Construction of a clinical survival prognostic model for middle-aged and elderly patients with stage III rectal adenocarcinoma

BACKGROUND Nomograms for prognosis prediction in colorectal cancer patients are few,and prognostic indicators differ with age.AIM To construct a new nomogram survival prediction tool for middle-aged and elderly patients with stage III rectal adenocarcinoma.METHODS A total of 2773 eligible patients were divided into the training cohort(70%)and the validation cohort(30%).Optimal cutoff values were calculated using the X-tile software for continuous variables.Univariate and multivariate Cox proportional hazards regression analyses were used to determine overall survival(OS)and cancer-specific survival(CSS)-related prognostic factors.Two nomograms were successfully constructed.The discriminant and predictive ability and clinical usefulness of the model were also assessed by multiple methods of analysis.RESULTS The 95%CI in the training group was 0.719(0.690-0.749)and 0.733(0.702-0.74),while that in the validation group was 0.739(0.696-0.782)and 0.750(0.701-0.800)for the OS and CSS nomogram prediction models,respectively.In the validation group,the AUC of the three-year survival rate was 0.762 and 0.770,while the AUC of the five-year survival rate was 0.722 and 0.744 for the OS and CSS nomograms,respectively.The nomogram distinguishes all-cause mortality from cancer-specific mortality in patients with different risk grades.The time-dependent AUC and decision curve analysis showed that the nomogram had good clinical predictive ability and decision efficacy and was significantly better than the tumor-node-metastases staging system.CONCLUSION The survival prediction model constructed in this study is helpful in evaluating the prognosis of patients and can aid physicians in clinical diagnosis and treatment.

An intervention to reduce psychosocial and biological indicators of stress in African American lupus patients: The balancing lupus experiences with stress strategies study

Objective: Very little is known about the impact of psychosocial stress on African American lupus patients. Due to the exposure of African Americans to a unique trajectory of stressors throughout life, it may be critical to understand the relationship between psychosocial stress and underlying biological mechanisms that influence disease activity and pathology in this high risk group. Methods: The Balancing Lupus Experiences with Stress Strategies (BLESS) study piloted the validated “Better Choices, Better Health” Chronic Disease Self-Management Program (CDSMP) in 30 African-American lupus patients participating in the SLE Clinic Database Project at the Medical University of South Carolina (MUSC). Measures of psychosocial and biological indicators of stress were collected in all of the patients in each of the study conditions before and after intervention activities, as well as four months’ post-intervention, to assess the effectiveness of the program in reducing perceived and biological indicators of stress. Results: Participation in the workshops had large effects upon depression (d = 1.63 and d = 1.68), social/role activities limitations (d =1.15), health distress (d = 1.13 and d = 0.78), fatigue (d = 1.03), pain (d = 0.96), and lupus self-efficacy (d = 0.85). Neither the differences in cortisol or DHEA levels pre- and post-intervention were found to be significantly different between intervention participants and controls. Conclusion: The intervention workshops acted to reduce perceived stress and improve quality of life. Our findings imply that comparable, if not more significant gains in relevant health indicators are possible in African American patients when provided the opportunity to participate in CDSMP’s.

Stress intervention and disease in African American lupus patients: The balancing lupus experiences with stress strategies (BLESS) study

Very little is known about the impact of psychosocial stress on underlying biological mechanisms in African American lupus patients, although African American women display the highest rates of lupus. Due to the exposure of African Americans to a unique trajectory of stressors throughout the life course, it may be critical to understand the relationship between psychosocial stress and underlying biological mechanisms that influence disease activity and pathology in this high risk group. To begin to fill this research void, an evidence-based self-management program was piloted among a cohort of African American lupus patients participating in a SLE database project at the Medical University of South Carolina (MUSC). To assess disease activity, during each clinic visit, a history is obtained, and physical examination, phlebotomy, and urine collection are performed. SLE Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) scores are assessed at each visit. Disease data corresponding with data collection timeframes for each participant were extracted from the MUSC SLE Database to assess the effectiveness of the program. Several differences were observed between the intervention and control groups on symptoms pertaining to lupus activity, and many of these differences had large effect sizes. Our findings can be rapidly translated into improved delivery of health care and targeted trials/interventions with relevance to health disparities, and if widely implemented, morbidities and mortality related to lupus could be drastically reduced in African-Americans.

The difference of immunologic parameters between SARS patients of mild type and severe type

The aim of this study is to study the difference of immunologic parameters between severe acute respiratory syndrome (SARS) patients of mild type and severe type. Data including white blood cell (WBC) count, lymphocyte count, CD3, CD4 and CD8 T lymphocyte count, levels of C3, C4, ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) from 1291 patients with SARS in each week from onset of illness were recorded. The clinical progress of each sign was analysed and the difference between mild type and severe type was compared. Lymphocyte count, CD8 T lymphocyte count declined in the first two weeks and recovered from the third week, while CRP and C4 levels rose in the first week and then recovered gradually. Lymphocyte count and CD8 T lymphocyte count of severe cases were much lower than that of mild type (P<0.01), while CRP and C4 levels in severe type were much higher than that of mild type (P<0.01). Lymphocyte count, CD8 T lymphocyte count, CRP and C4 levels are useful signs for the diagnosis of SARS of severe type and are valuable for the evaluation of its severity.

Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation

Genome-wide association studies(GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. In this study, by integrating lineage-specific enhancers from mesenchymal and myeloid compartments with bone mineral density loci, we were able to segregate osteoblast-and osteoclast(OC)-specific functions. Specifically, in OCs, a PU.1-dependent transcription factor(TF)network was revealed. Deletion of PU.1 in OCs in mice resulted in severe osteopetrosis. Functional genomic analysis indicated PU.1 and MITF orchestrated a TF network essential for OC differentiation. Several of these TFs were regulated by cooperative binding of PU.1 with BRD4 to form superenhancers. Further, PU.1 is essential for conformational changes in the superenhancer region of Nfatc1. In summary, our study demonstrates that combining GWASs with genome-wide binding studies and model organisms could decipher lineage-specific pathways contributing to complex disease states.

Anti-M₃Muscarinic Acetylcholine Receptor Antibodies in Systemic Lupus Erythematosus

Background: Evidences have shown that anti-M3 muscarinic acetylcholine receptor IgG (anti-M3 mAChR IgG) are clinically useful autoantibody that exert a cholinergic pharmacologic effect binding and interacting with M3 mAChR at the level of exocrine gland (salivary and ocular). Aims: The aim of this study was to determine the associations between serum level of anti-M3 mAChR IgG in patients with systemic lupus erythematosus (SLE) and other autoantibodies, serum prostaglandin E2 (PGE2), and clinical manifestations. Methods: Serum autoantibodies against M3 mAChR synthetic peptide were measured by enzyme-linked immuno absorbent assay (ELISA) using, as an antigen, a 25-mer peptide K-R-T-V-P-D-N-Q-C-F-I-Q-F-L-S-N-P-A-V-T-F-G-T-A-I corresponding to the amino acid sequence of the second extracellular loop of the human M3 mAChR. Serum levels of antinuclear antibodies (ANA), anti-Smith (Sm) antibodies, anti-phospholipid (APL) antibodies, and PGE2 were determined by ELISA in patients with SLE. Results: We found significantly enhanced titers of anti-M3 mAChR IgG in sera from SLE patients compared with healthy individuals (control). In addition, serum levels of PGE2 were significantly higher in SLE patients than in control patients and were significantly higher in active than in non-active SLE. No correlation was found with other autoantibodies present in SLE. By contrast, a positive correlation was found between anti-M3 mAChR IgG and PGE2 serum levels in SLE. Conclusions: As anti-M3 mAChR antibodies present in the sera of SLE patients may be another factor in the pathogenesis of this disease, and the increment of PGE2 in the sera of SLE has a modulatory action on the inflammatory process, suggesting that the presence of these autoantibodies against M3 mAChR may contribute to sustained immune deregulation and the strong inflammatory component observed in SLE.

Role of M₃Muscarinic Acethylcholine Receptor Antibodies as a New Marker in Primary Sjögren Syndrome

Aims: This paper investigates the presence of M3 muscarinic acetylcholine receptor autoantibody present in the serum of patients with primary Sj?gren syndrome (pSS). Main methods: We detected the levels of M3mAChR peptide IgG, PGE2, IL-1β in serum of SS patients using the enzyme-linked immune sorbent assay (ELISA). To measure the quantity of nitrite/nitrate, we used Griess reagent system. Key findings: Titres of M3mAChR antibody in sera from SS patients are significantly enhanced compared to healthy subjects (control). The enhancement of these autoantibodies is accompanied by the increase of the levels of PGE2, IL-1β and nitrite/nitrate in serum. Under in vitro conditions, the synthetic human M3 peptide impaires the increment of M3mAChR antibody but not that of nati-Ro/SSA antibody. In positive anti-Ro/SSA antibody patients, the increment of M3mAChR peptide IgG and the measured pro-inflammatory substances is related. Significance: On this basis, anti M3mAChR peptide IgG can be said to act as a modulator of the immune system and to play a role in the host-chronic increment of proinflammatory substances in SS patients with positive Ro/SSA antibody. This association between the antibody and the pathogenesis of SS disease may result in useful predicting SS.

Correlation research of serum APoM contents with disease activity for SLE patients

Objective:To study the correlation of serum APoM (Apolipoprotein M) contents with disease activity for SLE (systemic lupus erythematosus) patients.Method: A total of 80 SLE patients treated from January 2013 to March 2017 in our Rheumatology and Immunology Department were selected. The subjects were divided into activity group (44 cases) and relief group (36 cases) according to the SLEDAI scores. There were 31 cases with renal injury and 49 cases without renal injury. The index of CRP, ESR, ApoM and blood lipid level for each group was compared. The correlation of ApoM contents with CRP and ESR was analyzed.Result:The index of CRP and ESR for activity group was higher than relief group;the ApoM contents for activity group were lower than relief group;the index of CRP and ESR for renal injury group was higher than non-renal injury group;the ApoM contents for renal injury group was lower than non-renal injury group;the index of TG and LDL-C for activity group were higher than relief group;the index of TC and HDL-C for activity group were lower than relief group;the index of TG and LDL-C for renal injury group was higher than non-renal injury group;the index of TC and HDL-C for renal injury group was lower than non-renal injury group;the ApoM contents were negatively correlated with the index of ESR and CRP.Conclusion: At the activity and relief stage,, the ApoM contents for renal injury patients and non-renal injury patients are significantly different;the ApoM contents can be seen as the observation index of SEL activity. It may be correlated with the mediation of inflammatory response.

The development and function of follicular helper T cells in immune responses

小囊的助手 T 房间(Tfh ) 作为提供帮助让 B 房间增殖并且在幼芽的中心经历抗体亲密关系成熟的一个系被提交了。证据支持了那个 Tfh 子集开发象另外的系一样，依赖于一个特别 transcriptional 节目被开始的微型环境。它为 Tfh 房间的开发和函数作为主人管理者被看了那 Bcl-6 和 IL-21 行为。Tfh dysregulation 涉及自体免疫的病理的发展，例如全身的豺狼座 erythematosus，风湿性关节炎和另外的自体免疫的疾病。现在的评论在在他们的开发和函数的 Tfh 房间和焦点的域里加亮最近的进展。

Induced Foxp3^(+)regulatory T cells:a potential new weapon to treat autoimmune and inflammatory diseases?

Foxp3^(+)T regulatory cells(Tregs)consisting of natural and induced Treg subsets play a crucial role in the maintenance of immune homeostasis against self-antigen.The actions designed to correct defects in numbers or functions of Tregs may be therapeutic in the treatment of autoimmune diseases.While recent studies demonstrated that natural Tregs are instable and dysfunctional in the in-flammatory condition,induced Tregs(iTregs)may have a different feature.Here we review the progress of iTregs,particularly focus on their stability and function in the established autoimmune diseases.The advantage of iTregs as therapeutics used under inflammatory conditions is highlighted.Proper generation and manipulation of iTregs used for cellular therapy may provide a promise for the treatment of many autoimmune and inflammatory diseases.

Emerging topics and new perspectives on regulatory and effector T cells

It is well accepted that the balance of immunity between effector and regulatory T cells determines the outcome of autoimmune and chronic inflammatory diseases.Concerning the topic of‘Regulatory and Effector T Cells’as published in this issue of Journal of Molecular Cell Biology,several investigators have provided important new information.

Research progress of local characteristic drugs for treatment of rheumatoid arthritis in Xinjiang

Rheumatoid arthritis(RA)is a systemic autoimmune disease characterized by synovitis.This disease tends to recur,persist,and is difficult to cure.The pathogenesis of RA is complex.Currently,the commonly used treatments for RA—non-steroidal anti-inflammatory drugs(NSAIDs),disease-modifying anti-rheumatic drugs(DMARDs),glucocorticoids,and immunosuppressants—have notable side effects with long-term use and may be ineffective for some patients.Therefore,it is crucial to find drugs with limited side effects and significant curative effects.Xinjiang's local characteristic drugs have a long history,abundant resources,and are known for their safety and effectiveness in treating RA.In recent years,many studies have reported on the mechanisms of action and therapeutic effects of Xinjiang's local characteristic drugs on RA.This article reviews the pathogenesis of RA,as well as the research progress and treatment characteristics of Xinjiang-featured drugs.

Neuronal NR4A1 deficiency drives complement-coordinated synaptic stripping by microglia in a mouse model of lupus

Neuropsychiatric lupus(NPSLE)is a frequent manifestation of systemic lupus erythematosus(SLE)that occurs in 40-90%of SLE patients;however,the underlying mechanisms remain elusive,causing a severe lack of therapeutic targets for this condition.Here,we show that complement-coordinated elimination of synapses participated in NPSLE in MRL/lpr mice,a lupus-prone murine model.We demonstrated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglial reactivation before overt peripheral lupus pathology.

类风湿关节炎中心血管风险增加:机制和意义

类风湿关节炎是一种系统性自身免疫病,其特点之一为心血管疾病的高发病率和高病死率。类风湿关节炎和心血管疾病相关联的机制包括共有的炎症介质、肽/蛋白质的翻译后修饰,以及随后的免疫应答、脂蛋白组成和功能的改变、氧化应激增加和内皮细胞功能障碍。尽管人们对这些机制及其与传统心血管危险因素的复杂相互作用有了越来越多的了解,但对于在类风湿关节炎背景下进行最佳的危险分层、预防和治疗方法仍然未知。减少心血管疾病所致负担的综合性措施,除需对传统危险因素把控外,还要对类风湿关节炎固有的危险因素(如疾病活动度增加)进行优化管理。对类风湿关节炎的治疗似乎对心血管风险以及关联这些疾病的机制产生了不同的影响。需要更多的研究来确定是否存在优先的类风湿关节炎治疗方法可以预防心血管疾病。最终,对于在类风湿关节炎中心血管疾病的独特机制的了解将有助于危险分层,以及在该患者群体中确定有效降低心血管风险的新靶点。

Inflammasome-IL-1-Th17 response in allergic lung inflammation

Allergic asthma has increased dramatically in prevalence and severity over the last three decades.Both clinical and experimental data support an important role of Th2 cell response in the allergic response.Recent investigations revealed that airway exposure to allergen in sensitized individuals causes the release of ATP and uric acid,activating the NLRP3 inflammasome complex and cleaving pro-IL-1b to mature IL-1b through caspase-1.The production of pro-IL-1b requires a toll-like receptor(TLR)4 signal which is provided by the allergen.IL-1b creates a pro-inflammatory milieu with the production of IL-6 and chemokines which mobilize neutrophils and enhance Th17 cell differentiation in the lung.Here,we review our results showing that NLRP3 inflammasome activation is required to develop allergic airway inflammation in mice and that IL-17 and IL-22 production by Th17 cells plays a critical role in established asthma.Therefore,inflammasome activation leading to IL-1b production contributes to the control of allergic asthma by enhancing Th17 cell differentiation.

Effect of human umbilical cord mesenchymal stem cells on ovarian function in lupus mice

Background:Patients with systemic lupus erythematosus(SLE)suffer from a high incidence of premature ovarian failure,which might be due to cyclophosphamide gonadal toxicity,immune abnormalities,or other reasons.This study aimed to investigate whether the transplantation of human umbilical cord mesenchymal stem cells(HUC‐MSCs)can improve ovarian reserve function in lupus mice.Methods:We used MRL/lpr mice to observe changes in ovarian structure and secretory function in SLE.Lupus mice and controls were injected with HUC‐MSCs at Weeks 12 and 16.We detected serum concentrations of the sex hormones estradiol(E2),follicle‐stimulating hormone(FSH),and anti‐Müllerian hormone(AMH),using enzyme‐linked immunosorbent assays.Hematoxylin and eosin staining showed ovarian tissue structure and enabled the counting of follicles.Hepatocyte growth factor(HGF)and insulin‐like growth factor 1(IGF‐1)expression in ovarian tissue was observed by immunohistochemistry.Results:Ovarian function in lupus mice was abnormal,as indicated by decreased serum E2 and AMH concentrations,and increased FSH concentrations.HUC‐MSC transplantation caused significant upregulation of serum E2 and AMH and downregulation of FSH(all p<0.05).Ovarian structure improved and the follicle number increased after HUC‐MSC transplantation.Multiple infusions of HUC‐MSCs at Weeks 12 and 16 resulted in a significantly higher number of primordial follicles than infusions of HUC‐MSCs at only Week 12(p<0.05).Immunohistochemistry showed that IGF‐1 and HGF expression increased after HUC‐MSC transplantation,but this was not significant.Conclusions:HUC‐MSCs transplantation restores disturbed hormone secre-tion and folliculogenesis in lupus mice.HUC‐MSC transplantation should be repeated for the best treatment effect.