Identification of HSP90B1 in pan-cancer hallmarks to aid development of a potential therapeutic target.

Heat shock proteins play crucial roles in various biochemical processes, encompassing protein folding and translocation. HSP90B1, a conserved member of the heat shock protein family, growing evidences have demonstrated that it might be closely associated with cancer development. In the present study, we employed multi-omics analyses and cohort validations to explore the dynamic expression of HSP90B1 in pan-cancer and comprehensively evaluate HSP90B1 as a novel biomarker that hold promise for precision cancer diagnostics and therapeutics. The results suggest HSP90B1 was highly expressed in various kinds of tumors, often correlating with a poor prognosis. Notably, methylation of HSP90B1 emerged as a protective factor in several cancer types. In immune infiltration analysis, the expression of HSP90B1 in most tumors showed a negative association with CD8 + T cells. HSP90B1 expression was positively correlated with microsatellite instability and tumor mutational burden. HSP90B1 expression was also discovered to be positively correlated with tumor metabolism, cell cycle-related pathways and the expression of immune checkpoint genes. The expression of HSP90B1 was mainly negatively correlated with immunostimulatory genes and positively correlated with immunosuppressive genes, as well as strongly correlated with chemokines and their receptor genes. In addition, the HSP90B1 inhibitor PU-WS13 demonstrated significant efficacy in suppressing cancer cell proliferation in both leukemic and solid tumor cells, and remarkably reduced the expression of the cancer cell surface immune checkpoint PD-L1. The single-cell RNA sequencing analysis further highlighted that HSP90B1 was significantly higher in tumor cells compared to surrounding cells, revealing a potential target therapeutic window. Taken together, HSP90B1 emerges as a promising avenue for breakthroughs in cancer diagnosis, prognosis and therapy. This study provides a rationale for HSP90B1 targeted cancer diagnosis and therapy in future.

Analysis of differences in intestinal flora associated with different BMI status in colorectal cancer patients.

BACKGROUND: Overweight is known to be an important risk factor for colorectal cancer (CRC), and the differences in intestinal flora among CRC patients with different BMI status have not been clearly defined. The purpose of this study was to elucidate the differences in the abundance, composition and biological function of intestinal flora in CRC patients with different BMI status. METHOD: A total of 170 CRC patients were included and grouped according to the BMI data of CRC patients. BMI ≥ 24 kg/m2 was defined as overweight group, and BMI within the range of 18.5-23.9 kg/m2 was defined as normal weight group. Preoperative stool collection of patients in both groups was used for 16S rRNA sequencing. Total RNA was extracted from 17 CRC tumor tissue samples for transcriptome sequencing, and then CIBERSORT algorithm was used to convert the transcriptome data into the relative content matrix of 22 kinds of immune cells, and the correlation between different intestinal flora and immune cells and immune-related genes under different BMI states was analyzed. Finally, we identified BMI-related differential functional pathways and analyzed the correlation between these pathways and differential intestinal flora. RESULT: There was no significant difference in α diversity and ß diversity analysis between overweight group and normal weight group. Partial least square discriminant analysis (PLS-DA) could divide the flora into two different clusters according to BMI stratification. A total of 33 BMI-related differential flora were identified by linear discriminant effect size analysis (LEfSe), among which Actinomyces, Desulfovibrio and Bacteroides were significantly enriched in overweight group. ko00514: Other types of O-glycan biosynthesis are significantly enriched in overweight group. There was a significant positive correlation between Clostridium IV and Macrophages M2 and T cells regulatory (Tregs). There was a significant negative correlation with Dendritic cells activated and T cells CD4 memory activated. CONCLUSIONS: The richness and diversity of intestinal flora of CRC patients may be related to different BMI status, and the enrichment of Actinomyces, Desulphurvibrio and Bacteroides may be related to overweight status of CRC patients. The tumor microenvironment in which BMI-related differential flora resides has different immune landscapes, suggesting that some intestinal flora may affect the biological process of CRC by regulating immune cell infiltration and immune gene expression, but further experiments are needed to confirm this.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Mesorectal reconstruction with pedicled greater omental transplantation to relieve low anterior resection syndrome following total intersphincteric resection in patients with ultra-low rectal cancer.

BACKGROUND: Total intersphincteric resection (ISR) is the ultimate anus-preserving surgery for patients with ultra-low rectal cancer (ULRC), which can result in various degrees of anorectal dysfunction. Known as low anterior resection syndrome (LARS), it seriously affects the postoperative quality of life of patients. The aim of this study was to discuss the value of mesorectal reconstruction with pedicled greater omental transplantation (PGOT) to relieve LARS following total ISR in patients with ULRC, hoping to provide new ideas and strategies for the prevention and improvement of LARS. METHODS: We retrospectively analyzed hospitalization data and postoperative anorectal function of 26 ULRC patients, who were met inclusion and exclusion criteria in our center from January 2015 to February 2022. And combined with the results of anorectal manometry and rectal magnetic resonance imaging (MRI) defecography of some patients, we assessed comprehensively anorectal physiological and morphological changes of the patients after surgery, and their correlation with LARS. RESULTS: In this study, 26 patients with ULRC were enrolled and divided into observation group (n = 15) and control group (n = 11) according to whether PGOT was performed. There were no significant differences in surgical results such as operative time, intraoperative blood loss and postoperative complications between the two groups (P > 0.05). Postoperative follow-up showed that patients in both groups showed severe LARS within 3 months after surgery, but from the 3rd month after surgery, LARS in both groups gradually began to decrease, especially in the observation group, which showed faster recovery and better recovery, with statistically significant difference (P < 0.001). Through anorectal manometry, the mean rectal resting pressure in the observation group was significantly lower than that in the control group (P = 0.010). In addition, the postoperative thickness of the posterior rectal mesenterium in the observation group was significantly higher than that in the control group (P = 0.001), and also higher than the preoperative level (P = 0.018). Moreover, rectal MRI defecography showed that the neo-rectum had good compliance under the matting of greater omentum, and its intestinal peristalsis was coordinated. CONCLUSIONS: ULRC patients, with the help of greater omentum, coordinated their neo-rectum peristalsis after total ISR and recovery of LARS was faster and better. PGOT is expected to be an effective strategy for LARS prevention and treatment of ULRC patients after surgery and is worthy of clinical promotion.

Advantages of total proctocolectomy with straight ileoanal anastomosis plus pedicled omental transposition for familial adenomatous polyposis: a preliminary study.

PURPOSE: To achieve excellent postoperative bowel function in familial adenomatous polyposis (FAP) patients, it is important to reconstruct the digestive tract. The aim of this study is to preliminarily discuss the advantages of total proctocolectomy with straight ileoanal anastomosis (TPC-SIAA) plus pedicled omental transposition for FAP. METHODS: A retrospective study was carried out in two hospitals analysing data for FAP patients who underwent surgical treatments between 2015 and 2021. Perioperative outcomes and early and mid-term anal functions were analysed. RESULTS: After excluding 4 patients who underwent total proctocolectomy with permanent ileostomy, 10 patients were enrolled in the study. Among the 10 patients, 3 received TPC-SIAA plus pedicled omental transposition, 3 received total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA), and 4 received total colectomy with ileal pouch-rectal anastomosis (TC-IPRA). Except for one case conversion to laparotomy, laparoscopic surgery was performed for the other cases. The incidence of early postoperative complications was apparently higher with pouch anastomosis (57.1%) than straight anastomosis (0%). Frequencies of bowel movement and low anterior resection syndrome (LARS) score were higher for TPC-SIAA than the other two surgical procedures in the early term; over time, however, the frequencies of bowel movement and LARS score both showed a decreasing trend. In addition, combined with anorectal pressure detection and magnetic resonance imaging defecography at the 3rd month after TPC-SIAA plus pedicled omental transposition, defecation coordination was good. The dynamics and receptivity of the new rectum tended to be as expected. CONCLUSION: Although the three surgical procedures are safe and feasible surgical options for FAP, TPC-SIAA plus pedicled omental transposition is more consistent with intestinal physiology, with good intestinal compliance, and anal function tended to be as expected over time. Nevertheless, more extensive studies are needed to confirm these benefits.

MTUS1 is a promising diagnostic and prognostic biomarker for colorectal cancer.

BACKGROUND: The morbidity and mortality of colorectal cancer (CRC) remain high, posing a serious threat to human life and health. The early diagnosis and prognostic evaluation of CRC are two major challenges in clinical practice. MTUS1 is considered a tumour suppressor and can play an important role in inhibiting cell proliferation, migration, and tumour growth. Moreover, the expression of MTUS1 is decreased in different human cancers, including CRC. However, the biological functions and molecular mechanisms of MTUS1 in CRC remain unclear. METHODS: In the present study, data from The Cancer Genome Atlas (TCGA) database were analysed using R statistical software (version 3.6.3.) to evaluate the expression of MTUS1 in tumour tissues and adjacent normal tissues using public databases such as the TIMER and Oncomine databases. Then, 38 clinical samples were collected, and qPCR was performed to verify MTUS1 expression. We also investigated the relationship between MTUS1 expression and clinicopathological characteristics and elucidated the diagnostic and prognostic value of MTUS1 in CRC. In addition, the correlation between MTUS1 expression and immune infiltration levels was identified using the TIMER and GEPIA databases. Furthermore, we constructed and analysed a PPI network and coexpression modules of MTUS1 to explore its molecular functions and mechanisms. RESULTS: CRC tissues exhibited lower levels of MTUS1 than normal tissues. The logistic regression analysis indicated that the expression of MTUS1 was associated with N stage, TNM stage, and neoplasm type. Moreover, CRC patients with low MTUS1 expression had poor overall survival (OS). Multivariate analysis revealed that the downregulation of MTUS1 was an independent prognostic factor and was correlated with poor OS in CRC patients. MTUS1 expression had good diagnostic value based on ROC analysis. Furthermore, we identified a group of potential MTUS1-interacting proteins and coexpressed genes. GO and KEGG enrichment analyses showed that MTUS1 was involved in multiple cancer-related signalling pathways. Moreover, the expression of MTUS1 was significantly related to the infiltration levels of multiple cells. Finally, MTUS1 expression was strongly correlated with various immune marker sets. CONCLUSIONS: Our results indicated that MTUS1 is a promising biomarker for predicting the diagnosis and prognosis of CRC patients. MTUS1 can also become a new molecular target for tumour immunotherapy.

Feasibility and advantages analyses of wedge resection without mesentery detached approach applied to closure of loop ileostomy.

OBJECTIVES: To evaluate the feasibility and advantages of wedge resection plus transverse suture without mesentery detached approach applied to loop ileostomy closure by analyzing the surgical data and the incidence of postoperative complications of patients undergoing this procedure. METHODS: We performed a retrospective analysis of the hospitalization data of patients who underwent ileostomy closure surgery and met the research standards from January 2017 to April 2021 in Guangxi Medical University Cancer Hospital; all surgeries were performed by the same surgeon. The perioperative data were statistically analyzed by grouping. RESULTS: In total, 65 patients were enrolled in this study, with 12 in the wedge resection group, 35 in the stapler group, and 18 in the hand suture group. There was no significant difference in operation time between the wedge resection group and stapler group (P > 0.05), but both groups had shorter operation time than that in the hand suture group (P < 0.05). The postoperative exhaustion time of wedge resection group was earlier than that of the others, and cost of surgical consumables in the wedge resection group was significantly lower than that in the stapler group, all with statistically significant differences (P < 0.05). By contrast, there were no statistically significant differences in postoperative complication incidences among the three groups. CONCLUSIONS: The wedge resection plus transverse suture without mesentery detached approach is safe and easy for closure of loop ileostomy in selected patients, and the intestinal motility recovers rapidly postoperatively. It costs less surgical consumables, and is particularly suitable for the currently implemented Diagnosis-Related Groups payment method.

Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients.

BACKGROUND: KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated. METHODS: 535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated. RESULTS: NF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes. CONCLUSIONS: KRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.

Comparison between 3-dimensional and 2-dimensional endoscopic thyroidectomy for benign and malignant lesions: a meta-analysis.

BACKGROUND: The use of 3-dimensional (3D) endoscopic thyroidectomy (ET) has been increasing, but its feasibility and safety have not been well documented for thyroidectomy. Hence, to systematically investigate the comparative outcomes during 3D-ET and 2-dimensional (2D) ET for benign and malignant lesions, we conducted this meta-analysis. METHODS: Based on the PRISMA guidelines, a systematic database search of the PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and Chinese Wanfang databases was performed. The eligible studies were published in English and Chinese up to October 2020. The major endpoints evaluated were procedure time, blood loss, postoperative drainage, postoperative hospitalization, postoperative complications, total number of lymph node dissections (LNDs), and total cost. RESULTS: A total of 15 relevant studies including 1190 patients (583 for 3D-ET and 607 for 2D-ET) compared the application of 3D and 2D laparoscopic systems in thyroid surgery, of which 8 were endoscopic benign thyroidectomy (EBT) and 7 were endoscopic malignant thyroidectomy (EMT). Our meta-analysis indicated that 3D-ET generally had advantages over 2D-ET in terms of procedure time (P = 0.000), blood loss (P = 0.000), postoperative drainage (P = 0.000), postoperative complications (P = 0.000), and LNDs (P = 0.006). However, there were no significant differences between the two systems in terms of total cost (P = 0.245) or postoperative hospitalization (P = 0.068). Subgroup analysis showed consistency of the overall outcomes in each subset, but a shorter postoperative hospitalization in 3D-EBT was revealed. CONCLUSIONS: Compared to 2D-ET, 3D endoscopic thyroidectomy is an efficient, safe, and reliable method with better depth perception and stereoscopic vision, and an equally satisfactory outcome. More clinical RCTs with long-term follow-up are required to reproduce these promising results.

Analysis of presacral tissue structure in LARS and the prevention of LARS by reconstruction of presacral mesorectum with pedicled greater omentum flap graft.

BACKGROUND: The greater omentum has played a unique biological role in regenerative surgery. The aim of our study was to alter the anterior sacral structure by filling the anterior sacral space with the greater omentum and evaluate its effect on the low anterior resection syndrome (LARS) after total mesorectal excision (TME) surgery for low rectal cancer. METHODS: We retrospectively collected clinical data of patients with primary low rectal cancer who underwent TME and ileostomy closure in our hospital from March 2018 to March 2020. Spearman correlation analysis was conducted to analyze the correlation between postoperative mesorectal fascia (MRF) thickness and LARS score. Subsequently, we prospectively used a tipped greater omental flap graft to reconstruct the anterior rectal sacral structures (MRF reconstruction) in 17 patients and compared LARS scores and rectal compliance (RC) at week 12 after closure of the ileostomy in both groups. RESULTS: There were 47 patients with No-MRF reconstruction (31 males, mean age 60.68 ± 9.21 years) and 17 with MRF reconstruction (10 males, mean age 49.82 ± 14.74 years). Correlation analysis indicated that MRF thickness and RC were negatively correlated with LARS severity (p < 0.05). The LARS score of patients with MRF reconstruction at 12 weeks was significantly better than that of those with No-MRF reconstruction (32.97 ± 2.65 vs. 26.94 ± 1.52, p = 0.001), and the RC of MRF reconstruction were lower (2.80 ± 0.55 vs. 3.67 ± 0.38, p = 0.001). In addition, MRF reconstruction and No-MRF reconstruction have the similar incidence of postoperative complications (p = 0.156). No hemorrhage or necrosis of the greater omentum flap was observed in any of the patients. CONCLUSIONS: Greater omentum flap transplantation can significantly improve the symptoms of LARS at 12 weeks after ileostomy closure and we expect it to become a new surgical procedure for the treatment of low rectal cancer.

Clinical significance of HER2 and EGFR expression in colorectal cancer patients with ovarian metastasis.

BACKGROUND: EGFR and HER2 overexpression has been reported to play important roles in colorectal cancer (CRC) development and metastasis. Ovarian metastasis is rare yet is one of the most malignant metastases of CRC, but very few studies have focused on its biological features. This study aimed to investigate the expression of EGFR and HER2 in ovarian metastases of CRC and to reveal their clinical significance. METHODS: The expression of HER2 and EGFR in both primary tumours and ovarian metastases was analysed by immunohistochemistry (IHC) in 31 CRC patients with ovarian metastases as well as in the primary tumours of 26 CRC patients with non-ovarian metastases. The overall survival time was calculated with a Kaplan-Meier survival curve and compared with a log-rank test. RESULTS: HER2 positivity in primary tumours was significantly higher in patients with ovarian metastases than in those with non-ovarian metastases (54.5% vs. 36.4%, P < 0.05). The EGFR-positive rate in primary lesions was not significantly different between patients with ovarian metastases and those with non-ovarian metastases (63.6% vs. 58.3%, P > 0.05). HER2 expression was not correlated with age, primary tumour site, tumour differentiation, tumour diameter or vascular cancer embolus (P > 0.05). The positive rates of HER2 and EGFR in ovarian metastases were 44.8 and 69.0%, respectively. HER2 expression in ovarian metastases was correlated with peritoneal metastasis and bilateral ovarian metastasis (P < 0.05) but not with age, synchronous or metachronous ovarian metastases and the primary tumour site (P > 0.05). There was no significant correlation between EGFR expression and the clinicopathological features in ovarian metastases (P > 0.05). CRC patients with HER2-positive ovarian metastases showed a shortened overall survival time compared to that of CRC patients with HER2-negative metastases (17.0 ± 5.2 vs. 32.0 ± 8.3 months). CONCLUSION: Our studies revealed that EGFR and HER2 are highly expressed in the primary tumours and metastases of CRC patients with ovarian metastases. HER2 positivity may be a negative prognostic predictor in patients with ovarian metastases.

Systematic review and meta-analysis of single-incision versus conventional multiport laparoscopic splenectomy.

BACKGROUND: There is no consensus that single-incision laparoscopic surgery splenectomy (SILS-SP) is on a par with conventional multiport laparoscopic surgery splenectomy (CMLS-SP). AIMS: The aim of this systematic review and meta-analysis was to assess feasibility and safety of SILS-SP when compared with CMLS-SP. MATERIALS AND METHODS: Eligible articles were identified by searching several databases including PubMed, EMBASE, CNKI (China) and the Cochrane Library, up until February 2016. Studies were reviewed independently and rated by Newcastle-Ottawa Quality Assessment Scale. Evaluated outcomes were complications, operative time, post-operative hospital stay, blood loss, starting diet, post-operative pain scores, conversion and analgesic requirements. RESULTS: Ten retrospective studies met the eligibility criteria. Overall, there was no significant difference between SILS-SP and CMLS-SP in complications, operative time, post-operative hospital stay, blood loss, starting diet, post-operative pain scores, conversion and analgesic requirements. CONCLUSIONS: SILS-SP is feasible and safe in certain patients, with no obvious advantages over CMLS-SP. Therefore, it may be considered an alternative to CMLS-SP. We await high-quality, double-blind RCTs. These should include clear statements on standard scores of post-operative pain and cosmetic results, longer follow-up assessment and cost-benefit analysis.

Single-Incision Laparoscopic Inguinal Hernioplasty Versus Conventional Laparoscopic Inguinal Hernioplasty.

PURPOSE: Additional studies comparing single-incision laparoscopic inguinal hernioplasty (SILH) and conventional laparoscopic inguinal hernioplasty (CLH) have been published, and this study updates the meta-analysis of this subject. METHODS: Two reviewers independently searched the PubMed, Embase, Google Scholar, and Cochrane Library electronic databases to locate original articles that compared SILH and CLH for inguinal hernia that were published until October 2015. Operative time, conversions, complications, length of hospital stay, recurrence, postoperative pain at 24 hours, and postoperative pain at 7 days were compared using Stata software, version 12.0. RESULTS: Sixteen studies were selected for this analysis, which included a total of 1672 patients (907 in SILH and 765 in CLH). SILH showed a longer operative time; however, conversions, complications, length of hospital stay, recurrence, postoperative pain at 24 hours, and postoperative pain at 7 days were similar between the 2 groups. CONCLUSIONS: Our meta-analysis has shown that inguinal hernia repair using SILH is as safe as CLH. However, based on our evidence, we currently believe that SILH is not an efficacious surgical alternative to CLH for inguinal hernias due to the fact that it does not provide significant benefit in postoperative pain and cosmetic outcomes. However, large-scale, well-designed, and multicenter studies will be needed to further confirm the results of this study.

SATB2 suppresses gastric cancer cell proliferation and migration.

Gastric cancer is one of the death-related malignant tumors worldwide. It remains a challenge for the diagnosis and treatment of gastric cancer. Special AT-rich sequence-binding protein 2 (SATB2) is a new tumor suppressive gene and plays important roles in many cancers. However, the role of SATB2 in gastric cancer is still unknown. In the present study, we demonstrated that downregulation of SATB2 was associated with shortened survival in patients with gastric cancer. Ectopic expression of SATB2 inhibited gastric cancer cell proliferation, colony formation, and migration. Overexpression of SATB2 repressed the expression of extracellular signal-regulated kinase 5 (ERK5), and activation of ERK5 restored the SATB2-induced inhibition of proliferation and migration in gastric cancer. This study provided evidence that SATB2 acted as a tumor suppressive gene gastric cancer, serving as a potential therapeutic target.

E2F-1 promotes DAPK2-induced anti-tumor immunity of gastric cancer cells by targeting miR-34a.

Activation of the transcription factor E2F-1 gene is a negative event in dendritic cell (DC) maturation process. Down-regulation of E2F1 causes immaturity of DC thereby stopping antigen production which in turn leads to inhibition of immune responses. E2F-1-free stimulates the NF-kB signaling pathway, leading to activation of monocytes and several other transcription factor genes. In the study, we report that down-regulation of E2F-1 in DCs promote anti-tumor immune response in gastric cancer (GC) cells through a novel mechanism. DCs were isolated from peripheral blood mononuclear cells. E2F-1 small interfering RNA (E2F-1-shRNA) induced down-regulation of E2F-1 mRNA and protein expression in DCs. Furthermore, we identified the E2F-1-shRNA targeted the CD80, CD83, CD86, and MHC II molecules, promoted their expression, and induced T lymphocytes proliferation activity and up-regulation of IFN-I³ production and GC cell killing effect, which significantly correlated with the cytotoxic T lymphocytes activated by E2F-1-shRNA DCs. The higher expression of miR-34a was found which was significantly correlated with the DC enhancing anti-tumor immunity against gastric cancer cell, and miR-34a potently targeted DAPK2 and Sp1, both of which were involved in the deactivation of E2F-1. Moreover, in E2F-1-DC-down-regulation in mice, GC transplantation tumors displayed down-regulation of Sp1, DAPK2, Caspase3, and Caspase7 and progressed to anti-tumor immunity. Collectively, our data uncover an E2F-1-mediated mechanism for the control of DC anti-tumor immunity via miR-34a-dependent down-regulation of E2F-1 expression and suggest its contribution to GC immunotherapy.

Transcription factor NF-Y is a functional regulator of the transcription of core clock gene Bmal1.

The circadian clock enables organisms to adjust to daily environmental changes and synchronize multiple molecular, biochemical, physiological, and behavioral processes accordingly. In mammalian clock work, Bmal1 is the most important core clock gene, which works with another core clock gene Clock to drive the expression of other clock genes and clock-controlled genes. However, the regulation of Bmal1 has not been fully understood. This work was aimed at identifying the positive regulator(s) of Bmal1 transcription. A series of 5' deletion reporter constructs was generated, and binding site mutations of mouse Bmal1 promoter fragments were cloned into pGL3-basic and pGL3(R2.1)-basic plasmids and transfected into NIH 3T3 cells. Luciferase activity was either measured 48 h after transfection or recorded for 4 days after serum shock. DNA affinity precipitation assay was used to detect the transcription factors binding to Bmal1 promoter. Small interfering RNA against nuclear factor Y, subunit A (NF-YA) and dominant negative NF-YA were employed to study the role of NF-Y in Bmal1 transcription regulation. Deletion and mutation analyses identified two clusters of CCAAT/GC-boxes at the proximal region of Bmal1 promoter as the activating cis-elements. Bmal1 promoter activity was up-regulated by NF-Y and/or Sp1 and repressed by dominant negative NF-YA or siRNA against NF-YA. The activation of Bmal1 promoter activity by NF-Y and Sp1 was inhibited by Rev-Erbα. DNA affinity precipitation assay showed that NF-Y and Sp1 bound to the two CCAAT/GC clusters of Bmal1 promoter. These results indicate that NF-Y is a functional activator of Bmal1 transcription and it cooperates with Sp1 and Rev-Erbα to generate the daily cycle of Bmal1 expression.

Combined use of lysyl oxidase, carcino-embryonic antigen, and carbohydrate antigens improves the sensitivity of biomarkers in predicting lymph node metastasis and peritoneal metastasis in gastric cancer.

The purpose of this study was to determine whether lysyl oxidase (LOX) is a useful marker of metastasis in gastric cancer (GC) patients in combination with tumor markers carcino-embryonic antigen (CEA), carbohydrate antigen 724 (CA724), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125). There were 215 GC patients (67 without metastasis, 102 with lymph node metastasis, and 46 with peritoneal metastasis) who presented to the Affiliated Cancer Hospital of Guangxi Medical University between May 2009 and November 2012 that were enrolled in this study. The LOX expression level and the serum concentration of the four tumor markers were evaluated preoperatively. All patients underwent computed tomography (CT) and ultrasonography (US) before surgery. Statistical analysis, including receiver operating characteristic (ROC) curve analysis, area under the curve (AUC) analysis, and logistic regression analysis, was performed to evaluate the diagnostic value of these markers in predicting metastasis in GC. For predicting lymph node metastasis in GC, the sensitivity of LOX, CEA, CA724, CA199, and CA125 was 44.12, 12.75, 21.57, 23.53, and 15.69 %, respectively, and increased to 79.41 % in combination. For predicting peritoneal metastasis in GC, the sensitivity of these markers was 56.52, 23.91, 34.78, 36.96, and 34.78 %, respectively, and increased to 91.30 % in combination. Combining LOX with CEA, CA724, CA199, and CA125 could increase the sensitivity of predicting lymph nodes metastasis and peritoneal metastasis in GC. Surgeons can use these markers to determine the best treatment options for patients. Additional large-scale, prospective, multicenter studies are urgently needed to further confirm the results of this study.

Association between aflatoxin B1 occupational airway exposure and risk of hepatocellular carcinoma: a case-control study.

The aim of this study was to determine the airway exposure of sugar and papermaking factory workers to aflatoxin B1 (AFB1) and to explore the potential association between AFB1 airway exposure and the risk of hepatocellular carcinoma (HCC) in a case-control study. Dust samples were collected from the sugarcane bagasse warehouse, and presser and paper production workshops. Blood samples were collected from 181 workshop employees and 203 controls who worked outside the workshop. AFB1 albumin adducts were detected using a double antibody sandwich enzyme-linked immunosorbent assay (ELISA). To explore the association between AFB1 airway exposure and the risk of HCC, the medical records of 68 HCC patients who worked in a sugar and papermaking factory between January 1994 and December 2013 were analyzed. A questionnaire was used to collect information from 150 healthy controls who worked for the same company and lived near the factory. AFB1 was detected in the dust samples, but could not be detected in any of the rice samples. An analysis of serum samples revealed serum AFB1 albumin adducts in 102 (56.35 %) of the study participants. However, in the control group, only 12 (5.9 %) individuals had detectable levels of AFB1 albumin adducts. Those with airway exposure to Aspergillus flavus-contaminated dust had an elevated risk of HCC compared to those without exposure (odds ratio, 5.24; 95 % confidence interval, 2.77-9.88; P = 0.00). The findings of this study indicate that occupational AFB1 airway exposure might be associated with the risk of AFB1-related HCC among the population that was used in this study. Intervention programs aimed at reducing exposure to inhalational AFB1 are needed urgently. Additional suitably designed, multicenter, prospective studies using large samples are needed to further confirm the results.

Does carbon dioxide pneumoperitoneum enhance wound metastases following laparoscopic abdominal tumor surgery? A meta-analysis of 20 randomized control studies.

The mechanisms involved in the development of wound metastasis following laparoscopic abdominal tumor surgery remain unclear. The aim of this study was to accurately assess whether the duration of carbon dioxide pneumoperitoneum (CDP) during laparoscopic abdominal tumor surgery enhances wound metastases. We conducted a systematic review of PubMed, Cochrane Library, and Embase through December 2013 to identify animal experiments comparing wound recurrence between laparoscopic and gasless laparoscopic procedures or open procedures. The outcome of interest was the number of animals with a wound tumor. Meta-regression was used to assess whether heterogeneity was explained by study level covariates (animal model, study size, CDP pressure, duration, and evaluated time). Twenty randomized control studies involving 1,229 animals were included. Wound recurrence was not significant in the laparoscopic surgery (LP) vs. gasless laparoscopic surgery (GLP) subgroups [odds ratio (OR), 2.23; 95 % confidence interval (CI), 0.90-5.55; P = 0.08) or the LP vs. laparotomy (LA) subgroups (OR, 0.97; 95 % CI, 0.31-3.00; P = 0.08). Overall postoperative wound recurrence results were not significantly different between the study groups and controls (OR, 1.47; 95 % CI, 0.74-2.92; P = 0.28). A meta-regression analysis showed that the outcome was not correlated with the covariates (animal model: P = 0.82; evaluated time: P = 0.30; pressure of CDP: P = 0.12; duration time: P = 0.80). Current evidence suggests that CDP does not enhance wound metastases following laparoscopic abdominal tumor surgery. Additional large sample, well-designed, randomized, controlled trials are needed to further confirm whether CDP duration in laparoscopic abdominal tumor surgery significantly enhances wound recurrence.