Xia Kang

Bio: Xia Kang is an academic researcher from Third Military Medical University. The author has contributed to research in topics: Tendinopathy & Tendon. The author has an hindex of 10, co-authored 19 publications receiving 337 citations.

Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression

Abstract: Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages (TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor-dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy.

Aspirin inhibits inflammation and scar formation in the injury tendon healing through regulating JNK/STAT-3 signalling pathway.

Abstract: Objectively Tendinopathy is a common problem in sports medicine which can lead to severe morbidity. Aspirin, as the classical representative of non-steroidal anti-inflammatory drugs (NSAIDs) for its anti-inflammatory and analgesic actions, has been commonly used in treating tendinopathy. While its treatment effects on injury tendon healing are lacking, illuminating the underlying mechanism may provide scientific basis for clinical treatment. Materials and methods Firstly, we used immunohistochemistry and qRT-PCR to detect changes in CD14, CD206, iNOS, IL-6, IL-10, MMP-3, TIMP-3, Col-1a1, biglycan, Comp, Fibronectin, TGF-β1，ACAN，EGR-1 and FMOD. Next, Western blot was used to measure the protein levels (IL-6, IL-10, TGF-β1, COMP, TIMP-3, STAT-3/P-STAT-3 and JNK/P-JNK) in TSCs. Then, migration and proliferation of TSCs were measured through wound healing test and BrdU staining. Finally, the mechanical properties of injury tendon were detected. Results After aspirin treatment, the inflammation and scar formation in injury tendon were significantly inhibited by aspirin. Still, tendon's ECM was positively balanced. Increasing migration and proliferation ability of TSCs induced by IL-1β were significantly reversed. JNK/STAT-3 signalling pathway participated in the process above. In addition, biomechanical properties of injury tendon were significantly improved. Conclusions Taken together, the findings suggested that aspirin inhibited inflammation and scar formation via regulation of JNK/STAT-3 signalling and decreased rerupture risk of injury tendon. Aspirin could be an ideal therapeutic strategy in tendon injury healing.

Exosomes from tendon stem cells promote injury tendon healing through balancing synthesis and degradation of the tendon extracellular matrix.

Abstract: Tendon injuries are common musculoskeletal system disorders in clinical, but the regeneration ability of tendon is limited. Tendon stem cells (TSCs) have shown promising effect on tissue engineering and been used for the treatment of tendon injury. Exosomes that serve as genetic information carriers have been implicated in many diseases and physiological processes, but effect of exosomes from TSCs on tendon injury repair is unclear. The aim of this study is to make clear that the effect of exosomes from TSCs on tendon injury healing. Exosomes were harvested from conditioned culture media of TSCs by a sequential centrifugation process. Rat Achilles tendon tendinopathy model was established by collagenase-I injection. This was followed by intra-Achilles-tendon injection with TSCs or exosomes. Tendon healing and matrix degradation were evaluated by histology analysis and biomechanical test at the post-injury 5 weeks. In vitro, TSCs treated with interleukin 1 beta were added by conditioned medium including exosomes or not, or by exosomes or not. Tendon matrix related markers and tenogenesis related markers were measured by immunostaining and western blot. We found that TSCs injection and exosomes injection significantly decreased matrix metalloproteinases (MMP)-3 expression, increased expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) and Col-1a1, and increased biomechanical properties of the ultimate stress and maximum loading. In vitro, conditioned medium with exosomes and exosomes also significantly decreased MMP-3, and increased expression of tenomodulin, Col-1a1 and TIMP-3. Exosomes from TSCs could be an ideal therapeutic strategy in tendon injury healing for its balancing tendon extracellular matrix and promoting the tenogenesis of TSCs.

Exosomes Derived from Bone Marrow Stromal Cells (BMSCs) Enhance Tendon-Bone Healing by Regulating Macrophage Polarization

Abstract: BACKGROUND Inflammation after tendon-bone junction injury results in the formation of excessive scar tissue and poor biomechanical properties. Recent research has shown that exosomes derived from bone marrow stromal cells (BMSCs) can modulate inflammation during tissue healing. Thus, our study aimed to enhance tendon-bone healing by use of BMSC-derived exosomes (BMSC-Exos). MATERIAL AND METHODS The mouse tendon-bone reconstruction model was established, and the mice were randomly divided into 3 groups: the control group, the hydrogel group, and the hydrogel+exosome group, with 30 mice in each group. At 7 days, 14 days, and 1 month after surgery, tendon-bone junction samples were harvested, and the macrophage polarization and tendon-bone healing were evaluated based on histology, immunofluorescence, and quantitative RT-PCR (qRT-PCR) analysis. RESULTS In the early phase, we observed significantly higher numbers of M2 macrophages and more anti-inflammatory and chondrogenic-related factors in the hydrogel+BMSC-Exos group compared with the control group and the hydrogel group. The M1 macrophages and related proinflammatory factors decreased. Cell apoptosis decreased in the hydrogel+BMSC-Exos group, while cell proliferation increased; in particular, the CD146+ stem cells substantially increased. At 1 month after surgery, there was more fibrocartilage in the hydrogel+BMSC-Exos group than in the other groups. Biomechanical testing showed that the maximum force, strength, and elastic modulus were significantly improved in the hydrogel+BMSC-Exos group. CONCLUSIONS Our study provides evidence that the local administration of BMSC-Exos promotes the formation of fibrocartilage by increasing M2 macrophage polarization in tendon-to-bone healing, leading to improved biomechanical properties. These findings provide a basis for the potential clinical use of BMSC-Exos in tendon-bone repair.

Validation of Predictors of Disease Severity and Outcomes in COVID-19 Patients: A Descriptive and Retrospective Study.

Abstract: Summary Background The severity and outcome of COVID-19 cases has been associated with the percentage of circulating lymphocytes (LYM%), levels of C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), lactic acid (LA), and viral load (ORF1ab Ct). However, the predictive power of each of these indicators in disease classification and prognosis remains largely unclear. Methods We retrospectively collected information on the above parameters in 142 patients with COVID-19, stratifying them by survival or disease severity. Findings CRP, PCT, IL-6, LYM%, and ORF1ab Ct were significantly altered between survivors and non-survivors. LYM%, CRP, and IL-6 were the most sensitive and reliable factors in distinguishing between survivors and non-survivors. These indicators were significantly different between critically ill and severe/moderate patients. Only LYM% levels were significantly different between severe and moderate types. Among all the investigated indicators, LYM% was the most sensitive and reliable in discriminating between critically ill, severe, and moderate types and between survivors and non-survivors. Conclusions CRP, PCT, IL-6, LYM%, and ORF1ab Ct, but not LA, could predict prognosis and guide classification of COVID-19 patients. LYM% was the most sensitive and reliable predictor for disease typing and prognosis. We recommend that LYM% be further investigated in the management of COVID-19. Funding This study was supported in part by awards from the National Natural Science Foundation of China, the Foundation and Frontier Research Project of Chongqing, and the Chongqing Youth Top Talent Project.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis

Abstract: Summary Background Viral load kinetics and duration of viral shedding are important determinants for disease transmission. We aimed to characterise viral load dynamics, duration of viral RNA shedding, and viable virus shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in various body fluids, and to compare SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) viral dynamics. Methods In this systematic review and meta-analysis, we searched databases, including MEDLINE, Embase, Europe PubMed Central, medRxiv, and bioRxiv, and the grey literature, for research articles published between Jan 1, 2003, and June 6, 2020. We included case series (with five or more participants), cohort studies, and randomised controlled trials that reported SARS-CoV-2, SARS-CoV, or MERS-CoV infection, and reported viral load kinetics, duration of viral shedding, or viable virus. Two authors independently extracted data from published studies, or contacted authors to request data, and assessed study quality and risk of bias using the Joanna Briggs Institute Critical Appraisal Checklist tools. We calculated the mean duration of viral shedding and 95% CIs for every study included and applied the random-effects model to estimate a pooled effect size. We used a weighted meta-regression with an unrestricted maximum likelihood model to assess the effect of potential moderators on the pooled effect size. This study is registered with PROSPERO, CRD42020181914. Findings 79 studies (5340 individuals) on SARS-CoV-2, eight studies (1858 individuals) on SARS-CoV, and 11 studies (799 individuals) on MERS-CoV were included. Mean duration of SARS-CoV-2 RNA shedding was 17·0 days (95% CI 15·5–18·6; 43 studies, 3229 individuals) in upper respiratory tract, 14·6 days (9·3–20·0; seven studies, 260 individuals) in lower respiratory tract, 17·2 days (14·4–20·1; 13 studies, 586 individuals) in stool, and 16·6 days (3·6–29·7; two studies, 108 individuals) in serum samples. Maximum shedding duration was 83 days in the upper respiratory tract, 59 days in the lower respiratory tract, 126 days in stools, and 60 days in serum. Pooled mean SARS-CoV-2 shedding duration was positively associated with age (slope 0·304 [95% CI 0·115–0·493]; p=0·0016). No study detected live virus beyond day 9 of illness, despite persistently high viral loads, which were inferred from cycle threshold values. SARS-CoV-2 viral load in the upper respiratory tract appeared to peak in the first week of illness, whereas that of SARS-CoV peaked at days 10–14 and that of MERS-CoV peaked at days 7–10. Interpretation Although SARS-CoV-2 RNA shedding in respiratory and stool samples can be prolonged, duration of viable virus is relatively short-lived. SARS-CoV-2 titres in the upper respiratory tract peak in the first week of illness. Early case finding and isolation, and public education on the spectrum of illness and period of infectiousness are key to the effective containment of SARS-CoV-2. Funding None.

CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review.

Abstract: CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune-resistance. Cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8 + T cell-mediated antitumor immune responses. Thus, CD8 + T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8 + T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4 + T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so-called infiltrated-inflamed [I-I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8 + T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death-1 receptor (PD-1)-ligand (PD-L1) and CTL-associated antigen 4 (CTLA-4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8 + T cells and renewing their priming, respectively, and thereby eliminating antigen-expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells.