Objective: Data are limited on the psychological disorders of patients with cardiovascular disease during the post-COVID-19 period, although mental health status is associated with morbidity and mortality. We aimed to investigate the prevalence of anxiety and depression and risk factors among patients with cardiovascular disease in the post-pandemic period. Method: A cross-sectional survey was conducted through opportunistic and snowball sampling in southeast China from 10 October to 24 November. Anxiety and depression were assessed on the hospital anxiety and depression scale (HADS). Results: A total of 435 patients with hypertension (48.05%), atrial fibrillation (17.24%), coronary artery disease (14.48%), heart failure (9.89%) and other heart diseases (10.34%) completed the survey. Interestingly, most patients reported monthly income comparable to (90.11%) or even greater than (8.51%) pre-pandemic income. The occurrence of anxiety and depression was 11.72 and 9.20%, respectively. Marital status and treatment interruption during the pandemic were independent risk factors for both anxiety and depression. Moreover, current monthly income and access to telemedicine during the pandemic were independent risk factors for anxiety. Conclusion: Patients with cardiovascular disease may experience anxiety and depression not only because of disease complications but also because of the effects of the pandemic. In facing the global challenge posed by the coronavirus, efforts should be made to improve patients' psychological well-being in the management of populations with cardiovascular disease.

Dear Editor, Colorectal cancer (CRC) is the third most common cancer (10.0%) and the second leading cause of cancer-related deaths (9.4%) worldwide.1 Here we show cancer-derived DNA methylation (DNAm) enables sensitive and specific non-invasive diagnosis and monitoring of CRC. Cell-free DNA (cfDNA) containing tumour-derived biomarkers provide a promising avenue for non-invasive detection of minimal residual disease (MRD) after curative-intent surgery.2 Tumour-derived DNA, or circulating tumour DNA (ctDNA), could be detected by sequencing cfDNA from post-surgery or adjuvant therapy blood.3 We performed a prospective, observational, and multi-centre cohort study (Cancer HALLmark Epigenetics aNd GEnetics in CRC, Challenge-CRC) with 280 CRC patients (Stages I–IV) to assess the ability of a tumour-agnostic ctDNA assay to identify patients with MRD that would ultimately recur. Pre- and post-operative cfDNA were obtained from the patients. Somatic mutation and DNAm were sequenced and analysed. Statistics is performed to compare the performance to detect MRD from somatic mutation and DNAm (Figure 1). In this interim analysis, patients were divided into a surgery-naïve group (n = 64) and a post-curative-intent-surgery group (n = 40) (Tables S1 and S2). For the surgery-naïve group, 64 surgery-naïve, initially diagnosed, untreated CRC patients were enrolled. Enrolled patients include 37 (57.8%) colon cancer and 27 (42.2%) rectal cancer of clinical Stages I (3.1%, 2/64), II (20.3%, 13/64), III (34.4%, 22/64) and IV (42.2%, 27/64). Overall, 82.8% of patients (53/64) are lymph-node metastasis-free, and 68.8% (44/64) patients are distal metastasis-free. For the post-surgery group, enrolled patients include 10 (25.0%) colon cancer and 30 (75.0%) rectal cancer of clinical Stages II (10.0%, 4/40), III (27.5%, 11/40) and IV (62.5%, 25/40). Overall, 37.5% of patients (15/40) are lymph-node metastasis-free, whereas 62.5% (25/40) patients are with N1/N2. Overall, 22.5% (9/40) patients received neoadjuvant therapy and 67.5% (27/40) received adjuvant therapy. Overall, 22.5% (9/40) patients had surgery alone with no neoadjuvant or adjuvant therapy. Patients were followed up with a median of 239 days post-operatively. Overall, 32.5% (13/40) patients recurred with a median time to recurrence from surgery of 214 days (range, 6–384). Blood was drawn a median of 14 days (range, 6–307) post-operatively. In pre-operative blood cfDNA, with a limit-of-detection of 0.5% variant allelic frequency (VAF), 50.0% (32/64) patients were somatic mutation positive (Tables S3–S5). As expected, detected putative tumour-specific mutations include pathogenic mutations in TP53, KRAS, APC and SMAD4 (Figure 2A). Structural variants derived gene fusions of FGFR1 or NTRK1 were detected in two cases. These results closely resemble the reported mutation landscape in CRC.4 Mean frequency of CRC-specific DNAm haplotypes, or the mean VAF of tumour-specific somatic mutation (including structural variation) (Figure 2B), were independently used to derive tumour fraction (TF) in cfDNA. In samples with positive somatic mutation detected, methylation-derived TF linearly correlates with mutation-derived TF (adj. R2 = 0.9074, p < 2.2e − 16, Figure 3A). Furthermore, many samples without any detected somatic mutation were positive for methylation-derived TF (Figure 3A,B). Combining tumour-derived DNAm signal with tumour-associated, immune-related DNAm signal, age-related DNAm signal and cfDNA fragment size information further improved the performance of cfDNA methylation. Here, by leveraging DNAm correlating with multiple, orthogonal biological features, we constructed the MAFIT score to report an overall tumour-associated DNAm level in the sample (see the Supporting Information section). Overall, when considering both tumour-derived and tumour-associated, immune-related signals, DNAm was positive in 78.1% (50/64) of samples, whereas cfDNA mutation was positive in 50.0% (32/64) of samples. All samples positive with somatic mutation were also positive for DNAm, and DNAm additionally detected ctDNA signal in 56.3% (18/32) somatic-mutation-free samples. We conclude that compared to cfDNA mutation, DNAm is more sensitive for detecting presence of tumour (detection odds ratio 3.53 (1.56–8.36), p = 0.001595, Fisher's exact test). In post-operative blood cfDNA from 40 patients received curative-intent surgery, somatic mutation was positive in 47.5% (19/40) patients (Tables S4–S6), whereas DNAm was positive in 67.5% (27/40) patients (Figure 4A,C). In analysing progression-free survival (Figure 4B,D), 100% (13/13) of patients who are negative for DNAm, regardless of somatic mutation, were recurrence-free during the whole observation period (12 months). Tumour recurrence was found in 27.3% (3/11) of patients who are methylation-positive but somatic-mutation-negative with a median RFS of 384 days (95% CI: 356-Inf), or 62.5% (10/16) of patients who are double-positive for somatic mutation as well as DNAm, with a median RFS of 242 days (95% CI: 77-Inf.). Compared with somatic mutation predicted ctDNA positivity, methylation-derived ctDNA positivity has similar PPV (48.1% vs. 52.6%, p = 1, Fisher's exact test) but higher NPV (100% vs. 85.7%, p = 0.2701, Fisher's exact test). Overall, the cfDNA methylation assay shows a sensitivity of 100% and a specificity of 48.1%, whereas the cfDNA somatic mutation assay shows a sensitivity of 76.9% and a specificity of 66.7%. We conclude that methylation-derived ctDNA positivity was highly predictive for tumour recurrence and outperforms mutation-derived ctDNA positivity (p = 0.024, log-rank test) in our period of observation. Patients were grouped into risk strata according to their DNAm level (MAFIT score) in post-operative blood cfDNA as low- (<0.5), mid- (between 0.5 and 0.8) and high- (>0.8) risk. Overall, 100% low-risk group patients were progression-free within 400 days, whereas the medium survival days was 384 days for mid-risk group (28.6% recurred, 4/14) and 256 days for high-risk group (69.2% recurred, 9/13) (Figure 4F,G). We conclude that cfDNA methylation is capable of stratifying patients into risk groups with significant different risk of recurrence (Figure 4G and p = 0.0062, log-rank test). DNAm events predicting CRC have been reported in many studies and applied in several clinical practices for diagnosis and prognosis, for example, detecting methylated SEPT9 DNA in blood, or SDC2/BMP3/NDRG4 DNAm in faecal samples.5, 6 Diagnosis assays employing a genomic-epigenomic combined approach to detecting both tumour-specific somatic mutation (such as KRAS) and immune-cell-specific methylation (such as NDRG4)7 could enhance overall specificity of the assay and helped to discriminate between benign neoplasm and true malignancy, and monitor MRD.8 A major problem of all state-of-the-art MRD detection assay is sensitivity, that is, recurrence in the ctDNA-negative population. Here we found that cfDNA methylation-derived TF is linearly correlated with somatic mutation-derived TF. Furthermore, ctDNA positivity derived by methylation outperformed somatic mutation in terms of predicting recurrence in our period of observation. Superior performance of ctDNA by methylation could be due to two reasons: First, ctDNA detection by methylation is only cell-type specific and independent from the individualized mutation profile of each tumour, helping to normalize tumour-specific signal and to ‘rescue’ the detective power for tumours without canonical hotspot or targetable mutations. For example, certain tumour with a novel fusion driver or a DNAm driver (GIST with SDHC germline mutation) could be somatic mutation-free.9 Second, cfDNA methylation carried non-tumour-derived, tumour-associated signals such as remote immune cell activation to enhance detection sensitivity.10 The power of our conclusion is limited by a small number of patients with relatively short follow-up in this interim analysis. Additionally, such short follow-up has made the post-surgery cohort does not fully resemble pre-surgery cohort, which might impact the translation of prediction accuracy of DNAm for tumour load in cfDNA from the pre-surgery data towards post-surgery data. Long-term follow-up results from the full cohort would be reported in the future, and we expect that these limitations could be fully answered. As the study is carried out during the COVID-19 pandemic, blood collection times of the patients were not strictly restricted. However we did not notice any correlation between blood sampling time and tumour positivity detection by either somatic mutation or DNAm in our data. Furthermore, as we directly compared paired somatic mutation and DNAm sequencing results from the same blood draw, we did not consider the sampling time affects the power of this study. In conclusion, we found that DNAm on colorectal-cancer-specific DMR based on blood cfDNA sequencing enables an accurate detection of potential relapse of CRC. In the future, it is possible that cfDNAm test of pre-surgery blood could help one to distinguish between benign disease and truly malignant CRC, to reduce the unnecessary colonoscopy and even unnecessary surgery. Furthermore, post-surgery blood DNAm signature detects residual disease with high sensitivity to help in suggesting surveillance protocol and indicating time interval of follow-up or even guiding therapeutic interventions. The excellent technical assistance of Shanshan Zhang, Hongwei Peng, Wan Xiang, Ziyu Jiang, Wen Chen and Zongning Zhou at Hubei Biobank is gratefully acknowledged. Part of the analysis was performed on the High Performance Computing Platform of the Center for Life Science (Peking University). This study is partially supported by grants from the Improvement Project for Theranostic Ability on Difficulty Miscellaneous Disease (Tumour) from National Health Commission of China (ZLYNXM202006 and ZLYNXM202012), Medical Science Advancement Program (Clinical Medicine) of Wuhan University (TFLC2018002), Research Fund of Zhongnan Hospital of Wuhan University (SWYBK00-03, KY0100000109), Department of Science and Technology of Hubei Province (2018ZYYD023, 2022EJD001 and YYXKNL2022001) and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-PT320-004). The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that they have no conflict of interests. All the authors consent for publication. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Hepatitis B surface antigen (HBsAg) persists after liver transplantation in almost all patients receiving HBsAg-positive grafts. Chronic hepatitis B virus (HBV) infection is one of the main causes of hepatocellular carcinoma (HCC). We aimed to investigate possible interactions between HBsAg-positive donors, HCC, HBV-related transplant indication, and long-term outcomes. This retrospective study enrolled 1176 patients from two centers between January 2015 and May 2019, of which 135 (11.5%) were HBsAg-positive and 1041 (88.5%) were HBsAg-negative donors. Cox regression models were fitted to study the association between variables and patient and graft survival. In univariate and multivariate analyses, the donor HBsAg status was not significantly associated with patient and graft survival in the entire cohort, but there was a significant interaction between HBsAg-positive donors and HCC, independent of HBV-related transplant indication. The cumulative incidence of patient and graft survival was significantly lower in the subgroup of HCC recipients receiving HBsAg-positive grafts, but no significant difference was found in recipients with benign liver disease. In a subgroup analysis of HCC recipients, HBsAg-positive donors were significantly associated with an increased risk of HCC recurrence (hazard ratio: 1.73; 95% confidence interval: 1.20-2.48; p = 0.003) and similar results were obtained after propensity score matching analysis. We showed excellent outcomes of using HBsAg-positive grafts in patients with benign liver disease, regardless of HBV-related transplant indications. However, positive grafts should be used with caution in recipients with HCC, which are associated with an increased risk of HCC recurrence.

Growing evidences have revealed that exosomal miRNAs, lncRNAs, and circRNAs play a pleiotropic role in tumor biology. Cell-cell communication mediated by exosomes has been considered to be a key factor in the malignant progression of colorectal cancer. However, the importance of exosome-derived circRNAs in the biological function and clinical significance of colorectal adenoma remains elusive. In this study, we aimed to identify altered circRNA expression profiles in exosomes isolated from plasma of patients with colorectal adenoma using high-throughput sequencing. Exosomes were confirmed by western blotting, transmission electron microscopy, and NanoSight assay. The sequencing data indicated that there are 413 differentially expressed circRNAs including 112 upregulated and 301 downregulated circRNAs in colorectal adenoma patients compared with controls. GO analysis and the circRNA-miRNA-mRNA network were performed to predict the potential function of circRNAs, and demonstrate the putative mechanisms in colorectal adenoma. Collectively, our findings revealed that plasma exosomal circRNAs may be a potential noninvasive biomarker for the detection of colorectal adenoma, and provided new insights into colorectal adenoma-carcinoma sequence.

The relationship between aseptic systemic inflammation and postoperative bacterial infection is unclear. We investigated the correlation of systemic inflammation biomarkers with 30-day clinically significant bacterial infections (CSI) after liver transplantation (LT). This retrospective study enrolled 940 patients who received LT and were followed for 30 days. The primary end point was 30-day CSI events. The cohort was divided into exploratory (n = 508) and validation (n = 432) sets according to different centers. Area under the receiver operated characteristic (AUROC) and Cox regression models were fitted to study the association between baseline systemic inflammation levels and CSI after LT. A total of 255 bacterial infectious events in 209 recipients occurred. Among systemic inflammation parameters, baseline C-reactive protein (CRP) was independently associated with 30-day CSI in the exploratory group. The combination of CRP and organ failure number showed a good discrimination for 30-day CSI (AUROC = 0.80, 95% CI, 0.76–0.84) and the results were confirmed in an external verification group. Additionally, CRP levels were correlated with bacterial product lipopolysaccharide. In conclusion, our study suggests that pre-transplantation CRP is independent of other prognostic factors for 30-day CSI post-LT, and can be integrated into tools for assessing the risk of bacterial infection post-LT or as a component of prognostic models.

Background Colorectal cancer is a heterogeneous disease with complicated genetic alterations. Right colon and left colon have different features while right colon cancer displays an even worse prognosis. The randomized phase III FOxTROT trial demonstrated better downstaging effect with neoadjuvant plus adjuvant chemotherapy compared with adjuvant chemotherapy alone (P=0.04).1 Moreover, 2-year relapse rate was improved with neoadjuvant therapy, though the difference was not statistically significant. The NICHE study of neoadjuvant immunotherapy (maximum 6 weeks) showed that the pathological response was observed in 20/20 mismatch repair-deficient (dMMR) resectable colon cancers, with 19 major pathological responses and 12 pathological complete responses (pCRs).2 Recently, KEYNOTE-177 study showed improved progression-free survival with PD-1 inhibitor over chemotherapy (16.5 months vs. 8.2 months) in untreated microsatellite instability-high (MSI-H)/dMMR colon cancer patients, including 68% of right colon cancers.3 In addition, camrelizumab (PD-1 inhibitor) plus apatinib (vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor) demonstrated favorable antitumor effects and a manageable safety profile in advanced hepatocellular carcinoma and gastric cancer.4 5 This phase II trial aims to explore whether the combination of camrelizumab, apatinib and chemotherapy (mFOLFOX6) could significantly improve the pathological regression rate in locally advanced right colon cancer so as to bring considerable survival benefit for patients. Methods Eligible patients are aged 18–75 years, with locally advanced (T4 or T3 with extramural depth ≥5 mm, N0-2, M0, AJCC 8th) adenocarcinoma of right colon (including ileocecal area, ascending colon, and transverse colon to splenic flexion), and without prior systemic chemotherapy or immunotherapy. All patients will receive 5 cycles of camrelizumab (200 mg once every 2 weeks) plus mFOLFOX6 and 2 months of apatinib (250 mg orally once a day), followed by surgery and 7 cycles of adjuvant camrelizumab plus mFOLFOX6. The primary endpoint is the proportion of patients with tumor regression grade (TRG) 2–4 according to the Dworak criteria (TRG2: dominantly fibrotic changes with few tumor cells or groups; TRG3: very few tumor cells in fibrotic tissue; TRG4: no tumor cells). Secondary endpoints include downstaging rate, pCR rate, R0 resection rate, 2-year disease-free survival rate, 2-year event-free survival, overall survival, quality of life, and safety. Results To date, three of planned 64 patients have been enrolled. Two patients have completed surgery. According to Dworak criteria, TRG ranked 4 (pathologic complete response) for the first patient and 3 (very few tumor cells in fibrotic tissue) for the second patient. No severe adverse events have been observed for all patients. Trial Registration This trial has been registered at ClinicalTrials.gov (NCT04625803). References G. Foxtrot Collaborative. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol 13(11) (2012):1152–60. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, Lopez-Yurda M, Grootscholten C, Beets GL, Snaebjornsson P, Maas M, Mertz M, Veninga V, Bounova G, Broeks A, Beets-Tan RG, de Wijkerslooth TR, van Lent AU, Marsman HA, Nuijten E, Kok NF, Kuiper M, Verbeek WH, Kok M, Van Leerdam ME, Schumacher TN, Voest EE, Haanen JB. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 26(4) (2020):566–576. André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz Jr LA. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383(23) (2020):2207–2218. Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, Shao G, Zhang Y, Xu L, Yin T, Liu J, Ren Z, Xiong J, Mao X, Zhang L, Yang J, Li L, Chen X, Wang Z, Gu K, Chen X, Pan Z, Ma K, Zhou X, Yu Z, Li E, Yin G, Zhang X, Wang S, Wang Q. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res 27(4) (2021):1003–1011. Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, Shao G, Zhang Y, Xu L, Yin T, Liu J, Ren Z, Xiong J, Mao X, Zhang L, Yang J, Li L, Chen X, Wang Z, Gu K, Chen X, Pan Z, Ma K, Zhou X, Yu Z, Li E, Yin G, Zhang X, Wang S, Wang Q, Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, Zhang G, Zhao C, Zhang Y, Chen C, Wang Y, Yi X, Hu Z, Zou J, Wang Q. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res 27(4) (2021):1003–1011. Ethics Approval Study protocol was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (2020–119) Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Background: Gastrointestinal stromal tumor (GIST) is a common tumor that originates from mesenchyme in the alimentary system. Compared to the typical gastrointestinal carcinomas, GISTs exhibit unique malignant behaviors. Bioinformatic tools and subsequent experiments were applied to investigate novel targets involved in GIST progression and imatinib resistance. Methods: Differences of gene expression profiles between advanced and non-advanced GISTs were comprehensively analyzed based on Gene Expression Omnibus (GEO) dataset GSE136755. A protein-protein interaction (PPI) network was conducted to identify the potential target gene. Gene set enrichment analysis (GSEA) was used to elucidate relevant biological events of the target gene based on dataset GSE47911. Subsequently, immunohistochemistry and Kaplan-Meier analysis were performed to validate the prognostic value of the target gene in GISTs. Overexpression of the target gene was conducted to analyze its functions in proliferation, apoptosis, migration, and imatinib resistance of GIST/T1 cells. Results: In current study, a total of 606 differentailly expressed genes (DEGs) were screened based on dataset GSE136755 and the upregulated DEGs in advanced GISTs were mainly involved in cell division through functional annotations. The intersected hub gene, Aurora Kinase A (AURKA), was identified by degree and bottleneck algorithms. GSEA revealed that AURKA was involved in cell cycle-related biological processes. Oncomine and GEPIA databases supported an elevated expression pattern of AURKA in most human malignances. Clinical assay demonstrated that AURKA could be an independent prognostic factor for GISTs. Additionally, overexpression of AURKA was experimentally demonstrated to promote cell proliferation and survival, and enhance imatinib resistance of GIST/T1 cells. Conclusions: These findings indicated that overexpression of AURKA promoted GIST progression and enhanced imatinib resistance, implying the potential of AURKA as a therapeutic target for GISTs.

Background: Colorectal cancer (CRC) is one of the most common malignances worldwide. Several studies suggest a positive association between high plasma cholesterol level and CRC. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase in various organs and is involved in many processes. However, the critical role of 25-HC in the tumor growth and progression of CRC is largely unknown. Methods: CCK-8 assay, flow cytometry and Transwell migration and invasion assays were used to determine the effects of 25-HC on CRC cells proliferation, apoptosis and metastasis. Subcutaneous xenograft model and intra-splenic injection mouse model were established to investigate the effects of 25-HC on CRC in vivo . Immunohistochemistry staining was performed to determine the matrix metalloproteinases (MMPs) expressions in mice tumors and acetyl-CoA acyltransferase 1 (ACAA1) expression in human CRC tissues. The expressions of E-cadherin, N-cadherin and Vimentin were examined by immunofluorescent staining. MiR-92a-3p mimic, inhibitor and ACAA1 vector were constructed and transfected into LoVo cells. Results: 25-HC promotes CRC cells migration, invasion, and metastasis both in vitro and in vivo without affecting cells proliferation and apoptosis, accompanied by the upregulation of the expressions of MMPs and epithelial-mesenchymal transition (EMT) related markers. Mechanistically, miR-92a-3p expression is significantly elevated after 25-HC stimulation, while ACAA1 expression is down-regulated and negatively associated with tumor progression. Luciferase reporter assay confirms that miR-92a-3p could directly target ACAA1. Subsequent investigation indicates that nuclear factor (NF)-κB signaling is the downstream pathways of miR-92a-3p-ACAA1 axis in CRC cells. Conclusions: 25-HC promotes CRC cells metastasis by regulating cells migration, invasion and EMT through miR-92a-3p/ACAA1/NF-κB pathway. Trial registration: The current study was approved by the Ethics Committee of the First Affiliated Hospital, Zhejiang University on March22, 2018. The permission number was 2018-706 and 2020-1000.

BACKGROUND:Growing evidence suggests that irritable bowel syndrome (IBS) and Parkinson's disease (PD) share similar pathological mechanisms and risk factors.METHODS:We performed a systematic review and meta-analysis of the evidence for a relationship between IBS and PD. Risk estimates from individual studies were pooled using random-effects models.RESULTS:Six articles involving 58,645 patients with PD were included in our meta-analysis. The overall risk for PD in IBS patients was significantly higher than that in the general population (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.29-1.75; p < .001). Subgroup analysis revealed no significant differences in risk between men (OR = 1.47, 95% CI: 1.3-1.67; p < .001) and women (OR = 1.51, 95% CI: 1.29-1.75; p < .001); however, older (≥65 years) IBS patients (OR = 1.44, 95% CI: 1.3-1.59; p < .001) may be at higher risk for PD than younger (40-64 years) patients (OR = 1.32, 95% CI: 1.05-1.64; p = .017).CONCLUSION:Overall, the PD risk was higher in IBS patients than others, indicating that the intestinal disorder may serve as a warning sign for PD.

Circular RNAs (circRNAs) are a group of non-coding RNAs implicated in the pathogenesis of cancer progression, which exert their functions via regulation of microRNAs (miRNAs) and genes. The present study uses gain- and loss-of-function approaches to evaluate the functions of hsa_circRNA_002178 in angiogenesis along with energy metabolism and underlying downstream signals. The expression pattern of hsa_circRNA_002178 in clinical breast cancer tissues and its association with prognosis were characterized at first. Next, the energy metabolism and angiogenesis as well as cell viability were evaluated when the expression of hsa_circRNA_002178 in breast cancer cells was knocked down by siRNA. The interaction between hsa_circRNA_002178 and its downstream miR-328-3p was identified, followed by the analysis of their functions in regulation of breast cancer cellular behaviours. The target gene of miR-328-3p was predicted and verified, followed by identifying its role in the breast cancer progression. Higher expression of hsa_circRNA_002178 shared an association with worse prognosis in breast cancer. The inhibition of hsa_circRNA_002178 resulted in reductions in cell viability, energy metabolism and tube formation ability. Hsa_circRNA_002178 could competitively bind to miR-328-3p and down-regulated its expression. Restoration of miR-328-3p eliminated the tumour-promoting effects of hsa_circRNA_002178. COL1A1, as a target of miR-328-3p, could be up-regulated by overexpression of hsa_circRNA_002178. In vivo experiments further confirmed the inhibition of tumour growth and inflammation by silencing hsa_circRNA_002178 or up-regulating miR-328-3p. Taken together, hsa_circRNA_002178 is highlighted as a promising target for breast cancer due to the anti-tumour effects achieved by silencing hsa_circRNA_002178.

Background This study sought to detect the expression and clinical significance of miR-4516 and miR-21-5p in serum of patients with colorectal cancer. Methods Bioinformatics methods were used to analyze the expression patterns of miR-4516 and miR-21-5p in colorectal cancer. A total of 80 patients with colorectal cancer, 65 patients with benign colorectal tumors and 50 healthy persons were selected. qRT-PCR was performed to detect the expression levels of serum miR-4516 and miR-21-5p before and after operation or postoperative recurrence. The correlation of miR-4516 and miR-21-5p expression levels with the clinical characteristics and prognosis of colorectal cancer was analyzed, and that with the patient’s survival was further examined by Kaplan-Meier analysis. Results MiR-4516 was poorly expressed in colorectal cancer in the preoperative group, and miR-21-5p was highly expressed. While in the postoperative group, miR-4516 was up-regulated, and miR-21-5p was down-regulated. The low expression of miR-4516 was shown to be related to TNM staging, invasion degree, lymph node metastasis and distant metastasis of the patients. Whereas the high expression of miR-21-5p was proved to be correlated with TNM staging and lymph node metastasis. Kaplan-Meier survival analysis showed that high expression of miR-4516 or low expression of miR-21-5p could contribute to better overall survival. Conclusion Low miR-4516 or high miR-21-5p could be used as an independent risk factor for prognosis of colorectal cancer.

OBJECTIVES:Osteopontin (OPN) is reported to be particularly associated with the progression of several human malignancies. This study was designed to examine the clinicopathologic significance of OPN in gastrointestinal stromal tumor (GISTs).METHODS:The level of OPN expression in a large cohort of resectable GISTs was evaluated with immunohistochemistry. Its correlation with the clinicopathologic parameters of patients with resectable GISTs was analyzed. A survival analysis was performed to evaluate the prognostic significance of OPN expression using the Kaplan-Meier method.RESULTS:In 108 patients with resectable GISTs, the most high-risk GISTs had a strong level of OPN expression. Strong OPN expression was also significantly associated with tumor size, mitosis, and recurrence, but not gender and age. Patients with weak OPN expression had a relatively longer disease-free survival compared to patients with strong OPN expression.CONCLUSIONS:OPN expression is a putative marker for tumor progression and an adverse prognosis in GISTs.

Tumor associated macrophages (TAMs) in tumor microenvironment can interact with tumor cells and are related to tumor progression. However, the mechanisms that drive the anti-tumor functions of TAMs are not fully understood. The Src homology 2 domain-containing tyrosine phosphatase 2 (Shp2) has been reported to have tumor-suppressing roles in colorectal cancer (CRC). However, a role for Shp2 on TAMs in CRC has not been studied. Here we report that in CRC, Shp2 expression on TAMs is negatively associated with liver metastasis. TAMs require Shp2 for their anti-tumor functions in a cell-cell co-culture system and a mouse model of CRC. Mechanistically, absence of Shp2 on TAMs induces their polarization toward M2 phenotype through the activation of p-STAT3 and inhibition of p-NF-κB p65. The findings of our study imply that Shp2 is a key factor in the tumor microenvironment to facilitate the TAMs' tumor-suppressing functions in colorectal cancer.

Circular RNAs (circRNAs) have been reported that can be used as biomarkers for colorectal cancers (CRC) and other types of tumors. However, a limited number of studies have been performed investigating the potential role of circRNAs in tumor metastasis. Here, we examined the circRNAs in two CRC cell lines (a primary tumor cell SW480 and its metastasis cell SW620), and found a large set of circRNA (2,919 ncDECs) with significantly differential expression patterns relative to normal cells (NCM460). In addition, we uncovered a set of 623 pmDECs that differ between the primary CRC cells and its metastasis cells. Both differentially expressed circRNA (DEC) sets contain many previously unknown putative CRC-related circRNAs, thereby providing many new circRNAs as candidate biomarkers for CRC development and metastasis. These studies are the first large-scale identification of metastasis-related circRNAs for CRC and provide valuable candidate biomarkers for diagnostic and a starting point for additional investigations of CRC metastasis.

3Dprinting is defined as the use of printing technology to deposit living cells, and biomaterials on a given /a substrate. Graphene oxide nanoparticles (GO-np) have been used as a delivery vehicle for small molecule drugs in order to investigate the state of GO-np within 3D tissue constructs in terms of a composite 3D printing scaffold, which in turn is relevant to the protection of cartilage. We transplanted rats with hydrogel/GO-np and hydrogel, which in turn showed that hydrogel/GO-np protected the tissue of cartilage by the signal pathway of Rank/Rankl/OPG. Those findings indicated that GO-np may be potentially used to control the release of carrier materials and influence the signal pathway of Rank/Rankl/OPG.

It has previously been reported that cardamonin is able to regulate glycometabolism and vasodilation whilst also exhibiting anti-inflammatory and antitumor properties. The antitumor effect of cardamonin is multifaceted, and so it is necessary to investigate the antitumor mechanisms of cardamonin at the molecular level. Cardamonin alters chemotherapy-resistant colon cancer cell growth; however, the underlying mechanism is unknown. The present study was conducted to investigate the effect of cardamonin on chemotherapy-resistant colon cancer cells and the possible mechanisms of action. Cardamonin significantly suppressed the growth of chemotherapy-resistant colon cancer cells, induced apoptosis and promoted caspase-3/9 activity and Bax protein expression in 5-fluorouracil (5-FU)-resistant HCT-116 cells. Cardamonin significantly suppressed c-MYC, octamer-binding transcription factor 4, cyclin E, testes-specific protease 50 and nuclear factor-κB protein expression in 5-FU-resistant HCT-116 cells. The findings of the present study demonstrate that cardamonin suppresses chemotherapy-colon cancer cell via the NF-κB pathway in vitro.

Background: Experimental researches shows that adiponectin may have some regulatory roles in the mechanism of colorectal cancer, but epidemiological studies on the association between circulating adiponectin level and colorectal cancer reported inconsistent findings. A dose-response meta-analysis was thus performed to assess the evidence on the association between adiponectin and colorectal cancer. Methods: A systematic search of Pubmed and Embase was performed up to December 20, 2016. Relative risks (RR) and 95% confidence intervals (95% CI) were pooled to assess the risk of colorectal cancer associated with higher adiponectin level. In the dose-response meta-analysis, a two-stage generalized least-square trend method was used to calculate RR of colorectal cancer per 5 mu g/mL increase in circulating adiponectin level. Results: Eight prospective studies were identified. All those 8 studies were nested case-control studies, and they included a total of 4,076 colorectal cancer cases and 5,509 matched non-cancer controls. When compared with lower adiponectin level, higher adiponectin level was significantly associated with lower level of colorectal cancer (RR = 0.81, 95% CI 0.71-0.93; P = 0.002). Besides, dose-response meta-analysis suggested that the pooled RR of colorectal cancer per 5 mu g/mL increase in circulating adiponectin level was 0.86 (95% CI 0.77-0.95; P = 0.005). The pooled outcomes were not obviously influenced by the between-study heterogeneity. Conclusion: There is an obvious dose-response association between circulating adiponectin level and colorectal cancer risk, suggesting that adiponectin is an important protective mediator in the development of colorectal cancer.

3Dprinting is defined as the use of printing technology to deposit living cells, and biomaterials on a given /a substrate. Graphene oxide nanoparticles (GO-np) have been used as a delivery vehicle for small molecule drugs in order to investigate the state of GO-np within 3D tissue constructs in terms of a composite 3D printing scaffold, which in turn is relevant to the protection of cartilage. We transplanted rats with hydrogel/GO-np and hydrogel, which in turn showed that hydrogel/GO-np protected the tissue of cartilage by the signal pathway of Rank/Rankl/OPG. Those findings indicated that GO-np may be potentially used to control the release of carrier materials and influence the signal pathway of Rank/Rankl/OPG.

OBJECTIVE:To observe the effects of icariin on S-nitrosogultathione(GSNO) induced endothelial cell apoptosis, and to explore the relative mechanisms.METHODS:EA.hy926 cell line was provided by Zhejiang University and cells were divided into blank control group, GSNO group (1 mmol/L GSNO), icariin (ICA) intervention group (GSNO+ different concentrations (high, medium and low: 10, 1 and 0.1 μmol/L ICA) and 1 μmol/L LY294002 pretreatment groups (AKT protease pathway inhibitor on top of ICA groups) by cluster random sample method. After 48 hours. EA.hy 926 cell survival was detected by thiazolyl blue tetrazolium bromicle (MTT) method. Lactate dehydrogenase (LDH) activity, malonaldehyde (MDA) content, reactive oxygen species (ROS) level, mitochondrial membrane potential were also measured. The protein expression of protein kinase B(AKT)/phosphorylation protein kinase B(p-AKT), people tumor-suppressor protein (protein 53, P53), cytochrome C (CYC), endothelial nitric oxide synthetase (eNOS)/phosphorylation endothelial nitric oxide synthetase (p-eNOS), procaspase-3/caspase-3 was detected by Western blot.RESULTS:(1) The cell survival rate was significantly lower in GSNO group than in the blank control group (P< 0.01), which was significantly higher in the high, medium and low concentration ICA groups than in the GSNO group (all P< 0.01). (2) The LDH activity was significantly higher in the GSNO group than in the blank control group ((142.65±5.56) U/L vs. (50.01±3.42) U/L, P< 0.05), which was significantly reduced by high, medium and low concentration ICA ((98.02±3.52), (105.29±6.89) and (117.16±4.27) U/L vs. (142.65±5.56) U/L, all P< 0.05) in a dose-dependent manner. (3) The MDA content was significantly higher in GSNO group than in the blank control group ((11.14±0.37) nmol/mg vs. (5.21±0.18) nmol/mg, P< 0.05), which could be reduced by pretreatment with high, medium and low concentration ICA ((6.60±0.41), (6.83±0.21) and (8.29±0.07) nmol/mg vs. (11.14 ±0.37) nmol/mg, all P< 0.05). (4) The ROS content was significantly higher in GSNO group than in the blank control group ((173.15±11.12)% (relative ratio to the blank control group), P< 0.05), which could be significantly reduced by pretreatment with high, medium and low concentration ICA ((122.56±8.09)%, (134.52±9.09)%, and(149.89±9.16)% (the ratio of the above are compared with the blank control group), P< 0.05). (5) The mitochondrial membrane potential was significantly higher in the GSNO group (0.84 ± 0.04) than in the blank control group (0.12 ±0.12), which could be significantly reduced by pretreatment with high, medium and low concentration ICA ((0.57±0.08), (0.63±0.02), (0.66±0.04) vs. (0.84±0.04), all P<0.05). (6) The expression of AKT/p-AKT was significantly lower in GSNO group than in the blank control group (P< 0.05), which could be significantly upregulated by pretreatment with high, medium and low concentration ICA in a concentration-dependent manner, above effects could be blocked by LY294002 (all P<0.05). (7) The expression of P53 was significantly higher in GSNO group than in the blank control group (P< 0.05), which could be significantly down regulated by pretreatment with high, medium and low concentration ICA in a concentration-dependent manner, above effects could be blocked by LY294002(all P<0.05). (8) The expression of CYC and caspase-3 was significantly reduced in the mitochondria and increased in cytoplasm post GSNO treatment compared to blank control group, which could be reversed by pretreatment with high, medium and low concentration ICA(all P<0.05). (9) The expression of eNOS/p-eNOS was similar between GSNO and the blank control group, while it was significantly upregulated by pretreatment with high, medium and low concentration ICA and this effect could be blocked by LY294002(all P<0.05).CONCLUSION:Icariin could reduce GSNO induced endothelial cell apoptosis through activating AKT pathway and downregulating P53 activity.