Potent bromodomain and extraterminal domain inhibitor JAB-8263 suppresses MYC expression and exerts anti-tumor activity in colorectal cancer models.

BACKGROUND: The overexpression of the MYC gene plays an important role in the occurrence, development and evolution of colorectal cancer (CRC). Bromodomain and extraterminal domain (BET) inhibitors can decrease the function BET by recognizing acetylated lysine residues, thereby downregulating the expression of MYC. AIM: To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells. METHODS: The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay. The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay, respectively. The effect of JAB-8263 on the expression of c-MYC, p21 and p16 in CRC cells was detected by western blotting assay. The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model. RESULTS: JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro. The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines. JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line. SW837 xenograft model was treated with JAB-8263 (0.3 mg/kg for 29 d), and the average tumor volume was significantly decreased compared to the vehicle control group (P < 0.001). The MC38 syngeneic murine model was treated with JAB-8263 (0.2 mg/kg for 29 d), and the average tumor volume was significantly decreased compared to the vehicle control group (P = 0.003). CONCLUSION: BET could be a potential effective drug target for suppressing CRC growth, and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.

The impact of COVID-19 on gastric cancer surgery: a single-center retrospective study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has been declared a global pandemic by the World Health Organization. Patients with cancer are more likely to incur poor clinical outcomes. Due to the prevailing pandemic, we propose some surgical strategies for gastric cancer patients. METHODS: The 'COVID-19' period was defined as occurring between 2020 and 01-20 and 2020-03-20. The enrolled patients were divided into two groups, pre-COVID-19 group (PCG) and COVID-19 group (CG). A total of 109 patients with gastric cancer were enrolled in this study. RESULTS: The waiting time before admission increased by 4 days in the CG (PCG: 4.5 [IQR: 2, 7.8] vs. CG: 8.0 [IQR: 2,20]; p = 0.006). More patients had performed chest CT scans besides abdominal CT before admission during the COVID-19 period (PCG: 22 [32%] vs. CG: 30 [73%], p = 0.001). After admission during the COVID period, the waiting time before surgery was longer (PCG: 3[IQR: 2,5] vs. CG: 7[IQR: 5,9]; p < 0.001), more laparoscopic surgeries were performed (PCG: 51[75%] vs. CG: 38[92%], p = 0.021), and hospital stay period after surgery was longer (7[IQR: 6,8] vs.9[IQR:7,11]; p < 0.001). In addition, the total cost of hospitalization increased during this period, (PCG: 9.22[IQR:7.82,10.97] vs. CG: 10.42[IQR:8.99,12.57]; p = 0.006). CONCLUSION: This study provides an opportunity for our surgical colleagues to reflect on their own services and any contingency plans they may have to tackle the COVID-19 crisis.

RNF43 Inhibits Cancer Cell Proliferation and Could be a Potential Prognostic Factor for Human Gastric Carcinoma.

BACKGROUND/AIMS: RNF43 is a member of transmembrane E3 ubiquitin ligases and plays important roles in tumor formation progression. In current study, we aimed to explore RNF43 expression and analyze its role in gastric carcinoma. METHODS AND RESULTS: The level of RNF43 was detected in 77 cases of gastric carcinoma and matched normal tissues by real-time PCR, western blotting and immunohistochemistry. We found that the expression of RNF43 was significantly down-regulated in the gastric carcinoma tissues compared to the normal mucosae (all P<0.001). In addition, RNF43 was significantly correlated with histological differentiation (P = 0.001), T-stage cancer (P<0.001), depth of invasion (P<0.001), metastasis of regional lymph nodes (P<0.001), pTNM stage (P<0.001) and survival (P = 0.021). We further explored the biological functions of RNF43 in gastric carcinoma cell lines. Both gain- and loss-function assays show that RNF43 could suppress cell proliferation while promotes cell apoptosis. Further, we found that RNF43 was positively correlated with p53 and cleaved-caspase3 and negatively correlated with Ki67 and Lgr5. CONCOLUSION: In conclusion, RNF43 might act as a tumor suppressor in gastric carcinoma and might be a potential indicator for the clinical assessment of gastric cancer prognosis.

Clinical significance of immunotherapy with combined three kinds of cells for operable colorectal cancer.

Surgery, chemotherapy, and radiotherapy have presented with the ability of killing tumor cells, as well as damaging the immune function, which can be corrected by the immunotherapy. The purpose of this perspective cohort study was to evaluate the efficacy of postoperative immunotherapies of tumor lysate-loaded dendritic cells (DC), in vitro DC-activated T (DC-AT), and activated T cells (ATC) combined with chemotherapy on the survival of patients with operable colorectal cancer. A total of 253 patients with primary colorectal cancer resection including 181 patients receiving postoperative simple chemotherapy (control group) and 72 patients receiving immunotherapies of DC, DC-AT, and ATC combined with chemotherapy during the corresponding period (immunotherapy group) were enrolled in this perspective cohort study. The survival of these patients was analyzed. The immunotherapy group presented a higher 5-year overall survival rate than the control group (75.63 vs 67.81 %, P = 0.035), as well as 3-year overall survival rate (87.07 vs 74.80 %, P = 0.045). For patients with advanced cancer (TNM stages III and IV), immunotherapy significantly promotes mean survival than control subjects (59.74 ± 3.21 vs 49.99 ± 2.54 years, P = 0.034). Patients who received more than three cycles of immunotherapies had a higher 5-year overall survival rate than those with less than three cycles (82.10 vs 69.90 %, P = 0.035). No serious adverse effect was observed in the immunotherapy group. Postoperative immunotherapies with DC, DC-AT, and ATC combination can promote the survival of patients with operable colorectal cancer (Clinical Trials, ChiCTR-OCH-12002610).

Berberine suppresses in vitro migration of human aortic smooth muscle cells through the inhibitions of MMP-2/9, u-PA, AP-1, and NF-κB.

Berberine, a type of isoquinoline alkaloid isolated from Chinese medicinal herbs, has been reported to have various pharmacological activities. Studies have demonstrated that berberine has beneficial effects on vascular remodeling and alleviates restenosis after vascular injury. However, its mechanism of action on vascular smooth muscle cell migration is not fully understood. We therefore investigated the effect of berberine on human aortic smooth muscle cell (HASMC) migration. Boyden chamber assay was performed to show that berberine inhibited HASMC migration dosedependently. Real-time PCR and Western blotting analyses showed that levels of matrix metalloproteinase (MMP)-2, MMP-9, and urokinase-type plasminogen activator (u-PA) were reduced by berberine at both the mRNA and protein levels. Western blotting assay further confirmed that activities of c-Fos, c-Jun, and NF-κB were significantly attenuated. These results suggest that berberine effectively inhibited HASMC migration, possibly by down-regulating MMP-2, MMP-9, and u-PA; and interrupting AP-1 and NF-κB mediated signaling pathways.

[Application of laparoscopic technique in acute abdomen of gastrointestinal surgery].

OBJECTIVE: To explore the clinical application of laparoscopy in gastrointestinal abdominal emergency. METHODS: Clinical data of 44 cases with undefined acute abdomen undergoing laparoscopic surgery from October 2008 to October 2011 were analyzed retrospectively. Sixty-five cases treated by regular surgery during the same period were enrolled as controls. RESULTS: In laparoscopic surgery group, 42 cases were diagnosed under laparoscopy(95.5%, 42/44). Thirty-four (77.3%,34/44) patients received operation successfully after diagnosis, including 20 of total laparoscopy, 14 of assistant small incision. Compared with control group, laparoscopic group had shorter length of incision[(6.7±2.2) cm vs. (15.8±3.4) cm], less blood loss[(51.4±30.3) ml vs. (117.9±49.5) ml], faster recovery of postoperative gastrointestinal function[postoperative oral intake(15.0±6.1) d vs. (30.5±8.4) d], shorter hospital stay[(5.6±4.2) d vs. (8.4±4.8) d] (all P<0.05), lower complication rate, and less surgical cost(P>0.05). CONCLUSION: Laparoscopy is safe and effective in treating gastrointestinal abdominal emergency and therapeutic operation can be performed after a definite diagnosis.

[Diagnosis and surgical therapy of primary retroperitoneal neurogenic tumors].

OBJECTIVE: To explore the diagnosis and surgical therapy for retroperitoneal neurogenic tumors (PRNTs). METHODS: The clinical records of 79 surgically treated patients with retroperitoneal neurogenic tumor were retrospectively analyzed. RESULTS: Twenty-nine patients presented with abdominal pain, 26 with abdominal mass, 15 with inferior extremities pain and numbness and 9 patients without clinical symptoms. Type B ultrasound (BUS), CT scan and surgical resection were performed for all the patients. Pathological analysis identified 19 patients with neurofibroma, 8 with neurilemmoma, 4 with paraganglioma, 21 with neurofibrosarcoma, 14 with malignant neurilemmoma, 6 with malignant paraganglioma, 5 with neuroectodermal tumor and 2 with neuroblastoma. The mortality rate of PRNT operation is was 1.3%, 3-year recurrence rate of benign tumor 0%, 5-year recurrence rate of benign tumor 12.9%, reoperation rate 100%, 5-year survival rate 100%. 3 years recurrence rate of malignancy tumor 41.6%, reoperation rate 90%, 5 years recurrence rate of malignancy tumor 79.1% and 5 years survival rate is 62.5%. CONCLUSION: BUS, CT and MRI are decisive for localization diagnosis. Surgical resection is the mainstay of therapy for this disease. Pre-operative preparation of intestinal tract and blood, maintaining the intactness of involved nerve are important for tumor resection. To prevent tumor recurrence, the key surgical techniques are to minimize tumor residues and . to handle intervertebral foramen properly.

Structure-efficacy relationships of immunostimulatory activity of CpG-containing oligodeoxynucleotides on mouse spleen cells.

AIM: To study the relationship between primary structures of oligodeoxynucleotides (ODN) containing unmethylated deoxycytidyldeoxyguanosine (CpG) dinucleotide motifs and their immunostimulatory activities in mouse spleen cells. METHODS: A series of CpG ODN with different primary structures were synthesized. Their capabilities to stimulate mouse spleen cell proliferation were determined by [3H]thymidine incorporation assay. Cytokine (interleukin [IL]-6, IL-12, and IFN-alpha) secretion spectra induced by CpG ODN were assessed by ELISA. The ability of CpG ODN to activate natural killer cells was evaluated by standard 4 h (51)Cr-release assay. Flow cytometry was utilized to examine the expressions of various lymphocyte surface molecules on diverse immunocytes. An effective CpG ODN for murine, ODN1826, was set as the template of modification and the positive control. RESULTS: The immunostimulatory activities of CpG ODN with different sequences and compositions varied markedly, both in character and in extent. It was useless for improving the immunostimulatory activity of ODN1826 by simply increasing the functional hexameric CpG motif number, modifying the site of CpG motifs, or changing the distance between multi-CpG motifs. However, an addition of a self-complementary palindrome structure at the 3'-end, but not the 5'-end of CpG ODN, aroused marked improvement in its activity. Several designed ODN had superior comprehensive immunostimulatory properties compared to ODN1826. CONCLUSION: The immunostimulatory activity of a CpG ODN was relevant to its primary structure. It was useless for promoting immunostimulatory activity to simply change CpG motif number, space, or distance. The 3'-end palindrome structure of CpG ODN is associated with enhanced immunostimulatory activity.