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Volume 10 ， Issue 2 ， 2023
- Abstract：Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued "Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline" . Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette–Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.Keywords：Non-muscle invasive bladder cancer;Bladder cancer;Transurethral resection of bladder tumor;Treatment;Surveillance;Guideline104|3|0Updated：2023-05-10
POSITION ARTICLE AND GUIDELINE
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Abstract：Background:Due to the outbreak and rapid spread of coronavirus disease 2019 (COVID-19), more than 160 million patients have become convalescents worldwide to date. Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19. However, it is unknown whether their characteristics return to normal after the 1-year recovery.Methods:We recruited 35 confirmed patients to provide specimens at discharge and 1 year later, as well as 160 healthy controls. A total of 497 samples were prospectively collected, including 219 tongue-coating, 129 stool and 149 plasma samples. Tongue-coating and stool samples were subjected to 16S rRNA sequencing, and plasma samples were subjected to untargeted metabolomics testing.Results:The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal. In the recovery process, the microbial diversity gradually increased. Butyric acid-producing microbes and Bifidobacterium gradually increased, whereas lipopolysaccharide-producing microbes gradually decreased. In addition, sphingosine-1-phosphate, which is closely related to the inflammatory factor storm of COVID-19, increased significantly during the recovery process. Moreover, the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later.Conclusions:This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19. The key microbiome and metabolites in the process of recovery were identified, and provided new treatment ideas for accelerating recovery. And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.Keywords：Coronavirus disease 2019 (COVID-19);Gut microbiome;Oral microbiome;Plasma metabonomics;Convalescents;Individual outcomes;Patient stratification;Predictive;Preventive and personalized medicine (3PM)49|0|0Updated：2023-05-10 -
Abstract：Background:Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy.Methods:The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H+-ATPase (v-ATPase) activity, respectively, which were analysed by One‐way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofuorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One‐way ANOVA with post hoc tests. The autophagosome formation was detected by immunofuorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC).Results:We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P=0.0038; Glutamic acid, P=0.0348; Alanine, P=0.0037; Glycine, P=0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P<0.0001; phosphorylated 70 kD ribosomal protein S6 kinase 1 (p-p70S6K1), P=0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P=0.0015] and inhibition of autophagosome formation [microtubuleassociated protein light chain 3 II (LC3 II), P=0.0073; LC3 puncta, P<0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment.Conclusions:Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treat-ment and that of related tauopathies.Keywords：Tau;Autophagy;Amino acid pathway;Mammalian target of rapamycin kinase complex 1 (mTORC1);T cell intracellular antigen 1 (TIA1)52|4|1Updated：2023-05-10 -
Abstract：Background:Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis.Methods:A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku hospital pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis.Results:C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits (P<0.001), higher level of bone volume to tissue volume (BV/TV, P<0.001), bone mineral density (BMD, P<0.001), and a lower total porosity (P<0.001). C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleation-induced oligomerization, suppressing the cleavage of caspase-1 (P<0.05) and IL-1β (P<0.05) stimulated by CoCrMo alloy particles. C3 and C4 also inhibited the generation of gasdermin D-N-terminal fragment (GSDMD-NT) to regulate pyroptosis. Besides, C3 and C4 have a negative impact on osteoclast differentiation (P<0.05) and its function (P<0.05), affecting the podosome arrangement and morphologically normal podosome belts formation.Conclusions:Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.Keywords：NLRP3 inflammasome;Pyroptosis;Short chain fatty acids;Osteolysis;osteoclast47|2|0Updated：2023-05-10 -
Abstract：Background:Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells.Methods:ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes’ expression and prognosis of ESCC.Results:Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P<0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were significantly higher than the paired normal tissues from 148 ESCC patients (P<0.001). Then, the Kaplan-Meier survival analysis suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (log-rank P<0.001). Co-IP and Western blotting further revealed that HDAC7 physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells.Conclusions:Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.Keywords：melatonin;Histone deacetylase 7 (HDAC7);β-catenin;c-myc;Ubiquitin-specific peptidase 10 (USP10);Esophageal squamous cell carcinoma (ESCC)32|3|1Updated：2023-05-10
RESEARCH
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Abstract：Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.Keywords：Glucagon-like peptide-1 receptor agonists;Dipeptidyl peptidase-4 inhibitors;Type 2 diabetes mellitus;Cardiovascular outcome26|3|0Updated：2023-05-10 -
Abstract：Sepsis is a common complication of combat injuries and trauma, and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is also one of the significant causes of death and increased health care costs in modern intensive care units. The use of antibiotics, fluid resuscitation, and organ support therapy have limited prognostic impact in patients with sepsis. Although its pathophysiology remains elusive, immunosuppression is now recognized as one of the major causes of septic death. Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis. It is characterized by the release of anti-inflammatory cytokines, abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, and expression of immune checkpoints. By targeting immunosuppression, especially with immune checkpoint inhibitors, preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance. Here, we comprehensively discuss recent findings on the mechanisms, regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.Keywords：sepsis;immunosuppression;Immune monitoring;Immunomodulatory therapy34|4|0Updated：2023-05-10
REVIEW
- Abstract：Cholangiocarcinoma (CHOL) is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments, including immune checkpoint blockade therapy. The mRNA vaccine-based immunotherapeutic strategy has attracted much attention for various diseases, however, its application in CHOL is limited due to the thoughtlessness in the integration of vaccine design and patient selection. A recent study established an integrated path for identifying potent CHOL antigens for mRNA vaccine development and a precise stratification for identifying CHOL patients who can benefit from the mRNA vaccines. In spite of a promising prospect, further investigations should identify immunogenic antigens and onco-immunological characteristics of CHOL to guide the clinical application of CHOL mRNA vaccines in the future.Keywords：Cholangiocarcinoma (CHOL);mRNA vaccine;Tumor antigen;Immune subtype;Immune microenvironment24|0|0Updated：2023-05-10
PERSPECTIVE
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Abstract：Since its establishment in 2014, Military Medical Research has come a long way in becoming a premier journal for scientific articles from various different specialties, with a special emphasis on topics with military relevance. The field of military medicine may be obscure, and may not be readily encountered by the typical clinician on a day-to-day basis. This journal aims not only to pursue excellence in military research, but also to keep current with the latest advancements on general medical topics from each and every specialty. This editorial serves to recap and synthesize the existing progress, updates and future needs of military medical excellence, discussing foremostly the unique traits of literature published in this journal, and subsequently presenting the discourse regarding wartime and peacetime medicine, the role of the military in a public health emergency, as well as wound healing and organ regeneration. Special attention has been devoted to military topics to shed light on the effects of Chemical, Biological, Radiological and Explosive warfare, environmental medicine and military psychiatry, topics which rarely have a chance to be discussed elsewhere. The interconnectedness between military combat and soldier physical and mental well-being is intricate, and has been distorted by pandemics such as coronavirus disease 2019 (COVID-19). This journal has come a long way since its first article was published, steadily contributing to the existing knowledge pool on general medical topics with a military slant. Only with continuous research and sharing, can we build upon the work of the scientific community, with hopes for the betterment of patient care.Keywords：Military Medical Research;Military medicine;Clinical medicine;General medicine;Basic science;Coronavirus disease 2019 (COVID-19);Post-traumatic stress disorder (PTSD)21|2|1Updated：2023-05-10
EDITORIAL
- Keywords：Monkeypox virus;Poxvirus;Zoonotic virus;Human transmission14|0|0Updated：2023-05-10
- Keywords：Burn wound;Early excision;Enzymatic debridement18|0|0Updated：2023-05-10
LETTER TO THE EDITOR
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