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Zejun Wang,1,* Shichao Zhang,2,* Chaochao Zheng,3 Kaide Xia,4 Liangquan Sun,4 Xuejie Tang,4 Fulin Zhou,4 Yan Ouyang,2 Fuzhou Tang3 1Department of Gastrointestinal Surgery, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 2Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou Province/School of Biology and Engineering, Guizhou Medical University, Guiyang, People’s Republic of China; 3Immune Cells and Antibody Engineering Research Center of Guizhou province/School of Biology and Engineering, Guizhou Medical University, Guiyang, People’s Republic of China; 4Guiyang Maternal and Child Health Care Hospital, Guiyang Children’s Hospital, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fuzhou Tang, Immune Cells and Antibody Engineering Research Center of Guizhou province/School of Biology and Engineering, Guizhou Medical University, Guiyang, People’s Republic of China, Tel +86 085188174043, Email tangfuzhou@163.com Yan Ouyang, Key Laboratory of Infectious Immune and Antibody Engineering in Guizhou province/School of Biology and Engineering, Guizhou Medical University, Guiyang, People’s Republic of China, Email ouyangyan@gmc.edu.cnBackground: Tumor immune cell infiltration is closely associated with the occurrence and development of tumors. Collagen triple helix repeats containing 1 (CTHRC1), a regulator of collagen expression and cell migration, is involved in the metastasis and invasion of tumors. However, the role of CTHRC1 in breast cancer remains unclear. This study aimed to investigate the prognostic value of CTHRC1, and further explore its association with immune infiltration in breast cancer.Methods: CTHRC1 expression pattern and prognostic value were analyzed using ONCOMINE, PrognoScan, GEPIA, and Kaplan–Meier Plotter databases. We then detected CTHRC1 mRNA levels in breast cancer tissues and paired normal breast tissues by Q-PCR. Subsequently, the University of California Santa Cruz (UCSC) database was used to determine the methylation status of CTHRC1. Furthermore, CTHRC1 mutations were investigated using the Catalogue of Somatic mutations in Cancer (COSMIC) and cBioPortal databases. We also assessed the correlation between CTHRC1 expression and immune cell infiltration using TIMER. In addition, The relationship of CTHRC1 expression with the immune marker sets of various immune cells was evaluated using GEPIA and TIMER.Results: CTHRC1 was highly expressed in a variety of tumors, including breast cancer. Elevated CTHRC1 expression was related to a poor prognosis. Notably, CTHRC1 expression was significantly associated with macrophage infiltration, especially the immune infiltration gene marker set of M2. Copy number variations, DNA mutations and methylation states might be potential mechanisms for regulating CTHRC1 expression. Protein digestion and absorption, human papillomavirus infection, ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathways were identified as the potential CTHRC1-driven signaling pathways.Conclusion: These findings suggest that CTHRC1 could be a promising immune-related biomarker for the treatment of breast cancer patients.Keywords: CTHRC1, breast cancer, prognostic, macrophage, biomarker

Zhong-Wei Luo,1,2 Kun Xia,1,2 Yi-Wei Liu,1,2 Jiang-Hua Liu,1,2 Shan-Shan Rao,2,3 Xiong-Ke Hu,1,2 Chun-Yuan Chen,1,2 Ran Xu,4 Zhen-Xing Wang,1,2 Hui Xie1,2,5– 8 1Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Xiangya Nursing School, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 5Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 6Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan, People’s Republic of China; 7Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha, Hunan, People’s Republic of China; 8National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Hui XieDepartment of Orthopedics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of ChinaEmail huixie@csu.edu.cnRan XuDepartment of Urology, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People’s Republic of ChinaEmail xuran@csu.edu.cnPurpose: Prostate cancer (PCa) is one of the most common malignancies in males. Despite the success of immunotherapy in many malignant cancers, strategies are still needed to improve therapeutic efficacy in PCa. This study aimed to investigate the effects of Akkermansia muciniphila-derived extracellular vesicles (Akk-EVs) on PCa and elucidate the underlying immune-related mechanism.Methods: Akk-EVs were isolated by ultracentrifugation and intravenously injected to treat syngeneic PCa-bearing immune-competent mice. Immunophenotypic changes in immune cells, such as cytotoxic T lymphocytes and macrophages, were measured via flow cytometry analysis. Histological examination was used to detect morphological changes in major organs after Akk-EVs treatments. In vitro, flow cytometry was performed to confirm the effects of Akk-EVs on the activation of CD8+ T cells. Quantitative PCR and immunofluorescence staining were carried out to test the impact of Akk-EVs on macrophage polarization. Cell counting kit-8 (CCK-8) analysis, colony formation assays, and scratch wound healing assays were conducted to assess the effects of Akk-EVs-treated macrophages on the proliferation and invasion of PCa cells. CCK-8 assays also confirmed the impact of Akk-EVs on the viability of normal cells.Results: Intravenous injection of Akk-EVs in immune-competent mice reduced the tumor burden of PCa without inducing obvious toxicity in normal tissues. This treatment elevated the proportion of granzyme B-positive (GZMB+) and interferon γ-positive (IFN-γ+) lymphocytes in CD8+ T cells and caused macrophage recruitment, with increased tumor-killing M1 macrophages and decreased immunosuppressive M2 macrophages. In vitro, Akk-EVs increased the number of GZMB+CD8+ and IFN-γ+CD8+ T cells and M1-like macrophages. In addition, conditioned medium from Akk-EVs-treated macrophages suppressed the proliferation and invasion of prostate cells. Furthermore, the effective dose of Akk-EVs was well-tolerated in normal cells.Conclusion: Our study revealed the promising prospects of Akk-EVs as an efficient and biocompatible immunotherapeutic agent for PCa treatment.Keywords: Akkermansia muciniphila, extracellular vesicles, immunotherapy, prostate cancer, cytotoxic T lymphocytes, macrophages

Yu Liu,1 Le-Feng Wang,1 Li-Hong Liu,1 Xin-Chun Yang,1 Zheng-Hong Ren,2 Kui-Bao Li,1 Mu-Lei Chen,1 Hong-Shi Wang,1 Jiu-Chang Zhong,1 Li Xu,1 Zhu-Hua Ni,1 Wei-Ming Li,1 Kun Xia,1 Da-Peng Zhang,1 Hao Sun,1 Zong-Sheng Guo,1 Yong-Hui Chi,1 Ji-Fang He,1 Zhi-Yong Zhang,1 Feng Jiang1 1Heart Center & Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2School of Public Health, Peking University Health Science Center, Beijing, People’s Republic of ChinaCorrespondence: Le-Feng WangHeart Center & Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, No. 8 of Gongtinan Road, Chaoyang District, Beijing, People’s Republic of ChinaTel/Fax +86 10 85231173Email wanglefeng_dr66@163.comObjective: Patients presenting with acute myocardial infarction (AMI) with prior digestive system disease are more likely to suffer from gastrointestinal (GI) bleeding than those without these diseases. However, few articles reported how the different conditions of the digestive tract produced different risks of GI bleeding.Methods: A single-center study on 7464 patients admitted for AMI from December 2010 to June 2019 in the Beijing Chaoyang Heart Center was retrospectively examined. Patients with major GI bleeding (n = 165) were compared with patients without (n = 7299). Univariate and multivariate logistic regression models were constructed to test the association between GI bleeding and prior diseases of the digestive tract, including gastroesophageal reflux disease, chronic gastritis, peptic ulcer, hepatic function damage, diseases of the colon and rectum, and gastroenterological tract tumors.Results: Of the 7464 patients (mean age, 63.4; women, 25.6%; STEMI, 58.6%), 165 (2.2%) experienced major GI bleeding, and 1816 (24.3%) had a history of digestive system disease. The risk of GI bleeding was significantly associated with peptic ulcer (OR = 4.19, 95% CI: 1.86– 9.45) and gastroenterological tumor (OR = 2.74, 95% CI: 1.07– 7.04), indicated by multivariate logistic regression analysis.Conclusion: Preexisting peptic ulcers and gastroenterological tract tumors rather than other digestive system diseases were indicators of gastrointestinal bleeding in patients with AMI who undergo standard antithrombotic treatment during hospitalization.Keywords: gastrointestinal bleeding, digestive system disease, acute myocardial infarction, peptic ulcer, gastroenterological tract tumor

Kun Xia,1,2,* Zhuo Chen,3,4,* Jie Chen,1 Huaxing Xu,1 Yunfei Xu,1 Ting Yang,1 Qi Zhang1 1Department of Endodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, People’s Republic of China; 2Department of Preventive Dentistry, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, People’s Republic of China; 3Department of Endodontics, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou 310006, People’s Republic of China; 4Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou 310006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi ZhangDepartment of Endodontics, School and Hospital of Stomatology, Tongji University, Shanghai, Engineering Research Center of Tooth Restoration and Regeneration, Yanchang Road 399, Shanghai 200072, People’s Republic of ChinaTel +86-21-66311659Fax +86-21-66524025Email qizhang@tongji.edu.cnIntroduction: Cell-based tissue engineering is a promising method for dentin-pulp complex (DPC) regeneration. The challenges associated with DPC regeneration include the generation of a suitable microenvironment that facilitates the complete odontogenic differentiation of dental pulp stem cells (DPSCs) and the rapid induction of angiogenesis. Thus, the survival and subsequent differentiation of DPSCs are limited. Extracellular matrix (ECM)-like biomimetic hydrogels composed of self-assembling peptides (SAPs) were developed to provide an appropriate microenvironment for DPSCs. For functional DPC regeneration, the most important considerations are to provide an environment that promotes the adequate attachment of DPSCs and rapid vascularization of the regenerating pulp. Morphogenic signals in the form of growth factors (GFs) have been incorporated into SAPs to promote productive DPSC behaviors. However, the use of GFs has several drawbacks. We envision using a scaffold with SAPs coupled with long-term factors to increase DPSC attachment and vascularization as a method to address this challenge.Methods: In this study, we developed synthetic material for an SAP-based scaffold with RGD- and vascular endothelial growth factor (VEGF)-mimetic peptide epitopes with the dual functions of dentin and pulp regeneration. DPSCs and human umbilical vein endothelial cells (HUVECs) were used to evaluate the biological effects of SAP-based scaffolds. Furthermore, the pulpotomized molar rat model was employed to test the reparative and regenerative effects of SAP-based scaffolds.Results: This scaffold simultaneously presented RGD- and VEGF-mimetic peptide epitopes and provided a 3D microenvironment for DPSCs. DPSCs grown on this composite scaffold exhibited significantly improved survival and angiogenic and odontogenic differentiation in the multifunctionalized group in vitro. Histological and functional evaluations of a partially pulpotomized rat model revealed that the multifunctionalized scaffold was superior to other options with respect to stimulating pulp recovery and dentin regeneration in vivo.Conclusion: Based on our data obtained with the functionalized SAP scaffold, a 3D microenvironment that supports stem cell adhesion and angiogenesis was generated that has great potential for dental pulp tissue engineering and regeneration.Keywords: dentin-pulp complex regeneration, dental pulp stem cells, self-assembling peptides, cell adhesion, angiogenesis, multifunctionalization

Background Evidence suggests that mitochondrial abnormalities increase the risk of two neurodevelopmental disorders: undiagnosed developmental disorder (UDD) and autism spectrum disorder (ASD). However, which nuclear-encoded mitochondrial-related genes (NEMGs) were associated with UDD–ASD is unclear. Aim To explore the association between de novo variants (DNVs) of NEMGs and UDD–ASD. Design Comprehensive analysis based on DNVs of NEMGs identified in patients (31 058 UDD probands and 10 318 ASD probands) and 4262 controls. Methods By curating NEMGs and cataloging publicly published DNVs in NEMGs, we compared the frequency of DNVs in cases and controls. We also applied a TADA- denovo model to highlight disease-associated NEMGs and characterized them based on gene intolerance, functional networks and expression patterns. Results Compared with levels in 4262 controls, an excess of protein-truncating variants and deleterious missense variants in 1421 cataloged NEMGs from 41 376 patients (31 058 UDD and 10 318 ASD probands) was observed. Overall, 3.23% of de novo deleterious missense variants and 3.20% of de novo protein-truncating variants contributed to 1.1% and 0.39% of UDD–ASD cases, respectively. We prioritized 130 disease-associated NEMGs and showed distinct expression patterns in the developing human brain. Disease-associated NEMGs expression was enriched in both excitatory and inhibitory neuronal lineages from the developing human cortex. Conclusions Rare genetic alterations of disease-associated NEMGs may play a role in UDD–ASD development and lay the groundwork for a better understanding of the biology of UDD–ASD. [ABSTRACT FROM AUTHOR]

Shuaixi Yang,1,* Zhenqiang Sun,1,* Quanbo Zhou,1,* Weiwei Wang,2,3 Guixian Wang,1 Junmin Song,1 Zhen Li,1 Zhiyong Zhang,1 Yuan Chang,1 Kunkun Xia,1 Jinbo Liu,1 Weitang Yuan1 1Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, People’s Republic of China; 3Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan 450002, People’s Republic of China *These authors contributed equally to this work Abstract: Noncoding RNAs (ncRNAs) can be divided into microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), pRNAs, and tRNAs. Traditionally, miRNAs exert their biological function mainly through the inhibition of translation via the induction of target RNA transcript degradation. lncRNAs and circRNAs were once considered to have no potential to code proteins. Here, we will review the current knowledge on ncRNAs in relation to their origins, characteristics, and functions. We will also review how ncRNAs work as competitive endogenous RNA, gene transcription and expression regulators, and RNA-binding protein sponges in colorectal cancer (CRC). Notably, except for the abovementioned mechanisms, recent advances revealed that lncRNAs can also act as the precursor of miRNAs, and a small portion of lncRNAs and circRNAs was verified to have the potential to code proteins, providing new evidence for the significance of ncRNAs in CRC tumorigenesis and development. Keywords: biomarker, competitive endogenous RNA, tumorigenesis, epithelial-to-mesenchymal transition, invasion, metastasis, chemoresistance

Pengcheng Liu,* Junfeng Liu,* Liyang Chen, Kuo Xia, Xing Wu Department of Orthopedics, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China *These authors contributed equally to this work Objectives: To investigate the effectiveness of intermittent pneumatic compression (IPC) devices combined with anticoagulants for the prevention of deep vein thrombosis (DVT) after total knee arthroplasty (TKA). Patients and methods: In total 120 patients were involved in this pilot study. Patients in the control group received 10 mg of rivaroxaban per day after surgery. In addition to the prescription of rivaroxaban, IPC devices were used in the experimental group. The diagnosis of DVT was made by compression duplex ultrasound on postoperative day 9. Results: The incidence rates of overall, proximal, distal, and intermuscular DVT were 8.3%, 0%, 1.67%, and 6.67% in the experimental group; and 18.3%, 0%, 5%, and 13.33% in the control group, respectively. The incidence rates of total, distal, and intermuscular DVT in TKA patients was significantly lower in the experimental group than in the control group. For patients with DVT, enoxaparin was used instead of rivaroxaban, and DVT was found to have disappeared 10–14 days postoperatively. Conclusion: Compared with the use of rivaroxaban alone, IPC devices combined with anticoagulants can significantly reduce the incidence rate of distal DVT and intermuscular DVT in the early postoperative period after TKA. Keywords: total knee arthroplasty, deep vein thrombosis, DVT, rivaroxaban, intermittent pneumatic compression