Identification of matrix-remodeling associated 5 as a possible molecular oncotarget of pancreatic cancer.

Pancreatic cancer has an extremely poor prognosis. Here we examined expression, potential functions and underlying mechanisms of MXRA5 (matrix remodeling associated 5) in pancreatic cancer. Bioinformatics studies revealed that MXRA5 transcripts are significantly elevated in pancreatic cancer tissues, correlating with the poor overall survival, high T-stage, N1 and pathologic stage of the patients. MXRA5 mRNA and protein expression is significantly elevated in microarray pancreatic cancer tissues and different pancreatic cancer cells. In primary and immortalized (BxPC-3 and PANC-1 lines) pancreatic cancer cells, shRNA-induced MXRA5 silencing or CRISPR/Cas9-mediated MXRA5 knockout suppressed cell survival, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while provoking cell apoptosis. Conversely, forced overexpression of MXRA5 further promoted pancreatic cancer cell progression and EMT. Bioinformatics studies and the protein chip analyses revealed that differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in MXRA5-overexpressed primary pancreatic cancer cells were enriched in the PI3K-Akt-mTOR cascade. Indeed, Akt-mTOR activation in primary human pancreatic cancer cells was inhibited by MXRA5 shRNA or knockout, but was augmented following MXRA5 overexpression. In vivo, the growth of MXRA5 KO PANC-1 xenografts was largely inhibited in nude mice. Moreover, intratumoral injection of adeno-associated virus-packed MXRA5 shRNA potently inhibited primary pancreatic cancer cell growth in nude mice. Akt-mTOR activation was also largely inhibited in the MXRA5-depleted pancreatic cancer xenografts. Contrarily MXRA5 overexpression promoted primary pancreatic cancer cell growth in nude mice. Together, overexpressed MXRA5 is important for pancreatic cancer cell growth possibly through promoting EMT and Akt-mTOR activation. MXRA5 could be a potential therapeutic oncotarget for pancreatic cancer.

Bioinformatics analysis and experimental verification of the prognostic and biological significance mediated by fatty acid metabolism related genes for hepatocellular carcinoma.

Background: Liver cancer is among the leading causes of death related to cancer around the world. The most frequent type of human liver cancer is hepatocellular carcinoma (HCC). Fatty acid (FA) metabolism is an emerging hallmark that plays a promoting role in numerous malignancies. This study aimed to discover a FA metabolism-related risk signature and formulate a better model for HCC patients' prognosis prediction. Methods: We collected mRNA expression data and clinical parameters of patients with HCC using the TCGA databases, and the differential FA metabolism-related genes were explored. To create a risk prognostic model, we carried out the consensus clustering as well as univariate and multivariate Cox regression analyses. 16 genes were used to establish a prognostic model, which was then validated in the ICGC dataset. The accuracy of the model was performed using receiver operating characteristic (ROC) analyses, decision curve analysis (DCA) and nomogram. The immune cell infiltration level of risk genes was evaluated with single-sample GSEA (ssGSEA) algorithm. To reflect the response to immunotherapy, immunophenoscore (IPS) was obtained from TCGA-LIHC. Then, the expression of the candidate risk genes (p < 0.05) was validated by qRT-PCR, Western blotting and single-cell transcriptomics. Cellular function assays were performed to revealed the biological function of HAVCR1. Results: According to the TCGA-LIHC cohort analysis, the majority of the FA metabolism-related genes were expressed differentially in the HCC and normal tissues. The prognosis of patients with high-risk scores was observed to be worse. Multivariate COX regression analysis confirmed that the model can be employed as an independent prognosis factor for HCC patients. Furthermore, ssGSEA analysis revealed a link between the model and the levels of immune cell infiltration. Our model scoring mechanism also provides a high predictive value in HCC patients receiving anti-PDL1 immunotherapy. One of the FA metabolism-related genes, HAVCR1, displays a significant differential expression between normal and HCC cell lines. Hepatocellular carcinoma cells (Huh7, and HepG2) proliferation, motility, and invasion were all remarkably inhibited by HAVCR1 siRNA. Conclusion: Our study identified a novel FA metabolism-related prognostic model, revealing a better potential treatment and prevention strategy for HCC.

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis.

Background: The basic platelet counts of schistosomiasis patients are low. If it does not meet the requirements for chemotherapy, the patient's treatment will not be carried out, which directly affects their prognosis. Therefore the impact of treatment on platelet counts is critically important. The effects of bevacizumab plus oxaliplatin-based chemotherapy and bevacizumab plus irinotecan-based chemotherapy regimens on platelets are different but have not been determined. In order to find a more suitable plan for metastatic colorectal cancer (mCRC) patients with a history of schistosomiasis, we conducted a retrospective analysis of mCRC patients and evaluated the impact of bevacizumab on their platelets. Methods: The medical records of all mCRC patients with a history of schistosomiasis who received oxaliplatin-based chemotherapy or irinotecan-based chemotherapy as first-line treatment for no less than 4 cycles, with or without bevacizumab from September 1, 2017, to June 30, 2019, in Kunshan Hospital were reviewed. Six-month cumulative incidence rates of splenomegaly and thrombocytopenia of chemotherapy with and without bevacizumab groups, oxaliplatin-based chemotherapy with and without bevacizumab groups, irinotecan-based chemotherapy with and without bevacizumab groups were compared from the first cycle until the completion of chemotherapy using Kaplan-Meier analysis and Log-rank test. Results: Evaluable splenic enlargement and thrombocytopenia results were obtained from 153 mCRC patients. The 6-month cumulative incidence rates of splenomegaly (23.3% vs. 55%; P=0.01) and that of thrombocytopenia (43.8% vs. 57.5%; P=0.40) were lower in the bevacizumab group than the non-bevacizumab group, however there were no statistical differences for the rates of thrombocytopenia. For patients treated with oxaliplatin, the rates of splenomegaly (19.5% vs. 66.7%; P=0.01) and thrombocytopenia (31.7% vs. 77.2%; P=0.02) were lower in the bevacizumab-treated cohort than that in the non-bevacizumab cohort. When stratified for irinotecan, there were no statistical differences in the frequency of splenomegaly between the two groups. However, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the non-bevacizumab cohort (59.4% vs. 8.7%; P=0.01). Conclusions: The bevacizumab plus oxaliplatin-based chemotherapy regimen is safer for mCRC patients with a history of schistosomiasis, especially for patients with a lower platelet count.

Prognostic Nutritional Index Predicts Outcome of PD-L1 Negative and MSS Advanced Cancer Treated with PD-1 Inhibitors.

Purpose: Tumor mutational burden (TMB), microsatellite instability-high (MSI-H), and expression of programmed death ligand-1 (PD-L1) have emerged as predictive biomarkers for responsiveness to immune checkpoint inhibitors (ICIs) in several cancer types. However, for patients with negative PD-L1 expression, or microsatellite stability (MSS), some cases may experience favorable response to immunotherapy, and there is currently a lack of good relevant predictors. We tried to introduce several peripheral blood markers for predicting treatment outcome and immune-related adverse events (irAEs) in PD-L1 negative and MSS patients. Methods: A retrospective study of 142 PD-L1 negative and MSS patients was carried out. The association of peripheral blood markers including lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin-to-globulin ratio (AGR), prognostic nutrition index (PNI), and other factors with clinicopathological characters and prognosis were assessed by Cox regression and Kaplan-Meier methods. Results: Lower level of PNI and poor performance status (ECOG score of 2) was correlated with significantly shorter overall survival (OS) and worse outcome of ICIs. The multivariate analysis revealed that PNI (for OS HR = 0.465, 95% CI: 0.236-0.916, p = 0.027; for PFS HR = 0.493, 95% CI: 0.251-0.936, p = 0.031) and ECOG score (for OS HR = 4.601, 95% CI: 2.676-7.910, p < 0.001; for PFS HR = 2.830, 95% CI: 1.707-4.691, p < 0.001) were independent prognostic factors for OS and PFS. NLR was related to the onset of irAEs. Conclusions: Pretreatment level of PNI and NLR, beyond PD-L1 expression and MSS, can improve the predictive accuracy for immunotherapy outcomes and has the potential to expand the candidate pool of patients for treatment with ICIs.

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth.

Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo, daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical cancer growth in vitro and in vivo.

The requirement of phosphoenolpyruvate carboxykinase 1 for angiogenesis in vitro and in vivo.

We here examined the potential biological function of phosphoenolpyruvate carboxykinase 1 (PCK1) in angiogenesis. shRNA- or CRISPR-Cas9-induced PCK1 depletion potently inhibited endothelial cell proliferation, migration, sprouting, and tube formation, whereas ectopic PCK1 overexpression exerted opposite activity. In HUVECs, Gαi3 expression and Akt activation were decreased following PCK1 depletion, but were augmented by ectopic PCK1 overexpression. In vivo, retinal expression of PCK1 gradually increased from postnatal day 1 (P1) to P5. The intravitreous injection of endothelial-specific PCK1 shRNA adenovirus at P1 potently inhibited the radial extension of vascular plexus at P5. Conditional endothelial knockdown of PCK1 in adult mouse retina increased vascular leakage and the number of acellular capillaries while decreasing the number of RGCs in murine retinas. In diabetic retinopathy patients, PCK1 mRNA and protein levels were up-regulated in retinal tissues. Together, PCK1 is essential for angiogenesis possibly by mediating Gαi3 expression and Akt activation.

Identification of Gαi3 as a promising target for osteosarcoma treatment.

Sustained activation of multiple receptor tyrosine kinases (RTKs) simultaneously is vital for tumorigenesis and progression of osteosarcoma (OS). Gαi proteins recruitment to various RTKs mediates downstream oncogenic signaling activation. The expression, functions and underlying mechanisms of Gαi3 in human OS were examined. Expression of Gαi3 is robustly elevated in human OS tissues and is correlated with a poor overall survival. In patient-derived primary OS cells and immortalized lines (MG63 and U2OS), Gαi3 depletion, by shRNA and CRISPR/Cas9 strategies, robustly suppressed cell viability, proliferation and migration, while provoking G1-S arrest and apoptosis activation. Conversely, Gαi3 overexpressing ectopically can accelerate proliferation and migration of OS cells. In OS cells, Gαi3 immunoprecipitated with VEGFR2, FGFR, PGDFR and EGFR, mediating downstream cascade transduction. Akt-mTOR activation in primary OS cells was potently inhibited by Gαi3 shRNA, knockout or dominant negative mutation, but augmented after Gαi3 overexpression. In vivo studies showed that Gαi3 shRNA AAV (adeno-associated viruses) intratumoral injection largely inhibited the growth of subcutaneous xenografts of primary OS cells. Moreover, the growth of the Gαi3-knockout primary OS xenografts was much slower than that of OS xenografts with empty vector. In Gαi3-depleted OS xenografts tissues, Gαi3 downregulation and Akt-mTOR inactivation were detected. Taken together, overexpressed Gαi3 mediates RTK-Akt signaling to drive OS progression.

Gross perianal embryonal rhabdomyosarcoma with severe multiple bone metastases throughout the body: a case report.

In adults, embryonal rhabdomyosarcoma (ERMS) is rare and has a poor prognosis. Giant perianal ERMS with severe multiple bone metastases at initial diagnosis has not been reported and lacks effective treatment options. This current case report describes a 31-year-old female patient that presented with a large lump on the right side of the anus. ERMS was diagnosed, accompanied by multiple bone metastases throughout the body and severe thrombocytopenia. She had an extremely low platelet count at initial diagnosis, making systemic chemotherapy inappropriate. Genetic testing did not help identify effective targeted drugs. A multi-target tyrosine kinase inhibitor, anlotinib, was selected to control the tumours combined with local radiotherapy to relieve pain. The lump became smaller and this reduction was maintained for 5 months. At 7 months after the diagnosis, the patient died of thrombocytopenia. This current case may provide supportive evidence for a potential treatment for patients with advanced ERMS, especially those not suitable for chemotherapy or surgery.

Prognostic Value of CD9 in Solid Tumor: A Systematic Review and Meta-Analysis.

Numerous clinical studies investigated how low expression of CD9 predicts poor prognosis of solid tumor. However, the results were inconclusive. This present meta-analysis was therefore performed to determine the prognostic value of CD9 expression in solid tumors. In this meta-analysis, 25 studies involving 5,555 participants were included; the result showed strong significant associations between declined expression of CD9 and all endpoints: overall survival (OS) (hazard ratio (HR) = 1.88, 95% CI = 1.45-2.43, p < 0.000) and time to progression (TTP) (HR = 2.0, 95% CI = 1.38-2.88, p < 0.000). The subgroup analysis was also performed, which revealed that the associations between CD9 downregulated expression related to poor OS in lung cancer and head and neck cancer. Also, low expression of CD9 was significantly connected with poor TTP in patients with head and neck cancer. The adverse prognostic impact of decreased expression of CD9 was observed in patients of different ethnicities. In conclusion, these results showed that declined expression of CD9 was associated with poor survival in human solid tumors. CD9 may be a valuable prognostic predictive biomarker and a potential therapeutic target in human solid tumors.

Identification of phosphoenolpyruvate carboxykinase 1 as a potential therapeutic target for pancreatic cancer.

Pancreatic cancer is the third leading cause of cancer-related mortalities and is characterized by rapid disease progression. Identification of novel therapeutic targets for this devastating disease is important. Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme of gluconeogenesis. The current study tested the expression and potential functions of PCK1 in pancreatic cancer. We show that PCK1 mRNA and protein levels are significantly elevated in human pancreatic cancer tissues and cells. In established and primary pancreatic cancer cells, PCK1 silencing (by shRNA) or CRISPR/Cas9-induced PCK1 knockout potently inhibited cell growth, proliferation, migration and invasion, and induced robust apoptosis activation. Conversely, ectopic overexpression of PCK1 in pancreatic cancer cells accelerated cell proliferation and migration. RNA-seq analyzing of differentially expressed genes (DEGs) in PCK1-silenced pancreatic cancer cells implied that DEGs were enriched in the PI3K-Akt-mTOR cascade. In pancreatic cancer cells, Akt-mTOR activation was largely inhibited by PCK1 shRNA, but was augmented after ectopic PCK1 overexpression. In vivo, the growth of PCK1 shRNA-bearing PANC-1 xenografts was largely inhibited in nude mice. Akt-mTOR activation was suppressed in PCK1 shRNA-expressing PANC-1 xenograft tissues. Collectively, PCK1 is a potential therapeutic target for pancreatic cancer.

Neuronal-driven glioma growth requires Gαi1 and Gαi3.

Neuroligin-3 (NLGN3) is necessary and sufficient to promote glioma cell growth. The recruitment of Gαi1/3 to the ligand-activated receptor tyrosine kinases (RTKs) is essential for mediating oncogenic signaling. Methods: Various genetic strategies were utilized to examine the requirement of Gαi1/3 in NLGN3-driven glioma cell growth. Results: NLGN3-induced Akt-mTORC1 and Erk activation was inhibited by decreasing Gαi1/3 expression. In contrast ectopic Gαi1/3 overexpression enhanced NLGN3-induced signaling. In glioma cells, NLGN3-induced cell growth, proliferation and migration were attenuated by Gαi1/3 depletion with shRNA, but facilitated with Gαi1/3 overexpression. Significantly, Gαi1/3 silencing inhibited orthotopic growth of patient-derived glioma xenografts in mouse brain, whereas forced Gαi1/3-overexpression in primary glioma xenografts significantly enhanced growth. The growth of brain-metastatic human lung cancer cells in mouse brain was largely inhibited with Gαi1/3 silencing. It was however expedited with ectopic Gαi1/3 overexpression. In human glioma Gαi3 upregulation was detected, correlating with poor prognosis. Conclusion: Gαi1/3 mediation of NLGN3-induced signaling is essential for neuronal-driven glioma growth.

The histone acetyltransferase HBO1 functions as a novel oncogenic gene in osteosarcoma.

HBO1 (KAT7 or MYST2) is a histone acetyltransferase that acetylates H3 and H4 histones. Methods: HBO1 expression was tested in human OS tissues and cells. Genetic strategies, including shRNA, CRISPR/Cas9 and overexpression constructs, were applied to exogenously alter HBO1 expression in OS cells. The HBO1 inhibitor WM-3835 was utilized to block HBO1 activation. Results:HBO1 mRNA and protein expression is significantly elevated in OS tissues and cells. In established (MG63/U2OS lines) and primary human OS cells, shRNA-mediated HBO1 silencing and CRISPR/Cas9-induced HBO1 knockout were able to potently inhibit cell viability, growth, proliferation, as well as cell migration and invasion. Significant increase of apoptosis was detected in HBO1-silenced/knockout OS cells. Conversely, ectopic HBO1 overexpression promoted OS cell proliferation and migration. We identified ZNF384 (zinc finger protein 384) as a potential transcription factor of HBO1. Increased binding between ZNF384 and HBO1 promoter was detected in OS cell and tissues, whereas ZNF384 silencing via shRNA downregulated HBO1 and produced significant anti-OS cell activity. In vivo, intratumoral injection of HBO1 shRNA lentivirus silenced HBO1 and inhibited OS xenograft growth in mice. Furthermore, growth of HBO1-knockout OS xenografts was significantly slower than the control xenografts. WM-3835, a novel and high-specific small molecule HBO1 inhibitor, was able to potently suppressed OS cell proliferation and migration, and led to apoptosis activation. Furthermore, intraperitoneal injection of a single dose of WM-3835 potently inhibited OS xenograft growth in SCID mice. Conclusion: HBO1 overexpression promotes OS cell growth in vitro and in vivo.

Serum level of interleukin-35 as a potential prognostic factor for gastric cancer.

AIMS: Interleukin-35 (IL-35), a novel anti-inflammatory cytokine, has recently been implicated in tumor development, progression, and survival. However, the relationship between serum IL-35 levels and gastric cancer (GC) is inconclusive. Here, we performed this study to clarify the role of serum level of IL-35 in GC patients. METHODS: We enrolled 180 GC patients and 170 healthy controls and used enzyme-linked immunosorbent assay to detect serum IL-35 levels. The clinical relevance between IL-35 and clinical pathology parameters was assessed. Univariate and multivariate logistic regressions were used to determine the feasibility of IL-35 as a clinical biomarker. RESULTS: We observed that serum IL-35 levels were significantly higher in GC patients (17.559 ± 13.266 pg/mL) than in healthy controls (8.077 ± 3.801 pg/mL, P < .001). High serum IL-35 levels were significantly associated with clinical stage (P = .048) and Helicobacter pylori (HP) infection (P < .001). The Kaplan-Meier survival analysis indicated that patients in the high-IL-35 group had poor overall survival (OS) and progression-free survival (PFS) (median OS: 26.0 vs 36.0 months, P < .001; median PFS: 18.0 vs.26.0 months, P = .044). Multivariate analyses demonstrated that serum IL-35 was an independent prognostic factor for GC (OS: hazard ratio [HR] = 1.031 [95% CI, 1.017-1.045], P < .001; PFS: HR = 1.029 [95% CI, 1.015-1.043], P < .001). CONCLUSIONS: High serum IL-35 levels are associated with poor disease prognosis in GC patients, and it may be become a new and promising biomarker for prognosis of gastric cancer.

Prognostic value of LAT-1 status in solid cancer: A systematic review and meta-analysis.

BACKGROUND: The expression of the L-type amino acid transporter 1 (LAT1) plays a significant role in tumor progression. However, it remains unclear whether high LAT1 expression correlates with poor prognosis of solid tumor patients. Here, we conducted a meta-analysis to assess the potential of LAT1 in predicting the prognosis of tumor patients. METHODS AND FINDINGS: A total of 4,579 cases were analyzed from 35 qualified studies. In patients with solid tumors, elevated expression of LAT1 is associated with poor prognosis (overall survival [OS]: pooled hazard ratio (HR) = 1.848, 95% confidence interval (CI) = 1.620-2.108, P < 0.001; disease free survival [DFS]: pooled HR = 1.923, 95% CI = 1.585-2.333, P < 0.001; progression free survival [PFS]: pooled HR = 1.345, 95% CI = 1.133-1.597, P = 0.001). Furthermore, in subgroup analysis, we found an association between high LAT1 expression and poor OS in non-small cell lung cancer (HR = 1.554, 95% CI = 1.345-1.794, P < 0.001), pancreatic cancer (HR = 2.052, 95% CI = 1.613-2.724, P < 0.001) and biliary tract cancer (HR = 2.253, 95% CI = 1.562-3.227, P < 0.001). CONCLUSION: The results of this meta-analysis indicate the reliability and potential of using LAT1 expression as a predictive biomarker in solid cancers prior to treatment. However, further studies with larger sample sizes would be beneficial for fully evaluating the predictive value of LAT1 expression for clinical applications.

The therapeutic value of SC66 in human renal cell carcinoma cells.

The PI3K-AKT-mTOR cascade is required for renal cell carcinoma (RCC) progression. SC66 is novel AKT inhibitor. We found that SC66 inhibited viability, proliferation, migration and invasion of RCC cell lines (786-O and A498) and patient-derived primary RCC cells. Although SC66blocked AKT-mTORC1/2 activation in RCC cells, it remained cytotoxic in AKT-inhibited/-silenced RCC cells. In RCC cells, SC66 cytotoxicity appears to occur via reactive oxygen species (ROS) production, sphingosine kinase 1inhibition, ceramide accumulation and JNK activation, independent of AKT inhibition. The ROS scavenger N-acetylcysteine, the JNK inhibitor (JNKi) and the anti-ceramide sphingolipid sphingosine-1-phosphate all attenuated SC66-induced cytotoxicity in 786-O cells. In vivo, oral administration of SC66 potently inhibited subcutaneous 786-O xenograft growth in SCID mice. AKT-mTOR inhibition, SphK1 inhibition, ceramide accumulation and JNK activation were detected in SC66-treated 786-O xenograft tumors, indicating that SC66 inhibits RCC cell progression through AKT-dependent and AKT-independent mechanisms.

I-BET726 suppresses human skin squamous cell carcinoma cell growth in vitro and in vivo.

Bromodomain-containing protein 4 (BRD4) is a potential therapeutic target of skin squamous cell carcinoma (SCC). I-BET726 is a novel BRD4 inhibitor. Its potential effect in skin SCC cells was tested in the present study. We show that I-BET726 potently inhibited survival, proliferation, cell cycle progression, and migration in established (A431/SCC-9/SCC-12/SCC-13 lines) and primary human skin SCC cells. I-BET726 induced significant apoptosis activation in skin SCC cells. It was more efficient in inhibiting skin SCC cells than known BRD4 inhibitors (JQ1, CPI203, and AZD5153). I-BET726 not only downregulated BRD4-regulated proteins (c-Myc, Bcl-2, and cyclin D1), but also inhibited sphingosine kinase 1 (SphK1) and Akt signalings in SCC cells. Restoring Akt activation, by a constitutively active S473D mutant Akt1 ("caAkt1"), partially inhibited I-BET726-induced cytotoxicity in A431 cells. In vivo, I-BET726 oral administration potently inhibited A431 xenograft growth in severe combined immunodeficient mice. Downregulation of BRD4-regulated proteins and inhibition of the SphK1-Akt signaling were detected in I-BET726-treated A431 xenograft tumor tissues. Together, I-BET726 inhibits skin SCC cell growth in vitro and in vivo.

MicroRNA-4651 targets bromodomain-containing protein 4 to inhibit non-small cell lung cancer cell progression.

Bromodomain-containing protein 4 (BRD4) overexpression in non-small cell lung cancer (NSCLC) promotes cancer progression. Here, we show that miR-4651 selectively targets and negatively regulates BRD4 in A549 and primary human NSCLC cells. RNA pull-down experiments confirmed that miR-4651 directly binds to BRD4 mRNA. Further, ectopic overexpression of miR-4651 in A549 cells and primary NSCLC cells decreased BRD4 3'-UTR luciferase reporter activity and its expression, whereas miR-4651 inhibition elevated both. Functional studies demonstrated that NSCLC cell growth, proliferation, and migration were suppressed with ectopic miR-4651 overexpression but enhanced with miR-4651 inhibition. BRD4 re-expression using a 3'-UTR mutant BRD4 reversed A549 cell inhibition induced by miR-4651 overexpression. Further, miR-4651 overexpression or inhibition failed to alter the functions of BRD4-KO A549 cells. In vivo, miR-4651-overexpressing A549 xenografts grew slowly than control A549 xenografts in severe combined immunodeficient mice. Finally, miR-4651 was downregulated in human NSCLC tissues, correlating with BRD4 elevation. Together, miR-4651 targets BRD4 to inhibit NSCLC cell growth in vitro and in vivo.

The Value of Next-Generation Sequencing for Treatment in Non-Small Cell Lung Cancer Patients: The Observational, Real-World Evidence in China.

BACKGROUND: Great success has been made in the targeting therapy of advanced non-small cell lung cancer (NSCLC). Nowadays, next generation sequencing (NGS) is acquirable and affordable in developed area of China. Using this feasible and accurate method of detecting therapeutic genes would help to select optimal treatments to extend patients survival. Here, we identified somatic mutations by NGS and analyzed the value for treatment of NSCLC in a real-world clinical setting. METHODS: NGS was carried out on biopsy samples obtained from 66 advanced unresectable NSCLC patients who had not received any treatment. 23 patients received liquid biopsy after failure of first-line targeted treatment. The mutation profiling as well as associations between mutations and clinicopathological characters was analyzed. The study also assessed the values of NGS for choosing treatment options and predicting prognosis in NSCLC patients. RESULTS: 152 somatic mutations were identified in 45 (68.18%) tissue samples. The most frequently mutated genes were EGFR (42.42%), TP53 (31.82%) and KRAS (15.15%). Specifically, the most frequent EGFR (42.42%), EGFR (42.42%), p = 0.046). In addition, in the smoking group, patients with EGFR (42.42%), p = 0.046). In addition, in the smoking group, patients with EGFR (42.42%), EGFR (42.42%), p = 0.046). In addition, in the smoking group, patients with. CONCLUSIONS: The observational study from real-world demonstrated that using NGS in routine clinical detection may be useful in guiding the therapy decisions and benefit more Chinese NSCLC patients.

Predicting the Prognosis of Gastric Cancer by Albumin/Globulin Ratio and the Prognostic Nutritional Index.

Background: Albumin-to-globulin ratio (AGR) and the prognostic nutrition index (PNI) are used to assess the nutritional status and severity of disease for a cancer patient. However, the clinical significance of combining these two predictors in gastric cancer (GC) remains unclear. This study evaluated the prognostic value of pretreatment serum AGR and the PNI for GC.Methods: A total of 273 patients with GC, diagnosed between January 2010 and January 2014, were enrolled. The association of AGR, PNI with clinicopathological characters and prognosis were assessed by Cox regression and Kaplan-Meier methods.Results: Both low AGR group and low PNI group had poor overall survival (OS) and progression-free survival (PFS) (all p < 0.001), while patients with low AGR and PNI had the lowest OS rate. Multivariate analyses revealed that AGR (for OS HR = 0.657, 95%CI: 0.449-0.962, p = 0.031; for PFS HR = 0.684, 95%CI: 0.528-0.895, p = 0.035) was an independent prognostic factor for OS and PFS in patients with GC, and PNI was verified as a predictor for OS (HR = 0.782, 95%CI: 0.503 -0.997, p = 0.048).Conclusions: Low level of pretreatment AGR and PNI may be independent prognostic factors for patients with GC, and patients with both factors indicated the worst OS.

Elevated serum levels of interleukin-37 correlate with poor prognosis in gastric cancer

Background: interleukin-37 (IL-37) is as a natural suppressor of the innate inflammatory and immune responses. It has also been reported to be involved in carcinogenesis and metastasis. The present case-control study was designed to investigate the role of serum levels of IL-37 in patients with gastric cancer. Methods: serum IL-37 levels were determined using the enzyme-linked immunosorbent assay in 180 patients diagnosed with gastric cancer and 100 healthy controls. The association between IL-37 levels and clinical factors was assessed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters in gastric cancer. Results: serum IL-37 levels in gastric cancer patients (5.606 +/- 0.837 pg/ml) were significantly higher than those in healthy controls (2.364 +/- 0.210 pg/ml, p < 0.001). High serum IL-37 levels were related to a poorly differentiated histologic type (p = 0.046) and advanced T stage (p = 0.003). The Kaplan-Meier survival analysis indicated that the high-IL-37 group had a poorer overall survival and progression-free survival (overall survival [OS]: 39.0 months vs 13.0 months, p < 0.001, progression-free survival [PFS]: 25.0 months vs 10.0 months, p < 0.001). Multivariate analyses showed serum IL-37 to be an independent prognostic factor for gastric cancer patients (OS: hazard ratios [HR] = 1.842, 95% CI: 1.190-2.854, p = 0.006; PFS: HR = 1.547, 95% CI: 1.014-2.359, p = 0.043). Conclusions: in conclusion, serum IL-37 levels were associated with poor overall survival and progression-free survival in gastric cancer patients. IL-37 may be a potential predictor of prognosis in gastric cancer

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