Serum chitinase activity prognosticates metastasis of colorectal cancer.

BACKGROUND: This study aimed to evaluate the value of chitinase activity in prognosticating the occurrence of metastasis in and prognosis of patients with colorectal cancer (CRC). METHODS: The chitinase activity in four different groups, namely 335 CRC patients without distant metastasis at their first visit (Group 1), 51 patients with CRC having synchronous liver metastasis (Group 2), 100 healthy age-matched controls (Group 3) and 40 patients with liver cancer (Group 4), were assayed using an enzyme-linked immunosorbent assay. The Cox proportional hazards ratio model and Kaplan-Meier curve were used to identify the association between chitinase activity and the clinical outcome of CRC patients without metastasis in the training set and testing set at their first visit. An in vitro Transwell experiment was performed to evaluate the migration of colon cancer cells. RESULTS: Patients with high chitinase activity had a significantly higher metastasis risk than those with low chitinase activity in the training and testing sets during follow-up, both at stage I/II and stage III. Further, multivariate analysis revealed that chitinase activity was an independent risk factor prognosticating liver metastases (P = 0.001). The combination of chitinase activity and lymph node metastasis status increased the accuracy of the prognosis of liver metastases after radical resection (P = 0.454E-011). In addition, chitinase promoted CRC cell migration in vitro. CONCLUSIONS: Chitinase activity can prognosticate the occurrence of metastasis in patients with CRC. Moreover, the combination of chitinase activity and N stage increased the power of prognosticating the occurrence of metastasis. Inhibiting chitinase activity may serve as a new strategy to treat metastases of CRC.

Pyroptosis in cancer treatment and prevention: the role of natural products and their bioactive compounds.

Targeting programmed cell death (PCD) has been emerging as a promising therapeutic strategy in cancer. Pyroptosis, as a type of PCDs, leads to the cleavage of the gasdermin family and the secretion of pro-inflammatory factors. Gasdermin D (GSDMD) and gasdermin E (GSDME) are the two main executors of pyroptosis. Pyroptosis in tumor and immune cells is essential for tumor progression. Natural products, especially Chinese medicinal herb and their bioactive compounds have recently been regarded as anti-tumor agents that regulate cell pyroptosis under different circumstances. Here, we review the underlying mechanisms of natural products that activate pyroptosis in tumor cells and inhibit pyroptosis in immune cells. Pyroptosis activation in tumor cells leads to tumor cell death, yet pyroptosis inhibition in immune cells may prevent tumor occurrence. Elucidation of the signaling pathways involved in pyroptosis contributes to the understanding of the anti-tumor role of natural products and their potential clinical applications. Therefore, we outline a promising strategy for cancer therapy and prevention using natural products via modulation of pyroptosis.

Micro-power negative pressure wound technique reduces risk of incision infection following loop ileostomy closure.

BACKGROUND: Prophylactic loop ileostomy is an effective way to reduce the clinical severity of anastomotic leakage following radical resection of rectal cancer. Incisional surgical site infection (SSI) is a common complication after ileostomy closure. AIM: To evaluate the efficacy and safety of the micro-power negative pressure wound technique (MPNPWT) in preventing incisional SSI. METHODS: This was a prospective, randomized controlled clinical trial conducted at a single center. A total of 101 consecutive patients who underwent ileostomy closure after rectal cancer surgery with a prophylactic ileostomy were enrolled from January 2019 to December 2021. Patients were randomly allocated into an MPNPWT group and a control group. The MPNPWT group underwent intermittent suturing of the surgical incision with 2-0 Prolene and was covered with a micro-power negative pressure dressing. The surgical outcomes were compared between the MPNPWT (n = 50) and control (n = 51) groups. Risk factors for incisional SSI were identified using logistic regression. RESULTS: There were no differences in baseline characteristics between the MPNPWT (n = 50) and control groups (n = 51). The incisional SSI rate was significantly higher in the control group than in the MPNPWT group (15.7% vs 2.0%, P = 0.031). However, MPNPWT did not affect other surgical outcomes, including intra-abdominal complications, operative time, and blood loss. Postoperative hospital stay length and hospitalization costs did not differ significantly between the two groups (P = 0.069 and 0.843, respectively). None of the patients experienced adverse effects of MPNPWT, including skin allergy, dermatitis, and pain. MPNPWT also helped heal the infected incision. Our study indicated that MPNPWT was an independent protective factor [odds ratio (OR) = 0.005, P = 0.025)] and diabetes was a risk factor (OR = 26.575, P= 0.029) for incisional SSI. CONCLUSION: MPNPWT is an effective and safe way to prevent incisional SSI after loop ileostomy closure.

The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization.

Background: Many existing studies indicated that patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), tend to have the risk of low total body bone mineral density (BMD), and are more likely to have osteoporosis (OS). To determine the causal relationship between IBD and bone metabolic disorders, we herein performed a two-sample Mendelian randomization analysis (TSMR) using publicly available summary statistics. Methods: Summary statistics of total body BMD, OS and IBD were downloaded from the Open Genome-Wide Association Study (GWAS), FinnGen consortium and International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The European and East Asian populations have consisted in this Mendelian Randomization (MR) work. A range of quality control procedures were taken to select eligible instrument SNPs closely associated with total body BMD, OS and IBD. To make the conclusions more reliable, we applied five robust analytical methods, among which the inverse variance weighting (IVW) method acted as the major method. Besides, heterogeneity, pleiotropy and sensitivity were evaluated. Results: In the European population, the genetic association of UC on total body BMD (OR=0.97, 95%CI=0.96,0.99, P<0.001) and overall IBD on total body BMD (OR=0.98, 95%CI=0.97,1.00, P=0.013) were significant, while the effect of CD on total body BMD was not significant enough (OR=0.99, 95%CI=0.98,1.00, P=0.085). All of UC, CD and overall IBD can be the genetic risk factor of having OS with pathological fracture (UC: OR=1.13, 95%CI=1.02,1.26, P=0.024, CD: OR=1.14, 95%CI=1.05,1.25, P=0.003, overall IBD: OR=1.13, 95%CI=1.02,1.24, P=0.015). In East Asian groups, only CD had a causal relationship with OS (OR=1.04, 95% CI=1.01,1.07, P=0.019). Conclusion: Our study revealed genetically predicted associations between IBD on total body BMD and OS in European and East Asian populations. This work supplemented the results of previous retrospective studies and demonstrated the necessity of BMD monitoring in patients with IBD.

Therapeutic effects of dihydroartemisinin in multiple stages of colitis-associated colorectal cancer.

Colitis-associated colorectal cancer (CAC) develops from chronic intestinal inflammation. Dihydroartemisinin (DHA) is an antimalarial drug exhibiting anti-inflammatory and anti-tumor effects. Nonetheless, the therapeutic effects of DHA on CAC remain unestablished. Methods: Mice were challenged with azoxymethane (AOM) and dextran sulfate sodium (DSS) to establish CAC models. DHA was administered via oral gavage in different stages of CAC models. Colon and tumor tissues were obtained from the AOM/DSS models to investigate inflammatory responses and tumor development. Inflammatory cytokines in the murine models were detected through qRT-PCR and ELISA. Toll-like receptor 4 (TLR4) signaling-related proteins were detected by western blot. Macrophage infiltration was measured using immunostaining analysis, and apoptosis in the colon cancer cells was detected by flow cytometry and western blot. Results: DHA inhibited inflammatory responses in the early stage of the AOM/DSS model and subsequent tumor formation. In the early stage, DHA reversed macrophage infiltration in colon mucosa and decreased the expression of pro-inflammatory cytokines. DHA inhibited the activation of macrophage by suppressing the TLR4 signal pathway. In the late stage of CAC, DHA inhibited tumor growth by enhancing cell cycle arrest and apoptosis in tumor cells. Administration of DHA during the whole period of the AOM/DSS model generated an addictive effect based on the inhibition of inflammation and tumor growth, thereby improving the therapeutic effect of DHA on CAC. Conclusion: Our study indicated that DHA could be a potent agent in managing the initiation and development of CAC without obvious side effects, warranting further clinical translation of DHA for CAC treatment.

Postoperative carcinoembryonic antigen (CEA) levels predict outcomes after resection of colorectal cancer in patients with normal preoperative CEA levels.

BACKGROUND: Carcinoembryonic antigen (CEA) is a cancer biomarker used in colorectal cancer (CRC) for tumor screening and outcome prediction. However it is still lack of sensitivity and specificity in general population. The present study aimed to investigate the clinical significance of CEA in patients with normal preoperative CEA levels. METHODS: Ninety-four patients were included who received surgery and developed an elevated CEA level postoperatively. They were divided into group A1 and A2 according to the peak CEA level (whether more than 10 ng/mL); group B1 and B2 according to CEA variation (whether reached a normal level at least once). The association between postoperative CEA and overall survival (OS), and disease-free survival (DFS) were analyzed using Kaplan-Meier method and Cox's proportional hazards regression model. RESULTS: The median follow-up time was 38 months. Patients in Group A2 and Group B2 had greater opportunities for recurrence and metastasis (P<0.05) compared to Group A1 and Group B1. Cox regression analysis revealed that high CEA levels and consistently elevated CEA levels were significantly associated with worse OS and DFS. Furthermore, patients with p-stage II in group A2 had worse OS than patients with p-stage III in group A1. The same result was detected when comparing group B2 and B1. CONCLUSIONS: Among patients with an initially normal CEA level, postoperative CEA level and variation could be effective markers for tumor progression assessment. TNM stage, combined with CEA level might be more accurate in prognostic prediction.

Small molecule 2,3-DCPE induces S phase arrest by activating the ATM/ATR-Chk1-Cdc25A signaling pathway in DLD-1 colon cancer cells.

In our previous study, it was reported that 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE) induces apoptosis and cell cycle arrest. The current study aimed to investigate the molecular mechanism involved in 2,3-DCPE-induced S phase arrest. The results demonstrated that 2,3-DCPE upregulated phosphorylated (p-)H2A histone family member X, a biomarker of DNA damage, in the DLD-1 colon cancer cell line. Western blotting revealed that 2,3-DCPE increased the checkpoint kinase (Chk)1 (Ser317 and Ser345) level and decreased the expression of M-phase inducer phosphatase 1 (Cdc25A) in a time-dependent manner. Subsequently, the results demonstrated that the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) inhibitors wortmannin and caffeine had no effect on the cell cycle; however, the inhibitors partially abrogated 2,3-DCPE-induced S phase arrest. Flow cytometry assays revealed that caffeine (2 mM) reduced the proportion of S phase cells from 83 to 39.6% and that wortmannin (500 nM) reduced the proportion of S phase cells from 83 to 48.2%. Furthermore, wortmannin and caffeine inhibited the 2,3-DCPE-mediated phosphorylation of Chk1 and the degradation of Cdc25A. However, these ATM/ATR inhibitors had limited effect on 2,3-DCPE-induced apoptosis. Taken together, the data of the current study indicated that 2,3-DCPE caused DNA damage in colon cancer cells and that 2,3-DCPE-induced S phase arrest was associated with the activation of the ATM/ATR-Chk1-Cdc25A pathway.

Identification of Four Pathological Stage-Relevant Genes in Association with Progression and Prognosis in Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis.

Clear cell renal cell carcinoma (ccRCC) is a major histological subtype of renal cell carcinoma and can be clinically divided into four stages according to the TNM criteria. Identifying clinical stage-related genes is beneficial for improving the early diagnosis and prognosis of ccRCC. By using bioinformatics analysis, we aim to identify clinical stage-relevant genes that are significantly associated with the development of ccRCC. First, we analyzed the gene expression microarray data sets: GSE53757 and GSE73731. We divided these data into five groups by staging information-normal tissue and ccRCC stages I, II, III, and IV-and eventually identified 500 differentially expressed genes (DEGs). To obtain precise stage-relevant genes, we subsequently applied weighted gene coexpression network analysis (WGCNA) to the GSE73731 dataset and KIRC data from The Cancer Genome Atlas (TCGA). Two modules from each dataset were identified to be related to the tumor TNM stage. Several genes with high inner connection inside the modules were considered hub genes. The intersection results between hub genes of key modules and 500 DEGs revealed UBE2C, BUB1B, RRM2, and TPX2 as highly associated with the stage of ccRCC. In addition, the candidate genes were validated at both the RNA expression level and the protein level. Survival analysis also showed that 4 genes were significantly correlated with overall survival. In conclusion, our study affords a deeper understanding of the molecular mechanisms associated with the development of ccRCC and provides potential biomarkers for early diagnosis and individualized treatment for patients at different stages of ccRCC.

Multidisciplinary evaluation of locally advanced leiomyosarcoma in the lower rectum: a case report and literature review.

Rectal leiomyosarcoma is a rare neoplasm, and no standard therapeutic strategy has been established, other than surgical resection. The prognosis of advanced leiomyosarcoma in the rectum is poor. We describe a case of a 47-year-old man with a locally advanced rectal leiomyosarcoma who presented with anal bleeding and lower abdominal pain. After discussions by a multidisciplinary team (MDT), the patient received preoperative pelvic short-course radiotherapy followed by laparoscopic-assisted abdominoperineal resection. Adjuvant chemotherapy with doxorubicin and ifosfamide was administered postoperatively. Local recurrence was detected 13 months after the resection. The patient received chemotherapy with gemcitabine and docetaxel followed by radioactive particle implantation. Thereafter, apatinib was administered to gain systemic control. The patient died 24 months after the diagnosis. This case report draws attention to treatment with multidisciplinary therapy, as discussed by MDT, for rare locally advanced rectal leiomyosarcoma.

BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2.

An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2) as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX) heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway.

[Effect of a recombinant lentiviral vector carrying hepatocyte nuclear factor 6 gene on migration and invasion abilities of SW620 cells].

OBJECTIVE: To construct a recombinant lentiviral vector that stably express hepatocyte nuclear factor 6 (HNF6) in colorectal cancer cell line and examine its effects on the invasive ability of SW620 cells. METHODS: The lentiviral vector pLeno-DCE-HA-HNF6 was constructed and transfected into 293T cells. The supernatant containing the lentivirus particles was harvested to determine the virus titer. A stable cell line was established by infecting SW620 cells with the lentivirus particles, and the transfection efficiency was examined by fluorescence microscopy and flow cytometry. The invasion ability of the transfected SW620-HNF6 cells was assessed by wound healing and transwell assays. RESULTS: The recombinant lentiviral vector was correctly constructed and verified by sequencing. SW620-HNF6 cell line with stable HNF6 expression was established successfully, and the transfection efficiency reached 82.3%. Western blotting and quantitative PCR demonstrated significantly upregulated HNF6 expression in SW620-HNF6 cells, which showed obviously suppressed invasive ability in wound healing and transwell assays. CONCLUSION: We have successfully established a colorectal cancer cell line SW620-HNF6 stably expressing HNF6, which shows a lowered migration activity in vitro.