Features of colorectal cancer in China stratified by anatomic sites: A hospital-based study conducted in university-affiliated hospitals from 2014 to 2018.

OBJECTIVE: The clinical and biological characteristics of colorectal cancer have been found to differ depending on the anatomic site of the cancer. However, for Chinese patients, there is limited information on the proportion of cases at each site and the related features. In this study, we explored the location, distribution and other features of colorectal cancers at each anatomic site in Chinese patients. METHODS: We conducted a hospital-based study using hospitalization summary reports from 10 Peking University-affiliated hospitals from 2014 to 2018; the reports covered a total of 2,097,347 hospitalizations. Incident cases were chosen as the study population, and their epidemiological features were further analyzed. RESULTS: A total of 20,739 colorectal cancer patients were identified. Rectum was the most common location (48.3%) of the cancer, whereas the proportions of patients with distal and proximal colon cancer were 24.5% and 18.6%, respectively. Patients with rectal cancer were predominantly male and were the youngest for all anatomical sites (each P<0.001). The highest proportion of emergency admissions, the longest hospital stays and the highest hospitalization costs were found in patients with proximal colon cancer (each P<0.001). The proximal colon cancer subgroup included the highest proportions of patients with medical histories of cholecystectomy, cholecystolithiasis and/or gallbladder polyps and appendectomy (P=0.009, P<0.001 and P<0.001, respectively). The distal colon cancer subgroup included the highest proportions of patients with medical histories of diabetes and hypertension (P<0.001, respectively). CONCLUSIONS: The patterns of colorectal cancer observed in this study differ from those reported for Western patients and show a significantly higher proportion of patients with rectal cancer. Different epidemiological features were also found based on anatomic sites. Further studies based on tumor location should be conducted to facilitate more accurate screening and treatment.

Cortistatin protects against inflammatory airway diseases through curbing CCL2 and antagonizing NF-κB signaling pathway.

Asthma is a chronic inflammatory disease affecting millions of people around the world, yet much remains unknown about its underlying mechanisms. Cortistatin (CST) is a neuropeptide which is reported to be a potential endogenous anti-inflammatory factor in several conditions. To testify the potential involvement of CST in airway inflammatory reaction, an ovalbumin (OVA)-induced mice model was established in wild-type (WT) as well as CST-knockout (Cort-/-) mice. Thereafter, lung tissue or cell samples were gathered in each group, and histological analysis as well as cell counting assay indicated that Cort-/- mice exhibited exaggeration of asthma compared with WT control group. Moreover, mRNA sequencing assay revealed that CCL2 was a potential target of CST in asthma, and administration of CCL2 inhibitor alleviated airway inflammation of asthma in Cort-/- mice. Moreover, NF-κB signaling pathway might be closely associated with the protective function of CST in asthma, as enhanced activation of NF-κB signaling pathway was observed in OVA-induced asthma model of Cort-/- mice, and SN50, an inhibitor of NF-κB signaling pathway, antagonized asthma development in Cort-/- mice. In summary, CST might represent as a promising target for the treatment of asthma through interacting with CCL2 and NF-κB signaling pathway.

GDF11 antagonizes TNF-α-induced inflammation and protects against the development of inflammatory arthritis in mice.

Growth differentiation factor 11 (GDF11), a key member of the TGF-ß superfamily, plays critical roles in various medical conditions. Recently, GDF11 was found to suppress the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and protect against inflammation. This study aimed to investigate the role of GDF11 in the development of rheumatoid arthritis (RA). We demonstrated that GDF11 treatment antagonized TNF-α-induced inflammation in macrophages. Moreover, GDF11 inhibited the development of arthritis in the collagen-induced arthritis and collagen antibody-induced arthritis models. Local gene transfer of GDF11 via adeno-associated virus exerted therapeutic effects, while local knockdown of GDF11 exaggerated inflammation in our collagen-induced arthritis model, as detected by expression levels of inflammatory biomarkers and the destruction of joint structures. Additionally, the results from both in vitro experiments and luciferase reporter gene mouse experiments implied that the NF-κB pathway might play a critical role in the therapeutic effect of GDF11 in RA. This study presents GDF11 as a potential target for the treatment of inflammatory arthritis, including RA.-Li, W., Wang, W., Liu, L., Qu, R., Chen, X., Qiu, C., Li, J., Hayball, J., Liu, L., Chen, J., Wang, X., Pan, X., Zhao, Y. GDF11 antagonizes TNF-α-induced inflammation and protects against the development of inflammatory arthritis in mice.

Ghrelin protects against osteoarthritis through interplay with Akt and NF-κB signaling pathways.

Osteoarthritis (OA) is a common chronic degenerative disease characterized by degeneration in the joints and subsequent destruction of cartilage and bone, yet much remains to be elucidated regarding its molecular mechanism. Ghrelin is a recently discovered neuropeptide with anti-inflammatory actions, but it is unknown whether ghrelin is involved in OA. Human primary chondrocyte and cartilage samples were collected from patients with OA, and the expression pattern of ghrelin was assessed. Human chondrocyte and cartilage samples were stimulated with IL-1ß and TNF-α, and exogenous ghrelin-alleviated disorganization of catabolism and anabolism were mediated by IL-1ß and TNF-α. Destabilization of the medial meniscus and anterior cruciate ligament transection models were established in wild-type mice that were administered ghrelin or PBS. Severity of inflammation and degeneration in the joints were determined by measuring the levels of various inflammatory cytokines and degeneration-associated molecules. Ghrelin down-regulated the production of various inflammatory cytokines, inhibited apoptosis of chondrocytes, decreased the levels of metalloproteinases (including matrix metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motif-5), and maintained the expression of critical matrix components, such as aggrecan and collagen 2. Moreover, suppression of the Akt signaling pathway and activation of NF-κB signaling in chondrocytes during OA development was antagonized by ghrelin administration. This supports the assessment of ghrelin as a potential therapeutic approach to treat degenerative cartilage diseases, including OA.-Qu, R., Chen, X., Wang, W., Qiu, C., Ban, M., Guo, L., Vasilev, K., Chen, J., Li, W., Zhao, Y. Ghrelin protects against osteoarthritis through interplay with Akt and NF-κB signaling pathways.

LncRNA ZEB1-AS1/miR-409-3p/ZEB1 feedback loop is involved in the progression of non-small cell lung cancer.

Emerging evidence has illustrated that long noncoding RNA (LncRNA) ZEB1 antisense RNA 1 (ZEB1-AS1) involved in the development of various type of human cancers. However, the role of ZEB1-AS1 in non-small cell lung cancer (NSCLC) is still elusive and poorly understood. The present study aimed to provide functional evidence and elucidate the molecular mechanisms by which the ZEB1-AS1 promotes oncogenesis of NSCLC. Our study found that ZEB1-AS1 was upregulated in NSCLC cells and knockdown of ZEB1-AS1 significantly inhibited cell growth and induced cell apoptosis. Mechanically, miR-409-3p was confirmed as a direct target of ZEB1-AS1 and negatively regulated by ZEB1-AS1 via competing endogenous RNA (ceRNA) mechanism; miR-409-3p inhibited ZEB1 expression by directly binding to the 3'UTR. Importantly, as predicted by JASPAR and further confirmed by luciferase reporter gene and ChIP assays, we found ZEB1 could bind to the promoter region of ZEB1-AS1 to activate its expression. Restoration of ZEB1 could partially abolished the action of ZEB1-AS1 silencing on cell proliferation and apoptosis. Collectively, the results suggested that ZEB1-AS1/miR-409-3p/ZEB1 constitutes a positive feedback loop to promote the tumorigenesis of NSCLC, highlighting the possibility of improving NSCLC treatment by targeting the ZEB1-AS1 signaling pathway.

Role of the Gut Microbiota and Its Metabolites in Tumorigenesis or Development of Colorectal Cancer.

Colorectal cancer (CRC) is the most common cancer of the digestive system with high mortality and morbidity rates. Gut microbiota is found in the intestines, especially the colorectum, and has structured crosstalk interactions with the host that affect several physiological processes. The gut microbiota include CRC-promoting bacterial species, such as Fusobacterium nucleatum, Escherichia coli, and Bacteroides fragilis, and CRC-protecting bacterial species, such as Clostridium butyricum, Streptococcus thermophilus, and Lacticaseibacillus paracasei, which along with other microorganisms, such as viruses and fungi, play critical roles in the development of CRC. Different bacterial features are identified in patients with early-onset CRC, combined with different patterns between fecal and intratumoral microbiota. The gut microbiota may be beneficial in the diagnosis and treatment of CRC; some bacteria may serve as biomarkers while others as regulators of chemotherapy and immunotherapy. Furthermore, metabolites produced by the gut microbiota play essential roles in the crosstalk with CRC cells. Harmful metabolites include some primary bile acids and short-chain fatty acids, whereas others, including ursodeoxycholic acid and butyrate, are beneficial and impede tumor development and progression. This review focuses on the gut microbiota and its metabolites, and their potential roles in the development, diagnosis, and treatment of CRC.

Sigmoid take-off in rectosigmoid cancer as a landmark identifying benefit from neoadjuvant chemoradiation: A retrospective comparative cohort study.

INTRODUCTION: There is no standard treatment strategy for rectosigmoid cancer because of the diverse definitions of the proximal rectal origin. This study aimed to evaluate sigmoid take-off compared with other landmarks of the rectosigmoid junction in guiding oncological therapy and outcomes. MATERIALS AND METHODS: This retrospective, comparative cohort study included patients diagnosed with rectosigmoid carcinoma at our centre between January 2010 and December 2018. The patients were classified into the neoadjuvant treatment group and upfront surgery group. The oncological outcomes were compared between the two groups in relation to the tumor position. RESULTS: A total of 656 patients (median age 64 years) were included. After propensity score matching, the 3- and 5-year overall survival and disease-free survival in patients in both the groups were comparable. However, when only patients with rectal cancer as defined by the sigmoid take-off point were included, the disease-free survival rate in the upfront surgery group was significantly lower than that in the neoadjuvant treatment group (p = 0.03 in patients who underwent computed tomography, p = 0.03 in patients who underwent magnetic resonance imaging). The turning point of the beneficial hazard ratio of neoadjuvant therapy was compared according to the different definitions of the rectosigmoid junction and the sigmoid take-off was found to be the most effective. CONCLUSION: The sigmoid take-off point is a suitable landmark for identifying the rectosigmoid junction and is an important defining criterion for assessing the benefit of neoadjuvant therapy. The application of this definition in clinical practice and future trials is warranted.

Measuring distance from lowest boundary of rectal tumor to anal verge on CT images using pyramid attention pooling transformer.

Accurately measuring the Distance from the lowest boundary of rectal tumor To the Anal Verge (DTAV) is critical for developing optimal surgical plans for treating patients with rectal cancer. DTAV was traditionally estimated by colonoscopy or manual measurement on computed tomography (CT) images. However, colonoscopy brings substantial pains to the patient. As for manual measurement on CT images, it is time-consuming and its accuracy depends on the surgeon's expertise. In this work, we present a novel method for automatically measuring DTAV from sagittal CT images. The success of our method is mainly credited to a pyramid attention pooling (PAP) transformer architecture, which naturally entangles global lesion localization and local boundary delineation. Our method automatically generates the rectum's centerline based on a segmented rectum and tumor image to simulate the manual measurement of DTAV. We conduct a comprehensive evaluation of the method with a newly collected rectum tumor CT image dataset. On a test dataset of 48 patients' CT images with rectal tumors, the mean absolute difference between our method and the gold standard is 1.74 cm, which is a significant improvement of 1.29 cm over that measured by a resident surgeon (P < 0.001). In addition, The results measured by the resident surgeon referring to our segmentation results improved by 1.46 cm compared to the results measured independently by the residents. As experimentally demonstrated, our method exhibits great application potential in clinical scenarios.

A boundary-guided transformer for measuring distance from rectal tumor to anal verge on magnetic resonance images.

Accurate measurement of the distance from the tumor's lowest boundary to the anal verge (DTAV) provides an important reference value for treatment of rectal cancer, but the standard measurement method (colonoscopy) causes substantial pain. Therefore, we propose a method for automatically measuring the DTAV on sagittal magnetic resonance (MR) images. We designed a boundary-guided transformer that can accurately segment the rectum and tumor. From the segmentation results, we estimated the DTAV by automatically extracting the anterior rectal wall from the tumor's lowest point to the anal verge and then calculating its physical length. Experiments were conducted on a rectal tumor MR imaging (MRI) dataset to evaluate the efficacy of our method. The results showed that our method outperformed surgeons with 6 years of experience (p < 0.001). Furthermore, by referring to our segmentation results, attending and resident surgeons could improve their measurement precision and efficiency.

Prognostic effect of preoperative Controlling Nutritional Status score in patients with locally advanced rectal cancer: A two-center, retrospective study.

OBJECTIVES: This study aimed to identify the prognosis relevant to the Controlling Nutritional Status (CONUT) score in locally advanced rectal cancer patients who were treated with neoadjuvant chemoradiotherapy before radical surgery. METHODS: From a retrospective database of 568 patients undergoing radical surgery for rectal cancer at two Chinese institutions between 2012 and 2022, data for 300 patients with locally advanced rectal cancer were identified. The optimal cutoff value for the CONUT score in predicting overall survival (OS) was determined using X-tile software. The associations of the CONUT score with the recurrent metastasis and clinicopathologic parameters were analyzed. The CONUT score's ability to predict OS was also compared with other prognostic markers. Univariate and multivariate Cox regression analysis for OS was performed. Subgroup analysis was conducted to evaluate further the CONUT score's predicting value. RESULTS: The optimal CONUT score cutoff value was determined as 5 according to X-tile. Patients were divided into CONUT-high (CONUT score ≥ 5) and CONUT-low (CONUT score < 5) groups. CONUT score is significantly correlated with hemoglobin, globulin, and platelets. Time-dependent receiver operating characteristic of the CONUT score predicting OS outperformed all common prognostic markers. Multivariate Cox regression analysis identified CONUT score as an independent prognostic factor for OS (hazard ratio = 5.701; 95% CI, 2.336-13.914; P < 0.001). In the subgroups of age, sex, carcinoembryonic antigen, ypTNM, and tumor response status, significant statistical differences can be observed between CONUT-high and -low. CONCLUSIONS: The present study finds that the preoperative CONUT score may be a useful prognostic indicator in clinical scenarios.

Progress in the Study of Colorectal Cancer Caused by Altered Gut Microbiota After Cholecystectomy.

Epidemiological studies have found an increased incidence of colorectal cancer (CRC) in people who undergo cholecystectomy compared to healthy individuals. After cholecystectomy, bile enters the duodenum directly, unregulated by the timing of meals. Disruption of the balance of bile acid metabolism and increased production of primary bile acids, which in turn affects the composition and abundance of intestinal microorganisms. The link among cholecystectomy, the gut microbiota, and the occurrence and development of CRC is becoming clearer. However, due to the complexity of the microbial community, the mechanistic connections are less well understood. In this review, we summarize the changes of gut microbiota after cholecystectomy and illuminate the potential mechanisms on CRC, such as inflammation and immune regulation, production of genotoxins, metabolism of dietary ingredients, activation of signaling pathways, and so on. By reviewing these, we aimed to unravel the interactions between the gut microbiota and its host and be better positioned to develop treatments for CRC after cholecystectomy.

Promotion of Deoxycholic Acid Effect on Colonic Cancer Cell Lines In Vitro by Altering the Mucosal Microbiota.

Colorectal cancer (CRC) is the third most prevalent neoplasm and the second leading cause of cancer death worldwide. Microbiota and their products, such as bile acids (BAs), are important causal factors for the occurrence and development of CRC. Therefore, we performed 16S ribosomal RNA (16S rRNA) and liquid chromatography/mass spectrometry (LC-MS) to measure mucosal microbiota and BA composition in paired cancerous and noncancerous gut tissue samples from 33 patients with CRC at a hospital in Beijing. In cancerous tissues, we detected altered mucosal microbiota with increased levels of the genera Bacteroides, Curtobacterium, and Campylobacter and an increase in deoxycholic acid (DCA), which was the only BA elevated in cancerous tissues. Ex vivo coculture showed that the mucosal microbiota in cancerous tissues indeed had a stronger DCA production ability, indicating that DCA-producing bacteria are enriched in tumors. Results from the CCK8 and Transwell assays indicated that DCA enhances the overgrowth, migration, and invasion of CRC cell lines, and, through qPCR and Western blot analyses, downregulation of FXR was observed in CRC cell lines after DCA culture. We then verified the downregulation of FXR expression in cancerous tissues using our data and the TCGA database, and we found that FXR downregulation plays an important role in the development of CRC. In conclusion, differing mucosal microbiota, increased amounts of mucosal DCA, and lower FXR expression were demonstrated in cancerous tissues compared to normal tissue samples. The results of this study can be applied to the development of potential therapeutic targets for CRC prevention, such as altering mucosal microbiota, DCA, or FXR.

A novel prediction model for pathological complete response based on clinical and blood parameters in locally advanced rectal cancer.

Background: The aim of this study was to investigate whether clinical and blood parameters can be used for predicting pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). Methods: We retrospectively enrolled 226 patients with LARC [allocated in a 7:3 ratio to a training (n = 158) or validation (n = 68) cohort] who received nCRT before radical surgery. Backward stepwise logistic regression was performed to identify clinical and blood parameters associated with achieving pCR. Models based on clinical parameters (CP), blood parameters (BP), and clinical-blood parameters (CBP) were constructed for comparison with previously reported Tan's model. The performance of the four models was evaluated by receiver operating characteristic (ROC) curve analysis, calibration, and decision curve analysis (DCA) in both cohorts. A dynamic nomogram was constructed for the presentation of the best model. Results: The CP and BP models based on multivariate logistic regression analysis showed that interval, Grade, CEA and fibrinogen-albumin ratio index (FARI), sodium-to-globulin ratio (SGR) were the independent clinical and blood predictors for achieving pCR, respectively. The area under the ROC curve of the CBP model achieved a score of 0.818 and 0.752 in both cohorts, better than CP (0.762 and 0.589), BP (0.695 and 0.718), Tan (0.738 and 0.552). CBP also showed better calibration and DCA than other models in both cohorts. Moreover, CBP revealed significant improvement compared with other models in training cohort (P < 0.05), and CBP showed significant improvement compared with CP and Tan's model in validation cohort (P < 0.05). Conclusion: We demonstrated that CBP predicting model have potential in predicting pCR to nCRT in patient with LARC.

Features of gastric cancer by anatomic subsite in northern China: A multi-center Health Science Report database study.

BACKGROUND: The features of gastric cancer based on the anatomic site remain unknown in northern China patients. AIM: To analyze gastric cancer features and associated trends based on the anatomical site in northern China patients. METHODS: This cross-sectional study used incident gastric cancer case data from 10 Peking University-affiliated hospitals (2014 to 2018). The clinical and prevailing local features were analyzed. RESULTS: A total of 10709 patients were enrolled, including antral (42.97%), cardia (34.30%), and stomach body (18.41%) gastric cancer cases. Cancer in the cardia had the highest male:female ratio, proportion of elderly patients, and patients with complications, including hypertension, diabetes, cerebrovascular, and coronary diseases (P < 0.001). gastric cancer involving the antrum showed the lowest proportion of patients from rural areas and accounted for the highest hospitalization rate and cost (each P < 0.001). The proportion of patients with cancer involving the cardia increased with an increase in the number of gastroesophageal reflux disease cases during the same period (P < 0.001). Multivariate analysis revealed that tumor location in the cardia increased the risk of in-hospital mortality (P = 0.046). Anatomical subsite was not linked to postoperative complications. CONCLUSION: The features of gastric cancer based on the anatomical site differ between northern China and other regions, both globally and within the country. Social factors may account for these differences and should affect policy-making and clinical practice.

Correction to: Ghrelin Fights against Titanium Particle-Induced Inflammatory Osteolysis through Activation of ß-Catenin Signaling Pathway.

The original version of this article was published with incorrect Fig. 1B. The correct Fig. 1B is now presented in Fig. 1 shown at the next page.

Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation.

Background: Intervertebral disc (IVD) degeneration is a common degenerative disease that can lead to collapse or herniation of the nucleus pulposus (NP) and result in radiculopathy in patients. Methods: NP tissue and cells were isolated from patients and mice, and the expression profile of cortistatin (CST) was analysed. In addition, ageing of the NP was compared between 6-month-old WT and CST-knockout (CST-/-) mice. Furthermore, NP tissues and cells were cultured to validate the role of CST in TNF-α-induced IVD degeneration. Moreover, in vitro and in vivo experiments were performed to identify the potential role of CST in mitochondrial dysfunction, mitochondrial ROS generation and activation of the NLRP3 inflammasome during IVD degeneration. In addition, NF-κB signalling pathway activity was tested in NP tissues and cells from CST-/- mice. Results: The expression of CST in NP cells was diminished in the ageing- and TNF-α-induced IVD degeneration process. In addition, compared with WT mice, aged CST-/- mice displayed accelerated metabolic imbalance and enhanced apoptosis, and these mice showed a disorganized NP tissue structure. Moreover, TNF-α-mediated catabolism and apoptosis were alleviated by exogenous CST treatment. Furthermore, CST inhibited mitochondrial dysfunction in NP cells through IVD degeneration and suppressed activation of the NLRP3 inflammasome. In vitro and ex vivo experiments indicated that increased NF-κB pathway activity might have been associated with the IVD degeneration observed in CST-/- mice. Conclusion: This study suggests the role of CST in mitochondrial ROS and activation of the NLRP3 inflammasome in IVD degeneration, which might shed light on therapeutic targets for IVD degeneration.

Scutellarin suppresses cartilage destruction in osteoarthritis mouse model by inhibiting the NF-κB and PI3K/AKT signaling pathways.

Osteoarthritis (OA), a common and severe disease, is predominantly characterized by cartilage destruction, which results in the degeneration of joint surfaces. Nowadays, it is accepted that TNFα plays a critical role in OA. Scutellarin, the main bioactive flavonoid glycoside extracted form Erigeron breviscapus, has been reported to exert positive effects on anti-inflammatory reactions. However, the effect of scutellarin in OA is still unknown. In this study, we isolated and cultured primary murine chondrocytes, stimulating TNF-α, in the presence or absence of scutellarin treatment. We found that the inflammatory response stimulated by TNF-α was significantly inhibited by the addition of scutellarin. Moreover, we established OA mouse models induced by surgery. In this mouse model, both inflammatory reaction and cartilage degeneration were markedly inhibited by oral administration of scutellarin. Furthermore, the cellular mechanism underlying the protective effect of scutellarin in OA was clearly associated with the NF-κB and PI3K/AKT signaling pathways. Collectively, this study proposes scutellarin as a potential therapeutic to treat joint degenerative diseases, including OA.