HKDC1 Silencing Inhibits Proliferation and Glycolysis of Gastric Cancer Cells.

Gastric cancer (GC) is the third most lethal and fifth most common cancer in the world. In a variety of cancers, the hexokinase domain component 1 (HKDC1) is carcinogenic. This study was to investigate into how HKDC1 contributes to the development and progression of GC. Three different datasets (GSE103236, GSE13861, and GSE55696) were extracted from the Gene Expression Omnibus (GEO) database and then analyzed using the sva package. The R software was used to identify 411 differentially expressed genes (DEGs) in the pooled dataset. We discovered 326 glycolysis-related genes (glyGenes) in the cancer genome atlas-stomach adenocarcinoma (TCGA-STAD) cohort using gene set enrichment analysis set (GSEA). HKDC1 is one of the most prevalent glyGenes in GC tumor tissues and cells, as seen in the Venn diagram. According to the results of the Cell Count Kit-8 assay, the proliferation of AGS and MKN-45 cells decreased when HKDC1 was knocked down. Lack of HKDC1 in cells enhanced oxygen consumption and decreased glycolytic protein expression while suppressing glucose absorption, lactate production, ATP level, and extracellular acidification ratio. As an oncogene in gastric cancer development, HKDC1 influences cell proliferation and glycolysis.

Development and Validation of a New Integrative Score Based on Various Systemic Inflammatory and Nutritional Indicators in Predicting Prognosis in Patients With Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Recent studies revealed that various inflammatory and nutritional indexes were associated with prognosis in esophageal cancer (EC). However, these studies only evaluated one or two indexes, and the prognostic value of these indexes individually or in combination is unclear. This study aimed to construct an integrative score based on various inflammatory and nutritional indexes for prognosis in resectable esophageal squamous cell carcinoma (ESCC). METHODS: A total of 421 consecutive patients were randomly divided into either a training or validation cohort at a ratio of 7:3 for retrospective analysis. Using logic regression analyses, independent risk factors from peripheral blood indexes were screened to construct an integrative score. The associations regarding the integrative score, clinical characteristics, cancer-specific survival (CSS), and overall survival (OS) were analyzed. RESULTS: Out of 20 indexes, hemoglobin (HB), C-reactive protein to albumin ratio (CAR), and platelet to lymphocyte ratio (PLR) were independent risk factors based on logical regression analyses. Then, an integrative score with the optimal cut-off value of .67 was established according to the Combination Of HB, CAR, and PLR (COHCP). The area under the curve (AUC) indicated higher predictive ability of COHCP on prognosis than other indicators. Multivariate analyses revealed that COHCP serves as an independent prognostic score. Patients with COHCP low group (≤.67) had better 5-year CSS (57.3% vs 13.5%, P < .001) and OS (51.1% vs 12.3%, P < .001) than those with high group, respectively. Finally, the nomogram based on COHCP was established and validated regarding CSS and OS, which can accurately and effectively predict individual survival in resected ESCC. CONCLUSION: The COHCP was a novel, simple, and useful predictor in resectable ESCC. The COHCP-based nomogram may accurately and effectively predict survival.

A new immunotherapy strategy targeted CD30 in peripheral T-cell lymphomas: CAR-modified T-cell therapy based on CD30 mAb.

Chimeric antigen receptor T-cell immunotherapy (CAR-T) has shown remarkable efficacy in treating tumors of lymphopoietic origin. Herein, we demonstrate an effective CAR-T cell treatment for recurrent and malignant CD30-positive peripheral T-cell lymphomas (PTCL) has been demonstrated. The extracellular fragment gene sequences of CD30 were obtained from tumor tissues of PTCL patients and cloned into a plasmid vector to express the CD30 antigen. The CD30 targeting single-chain antibody fragment (scFv) was obtained from CD30-positive monoclonal hybridoma cells, which were obtained from CD30 antigen immunized mice. After a second-generation of CAR lentiviral construction, CD30 CAR T cells were produced and used to determine the cytotoxicity of this construct toward Karpas 299 cells. The results of CD30 CAR T-mediated cell lysis show that 9C11-2 CAR T cells could significantly promote the lysis of CD30-positive Karpas 299 cells in both LDH and real-time cell electronic sensing (RTCA) assays. In vivo data show that 9C11-2 CAR T cells effectively suppress the tumor growth in a Karpas 299 cell xenograft NCG mouse model. The CD30 CAR T cells exhibited an efficient cytotoxic effect after being co-cultured with the target cells and they also exhibited a significant tumor-inhibiting ability after being intravenously injected into PTCL xenograft tumors; these observations suggest that the new CD30 CAR-T cell may be a promising therapeutic candidate for cancer therapy.

The Prognostic Impact of Preoperative Serum Apolipoprotein A-I in Patients with Esophageal Basaloid Squamous Cell Carcinoma.

BACKGROUND: Esophageal basaloid squamous cell carcinoma (EBSCC) is a rare malignancy. Serum apolipoprotein A-I (APO A-I) has proved to be a potentially useful prognostic indicator in various cancers. However, no studies have analyzed the prognostic significance of serum APO A-I in patients with EBSCC. The aim of this study was to investigate the prognostic impact of preoperative serum APO A-I in patients with EBSCC. METHODS: Between 2007 and 2018, a retrospective study of 4050 patients with resectable esophageal squamous cell carcinoma (ESCC) including the levels of preoperative serum lipids was conducted and evaluated. The best cut-off values of the preoperative serum lipids were evaluated by receiver operating characteristic (ROC) curves. Kaplan-Meier analyses and Cox regression analyses were analyzed the overall survival (OS) and recurrence-free survival (RFS). A prediction model of nomogram was developed to predict individual OS and RFS in EBSCC. RESULTS: There were 53 patients enrolled in the study, which accounted for 1.31% (53/4050) of all primary ESCC. The best cut-off point was 1.305 g/L for serum APO A-I according to the ROC curve. Patients with lower levels of serum preoperative APO A-I were associated with worse RFS (16.1% vs 54.5%, P = 0.006) and OS (29.0% vs 63.6%, P = 0.010). The results indicated that serum APO A-I serves as an independent predictor in patients with EBSCC regarding OS [hazard ratio (HR): 0.352; 95% confidence interval (CI): 0.154-0.808; P = 0.014] and RFS (HR: 0.397; 95% CI: 0.185-0.850; P = 0.017). CONCLUSION: Preoperative serum APO A-I is an independent predictor regarding OS and RFS in EBSCC. As far as we know, this is the first study in EBSCC to explore the serum APO A-I in patients with EBSCC.

Bortezomib in combination with fludarabine plus cyclophosphamide for patients with relapsed or refractory mantle-cell lymphoma: results of the LYM-4003 study.

This study aimed to identify the maximum-tolerated dose (MTD) of cyclophosphamide when combined with bortezomib and fludarabine (B-FC) in a phase 1b trial, and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL (rrMCL). Forty patients were enrolled between April 8, 2011, and October 10, 2015. The MTD of cyclophosphamide was identified to be 250 mg/m2 days 1-2. At a median follow-up of 31.6 months (13.5-47.4), among 32 patients in phase 2, 10 (31%) had a complete response and 13 (41%) had a partial response. The median progression-free survival was 21 months (95% CI 7.3-34.7), and the median overall survival was 32.4 months (95% CI 17.8-47.0). Grade 3-4 hematologic AEs included neutropenia (27%) and thrombocytopenia (39%). The B-FC regimen has satisfactory responses and manageable toxicities in rrMCL patients (ClinicalTrials.gov NCT01322776).

Naples Prognostic Score: A Novel Prognostic Score in Predicting Cancer-Specific Survival in Patients With Resected Esophageal Squamous Cell Carcinoma.

BACKGROUND: Naples prognostic score (NPS) serves as a new prognostic index based on nutritional and inflammatory status in recent years. The aim of the current study was to explore the prognostic effect of NPS and to develop and validate a reliable nomogram based on NPS for individual cancer-specific survival (CSS) prediction in patients with resected ESCC without neoadjuvant therapy. METHODS: The clinical data for 287 (Jan. 2010 to Jun. 2012, Training sets) and 118 (Jan. 2015 to Dec 2015, Validation sets) consecutive resected ESCC cases were retrospectively analyzed. Two NPS models based on the different cut-off values of parameters were compared. Cut-off values in model 1 were derived from previous published studies, while cut-off values in model 2 were obtained in this study based on receiver operating characteristic (ROC) curves. The relationships between NPS and clinical characteristics and CSS were analyzed. The prediction model of nomogram was developed with independent prognostic factors in the training sets and was validated in the validation sets. RESULTS: The 5-year CSS for NPS 0, 1 and 2 were 61.9%, 34.6% and 13.4% in model 1 and 75.0%, 42.4% and 13.0% in model 2, respectively (P<0.001). Subgroup analyses revealed that NPS was also significantly associated with CSS in both model 1 and model 2 in different TNM stages. Multivariate analyses revealed that NPS was an independent prognostic marker regarding CSS in patients with resected ESCC (P<0.001). A predictive nomogram based on NPS was established and validated. The C-indexes of the nomogram in the training sets and validation sets were 0.68 and 0.72 in model 1 and 0.69 and 0.73 in model 2, respectively. These results confirmed that NPS-based nomogram was a more accurate and effective tool for predicting CSS in patients with resected ESCC. CONCLUSION: The current study confirmed that NPS was still a useful independent prognostic score in patients with resected ESCC. The NPS-based nomogram was successfully developed and validated, which may contribute to individual CSS prediction for resected ESCC patients.

The preoperative hemoglobin, albumin, lymphocyte and platelet (HALP) score is a useful predictor in patients with resectable esophageal squamous cell carcinoma.

The hemoglobin, albumin, lymphocyte and platelet (HALP) score has been confirmed as a prognostic factor in several types of cancers. The current study aimed to assess the prognostic value of preoperative HALP score, an inflammatory and nutritional based score, in predicting cancer-specific survival (CSS) in resectable patients undergoing curative resection for esophageal squamous cell carcinoma (ESCC). The clinical data of 355 consecutive patients with ESCC who underwent curative resection were retrospectively conducted and analyzed. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value for preoperative HALP. The areas under the curve (AUC) for preoperative HALP and other variables were calculated and compared. Cox regression analyses and Kaplan-Meier methods were used to identify the factors associated with CSS. According to the ROC curve, the optimal cut-off value for preoperative HALP was 31.8. The 5-year CSS for preoperative HALP low (≤31.8) and high (>31.8) was 15.1% and 47.5%, respectively (p < 0.001). Preoperative HALP had reliable abilities to predict CSS in resectable ESCC patients in any stage or gender, according to the subgroup analysis based on the patients' cancer stage and gender. Multivariate analyses confirmed that preoperative HALP was an independent prognostic score regarding CSS in patients with resectable ESCC (p < 0.001). This study confirmed that the postoperative HALP score could be regarded as a potential independent prognostic factor for CSS in patients with resectable ESCC.

Tumor-associated macrophages are associated with response to neoadjuvant chemotherapy and poor outcomes in patients with triple-negative breast cancer.

Background and objective: Tumor-associated macrophages (TAMs) play an essential role in tumor progression and metastasis. However, the role of TAMs in neoadjuvant chemotherapy (NAC) is unclear and need to be identified. The main subject of this study was to investigate whether TAMs are related to the chemotherapeutic response with triple-negative breast cancers (TNBC). Methods: We retrospectively analyzed pretreatment tissue from patients who received NAC and followed by a mastectomy or breast-conservation for stage II-III TNBC in this study. The association between TAMs and the pathological complete response (pCR) rate of TNBC to NAC was analyzed. In addition, the correlation of the TAMs with recurrence-free survival (RFS) in patients with TNBC was also evaluated. Results: Of the 91 patients, 31 (34.1%) patients experienced pathological complete response (pCR) after completion of NAC. Regarding the chemotheraptic response, patients with low infiltration of CD163+ macrophages achieved a significantly higher rate of pCR. Importantly, Kaplan-Meier survival shown that patients with high infiltration of CD163+ macrophages and non-pCR had poor OS and RFS. Conclusions: our data showed that TAMs may predict chemotherapeutic response and can be used as a promising prognostic candidate for poor survival in TNBC patients treated with NAC.

Prognostic Significance of the Lung Immune Prognostic Index in Patients with Resected Esophageal Squamous Cell Carcinoma.

BACKGROUND: The lung immune prognostic index (LIPI), a novel index combined with serum lactate dehydrogenase (LDH) and derived neutrophil to lymphocyte ratio (dNLR), is recently proposed to predict prognosis in lung cancer. The LIPI is not a unique indicator for lung cancer. However, the prognostic role of LIPI has not yet been evaluated in extra-pulmonary cancer. The aim of this study was to determine whether LIPI is still a useful prognostic indicator for patients with resected esophageal squamous cell carcinoma (ESCC). METHODS: The clinical data including preoperative laboratory results for 361 consecutive resected ESCC cases from 2007 to 2010 were retrospectively analyzed. A LIPI based on serum LDH and dNLR was conducted, characterizing into 3 groups (LIPI 0, 1 and 2). The association between LIPI and cancer-specific survival (CSS) was analyzed according to the Kaplan-Meier method and Cox regression analysis with hazard ratio (HR) and 95% confidence interval (CI). A nomogram model was conducted by R 3.6.0 software. RESULTS: In this study, 220 (60.9%), 100 (27.7%) and 41 (11.4%) patients had a LIPI of 0, 1 and 2, respectively. The 5-year CSS for LIPI 0, 1 and 2 was 40.9%, 19.0% and 9.8%, respectively (P<0.001). Subgroup analysis based on TNM stage revealed that HALP was also significantly related to CSS in any stage (TNM I: P=0.002; TNM II: P=0.009; TNM III: P=0.031). The LIPI serves as an independent predictor regarding CSS in multivariate analyses in patients with resected ESCC. Compared to LIPI 0, LIPI 1 and 2 had an HR of 1.419 (95% CI: 1.063-1.895, P=0.018) and 2.064 (95% CI: 1.403-3.036, P<0.001) regarding CSS, respectively. A nomogram was also developed in individualized CSS prediction based on LIPI in patients with resected ESCC. CONCLUSION: To the best of our knowledge, the present study is the first study to explore the association between LIPI and prognosis in patients with extra-pulmonary cancer. The LIPI, combined with LDH and dNLR, is still a potential independent prognostic marker in patients with resected ESCC.

PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression.

Background: Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that symmetrically di-methylates arginine residues on both histone and non-histone protein substrates. Accumulating evidence suggests that PRMT5 exerts its oncogenic properties in a wide spectrum of human malignancies. However, the underlying mechanisms by which PRMT5 contributes to the progression of colorectal cancer (CRC) remain to be defined. Methods: Western blot and real-time PCR were used to analyze the expression of CDKN2B. Co-immunoprecipitation (Co-IP), immunofluorescence and GST pulldown assays were employed to investigate the interaction between PRMT5 and EZH2. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to validate CDKN2B as a direct target of PRMT5/EZH2. DNA methylation status at the CpG islands of promoter region of CDKN2B gene was analyzed by bisulfite sequencing. The effect of PRMT5/EZH2 on malignant phenotypes was examined through in vitro and in vivo assays. PRMT5 and EZH2 protein expression levels in CRC tissues were analyzed by immunohistochemistry (IHC) staining. Results: We observed that PRMT5-deficient CRC cells exhibit proliferation defects in vitro. PRMT5 was identified as a major transcriptional repressor of CDKN2B (p15INK4b) for determining CRC progression. Mechanistically, PRMT5-mediated histone marks H4R3me2s and H3R8me2s were predominantly deposited at the promoter region of CDKN2B gene in CRC cells. Knockdown of PRMT5 in CRC cells decreased the accumulation of H4R3me2s and H3R8me2s marks and reduced the CpG methylation level of CDKN2B promoter, then re-activated CDKN2B expression. Strikingly, silencing of CDKN2B partially abrogated the proliferation defects caused by PRMT5 depletion in vitro and in vivo. Furthermore, we proved that PRMT5 interacted with Enhancer of zeste homolog 2 (EZH2), leading to enhanced EZH2 binding and H3K27me3 deposition together with decreased transcriptional output of CDKN2B gene. Importantly, we found that the combined interventions exerted a synergistic inhibitory effect of combined treatment with PRMT5i (GSK591) and EZH2i (GSK126) on the growth of CRC cells/xenografts in vitro and in vivo. Moreover, PRMT5 and EZH2 were found to be significantly elevated and associated with poor prognosis in CRC patients. Conclusion: PRMT5 functionally associates with EZH2 to promote CRC progression through epigenetically repressing CDKN2B expression. Thus, our findings raise the possibility that combinational intervention of PRMT5 and EZH2 may be a promising strategy for CRC therapy.

MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2- advanced breast cancer: the multinational randomized phase III study.

AIM: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. METHODS: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. RESULTS: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346-0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240-0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). CONCLUSION: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Long non-coding RNA BCYRN1 exerts an oncogenic role in colorectal cancer by regulating the miR-204-3p/KRAS axis.

BACKGROUND: It has been well documented that long non-coding RNAs (lncRNAs) regulate numerous characteristics of cancer, including proliferation, migration, metastasis, apoptosis, and even metabolism. LncRNA BCYRN1 (BCYRN1) is a newly identified brain cytoplasmic lncRNA with 200 nucleotides that was discovered to be highly expressed in tumour tissues, including those of hepatocellular carcinoma, gastric cancer and lung cancer. However, the roles of BCYRN1 in colorectal cancer (CRC) remain obscure. This study was designed to reveal the role of BCYRN1 in the occurrence and progression of CRC. METHODS: RT-PCR was used to detect the expression level of BCYRN1 in tumour tissues and CRC cell lines. BCYRN1 was knocked down in CRC cells, and cell proliferation changes were evaluated by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and Ki-67 and proliferating cell nuclear antigen (PCNA) expression assays. Cell migration and invasion changes were evaluated by wound healing, Transwell and invasion-related protein expression assays. Flow cytometry analysis was used to assess whether BCYRN1 regulates the apoptosis of CRC cells. The dual luciferase reporter gene detects the competitive binding of BCYRN1 to miR-204-3p. In vivo experiments were performed to evaluate the effect of BCYRN1 on tumour development. TargetScan analysis and dual luciferase reporter gene assays were applied to detect the target gene of miR-204-3p. Rescue experiments verified that BCYRN1 affects CRC by regulating the effect of miR-204-3p on KRAS. RESULTS: We found that compared with normal tissues and human intestinal epithelial cells (HIECs), CRC tumour tissues and cell lines had significantly increased BCYRN1 levels. We further determined that knockdown of BCYRN1 inhibited the proliferation, migration, and invasion and promoted the apoptosis of CRC cells. In addition, bioinformatics analysis and dual luciferase reporter assay showed that BCYRN1 served as a competitive endogenous RNA (ceRNA) to regulate the development of CRC through competitively binding to miR-204-3p. Further studies proved that overexpression of miR-204-3p reversed the effects of BCYRN1 on CRC. Next, TargetScan analysis and dual luciferase reporter assay indicated that KRAS is a target gene of miR-204-3p and is negatively regulated by miR-204-3p. A series of rescue experiments showed that BCYRN1 affected the occurrence and development of CRC by regulating the effects of miR-204-3p on KRAS. In addition, tumorigenesis experiments in a CRC mouse model confirmed that BCYRN1 downregulation effectively inhibited tumour growth. CONCLUSIONS: Our findings suggest that BCYRN1 plays a carcinogenic role in CRC by regulating the miR-204-3p/KRAS axis.

A NOVEL PROGNOSTIC INDEX IN PATIENTS WITH RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA: FIBRINOGEN/PREALBUMIN RATIO.

BACKGROUND: Fibrinogen (Fib) to albumin (ALB) fibrinogen-to-albumin ratio as a prognostic index for esophageal cancer has been confirmed. A novel prognostic index was initially proposed with fibrinogen to prealbumin ratio (FPR) in patients with resectable esophageal squamous cell carcinoma (ESCC). OBJECTIVE: The objective of the study was to study the prognostic role of the novel prognostic index (FPR) in patients with resectable ESCC without any neoadjuvant treatment. METHODS: In this retrospective study, a total of 372 resectable ESCC patients without any neoadjuvant treatment were included. The best cutoff values were selected by the receiver operating characteristic curves. Two Cox regression analyses with forward stepwise (one for categorical variables and the other for continuous variables) were used to evaluate the overall survival (OS) and cancer-specific survival (CSS). RESULTS: The best cutoff point was 0.014 for FPR. Patients with lower levels of FPR (≤0.014) had better CSS (50.7% vs. 18.0%, p < 0.001) and OS (48.0% vs. 17.6%, p < 0.001) than patients with higher levels of FPR (> 0.014). Multivariate Cox analyses (categorical and continuous) demonstrated that FPR was an independent prognostic factor in CSS (categorical: hazard ratio [HR]: 2.014, 95% confidence interval [CI]: 1.504-2.697, p < 0.001; continuous per 0.01: HR: 1.438, 95% CI: 1.154-1.793, p = 0.001) and OS (categorical: HR: 1.964, 95% CI: 1.475-2.617, p < 0.001; continuous per 0.01: HR: 1.429, 95% CI: 1.146-1.781, p = 0.002). CONCLUSIONS: Our study indicated that FPR served as an independent prognostic factor in patients with resectable ESCC.

Gustave Roussy Immune Score (GRIm-Score) is a prognostic marker in patients with resectable esophageal squamous cell carcinoma.

Background: The Gustave Roussy Immune Score (GRIm-Score) was initially reported to select patients for immunotherapy. Therefore, the purpose of the current retrospective study was to determine whether GRIm-Score, a novel nutritional and inflammatory-based prognostic score, is a useful prognostic marker in patients with esophageal squamous cell carcinoma (ESCC) undergoing surgical resection. Methods: A retrospective single institutional study including 372 ESCC patients undergoing surgical resection was performed. The GRIm-Score was simply calculated by lactate dehydrogenase (LDH), neutrophil lymphocyte ratio (NLR) and albumin (ALB). The cancer-specific survival (CSS) was analyzed for the current study with Cox regression analyses with forward stepwise and Kaplan-Meier methods. Results: There were 284 (76.3%) men and 88 (23.7%) women with the mean age of 59.3 ± 8.0 years (range: 36-80 years). Patient with a high GRIm-Score had poor CSS (10.3% vs. 35.0%, P < 0.001). The GRIm-Score, in multivariate analyses, instead of NLR, LDH or ALB, was an independent prognostic factor for CSS (P = 0.004). Conclusion: The GRIm-Score was an independent prognostic marker in patients with ESCC undergoing surgical resection. Our study is also the first study to discuss the prognostic value of GRIm-Score in patients with resectable ESCC.

A novel prognostic index in patients with resectable esophageal squamous cell carcinoma: fibrinogen/prealbumin ratio

ABSTRACT Background: Fibrinogen (Fib) to albumin (ALB) fibrinogen-to-albumin ratio as a prognostic index for esophageal cancer has been confirmed. A novel prognostic index was initially proposed with fibrinogen to prealbumin ratio (FPR) in patients with resectable esophageal squamous cell carcinoma (ESCC). Objective: The objective of the study was to study the prognostic role of the novel prognostic index (FPR) in patients with resectable ESCC without any neoadjuvant treatment. Methods: In this retrospective study, a total of 372 resectable ESCC patients without any neoadjuvant treatment were included. The best cutoff values were selected by the receiver operating characteristic curves. Two Cox regression analyses with forward stepwise (one for categorical variables and the other for continuous variables) were used to evaluate the overall survival (OS) and cancer-specific survival (CSS). Results: The best cutoff point was 0.014 for FPR. Patients with lower levels of FPR (≤0.014) had better CSS (50.7% vs. 18.0%, p < 0.001) and OS (48.0% vs. 17.6%, p < 0.001) than patients with higher levels of FPR (> 0.014). Multivariate Cox analyses (categorical and continuous) demonstrated that FPR was an independent prognostic factor in CSS (categorical: hazard ratio [HR]: 2.014, 95% confidence interval [CI]: 1.504-2.697, p < 0.001; continuous per 0.01: HR: 1.438, 95% CI: 1.154-1.793, p = 0.001) and OS (categorical: HR: 1.964, 95% CI: 1.475-2.617, p < 0.001; continuous per 0.01: HR: 1.429, 95% CI: 1.146-1.781, p = 0.002). Conclusions: Our study indicated that FPR served as an independent prognostic factor in patients with resectable ESCC.

miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy.

OBJECTIVE: Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis. DESIGN: Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality. RESULTS: The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment. CONCLUSIONS: Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients' responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

Protein C-ets-2 epigenetically suppresses TLRs-induced interleukin 6 production in macrophages.

Interleukin 6 (IL-6) is a major proinflammatory cytokine involved in several aspects of the immune response. Excessive IL-6 production and dysregulated IL-6 receptor signaling lead to multiple inflammatory and autoimmune diseases, such as asthma, even cancer. Thus, its precise regulatory mechanisms need to be fully addressed. Here we found that knockdown of protein C-ets-2 (Ets2) resulted in higher IL-6 production after TLRs activation in macrophages. Mechanistically, Ets2 associated with an epigenetic modifier histone deacetylase 1 (HDAC1) and promoted its recruitment to the Il6 promoter after TLRs activation. Subsequentially, it enhanced histone deacetylation and inhibited Il6 mRNA transcription. Thus, Ets2 epigenetically suppresses TLRs-induced IL-6 production in both human and murine macrophages via promoting histone deacetylation of the Il6 promoter, serving as a new potential therapeutic target in inflammatory diseases therapy.

C-Reactive Protein to Prealbumin Ratio (CPR): A Novel Inflammatory-Nutritional Prognostic Factor for Predicting Cancer-Specific Survival (CSS) and Overall Survival (OS) in Patients with Resectable Esophageal Squamous Cell Carcinoma.

BACKGROUND: The inflammation and nutrition play an important role in prognosis. A novel index combined with inflammatory and nutritional biomarkers, named C-reactive protein (CRP) to prealbumin (PALB) ratio (CPR), was initially reported to predict the prognosis in resectable esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A retrospective study was conducted including 346 resectable ESCC patients. The X-tile program was used to confirm the optimal cut-off value. The Kaplan-Meier methods and Cox regression analyses were performed to analyze the cancer-specific survival (CSS) and overall survival (OS). RESULTS: The optimum cut-off point was 0.03 for CPR. Patients with a high level of CPR (> 0.03) were associated with poor CSS (12.0% vs. 43.0%, P<0.001) and OS (11.2% vs. 40.7%, P<0.001). Multivariate analyses revealed that CPR was an independent predictor in resectable ESCC patients (CSS, P=0.008; OS, P=0.007). CONCLUSION: This study, to the best of our knowledge, is the first to investigate prognostic role of CPR in patients with ESCC. Our retrospective observations indicate that CPR, with the optimal cut-off value of 0.03, is a useful potential predictor in resectable ESCC patients.

Prognostic value of lactate dehydrogenase to albumin ratio (LAR) in patients with resectable esophageal squamous cell carcinoma.

BACKGROUND: We firstly identified a combination of lactate dehydrogenase (LDH) along with albumin (ALB), which was defined as LAR (LDH/ALB ratio). The purpose of our study here was initially to explore the prognostic role of LAR in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophagectomy. PATIENTS AND METHODS: A retrospective study was conducted including 346 resectable ESCC patients. Patients who received curative surgery without any neoadjuvant therapy were included in the current study. The X-tile program was performed to calculate the optimal cut-off values for LDH, ALB and LAR. The Kaplan-Meier methods, Cox regression univariate and multivariate analyses were utilized to analyze the prognostic factors for cancer-specific survival (CSS). RESULTS: There were 76 (22.0%) women and 270 (78.0%) men in all 346 patients. The mean value for serum LDH, ALB and LAR were 180±62 U/L (range 28-473 U/L), 40.3±5.3 g/L (range 26.6-52.4 g/L) and 4.6±1.8 (range 0.64-14.97), respectively. According to the X-tile program, the optimum cut-off points were 220 (U/L), 40.5 (g/L), and 5.5 for LDH, ALB, and LAR, respectively. The 5-year CSS was 31.8%. Patients with a high level of LAR (>5.5) were associated with poor CSS (13.3% vs 38.3%, P<0.001). Multivariate analyses revealed that LAR was an independent predictor in resectable ESCC patients (P=0.038). CONCLUSION: Our retrospective observations indicate that LAR is a useful potential prognostic biomarker in resectable ESCC patients who received curative surgery without any neoadjuvant therapy with the optimal cut-off value of 5.5.

Prognostic value of mean platelet volume/platelet count ratio in patients with resectable esophageal squamous cell carcinoma: a retrospective study.

BACKGROUND: Mean platelet volume (MPV) to platelet count (PC) ratio (MPV/PC) is a useful indicator in several cancers. However, the role for MPV/PC ratio in esophageal squamous cell carcinoma (ESCC) is still controversial. METHODS: A retrospective study was conducted including 277 resectable ESCC patients. The optimal cut-off values were calculated by the X-tile program. The receiver operator characteristic (ROC) curves were also created to show the candidate cut-off points. The comparisons between the X-tile plot and ROC curve were performed. The Kaplan-Meier method was utilized to analyze the cancer-specific survival (CSS). Prognostic factors for CSS were calculated with Cox regression univariate and multivariate analyses. RESULTS: According to the X-tile program, the cut-off values for MPV, PC and MPV/PC ratio were 8.5 (fl), 200 (giga/l) and 0.04, respectively. However, the cut-off values for MPV, PC and MPV/PC ratio by the ROC curves were 8.25 (fl), 243.5 (giga/l) and 0.0410, respectively. The cut-off values were similar between the X-tile and ROC curve. A low MPV/PC ratio level (≤0.04) was associated with poor CSS (22.4% vs. 43.1%, P < 0.001). In multivariate analyses, we found that MPV/PC ratio was an independent predictor for CSS (P < 0.001). When we set the cut-off point using ROC curve, the MPV/PC ratio was still an independent predictor for CSS (P < 0.001). CONCLUSION: The MPV/PC ratio is a useful predictive indicator in patients with ESCC.