Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers.

BACKGROUND: Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers. METHODS: Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk. RESULTS: A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88-0.95, P = 2.92 × 10-7) and Europe (OR = 0.92, 95%CI 0.88-0.95, P = 4.61 × 10-6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field. CONCLUSION: Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.

A review of immunotargeted therapy for Philadelphia chromosome positive acute lymphoblastic leukaemia: making progress in chemotherapy-free regimens.

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation. More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin. For patients with ABL1 mutations and those who have relapsed or are refractory to other treatments, targeted oral small molecule drugs, monoclonal antibodies, Bispecific T cell Engagers (BiTE), and chimeric antigen receptor (CAR) T cells immunotherapy are emerging as potential treatment options. These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

Identification of a lipid homeostasis-related gene signature for predicting prognosis, immunity, and chemotherapeutic effect in patients with gastric cancer.

Gastric cancer (GC) is one of the most common and deadliest cancers worldwide. Lipid homeostasis is essential for tumour development because lipid metabolism is one of the most important metabolic reprogramming pathways within tumours. Elucidating the mechanism of lipid homeostasis in GC might significantly improve treatment strategies and patient prognosis. GSE62254 was applied to construct a lipid homeostasis-related gene signature score (HGSscore) by multiple bioinformatic algorithms including weighted gene coexpression network analysis (WGCNA) and LASSO-Cox regression. A nomogram based on HGSscore and relevant clinical characteristics was constructed to predict the survival of patients with GC. TIMER and xCell were used to evaluate immune and stromal cell infiltration in the tumour microenvironment. Correlations between lipid homeostasis-related genes and chemotherapeutic efficacy were analysed in GSCAlite. RT‒qPCR and cell viability assays were applied to verify the findings in this study. HGSscore was constructed based on eighteen lipid homeostasis-related genes that were selected by WGCNA and LASSO-Cox regression. HGSscore was strongly associated with advanced TNM stage and showed satisfactory value in predicting GC prognosis in three independent cohorts. Furthermore, we found that HGSscore was associated with the tumour mutation burden (TMB) and immune/stromal cell infiltration, which are related to GC prognosis, indicating that lipid homeostasis impacts the formation of the tumour microenvironment (TME). With respect to the GSCAlite platform, PLOD2 and TGFB2 were shown to be positively related to chemotherapeutic resistance, while SLC10A7 was a favourable factor for chemotherapy efficacy. Cell viability assays showed that disrupted lipid homeostasis could attenuate GC cell viability. Moreover, RT‒qPCR revealed that lipid homeostasis could influence expression of specific genes. We identified a lipid homeostasis-related gene signature that correlated with survival, clinical characteristics, the TME, and chemotherapeutic efficacy in GC patients. This research provides a new perspective for improving prognosis and guiding individualized chemotherapy for patients with GC.

Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms.

BACKGROUND & AIMS: Dysregulation of alternative splicing is implicated in many human diseases, and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms. METHODS: We performed a comprehensive sQTL analysis to identify genetic variants that control messenger RNA splicing across 33 cancer types from The Cancer Genome Atlas and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multi-ethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes. RESULTS: The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. In addition, functionally informed polygenic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese (odds ratio, 1.20; 95% CI, 1.12-1.29; P = 8.82 × 10-7) and European (odds ratio, 1.11; 95% CI, 1.07-1.16; P = 1.13 × 10-7) populations. rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RNA-binding protein PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells. CONCLUSIONS: Our study provides an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk and serving as biomarkers and therapeutic targets.

A New Prognostic Indicator of Immune Microenvironment and Therapeutic Response in Lung Adenocarcinoma Based on Peroxisome-Related Genes.

Lung adenocarcinoma (LUAD) has been the major cause of tumor-associated mortality in recent years and exhibits a poor outcome. New data revealed that peroxisomes have a function in the regulation of the development and progression of several tumors. However, the prognostic values of peroxisome-related genes (PRGs) were rarely reported. Genomic sequence, mutation, and clinical data of 535 LUAD tissues were obtained from TCGA data sets. Within the TCGA cohort, a multigene signature was constructed with the assistance of the LASSO Cox regression model. Three GEO data sets, including GSE3141, GSE31210, and GSE72094, were obtained as validation cohorts. ROC assays, Kaplan-Meier methods, and multivariate assays were applied to examine the prognostic capacities of the novel signature. Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. In this study, we identified 47 differentially expressed peroxisome-related genes (PRGs), including 25 increased and 22 decreased PRGs. A prognostic model of six PRGs was established. The univariate and multivariate Cox analyses both showed that the p value of risk score was less than 0.05. In LUAD patients, the strong connection between the risk score and overall survival was further verified in three other GEO data sets. TMB and cancer stem cell infiltration were shown to be significantly higher in the high-risk group in comparison to the low-risk group. The TIDE score of the group with the low risk was considerably greater than that of the group with the high risk. Several drugs, targeting PRG-related genes, were available for the treatments of LUAD. Overall, we developed a novel peroxisome-related prognostic signature for LUAD patients. This signature could successfully indicate LUAD patients' chances of survival as well as their immune system's responsiveness to treatments. In addition, it has the potential to serve as immunotherapeutic targets for LUAD patients.

Safety and feasibility of laparoscopy-assisted surgery for gastrointestinal stromal tumors larger than 5 cm: Results of a retrospective, single-center series of 1,802 consecutive patients.

BACKGROUND: The role of laparoscopy-assisted resection for treating gastrointestinal stromal tumors >5 cm is still disputed. We aimed to assess the advantages of laparoscopy-assisted resection for treating gastrointestinal stromal tumors >5 cm. METHODS: In total, 1,802 patients with primary gastrointestinal stromal tumors who underwent laparoscopy-assisted surgery or open surgery were retrospectively evaluated. Propensity score matching was performed to reduce confounders. RESULTS: In total, 518 patients with tumor size >5 cm were enrolled in this study (males: 292, 56.4%; females: 226, 43.6%; median age: 58 years, range: 23-85 years). One hundred and twenty-three (23.7%) patients underwent laparoscopy-assisted resection, and 395 (76.3%) patients underwent open resection. After propensity score matching, 190 patients were included (95 in each group). The laparoscopy-assisted surgery group was superior to the open surgery group considering the blood loss (>200 mL: 6.3% vs 22.1%, P = .005), length of midline incision (6.0 ± 0.9 cm vs 9.6 ± 2.1 cm, P < .001), time to first flatus (49.7 ± 10.5 hours vs 63.9 ± 7.4 hours, P < .001), and shorter hospital stay (10.3 ± 3.2 days vs 11.9 ± 2.9 days, P < .001). The difference in relapse-free survival or overall survival between the laparoscopy-assisted surgery and open surgery groups after matching was not significant (all P > .05). On subgroup analysis, the relapse-free survival and overall survival of the laparoscopy-assisted surgery group were comparable to those of the open surgery group, irrespective of tumor location (gastric or nongastric locations) (all P > .05). CONCLUSION: When performed by experienced surgeons, laparoscopy-assisted resection is feasible and safe for gastrointestinal stromal tumors >5 cm, which showed improved short-term outcomes and comparable oncological outcomes, regardless of whether the tumor had a gastric or nongastric location.

[Corrigendum] Downregulation of heparanase by RNA interference inhibits invasion and tumorigenesis of hepatocellular cancer cells in vitro and in vivo.

Following the publication of this article, an interested reader drew to the authors' attention that two images in Fig. 1B (the a and d panels) appeared to represent the same clone, albeit with different intensities and the panels were cropped differently. The authors were able to confirm that Figs. 1B(a) and B(d) were inadvertently selected from the same set of images but with different exposure times: Owing to an error in data handling, a wrong image was chosen during the grouping the figures. The corrected version of Fig. 1 is shown on the next page, featuring the correct image for Fig. 1B(d). The authors regret that this error was not picked up upon before the paper was sent to press, although the error did not affect the major conclusions reported in the paper. The authors thank the Editor of International Journal of Oncology for allowing them the opportunity to publish a Corrigendum. and regret any inconvenience caused to the readership. [the origional article was published on International Journal of Oncology 40: 1601­1609, 2012; DOI: 10.3892/ijo.2012.1338].

Exploration of Lipid Metabolism in Gastric Cancer: A Novel Prognostic Genes Expression Profile.

BACKGROUND: Alterations in lipid metabolism are increasingly being recognized. However, the application of lipid metabolism in the prognosis of gastric cancer (GC) has not yet been explored. METHODS: A total of 204 lipid metabolism relative genes were analyzed in the GC cohort from The Cancer Genome Atlas (TCGA), and four independent cohorts from Gene Expression Omnibus (GEO) and one cohort from Wuhan Union Hospital were applied for external validation. Differential expression and enrichment analyses were performed between GC and normal tissue. The LASSO-Cox proportional hazard regression model was applied to select prognostic genes and to construct a gene expression profile. RESULTS: Our research indicated that higher expression level of AKR1B1, PLD1, and UGT8 were correlated with worse prognosis of GC patients, while AGPAT3 was correlated with better prognosis. Furthermore, we developed a gene profile composed of AGPAT3, AKR1B1, PLD1, and UGT8 suggested three groups with a significant difference in overall survival (OS). The profile was successfully validated in an independent cohort and performed well in the immunohistochemical cohort. Furthermore, we found that ether lipid metabolism, glycerophospholipid metabolism, and glycerolipid metabolism were upregulated, and fatty acid ß-oxidation and other lipid peroxidation processes were reduced in GC. CONCLUSION: Collectively, we found lipid metabolism is reliable and clinically applicable in predicting the prognosis of GC based on a novel gene profile.

Silencing of H19 alleviates oxygen-glucose deprivation/reoxygenation-triggered injury through the regulation of the miR-1306-5p/BCL2L13 axis.

Cerebral ischemia/reperfusion (I/R) injury remains a leading cause of death and disability. Long noncoding RNAs (lncRNAs) exert key functions in cerebral I/R injury. Here, we sought to elucidate the mechanism underlying the regulation of H19 in cerebral I/R cell injury. An in vitro model of cerebral I/R injury was created using oxygen-glucose deprivation/reoxygenation (OGD/R). The levels of H19, miR-1306-5p and B cell lymphoma-2 (Bcl-2)-like 13 (BCL2L13) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell viability and apoptosis were determined by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. The levels of lactate dehydrogenase (LDH) and cytokines were evaluated by enzyme-linked immunosorbent assays (ELISA). Direct relationships among H19, miR-1306-5p and BCL2L13 were verified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pulldown assays. Our data showed that H19 and BCL2L13 were highly expressed in the cerebral I/R injury rats and OGD/R-triggered SK-N-SH and IMR-32 cells. The knockdown of H19 or BLC2L13 alleviated OGD/R-triggered injury in SK-N-SH and IMR-32 cells. Moreover, H19 silencing protected against OGD/R-triggered cell injury by down-regulating BCL2L13. H19 acted as a sponge of miR-1306-5p and BCL2L13 was a direct target of miR-1306-5p. H19 mediated BCL2L13 expression by sequestering miR-1306-5p. Furthermore, miR-1306-5p was a molecular mediator of H19 function. These results suggested that H19 silencing alleviated OGD/R-triggered I/R injury at least partially depending on the regulation of the miR-1306-5p/BCL2L13 axis.

Risk Factors and a New Prediction Model for Pancreatic Fistula After Pancreaticoduodenectomy.

AIM: In order to find the risk factors of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) according to the latest definition and grading system of International Study Group of Pancreatic Surgery (ISGPS) (version 2016) and propose a nomogram for predicting POPF. METHODS: We conducted a retrospective analysis of 232 successive cases of PD performed at our hospital by the same operator from August 2012 to June 2020. POPF was diagnosed in accordance with the latest definition of pancreatic fistula from the ISGPS. The risk factors of POPF were analyzed by univariate and multivariate logistic regression analysis. A nomogram model to predict the risk of POPF was constructed based on significant factors. RESULTS: There were 18 cases of POPF, accounting for 7.8% of the total. Among them, 17 cases were classified into ISGPF grade B and 1 case was classified into ISGPF grade C. In addition, 35 cases were classified into biochemical leak. Univariate and multivariate analysis showed that hypertension, non-diabetes, no history of abdominal surgery, antecolic gastrojejunostomy and soft pancreas were independent risk factors of POPF. Based on significant factors, a nomogram is plotted to predict the risk of POPF. The C-index of this nomogram to assess prediction accuracy was 0.916 (P < 0.001) indicating good prediction performance. CONCLUSION: Hypertension, non-diabetes, no history of abdominal surgery, antecolic gastrojejunostomy and soft pancreas were independent risk factors of POPF. Meanwhile, a nomogram for predicting POPF with good test performance and discriminatory capacity was constituted.

Chronic nickel (II) exposure induces the stemness properties of cancer cells through repressing isocitrate dehydrogenase (IDH1).

BACKGROUND: Nickel is a component of biomedical alloys that is released during corrosion or friction and causes cytotoxicity, mutation, differentiation or even carcinogenesis in tissues. However, the mechanisms underlying the potential hazards of Nickel-containing alloys implanted in the human body by surgery remain uncertain. OBJECTIVE: To study the effect of Ni(II) (NiCl2•6H2O) on cancer cells. METHODS: A549 and RKO cells were treated with various concentrations of Ni(II) to determine the effect of Ni(II) on cellular viability using a CCK8 assay. Flow cytometry was performed to analyze the effect of Ni(II) on apoptosis and the cell cycle. Sphere-forming assays were conducted to examine the stemness properties of A549 and RKO cells. Western blotting was to evaluate the expression levels of SOX2, IDH1, HIF-1ɑ and ß-catenin. The expression of isocitrate dehydrogenase (IDH1) in rectum adenocarcinoma (READ) was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier analysis was used to calculate the correlation between survival and IDH1 expression. RESULTS: Long-term exposure (120 days) to 100 µM Ni(II) significantly repressed cell proliferation, decreased colony formation and arrested the cell cycle at the G0/G1 phase. In addition, the stem-like traits of A549 and RKO cells were significantly augmented. Ni(II) also significantly decreased the protein expression of IDH1 and the synthesis rate of NAPDH, which competitively inhibited α-ketoglutarate (α-KG) generation. The downregulation of IDH1 not only promoted ß-catenin accumulation in the cell nucleus in a HIF-1ɑ signaling-dependent manner but also induced the expression of the transcription factor SOX2 to maintain the stemness properties of cancer cells. Moreover, IDH1 expression negatively correlated with the clinicopathologic characteristics of READ. CONCLUSION: These findings demonstrate that chronic and continuous release of Ni(II) to the microenvironment suppresses IDH1 expression and augments the stemness properties of cancer cells via the activation HIF-1ɑ/ß-catenin/SOX2 pathway to enhance local tumor recurrence in patients with implanted Nickel-containing alloys at surgical sites.

Oxymatrine exerts a protective effect in myocardial ischemia/reperfusion­induced acute lung injury by inhibiting autophagy in diabetic rats.

Oxymatrine (OMT) is the primary active component of Sophora flavescens Ait., and is widely used for the treatment of diabetic complications. The present study aimed to investigate the effects of OMT on acute lung injury (ALI) in diabetic rats subjected to myocardial ischemia/reperfusion (I/R). ALI in a myocardial I/R model was established in streptozocin­induced diabetic rats. Enzyme­linked immunosorbent assays were used to evaluate the levels of creatine kinase isoenzyme MB and lactate dehydrogenase, and the inflammatory response was assessed via leukocyte counts and the levels of tumor necrosis factor (TNF)­α, interleukin (IL)­6 and IL­8 in the bronchoalveolar lavage (BAL) fluid. Hematoxylin and eosin staining was used to determine pathological changes to the lung tissue, and the autophagy­related proteins LC­3II/LC­3I, Beclin­1, autophagy protein 5 (Atg5) and p62 were detected by western blotting. Diabetic rats subjected to myocardial I/R showed increased levels of ALI with a higher lung injury score and WET/DRY ratio, and lower partial pressure of oxygen. This was accompanied by aberrant autophagy, indicated by an increased LC­3II/LC­3I ratio, decreased p62 expression levels, increased Atg5 and beclin­1 expression levels, decreased superoxide dismutase activity and increased 15­F2t­isoprostane formation in lung tissues, as well as increased levels of leukocytes, TNF­α, IL­6 and IL­8 in the BAL fluid. Administration of the autophagy inducer rapamycin significantly accelerated these alterations, while the autophagy inhibitor 3­Methyladenine exerted the opposite effects. These results indicated that diabetic lungs are more vulnerable to myocardial I/R, which was associated with aberrant autophagy. Furthermore, oxymatrine was observed to reverse and alleviate ALI in diabetic rats with myocardial I/R in a concentration­dependent manner, the mechanism of which may be associated with the inhibition of autophagy.

Association between serum cystatin C level and hemodynamically significant aortic stenosis: a prospective cohort study.

BACKGROUND: Cystatin C (CysC) is a cysteine protease inhibitor involved in proteins catabolism and plays an essential role in human vascular pathophysiology. CysC may also increase the risk of aortic stenosis (AS), but limited studies have reported on this association. This study aimed to investigate if elevated serum CysC levels are associated with hemodynamically significant AS. METHODS: Serum CysC levels were estimated in 4,791 participants, samples were collected in 1990-1992. The study population was divided into quintile groups. Follow-up continued in 2011-2013 when participants returned for echocardiography examination. Incidence of aortic valve disease (AVD) was ascertained by Doppler echocardiography through the end of 2013. AVD defined in hemodynamic progression was assessed and classified as aortic sclerosis, mild stenosis, and moderate-to-severe stenosis. RESULTS: Overall, a total of 4,791 participants (mean age: 54.8 ± 5.0 years, females: 57.6%, blacks: 8.2%) were included in this study. During a follow-up of 21 years, we identified 736 cases (15.4%) of aortic sclerosis, 194 cases (4.0%) of mild stenosis, and 42 cases (0.7%) of moderate-to-severe stenosis. Compared with serum CysC levels within individual quintile groups, the odds ratio (OR) was per standard deviation associated with an increased incidence of AVD (OR = 1.15, 95% CI: 1.05-1.26,P = 0.002). CONCLUSIONS: In this large population-based study, an increased serum CysC levels is independently associated with the incidence of hemodynamically significant AS. However, this association appears not to extend to patients with extremely high serum CysC levels and necessitate further investigation.

Leucandioxoles A and B, two 1,3-benzodioxole derivatives from the South China Sea sponge Leucandra sp.

Two new 1,3-benzodioxole derivatives, leucandioxoles A and B (1-2), together with two known related compounds (3-4), have been isolated from the South China Sea sponge Leucandra sp. The structures of all compounds were clearly elucidated on the basis of spectroscopic analyses and compared with the literatures. The cytotoxicity against A549, Hep G2, MDA-MB-231, and HeLa cell lines of 1-4 were evaluated. Only compound 1 exhibited moderate activity against MDA-MB-231 cells with the IC50 value of 7.98 ± 0.74 µM.

Predictive value of protease-activated receptor-2 (PAR2 ) in cervical cancer metastasis.

Metastasis is the primary cause of an unfavourable prognosis in patients with malignant cancer. Over the last decade, the role of proteinases in the tumour microenvironment has attracted increasing attention. As a sensor of proteinases, proteinase-activated receptor 2 (PAR2 ) plays crucial roles in the metastatic progression of cervical cancer. In the present study, the expression of PAR2 in multiple types of cancer was analysed by Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier plotter was used to calculate the correlation between survival and the levels of PAR2 , Grb-associated binding protein 2(Gab2) and miR-125b. Immunohistochemistry (IHC) was performed to examine PAR2 expression in a tissue microarray (TMA) of CESCs. Empower Stats was used to assess the predictive value of PAR2 in the metastatic potential of CESC. We found that PAR2 up-regulation was observed in multiple types of cancer. Moreover, PAR2 expression was positively correlated with the clinicopathologic characteristics of CESC. miR-125b and its target Gab2, which are strongly associated with PAR2 -induced cell migration, are well-characterized as predictors of the prognostic value of CESC. Most importantly, the Cancer Genome Atlas (TCGA) data set analysis showed that the area under the curve (AUC) of the PAR2 model was significantly greater than that of the traditional model (0.833 vs 0.790, P < .05), demonstrating the predictive value of PAR2 in CESC metastasis. Our results suggest that PAR2 may serve as a prognostic factor for metastasis in CESC patients.

Elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis of patients with primary gastrointestinal stromal tumor.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are considered to reflect the systemic inflammatory response and clinical prognosis. However, the independent prognostic values of the NLR and PLR for patients with gastrointestinal stromal tumor (GIST) remain debatable. This study aims to evaluate the prognostic value of preoperative NLR and PLR in GIST patients. METHODS: We retrospectively reviewed all GIST patients diagnosed and surgically treated at Union Hospital between 2005 and 2018. The preoperative NLR and PLR were calculated to evaluate recurrence-free survival (RFS) and overall survival (OS) by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were performed to estimate the independent prognostic values. RESULTS: The median follow-up time was 49 months (interquartile range, 22-74 months). The preoperative PLR was significantly increased in the GIST patients with intermediate and high tumor risks. Increases in the NLR (≥2.34) and PLR (≥185.04) were associated with shorter RFS and OS (P < 0.01). Moreover, the multivariate analysis revealed that elevated PLR was an independent factor for shorter RFS (hazard ratio [HR]: 3.041; 95% confidence interval [CI]: 2.001-4.622; P < 0.001) and OS (HR: 1.899; 95% CI: 1.136-3.173; P = 0.014). CONCLUSIONS: The preoperative PLR is a potential biomarker of GIST and is related to the clinical outcome. An elevated preoperative PLR predicts poor prognosis of patients with primary GIST after complete surgical resection.

Clinical significance of RAD51C and its contribution to ovarian carcinogenesis.

AIM: The underlying mechanisms of chemoresistance-induced recurrence of ovarian carcinoma are largely unknown. The purpose of this study was to investigate the clinical significance of RAD51C and its role in ovarian tumorigenesis and progression. METHODS: 60 cases of ovarian epithelial tumors (30 benign and 30 malignant tumors, respectively) were enrolled from 2014 to 2016. Immunohistochemistry was used to evaluate RAD51C expression in tumor tissues, and RT-PCR was employed to test RAD51C mRNA levels in SKOV3, A2780, and CAOV3 cell lines. Targeted knockdown of RAD51C was achieved with siRNA to explore the changes of cell proliferation, migration, and apoptosis. RESULTS: RAD51C protein level in carcinoma tissues, especially in the high-grade group (P<0.001), was significantly higher than that of benign tumors and associated with pathological type, stage, and overall survival (P<0.05). Downregulation of RAD51C promoted apoptosis and decreased cell survival rate and migration. CONCLUSIONS: Our results supported that RAD51C contributes to the progression of ovarian carcinoma, suggesting its promising application as an independent prognostic marker for diagnosis and treatment.

Laparoscopic Versus Open Surgery for Gastric Gastrointestinal Stromal Tumors: a Propensity Score Matching Analysis.

BACKGROUND: Surgery is the first choice for the treatment of gastric gastrointestinal stromal tumors (GISTs). With the development of new instruments and techniques, the popularity of laparoscopic resection of GISTs has increased rapidly. Previous studies on the advantages of laparoscopic resection over open surgery are generally limited by methodology or data capacity. This study evaluated the efficacy of laparoscopic resection and open surgery in gastric GISTs using the propensity score matching (PSM) method. METHODS: Between January 2005 and December 2017, 1027 patients were diagnosed with primary GIST at our institution. Among them, 548 patients were enrolled in this study. Standard demographic and clinicopathological data were collected from our database. Selection bias was eliminated using the PSM methods. RESULTS: After PSM, 256 cases involved in the comparison (128 laparoscopic (LAP) vs. 128 open surgery (OPEN)) were randomly matched (1:1) by age, sex, body mass index, hypertension, diabetes, heart disease, year of surgery, tumor location, tumor size, mitotic rate, and treatment with adjuvant tyrosine kinase inhibitors. The LAP group was superior to the OPEN group in blood loss (χ2 = 6.048, P = 0.049), time to first flatus (49.41 ± 7.56 vs. 71.31 ± 4.87 h, P < 0.001), and hospital stay (10.21 ± 6.05 vs. 12.56 ± 5.43 days, P = 0.001). No significant differences were seen in either the relapse-free survival or overall survival between the LAP and OPEN groups. In tumors located in favorable locations, the LAP group showed less blood loss (P = 0.008) and less multivisceral resection (17.8% vs. 5.5%, P = 0.02). CONCLUSIONS: Laparoscopic resection for gastric GISTs is associated with improved surgical outcomes and postoperative courses and comparable oncological outcomes, regardless of favorable or unfavorable tumor location.

Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis.

All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here, we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression, leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.

The prognostic value of gastrointestinal bleeding in gastrointestinal stromal tumor: A propensity score matching analysis.

BACKGROUND AND OBJECTIVES: Whether gastrointestinal (GI) bleeding indicates gastrointestinal stromal tumor (GIST) rupture and impacts prognosis is unclear. We examined the prognostic value of GI bleeding in GIST. METHODS: Primary GIST patients with (GB group) or without (NGB group) initial symptoms of GI bleeding were retrospectively studied. Propensity score matching (PSM) was conducted to reduce confounders. RESULTS: Eight hundred patients were enrolled. Male gender [odds ratio (OR) = 1.517, P = 0.011], tumors in the small intestine (OR = 2.539, P < 0.001), and tumor size 5-10 cm (OR = 2.298, P = 0.004) increased the odds of GI bleeding; age >60 years decreased the odds (OR = 0.683, P = 0.031). After PSM, 444 patients were included (222 in each group). Relapse-free survival (RFS) (P = 0.001) and overall survival (OS) (P = 0.002) were both superior in the GB group. In subgroup analysis, the GB group achieved a superior RFS (P = 0.005) and OS (P = 0.007) in patients with small intestine GIST, but not stomach or colorectal GIST. CONCLUSIONS: GIST patients with age <60, male gender, tumors located in the small intestine, and tumors 5-10 cm in size had a higher risk of GI bleeding. GIST patients with GI bleeding had a superior RFS and OS. This difference was statistically significant only in small intestine GIST.