted in the opposite results. Taken together, our results strongly suggested that the HBx protein may inhibits apoptosis of hepatic progenitor cells, at least in part by activating the WNT/ß-catenin pathway. This provided a new insight into the molecular mechanism of HBx-mediated live carcinogenesis.

Post-Emergence Water-Dispersal Application Provides Equal Herbicidal Activity against Echinochloa crus-galli and Rice Safety as Foliar Spraying of Penoxsulam.

Penoxsulam is an acetolactate synthase (ALS)-inhibiting herbicide usually applied by post-emergence foliar spraying (PFS) for the control of Echinochloa crus-galli and numerous annual weeds in paddy fields. Herbicides applied by foliar spraying can have negative impacts on the environment, ecosystems, and human health. In this study, the response of E. crus-galli and rice to the PFS and post-emergence water-dispersal (PWD) applications of penoxsulam, and the differences in the detoxification displayed by them between the two treatment methods were compared. The results showed that the PWD application of penoxsulam provides a similar control efficacy against E. crus-galli as PFS at the 1-, 3-, and 5-leaf stages. Meanwhile, the PWD application had a higher safety for the rice. After being treated with 30 g a.i. ha-1 penoxsulam, residues were not detected in the rice treated by the PWD application method, whereas, with the PFS treatment, there was 59.0 µg/kg penoxsulam remaining. With the PFS application, there were many more residues of penoxsulam in the E. crus-galli than with the PWD method; the amount of residues was 32-fold higher 12 h after treatment. The in vitro enzyme activity assays revealed that the activities of ALS, glutathione-S-transferase (GST), and cytochrome P450 monooxygenases (P450) were increased in the PWD treatments, and were 1.5-, 1.3-, and 2.3-fold higher than with PFS 72 h after treatment. The real-time quantitative PCR (qRT-PCR) revealed that the GST1 and P450 genes, CYP81A14, CYP81A12, CYP81A18, and CYP81A21 were upregulated with the PWD application versus PFS in the E. crus-galli. In summary, these results demonstrate that the herbicidal activity was not affected by the upregulation of target and metabolic enzyme activities with the PWD application of penoxsulam. This research could contribute to application strategies reducing the risk of rice injury and environmental impacts by using water-dispersal formulations of penoxsulam.

Long-term effect of transurethral partial cystectomy with a 2-micrometer continuous-wave laser for non-muscle-invasive bladder cancer.

Purpose: We have reported the efficacy and safety of 2-micrometer continuous-wave laser cystectomy of non-muscle invasive bladder tumor (NMIBC) (J Urol. 2009;182:66-9). In this study, we evaluated the long-term outcomes of patients with NMIBC who underwent transurethral partial cystectomy with a 2-micrometer continuous-wave laser, and explored the risk factors for tumor recurrence. Methods: This was a retrospective study of patients with NMIBC planned to undergo transurethral partial cystectomy with a 2-micrometer continuous-wave laser at the Fourth Medical Center of the PLA General Hospital between January 2012 and December 2014. The primary outcome was bladder cancer recurrence. Results: A total of 75 patients were enrolled. Sixty-two (82.7%) were male. The patients were 59.8 ± 12.9 years of age. The mean operation time was 38.7 ± 20.4 min. No Clavien grade >2 complications occurred. The duration of catheter indwelling was 3.6 ± 1.8 days. The hospital stay was 6.0 ± 2.3 days. The median follow-up was 80 months. A total of 17 patients had a recurrence during follow-up, and the recurrence-free survival (RFS) rate was 77.3%. In the multivariable analysis, the tumor risk group were independently associated with the recurrence of NMIBC (p = 0.026). Conclusions: After TURBT with a 2-micrometer continuous-wave laser, RFS was 77.3% at the median follow-up of 80 months. All complications were mild. Only tumor risk group was independently associated with the recurrence of NMIBC.

Solving the clustered traveling salesman problem via traveling salesman problem methods.

The Clustered Traveling Salesman Problem (CTSP) is a variant of the popular Traveling Salesman Problem (TSP) arising from a number of real-life applications. In this work, we explore a transformation approach that solves the CTSP by converting it to the well-studied TSP. For this purpose, we first investigate a technique to convert a CTSP instance to a TSP and then apply powerful TSP solvers (including exact and heuristic solvers) to solve the resulting TSP instance. We want to answer the following questions: How do state-of-the-art TSP solvers perform on clustered instances converted from the CTSP? Do state-of-the-art TSP solvers compete well with the best performing methods specifically designed for the CTSP? For this purpose, we present intensive computational experiments on various benchmark instances to draw conclusions.

Improved Bioherbicidal Efficacy of Bipolaris eleusines through Herbicide Addition on Weed Control in Paddy Rice.

Bipolaris eleusines was mixed with herbicides to improve the control of barnyardgrass (Echinochloa crus-galli), a noxious weed in rice fields. The compatibility of B. eleusines with herbicides was evaluated for toxic effects on spore germination and mycelium growth in vitro tests, and varied effects were observed with different chemical products. Briefly, 25 g/L penoxsulam OD plus 10% bensulfuron-methyl WP were much more compatible with B. eleusines, and there was no inhibition of spore germination but the promotion of mycelium growth of B. eleusines at all treatment rates. Under greenhouse conditions, the coefficient of the specificity of B. eleusines conidial agent was determined as 3.91, closer to the herbicidal control of 2.89, showing it is highly specific between rice and barnyardgrass. Field experiments in 2011 and 2012 showed that B. eleusines conidial agent displayed good activity on barnyardgrass, monochoria [Monochoria vaginalis (Burm.f.) Presl. Ex Kunth.], and small-flower umbrella sedge (Cyperus difformis L.) and had no negative impact on the rice plant. It also reduced the loss of rice yield when compared with the non-treated control and could make this pathogen a conidial agent for commercial bioherbicidal development in the future.

3-Indoleacrylic acid from canola straw as a promising antialgal agent - Inhibition effect and mechanism on bloom-forming Prorocentrum donghaiense.

Harmful algal blooms (HABs) have induced severe damage worldwide. A novel high-efficient antialgal natural chemical, 3-indoleacrylic acid (3-IDC) with a 5-day half-maximal inhibitory concentration (IC50, 5d), was discovered from canola straw, and its algal inhibition mechanism was investigated. Adverse effects were observed on the growth of P. donghaiense with 3-IDC addition, following an increase in reactive oxygen species (ROS) production. 3-IDC also hindered the photosynthetic mechanism of P. donghaiense cells. Transcriptional results showed 3-IDC inhibiting the functions of all the nutrient assimilating genes, down-regulated ribulose-1,5-bisphosphate carboxylase/oxygenase II, and cytochrome f genes. The expression of heat shock protein (HSP) 70 and 90 and rhodopsin genes were also suppressed. The binding affinity of investigated receptors was observed. The conformational changes induced by the spatial microstructural alteration through 3-IDC may further contribute to the perturbation of those enzyme catalytic activities. The present results provide new insights on controlling HABs using 3-IDC.

Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity.

Recent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitro and in xenograft mouse models in vivo. In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4+ and CD8+ T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC.

The Correlation Between Platelet-to-Lymphocyte Ratio and Neutrophil-to-Lymphocyte Ratio with Hepatic Echinococcosis.

OBJECTIVE: To explore the correlation between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with hepatic hydatid diseases. METHODS: The clinical data of 420 patients with hydatid disease who were treated in our hospital from October 2015 to October 2018 were collected from the database of our hospital. According to the postoperative pathological diagnosis, 200 patients were assigned into the alveolar echinococcosis (AE) group, and 220 patients were assigned into the cystic echinococcosis (CE) group. A total of 160 healthy examinees were enrolled as the control group. The main observation indexes included preoperative PLR and NLR. Pearson's correlation was used to analyze the correlation between PLR and NLR with clinical indicators in HE patients, and the receiver operator characteristic (ROC) curve was used to evaluate the clinical values of PLR and NLR in diagnosing different types of hydatid diseases. RESULTS: The results revealed that the expressions of PLR and NLR were significantly higher in the AE group than in the CE and control groups (P<0.05). The results of multiple linear regression analysis revealed that PLR was positively correlated with aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, alkaline phosphatase and γ-glutamyltranspeptidase (P<0.05). NLR was correlated with albumin content (P<0.05). ROC curve analysis results revealed that the area under the curve (AUC) of PLR and NLR for AE was 0.800 and 0.700 respectively, and the AUC for CE was 0.78 and 0.75 respectively. CONCLUSION: The NLR and PLR of AE patients were higher than those of CE patients, and the high inflammation of CE patients may be correlated to the reproductive mode of Echinococcus multilocularis. PLR and NLR have certain diagnostic values for disease classification, but PLR has higher specificity when compared with NLR.

The Basis of Tolerance Mechanism to Metsulfuron-Methyl in Roegneria kamoji (Triticeae: Poaceae).

Roegneria kamoji, a perennial monocot weed that belongs to the tribe Triticeae (family: Poaceae), is an emerging problematic weed in winter wheat (Triticum aestivum) fields in China. We have previously confirmed four R. kamoji populations tolerant to acetyl-CoA carboxylase (ACCase) inhibitors, and failed control of these populations by metsulfuron-methyl was observed. The objective of this study was to characterize the level of tolerance to metsulfuron-methyl, the basis of tolerance mechanism, and cross-tolerance to acetolactate synthase (ALS) inhibitors in R. kamoji. A whole-plant dose-response assay showed that plants of all R. kamoji populations (both from wheat fields and uncultivated areas) exhibited high tolerance to metsulfuron-methyl, based on their 100% survival at 6-fold recommended field dose (RFD) and ED50 values >6.84-fold RFD, no susceptible population was found. Gene sequencing indicated that no reported amino acid substitutions associated with resistance to ALS inhibitor were found in the ALS gene among the R. kamoji populations. Pretreatment with the known cytochrome P450 monooxygenases (CytP450) inhibitor malathion reduced the ED50 values of metsulfuron-methyl in two R. kamoji populations. These populations also exhibited cross-tolerance to RFD of mesosulfuron-methyl and bispyribac-sodium. The activities of glutathione-S-transferase (GST) and CytP450 could be induced by metsulfuron-methyl in R. kamoji, which is similar to the known tolerant crop wheat. This is the first report elucidating metsulfuron-methyl tolerance in R. kamoji. The reversal of tolerance by malathion and the GST and/or CytP450 enhanced herbicide metabolism suggests that non-target-site mechanisms confer tolerance to metsulfuron-methyl in R. kamoji.