Mechanism of Preventing Recurrence of Stage II-III Colorectal Cancer Metastasis with Immuno-inflammatory and Hypoxic Microenvironment by a Four Ingredients Chinese Herbal Formula: A Bioinformatics and Network Pharmacology Analysis.

BACKGROUND: Colorectal Cancer (CRC) is one of the top three malignancies with the highest incidence and mortality. OBJECTIVE: The study aimed to identify the effect of Traditional Chinese Medicine (TCM) on postoperative patients with stage II-III CRC and explore the core herb combination and its mechanism. METHODS: An observational cohort study was conducted on patients diagnosed with stage II-III CRC from January 2016 to January 2021. The primary outcome was disease-free survival, which was compared between the patients who received TCM or not, and the secondary outcome was the hazard ratio. The relevance principle was used to obtain the candidate herb combinations, and the core combination was evaluated through an assessment of efficacy and representativeness. Then, biological processes and signaling pathways associated with CRC were obtained by Gene Ontology function, Kyoto Encyclopedia of Gene and Genomes pathway, and Wikipathway. Furthermore, hub genes were screened by the Kaplan-Meier estimator, and molecular docking was employed to predict the binding sites of key ingredients to hub genes. The correlation analysis was employed for the correlations between the hub genes and tumor-infiltrating immune cells and hypoxiarelated genes. Ultimately, a quantitative polymerase chain reaction was performed to verify the regulation of hub genes by their major ingredients. RESULTS: A total of 707 patients were included. TCM could decrease the metastatic recurrence associated with stage II-III CRC (HR: 0.61, log-rank P < 0.05). Among those patients in the TCM group, the core combination was Baizhu → Yinchen, Chenpi, and Fuling (C combination), and its antitumor mechanism was most likely related to the regulation of BCL2L1, XIAP, and TOP1 by its key ingredients, quercetin and tangeretin. The expression of these genes was significantly correlated with both tumor-infiltrating immune cells and hypoxia- related genes. In addition, quercetin and tangeretin down-regulated the mRNA levels of BCL2L1, XIAP, and TOP1, thereby inhibiting the growth of HCT116 cells. CONCLUSION: Overall, a combination of four herbs, Baizhu → Yinchen, Chenpi, and Fuling, could reduce metastatic recurrence in postoperative patients with stage II-III CRC. The mechanism may be related to the regulation of BCL2L1, XIAP, and TOP1 by its key ingredients quercetin and tangeretin.

Quma Tongluo Prescription in the Treatment of Chronic Oxaliplatin Related Peripheral Neuropathy: A Single-Center, Open, Randomized Controlled Study.

Objective: To observe the effect of oral Quma Tongluo decoction on oxaliplatin-related chronic peripheral neuropathy. Methods: A total of 64 patients who met the inclusion criteria were randomly divided into an experimental group and a control group, with 32 cases in each group. The experimental group took Quma Tongluo decoction granules orally (2 times a day, 1 package each time, morning and evening after meals), and the control group took mecobalamin tablets orally (1 tablet each time, 3 times a day, after meals). After 4 weeks of treatment, the quantitative score of chronic peripheral neuropathy severity, a quantitative score of numbness, a quantitative score of pain, a chemotherapeutic peripheral neurotoxicity score, comprehensive neuropathy score, peripheral neurotoxicity grade, KPS score, and neuropathy area range score were compared between the two groups before and after treatment. Results: Before treatment, there were no significant differences between the two groups in the quantitative score of chronic peripheral neuropathy severity, quantitative score of numbness, chemotherapeutic peripheral neurotoxicity score, total neuropathy score, peripheral neurotoxicity grade, and chronic OIPN symptom range score (P > .05). After 4 weeks of treatment, there were significant differences in the quantitative score of chronic peripheral neuropathy severity, quantitative score of numbness, chemotherapeutic peripheral neurotoxicity score, total neuropathy score, peripheral neurotoxicity grade, and chronic OIPN symptom range score between the two groups (P < .05). There was no significant difference in pain quantification score and KPS score between the two groups before and after treatment (P > .05). The total effective rate of Quma Tongluo decoction in the treatment of oxaliplatin-related chronic peripheral neuropathy was higher than that of mecobalamin (87.1% > 20.6%), and no obvious adverse reactions such as Gastrointestinal reactions and allergic reactions were observed.One patient in the experimental group had diarrhea, the incidence of adverse reactions was about 3.2%, and the control group had no adverse reactions. Conclusions: Quma Tongluo decoction can effectively treat oxaliplatin-related chronic peripheral neuropathy, reduce the symptoms while reducing the scope of symptoms, and has no obvious adverse reactions in clinical practice, with good safety.

Tumor-draining lymph nodes: opportunities, challenges, and future directions in colorectal cancer immunotherapy.

Tumor-draining lymph nodes (TDLNs) are potential immunotherapy targets that could expand the population of patients with colorectal cancer (CRC) who may benefit from immunotherapy. Currently, pathological detection of tumor cell infiltration limits the acquisition of immune information related to the resected lymph nodes. Understanding the immune function and metastatic risk of specific stages of lymph nodes can facilitate better discussions on the removal or preservation of lymph nodes, as well as the timing of immunotherapy. This review summarized the contribution of TDLNs to CRC responses to immune checkpoint blockade therapy, local immunotherapy, adoptive cell therapy, and cancer vaccines, and discussed the significance of these findings for the development of diagnostics based on TDLNs and the potential implications for guiding immunotherapy after a definitive diagnosis. Molecular pathology and immune spectrum diagnosis of TDLNs will promote significant advances in the selection of immunotherapy options and predicting treatment efficacy.

Early prediction of sepsis using double fusion of deep features and handcrafted features.

Sepsis is a life-threatening medical condition that is characterized by the dysregulated immune system response to infections, having both high morbidity and mortality rates. Early prediction of sepsis is critical to the decrease of mortality. This paper presents a novel early warning model called Double Fusion Sepsis Predictor (DFSP) for sepsis onset. DFSP is a double fusion framework that combines the benefits of early and late fusion strategies. First, a hybrid deep learning model that combines both the convolutional and recurrent neural networks to extract deep features is proposed. Second, deep features and handcrafted features, such as clinical scores, are concatenated to build the joint feature representation (early fusion). Third, several tree-based models based on joint feature representation are developed to generate the risk scores of sepsis onset that are combined with an End-to-End neural network for final sepsis detection (late fusion). To evaluate DFSP, a retrospective study was conducted, which included patients admitted to the ICUs of a hospital in Shanghai China. The results demonstrate that the DFSP outperforms state-of-the-art approaches in early sepsis prediction.

MicroRNAs and angiogenesis: a new era for the management of colorectal cancer.

MicroRNAs (miRNAs) are a class of small noncoding RNA molecules containing only 20-22 nucleotides. MiRNAs play a role in gene silencing and translation suppression by targeting and binding to mRNA. Proper control of miRNA expression is very important for maintaining a normal physiological environment because miRNAs can affect most cellular pathways, including cell cycle checkpoint, cell proliferation, and apoptosis pathways, and have a wide range of target genes. With these properties, miRNAs can modulate multiple signalling pathways involved in cancer development, such as cell proliferation, apoptosis, and migration pathways. MiRNAs that activate or inhibit the molecular pathway related to tumour angiogenesis are common topics of research. Angiogenesis promotes tumorigenesis and metastasis by providing oxygen and diffusible nutrients and releasing proangiogenic factors and is one of the hallmarks of tumour progression. CRC is one of the most common tumours, and metastasis has always been a difficult issue in its treatment. Although comprehensive treatments, such as surgery, radiotherapy, chemotherapy, and targeted therapy, have prolonged the survival of CRC patients, the overall response is not optimistic. Therefore, there is an urgent need to find new therapeutic targets to improve CRC treatment. In a series of recent reports, miRNAs have been shown to bidirectionally regulate angiogenesis in colorectal cancer. Many miRNAs can directly act on VEGF or inhibit angiogenesis through other pathways (HIF-1a, PI3K/AKT, etc.), while some miRNAs, specifically many exosomal miRNAs, are capable of promoting CRC angiogenesis. Understanding the mechanism of action of miRNAs in angiogenesis is of great significance for finding new targets for the treatment of tumour angiogenesis. Deciphering the exact role of specific miRNAs in angiogenesis is a challenge due to the high complexity of their actions. Here, we describe the latest advances in the understanding of miRNAs and their corresponding targets that play a role in CRC angiogenesis and discuss possible miRNA-based therapeutic strategies.

A Chinese Herbal Formula Suppresses Colorectal Cancer Migration and Vasculogenic Mimicry Through ROS/HIF-1α/MMP2 Pathway in Hypoxic Microenvironment.

Various malignant tumors, including colorectal cancer, have the ability to form functional blood vessels for tumor growth and metastasis. Vasculogenic mimicry (VM) refers to the ability of highly invasive tumor cells to link each other to form vessels, which is associated with poor cancer prognosis. However, the antitumor VM agents are still lacking in the clinic. Astragalus Atractylodes mixture (AAM), a traditional Chinese medicine, has shown to inhibit VM formation; however the exact mechanism is not completely clarified. In this study, we found that HCT-116 and LoVo could form a VM network. Additionally, hypoxia increases the intracellular reactive oxygen species (ROS) level and accelerates migration, VM formation in colorectal cancer cells, while N-Acetylcysteine (NAC) could reverse these phenomena. Notably, further mechanical exploration confirmed that the matrix metalloprotease 2 (MMP2) induction is ROS dependent under hypoxic condition. On the basis, we found that AAM could effectively inhibit hypoxia-induced ROS generation, migration, VM formation as well as HIF-1α and MMP2 expression. In vivo, AAM significantly inhibits metastasis of colorectal cancer in murine lung-metastasis model. Taken together, these results verified that AAM effectively inhibits migration and VM formation by suppressing ROS/HIF-1α/MMP2 pathway in colorectal cancer under hypoxic condition, suggesting AAM could serve as a therapeutic agent to inhibit VM formation in human colorectal cancer.

The prognostic value of hypoxia-inducible factor-1α in advanced cancer survivors: a meta-analysis with trial sequential analysis.

BACKGROUND: Expression of hypoxia-inducible factors (HIFs) has been observed, but their prognostic role in advanced cancers remains uncertain. We conducted a meta-analysis to establish the prognostic effect of HIFs and to better guide treatment planning for advanced cancers. METHODS: Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Trial sequential analysis (TSA) was also performed. The clinical outcomes included overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), relapse/recurrence-free survival (RFS), and metastasis-free survival (MFS) in patients with advanced tumors according to multivariate analysis. RESULTS: A total of 31 studies including 3453 cases who received chemotherapy, radiotherapy, or chemoradiotherapy were identified. Pooled analyses revealed that HIF-1α expression was correlated with worse OS (HR = 1.61, p < 0.001), DFS (HR = 1.61, p < 0.001), PFS (HR = 1.49, p = 0.01), CSS (HR = 1.65, p = 0.056), RFS (HR = 2.10, p = 0.015), or MFS (HR = 2.36, p = 0.002) in advanced cancers. HIF-1α expression was linked to shorter OS in the digestive tract, epithelial ovarian, breast, non-small cell lung, and clear cell renal cell carcinomas. Subgroup analysis by study region showed that HIF-1α expression was correlated with poor OS in Europeans and Asians, while an analysis by histologic subtypes found that HIF-1α expression was not associated with OS in squamous cell carcinoma. No relationship was found between HIF-2α expression and OS, DFS, PFS, or CSS. CONCLUSIONS: Targeting HIF-1α may be a useful therapeutic approach to improve survival for advanced cancer patients. Based on TSA, more randomized controlled trials are strongly suggested.

Prognostic value of ALDH1 and Nestin in advanced cancer: a systematic meta-analysis with trial sequential analysis.

BACKGROUND: Novel prognostic markers and therapeutic targets for advanced cancer are urgently needed. This report with trial sequential analysis (TSA) was first conducted to provide robust estimates of the correlation between aldehyde dehydrogenase 1 (ALDH1) and Nestin and clinical outcomes of advanced cancer patients. METHODS: Hazard ratios (HRs) with 95% confidence intervals (CIs) were summarized for overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), relapse/recurrence-free survival (RFS), and metastasis-free survival (MFS) from multivariable analysis. TSA was performed to control for random errors. RESULTS: A total of 20 studies with 2050 patients (ALDH1: 15 studies with 1557 patients and Nestin: 5 studies with 493 patients) were identified. ALDH1 (HR = 2.28, p < 0.001) and Nestin (HR = 2.39, p < 0.001) were associated with a worse OS, as confirmed by TSA. Nestin positivity was linked to a poor PFS (HR = 2.08, p < 0.001), but ALDH1 was not linked to DFS, RFS, MFS, or PFS, and TSA showed that more studies were needed. Subgroup analysis by tumor type indicated that ALDH1 positivity may be associated with shorter OS in breast, head and neck cancers, but there was no association with colorectal cancer. Subgroup analysis by study source showed that ALDH1 positivity was correlated with a worse OS for Japanese (HR = 1.94, p = 0.002) and European patients (HR = 4.15, p < 0.001), but there was no association for Chinese patients. Subgroup analysis by survival rate showed that ALDH1 positivity correlated with poor OS at ⩾ 5 years (HR = 2.33, p < 0.001) or 10 years (HR = 1.76, p = 0.038). CONCLUSIONS: ALDH1 may be more valuable as an effective therapeutic target than Nestin for improving the long-term survival rate of advanced cancer. Additional prospective clinical trials are needed across different cancer types.

Prognostic Value of CD44 and Its Isoforms in Advanced Cancer: A Systematic Meta-Analysis With Trial Sequential Analysis.

Objective: Cancer stem cell marker CD44 and its variant isoforms (CD44v) may be correlated with tumor growth, metastasis, and chemo-radiotherapy resistance. However, the prognostic power of CD44 and CD44v in advanced cancer remains controversial. Therefore, the purpose of our study was to generalize the prognostic significance of these cancer stem cell markers in advanced cancer patients. Methods: Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated from multivariable analysis to assess the associations among CD44, CD44v6, and CD44v9 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Trial sequential analysis (TSA) was also conducted. Results: We included 15 articles that reported on 1,201 patients with advanced cancer (CD44: nine studies with 796 cases, CD44v6: three studies with 143 cases, and CD44v9: three studies with 262 cases). CD44 expression was slightly linked to worse OS (HR = 2.03, P = 0.027), but there was no correlation between CD44 expression and DFS, RFS, or PFS. Stratified analysis showed that CD44 expression was not correlated with OS at ≥5 years or OS in patients receiving adjuvant therapy. CD44v6 expression was not associated with OS. CD44v9 expression was closely associated with poor 5-years CSS in patients treated with chemo/radiotherapy (HR = 3.62, P < 0.001). However, TSA suggested that additional trials were needed to confirm these conclusions. Conclusions: CD44 or CD44v9 might be novel therapeutic targets for improving the treatment of advanced cancer patients. Additional prospective clinical trials are strongly needed across different cancer types.

Prognostic Value of CD133 and SOX2 in Advanced Cancer.

BACKGROUND: The prognostic value of CD133 and SOX2 expression in advanced cancer remains unclear. This study was first conducted to investigate the association between CD133 or SOX2 positivity and clinical outcomes for advanced cancer patients. METHODS: Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the correlation between CD133 or SOX2 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), or recurrence-free survival (RFS) from multivariable analysis. Trial sequential analysis (TSA) was also performed. RESULTS: 13 studies with 1358 cases (CD133) and five studies with 433 cases (SOX2) were identified. CD133 positivity was correlated with worse CSS and OS, but there was no correlation between CD133 positivity and DFS. SOX2 positivity was associated with poor DFS and RFS but was not linked to PFS. Stratified analysis by study source showed that only CD133 positivity can decrease OS for Chinese patients. Stratified analysis by treatment regimens indicated that CD133 positivity was linked to poor OS in patients treated with adjuvant therapy. TSA showed that additional studies were necessary. CONCLUSIONS: CD133 and SOX2 might be associated with worse prognosis in advanced cancer. More prospective studies are strongly needed. IMPACT: CD133 and SOX2 may be promising targeted molecular therapy for advanced cancer patients.

Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis.

BACKGROUND/AIMS: Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC. METHODS: Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Trial sequential analysis (TSA) was used to estimate the required sample information. RESULTS: HIF-2α protein expression was more frequent in CRC than in normal colonic tissues (OR = 150.49, P < 0.001), higher in male than female CRC patients (OR = 1.47, P = 0.008), and lower in high-grade than low-grade CRC (OR = 0.49, P = 0.029). TSA verified the reliability of the above results. HIF-2α expression was not linked to the prognosis of CRC in overall survival (OS), disease-specific survival (DSS), metastasis-free survival, and relapse-free survival, and no significant correlation was found between HIF-2α alteration and OS or disease-free survival (DFS) of CRC. Expression of both HIF-2α and vascular endothelial growth factor (VEGFA, VEGFB, or VEGFC) was associated with a poor metastasis-free survival of CRC (HR = 6.95, HR = 113.51, and HR = 8.11, respectively). No association was observed between HIF-2α expression and DFS in other cancers, but HIF-2α expression was correlated with a worse DFS of CRC (HR = 1.23, P = 0.037). Moreover, HIF-2α expression was linked to a good survival benefit in some cancers (B-cell lymphoma and lung adenocarcinoma: OS, multiple myeloma: DSS, breast cancer: distant metastasis-free survival, liposarcoma: distant recurrence-free survival) (all HRs < 1, Ps < 0.05). CONCLUSIONS: HIF-2α expression may be associated with the carcinogenesis of CRC, which is higher in males than in females, negatively linked to tumor differentiation, and correlated with a worse DFS of CRC. Additional prospective studies are needed.

Right- and left-sided colorectal cancers respond differently to traditional Chinese medicine.

AIM: To explore the differences in the responses of left-sided colorectal cancer (LSCRC) and right-sided colon cancer (RSCC) to traditional Chinese medicine (TCM). METHODS: Patients with postoperative stage I-III colorectal cancer (CRC) were enrolled and divided into the LSCRC with or without TCM and RSCC with or without TCM groups depending on the primary tumor side and TCM administration. Patients in the TCM group were given TCM for at least 6 mo. Our research adopted disease-free survival (DFS) as the primary endpoint. We applied a Cox proportional hazards regression model for the multivariate factor analysis using Stata 12.0 and SPSS 22.0 software for data analysis. RESULTS: Of the 817 patients included in our study, 617 had LSCRC (TCM group, n = 404; Non-TCM group, n = 213), and 200 had RSCC (TCM group, n = 132; Non-TCM group, n = 68). The 6-year DFS for patients with LSCRC was 56.95% in the TCM group and 41.50% in the Non-TCM group (P = 0.000). For patients with RSCC, the 6-year DFS was 52.92% in the TCM group and 37.19% in the Non-TCM group (P = 0.003). Differences between LSCRC and RSCC were not statistically significant regardless of TCM ingestion. CONCLUSION: Patients with either LSCRC or RSCC and who took TCM experienced longer DFS; furthermore, patients with RSCC benefited more from TCM in DFS.

Clinicopathological, prognostic and predictive value of CD166 expression in colorectal cancer: a meta-analysis.

CD166 has been identified as an important cancer stem cell (CSC) marker in colorectal cancer (CRC). The purpose of our study was to investigate the relationship between CD166 expression and clinical features and to examine the role of CD166 expression on the survival of patients with CRC. A total of 15 studies with 3,332 cases were identified in this meta-analysis. The pooled OR indicated that CD166 expression was significantly higher in CRC than in colonic adenomas or normal colonic mucosa (OR = 3.48, P = 0.002 and OR = 55.13, P = 0.017, respectively). CD166 expression was found to be negatively correlated with vascular invasion (OR = 0.75, P = 0.017), but it was not associated with gender, tumor location, lymph node status, distant metastasis, clinical stage, T classification or tumor differentiation. Meanwhile, CD166 expression was not associated with the prognosis of overall survival (OS) (HR = 1.20, 95% CI = 0.45-3.22, P = 0.72) in multivariate regression analysis. One study reported that CD166 expression may be a predictor of survival in stage II CRC patients using multivariate logistic regression analysis (OS: OR = 9.97, P = 0.035; disease-specific survival: OR = 29.02, P = 0.011). Our findings suggest that CD166 expression may be correlated with CRC carcinogenesis and a decreased risk of vascular invasion, and it may become a predictive biomarker of survival for stage II CRC patients, but additional studies with large sample sizes are essential to validate the prognostic and predictive values of CD166 expression.

Identification of hypoxia-regulated angiogenic genes in colorectal cancer.

The tumour hypoxia would trigger the angiogenesis switch for survival, and increase the ability of cancer cells to invade and metastasis. However, hypoxia regulated genes that invovled in angiogenesis in colorectal cancer (CRC) have not been explored in detail. The aim of this study was to explore angiogenic genes under hypoxia condition in CRC. Here, we found that endothelial cells tube formation and cancer cells invasion ability were promoted even under chronic hypoxia condition (72 h) in colon adenocarcinoma HCT-116 cells. Then, we explored the differentially expressed genes (DEGs) under chronic hypoxia condition by microarray from Gene Expression Omnibus (GEO) database. Subsequent bioinformatic analysis identified 17 genes that invovled in angiogenesis, blood vessel development, blood vessel morphgensis, vascular development. of these genes, VEGF-A, Smad7, Jun, IL-8, CXCR-4, PDGF-A, TGF-A, ANGPTL-4 expression levels up-regulated under hypoxia condition. Additionally, the gene expression level in acute hypoxia (24 h) was significantly higher than chronic condition (72 h). Finally, knockdown of hypoxia inducible factor (HIF-1α) by shRNA reversed the role of Smad7, CXCR-4, PDGF-A, TGF-A and ANGPTL-4 overexpression in HCT-116 cells, these findings provide the potential angiogenic targets for the treatment of colorectal cancer.

Is Ep-CAM Expression a Diagnostic and Prognostic Biomarker for Colorectal Cancer? A Systematic Meta-Analysis.

BACKGROUND: Cancer stem cell (CSC) epithelial cell adhesion molecule (Ep-CAM) is frequently expressed in colorectal cancer (CRC). However, the clinical significance of Ep-CAM expression in CRC is not clear. This study evaluated whether Ep-CAM provided valuable insight as a molecular biomarker for CRC diagnosis and prognosis and the potential of Ep-CAM as a novel therapeutic target in CRC. METHODS: Publications were selected online using electronic databases. The pooled odds ratios (ORs) or hazard ratios (HRs) with their 95% confidence intervals (95% CIs), and the combined sensitivity, specificity, and area under the curve (AUC) were calculated and summarized. RESULTS: Eleven eligible articles published in English involving 4561 cases were analyzed in this study. Ep-CAM expression was significantly higher in CRC compared with normal controls, and its overexpression was negatively linked to tumor differentiation, tumor stage, vascular invasion, depth of tumor invasion, lymph node metastasis, distant metastasis, and tumor budding in CRC patients. The loss of Ep-CAM expression positively correlated with these characteristics. Multivariate analysis of loss of Ep-CAM expression correlated with a poor prognosis in disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). The pooled sensitivity, specificity and AUC values of Ep-CAM expression in patients with CRC vs. normal controls were 0.93, 0.90, and 0.94, respectively. CONCLUSIONS: The present findings suggest that Ep-CAM expression may be associated with CRC carcinogenesis, while the loss of Ep-CAM expression is correlated with the progression, metastasis, and poor prognosis of CRC. Ep-CAM expression may be a useful biomarker for the clinical diagnosis of CRC.

Exploring the medication duration based on the effect of traditional Chinese medicine on postoperative stage I-III colorectal patients: a retrospective cohort study.

PURPOSE: To clarify the effect of tradional Chinese medicine (TCM) on different stage patients and to explore medication duration based on survival analysis. RESULTS: 523 and 294 patients were respectively in the TCM group and the control group. For all patients, 6-year disease-free survival (DFS) was 57.6% after TCM and 46.6% after non-TCM (p = 0.0006). 6-year DFS for patients with stage I disease in the TCM group was 79.5% compared with 89.1% in the control group (p = 0.65). For patients with stage II disease, 6-year DFS was 63.1% in the TCM group compared with 50.2% in the control group (p = 0.054), and for patients with stage III disease, it was 43.3% in the TCM group compared with 22.0% in the control group (p = 0.0000). MATERIALS AND METHODS: Data for patients with stage I-III disease between 2004 and 2013 were retrieved for this study, who underwent TCM after surgery were in the TCM group and the others were in the control group. Clinic appointments or phone were used to collect data by research assistants. Survival data were collected on Nov 2015 from the database, which is continuously updated by the researchers. CONCLUSIONS: TCM is associated with significantly improved disease-free survival, in particular for patients with stage III disease. Among of these, TCM is not necessary for patients with stage I disease, and postoperative patients with stage II disease should be recommended to take 2 years of TCM. For patients with stage III disease, adherence to medication of TCM during the 6-year follow-up is worthy of being recommended.

Yi Ai Fang, a traditional Chinese herbal formula, impacts the vasculogenic mimicry formation of human colorectal cancer through HIF-1α and epithelial mesenchymal transition.

BACKGROUND: Yi Ai Fang (YAF), a traditional Chinese medicine (TCM) formula, has been identified to have anticancer activity in our previously studies. The present study aimed to explore the potential mechanism of YAF suppression of VM on colorectal cancer (CRC) in vitro and in vivo. METHODS: Cell viability was measured by CCK-8 assay. HIF-1α, E-cd(E-cadherin), Claudin-4, and VIM (Vimentin) expressions level in vitro were evaluated by Western blot or RT-PCR. In addition, Human CRC HCT-116 cells were implanted in BALB/c nude mice; mice with xenografted tumors were randomly administrated vehicle (control), 8, 16, or 32 mg/mL YAF, or 1 mg/mL fluorouracil (5-FU). HIF-1α, E-cd, Claudin-4, and VIM expression in these tumors were determined by IHC. RESULTS: YAF effectively inhibited the growth and the formation of vasculogenic mimicry (VM) of CRC cells in a dose-dependent trend. YAF restrained the formation of vasculogenic mimicry(VM) through HIF-1α/EMT pathway in CRC. YAF suppressed VM was triggered by activation of E-cd and Claudin-4,which are characteristics of endothelial cells,and inhibition of HIF-1α and VIM in vitro. In vivo data showed that YAF remarkably inhibited growth of the xenografted tumors. The YAF-treated tumor samples were analyzed by IHC for levels of HIF-1α/EMT related proteins HIF-1α, E-cd, Claudin-4, and VIM. The results indicated that YAF significantly enhanced expression of E-cd and Claudin-4,but decreased expression of HIF-1α, VIM in a dose-dependent manner. CONCLUSIONS: In conclusion, this study provided the first direct evidence that YAF inhibited the formation of VM in human CRC, suggesting that YAF may be considered as a useful target for cancer therapy.

Hypoxia-induced vasculogenic mimicry formation in human colorectal cancer cells: Involvement of HIF-1a, Claudin-4, and E-cadherin and Vimentin.

Vasculogenic mimicry (VM) plays an important role in colorectal cancer (CRC) metastasis, and both hypoxia and the epithelial-mesenchymal transition (EMT) are necessary for VM. In this study, HIF-1α expression was upregulated in the VM-positive CRC cell line HCT-116 and thereby affected the expression of the EMT-related markers Claudin-4, E-cadherin (E-cd) and Vimentin(VIM). SB431542 and U0126EtOH, which can inhibit of EMT were used to treat HCT-116 and HCT-8 in these experiments. Both of the inhibitors had significant effect on EMT markers and the formations of VM in CRC cells. In addition, knockdown of HIF-1α in the HCT-116 cells inhibited their capacity for VM. Our study reveals a regulatory role for HIF-1α in VM and suggests that targeting either HIF-1α or EMT may be a valuable strategy for the elimination of CRC metastasis.

Dietary attitudes and behaviours of women in China after the 2008 Wenchuan earthquake in three seismically different zones.

BACKGROUND AND OBJECTIVES: The sudden occurrence of the 2008 Wenchuan Earthquake not only devastated people's health, but also may have impacted on the psychological and dietary attitudes and behaviours of the survivors. Although the influence of natural disaster on people's health has been extensively investigated, there is a lack of information about the effects on people's dietary attitudes and behaviours. Our aim was to evaluate the influence of the Wenchuan earthquake on the dietary attitudes and behaviours of adult women from different zones of China in July 2008. METHODS AND STUDY DESIGN: 736 women, aged 18-55 years old, were randomly selected and interviewed after the earthquake. Women were selected from three zones: the earthquake zone (n=206), the shaking zone (n=326), and the non-seismic zone (n=204). RESULTS: Although nutrition knowledge mean scores of women in the three zones were relatively low, the women in the earthquake zone became more vigilant about the nutritional value and acceptability of food than women in the other two zones. Nevertheless, women in the earthquake zone also developed some arguably untoward, if understandable, behaviour after the disaster. They increased their consumption and tendency to stock instant food and snack items. That said, these findings were modulated by other factors such as age, residence, Body Mass Index (BMI), and nutrition knowledge itself, as were post-earthquake eating behaviours, as judged by the ordinal logistic regression analyses performed. CONCLUSIONS: The major Wenchuan earthquake was associated with differentials in dietary attitudes and behaviours among women by seismic zone.

DNMT1, DNMT3A and DNMT3B Polymorphisms Associated With Gastric Cancer Risk: A Systematic Review and Meta-analysis.

BACKGROUND: Increasing studies showed that abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B) were associated with occurrence or decrease of various tumors. However, the associations between DNMTs variations and gastric cancer (GC) risk were still conflicting. We aimed to assess the effect of DNMTs polymorphisms on the susceptibility to GC. METHODS: Firstly, we did a meta-analysis for 7 SNPs (rs16999593, rs2228611, rs8101866 in DNMT1, rs1550117, rs13420827 in DNMT3A, rs1569686, rs2424913 in DNMT3B). Four genetic models (homozygote, heterozygote, dominant and recessive model) were used. Moreover, a meta-sensitivity and subgroup analysis was performed to clarify heterogeneity source. Lastly, 17 SNPs that couldn't be meta-analyzed were presented in a systematic review. FINDINGS: 20 studies were included, 13 studies could be meta-analyzed and 7 ones could not. Firstly, a meta-analysis on 13 studies (3959 GC cases and 5992 controls) for 7 SNPs showed that GC risk increased in rs16999593 (heterozygote model: OR 1.36, 95%CI 1.14-1.61; dominant model: OR 1.36, 95%CI 1.15-1.60) and rs1550117 (homozygote model: OR 2.03, 95%CI 1.38-3.00; dominant model: OR 1.20, 95%CI 1.01-1.42; recessive model: OR 1.96, 95%CI 1.33-2.89) but decreased in rs1569686 (dominant model: OR 0.74, 95%CI 0.61-0.90). The remaining SNPs were not found associated with GC risk. Furthermore, the subgroup analysis indicated that for rs1550117 and rs1569686, the significant associations were particularly found in people from Chinese Jiangsu province (rs1550117, OR 1.77, 95%CI 1.25-2.51; rs1569686, OR 0.48, 95%CI 0.36-0.64) and that PCR-RFLP was a sensitive method to discover significant associations (rs1550117, OR 1.77, 95%CI 1.25-2.51; rs1569686, OR 0.49, 95%CI 0.37-0.65). Lastly, a systematic review on 7 studies for 17 SNPs suggested that rs36012910, rs7560488 and rs6087990 might have a potential effect on GC initiation. CONCLUSION: This meta-analysis demonstrated that rs16999593 and rs1550117 could contribute to GC risk and that rs1569686 might be a protective factor against gastric carcinogenesis. By using these SNPs as biomarkers, it is feasible to estimate the risk of acquiring GC and thus formulate timely preventive strategy.