Intervertebral disc degeneration (IVDD) is a leading cause of chronic back pain, contributing significantly to reduced quality of life and global public health burdens. The TRIM (Tripartite Motif-containing) protein family, with its diverse regulatory roles, has emerged as a key player in critical cellular processes such as inflammation, cell death, and extracellular matrix (ECM) metabolism. Recent findings underscore the involvement of TRIM proteins in IVDD pathogenesis, where they regulate stress responses, maintain cellular homeostasis, and influence the functional integrity of nucleus pulposus (NP) and annulus fibrosus (AF) cells. This review explores the multifaceted roles of TRIM proteins in IVDD, highlighting their contributions to pathological pathways and their potential as therapeutic targets. Advancing our understanding of TRIM protein-mediated mechanisms may pave the way for innovative and precise therapeutic strategies to combat IVDD.

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The dysregulation of ubiquitin ligase is the cause of many human diseases. Tripartite motif protein 32 (TRIM32) is an E3 ubiquitin ligase whose role in nucleus pulposus (NP) cell apoptosis is unclear. The expression of TRIM family protein and β-catenin in 40 NP tissue samples was detected by RT-PCR. Interleukin (IL)-1β or tumor necrosis factor (TNF)-α was used to treat rat NP cells. Knockdown and overexpression of Trim32 were achieved using specific siRNA and recombinant plasmids. Western blotting, RT-PCR, and flow cytometry were used to assess the expression of TRIM32/β-catenin and the apoptosis rate of NP cells. Coimmunoprecipitation was adopted to analyze the possible interactions between AXIN1 and TRIM32. In clinical samples, TRIM32 expression was of positive relevance with the expression of CTNNB1 (β-catenin). In vitro, apoptosis of IL-1β- or TNF-α-treated rat NP cells was induced through upregulated Trim32 expression and activated β-catenin signaling, whereas Trim32 siRNA and inhibition of β-catenin reversed the induction effect of cytokines. Further studies indicated that TRIM32 activated the β-catenin signaling pathway through ubiquitination of AXIN1, thereby regulating apoptosis. Collectively, this study reveals that TRIM32 promotes inflammatory factor-induced apoptosis of rat NP cells, in part by direct degradation of AXIN1 to trigger β-catenin signaling.

BACKGROUND:Ghrelin (GHRL) is a polypeptide that can specifically bind to the growth hormone secretagogue receptor (GHSR). The expression of GHSR is significantly different in normal and prostate cancer (PC) tissues in humans. It is important to find an effective diagnostic method for the diagnosis and prognosis of invasive PC/neuroendocrine prostate cancer (NEPC). METHODS:GHRL and GHSR mRNA levels were determined by a quantitative real-time polymerase chain reaction in PC tissues. The expression of GHRL and GHSR proteins was assessed by Western blot assay and immunohistochemistry. A GHRL polypeptide probe was synthesized by standard solid-phase polypeptide synthesis, and labeled with Alexa Fluor 660. Confocal microscopy was used to capture fluorescence images. Living imaging analysis showed tumor areas of different invasiveness in mice models. RESULTS:The levels of GHRL and GHSR copy number amplification and mRNA expression were increased in invasive PC/NEPC, and the protein expression levels of GHRL and GHSR were similarly increased in NEPC. The GHRL polypeptide probe could effectively bind to GHSR. In PC3 cells, it was found that the GHRL probe specifically binds to GHSR on the cell membrane and accumulates in the cells through internalization after binding. Live imaging in mice models showed that there were different signal intensities in tumor areas with different invasiveness. CONCLUSION:GHSR and GHRL might be used in molecular imaging diagnosis for invasive PC/NEPC in the future.

目的:探讨原发性舍格伦综合征(pSS)患者血清炎症因子、外周血淋巴细胞亚群分布与病情严重程度的相关性.方法:选取2016年1月至2018年8月我院收治的105例pSS患者为研究对象,根据病程将全部患者分为初发组(n=51)、复发组(n=22)与稳定组(n=32),并选取同期来我院体检的50例健康成人作为对照组.比较各组患者的血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)与白细胞介素-32(IL-32)水平以及外周血淋巴细胞亚群分布.采用Pearson相关分析探讨pSS患者欧洲抗风湿联盟干燥综合征疾病活动指数(ESSDAI)与其血清炎症因子、外周血淋巴细胞亚群分布的相关性.结果:(1)血清TNF-α、IL-1β水平:初发组、复发组＞稳定组＞对照组;血清IL-32水平:初发组、复发组＞对照组,复发组＞稳定组.(2)外周血CD4+/CD8+比值:初发组、复发组、稳定组＞对照组;外周血Th1/Th2比值:初发组、复发组＞对照组;外周血Th 17/Treg比值:初发组、复发组、稳定组＞对照组,且复发组＞稳定组.四组研究对象的外周血T淋巴细胞、B淋巴细胞、NK细胞的百分比比较差异均无统计学意义(P＞0.05).(3)Pearson相关分析显示pSS患者的ESSDAI评分与血清TNF-α、IL-1β、IL-32水平及外周血Th 17/Treg比值均呈显著正相关(r=0.271、0.306、0.251、0.198,P＜0.05).结论:pSS患者的血清TNF-α、IL-1β与IL-32水平及外周血CD4+/CD8+、Th1/Th2、Th 17/Treg比值均明显升高,其中血清TNF-α、IL-1β、IL-32水平、外周血Th 17/Treg比值与疾病活动度呈明显正相关.

BackgroundThe prognosis of bladder urothelial carcinoma (BLCA) varies greatly among patients, and conventional pathological predictors are generally inadequate and often inaccurate to predict the heterogeneous behavior of BLCA. This study aims to investigate the prognostic value and function of TOP2A in BLCA.MethodsTOP2A expression level was examined by RNA-sequencing, quantitative real time polymerase chain reaction and immunohistochemistry from 10, 40 and 209 BLCA samples, respectively. Public databases were analyzed for validation. Cell proliferation, migration, invasion assays were performed to explore potential functions of TOP2A in BLCA. Flow cytometry was performed for cell cycle and apoptosis analysis. Univariable and multivariable Cox regression models were performed to identify independent risk factors for the prognosis of BLCA.ResultsWe found TOP2A was significantly upregulated in BLCA samples, especially for high-grade and advanced stage tumors, compared with matched normal epithelial tissue. Univariable COX regression analysis revealed high TOP2A expression was significantly associated with poorer cancer-specific, progression-free and recurrence-free survival, but not independently of clinical characteristics in the multivariable models. Knockdown of TOP2A remarkably inhibited the proliferation of BLCA cells and non-cancerous urothelial cells. Furthermore, migration and invasion capacity of BLCA cells were strongly suppressed after TOP2A knockdown. Moreover, flow cytometry suggested TOP2A had anti-apoptotic function, and knockdown of TOP2A could induce resistance to doxorubicin in J82 cells.ConclusionsIn our study, TOP2A was overexpressed in BLCA and could serve as a prognostic biomarker for BLCA. Moreover, TOP2A is functionally important for the proliferation, invasion and survival of BLCA cells.

Objective: To create multivariable models with readily available clinicopathologic variables for predicting the prognosis of upper tract urothelial carcinomas (UTUC). Patients and methods: We retrospectively analyzed patients diagnosed as UTUC and underwent radical nephroureterectomy in 2 high volumes, tertiary care centers. A total of 445 patients and 227 patients met the inclusion criteria were included for constructing the prediction model and external validation, respectively. Univariable and multivariable Cox regression models were used to analyze independent risk factors, and nomogram and calibration curve were constructed by R project. Results: The median follow-up for the development and external validation cohorts were 33.5 and 32.5 months, respectively. Multivariable analysis detected older age (>= 65 years), with concurrent bladder cancer at diagnosis, with both ureter and renal pelvic tumor, lymphovascular invasion, urothelial carcinoma with divergent differentiation, higher pathological grade and stage, and positive lymph node were significantly associated with poorer outcome of UTUC. The c-index of the nomogram with these above-mentioned independent risk factors to predict the cancer specific survival was 0.74 (95% CI, 0.64-0.84) and 0.73 (95% CI, 0.59-0.87) for the development cohort and external validation cohort, respectively. Conclusions: We developed and externally validated a novel and accurate nomogram with readily available clinicopathological information for predicting the cancer specific survival of UTUC. This nomogram could help clinicians stratify patients with UTUC into different risk groups with distinct prognosis by the total scores obtained from the prediction tool, thus facilitate decision-making and clinical trial designing. (C) 2018 Elsevier Inc. All rights reserved.

Study Design. A retrospective case series study with at least 10 years of follow-up data. Objective. To validate the reliability of bilateral C1–2 transarticular screws and C1 laminar hooks and a bone autograft for acute pediatric atlantoaxial instability. Summary of Background Data. The reliability of initial posterior atlantoaxial fusion in pediatric patients is still controversial. To date, however, only a few published articles with short-term follow-up data are available to help spinal surgeons understand the effects of posterior atlantoaxial fusion in the skeletally immature spine. Methods. Five pediatric patients with acute atlantoaxial instability underwent atlantoaxial fusion using the above technique over a 3-year period. During a minimum 10-year follow-up period, not only outcomes and complications were investigated, but the vertical growth of the constructed spine in relation to the growth of the entire cervical spine, overall cervical spinal alignment, and adjacent-segment instability were evaluated. Results. The clinical follow-up indicated solid fusion and complete clinical relief from symptoms. No neural or vascular impairment was observed. The radiological evaluation showed that all patients had growth within the fusion construct reaching a mean 35.4% of the entire cervical spine. There were no radiological indicators of subaxial instability, even when cervical sagittal alignments became straight with a mean C2–7 angle of 6.4°. Conclusion. The results showed that initial posterior atlantoaxial fusion accomplished with bilateral C1–2 transarticular screws, C1 laminar hooks fixation, and bony autograft is a reliable surgical technique for treating acute pediatric atlantoaxial instability without negative effects on vertical growth at the fused level or the stability of the subaxial spine. Level of Evidence: 3

Objective To analyze the characteristics of peripheral blood N-alpha-acetyltransferase 10 (Naa10) and lymphocyte immunophenotyping in patients with oral squamous cell carcinoma (OSCC) and to explore its clinical significance. Methods 97 OSCC patients and 50 health examinees were enrolled in the patient group and the control group respectively. Naa10 and lymphocyte immunophenotyping in the peripheral blood of the two groups were detected. The differences of Naa10 and lymphocyte immunophenotyping in the peripheral blood of patients with different TNM stages and lymph node metastasis status were compared, and their characteristics and clinical significance were summarized. Results The serum Naa10 in the patients group was (62.91±17.15) pg/ml, which was higher than that in the control group (38.82±9.04) pg/ml (t = 9.280, P 0.05) . There were 34 cases with lymph node metastasis, and the serum Naa10 was (65.15 ±14.07) pg/ml. There was no significant difference between those without lymph node metastasis and those without lymph node metastasis (61.45±12.66) pg/ml (t = 1.321, P > 0.05) . The percentages of CD3+, CD4+, CD4+/CD8+, NK cells in stageⅠ~Ⅱ patients were lower than those in stage Ⅲ~Ⅳ patients, and the percentages of CD8+, B lymphocyte in stageⅠ~Ⅱpatients were higher than those in stage Ⅲ~Ⅳ patients (P < 0.05) . Pearson correlation analysis showed that Naa10 in peripheral blood was negatively correlated with CD3+ (-0.631) , CD4+ (-0.529) , CD4+/CD8+ (-0.587) , percentage of NK cells (-0.603) , and positively correlated with CD8+ (0.558) and percentage of B lymphocyte (0.670) (P < 0.05) . Conclusion Naa10 in peripheral blood of OSCC patients was increased significantly, but not related to TNM stage and lymph node metastasis. The lymphocyte immunophenotype of OSCC patients changed significantly, and the increase of TNM stage and lymph node metastasis was accompanied by the decrease of CD3+, CD4+, CD4+/CD8+, NK cell percentage and the increase of CD8+, B lymphocyte percentage. Key words: Oral squamous cell carcinoma; N-alpha-acetyltransferase 10; Lymphocyte; Immunophenotyping

An expansion of regulatory T cells (Tregs) in ankylosing spondylitis (AS) was observed. However, AS patients continue to exhibit aberrant inflammation. In this study, we collected PBMCs from 26 AS patients and 26 healthy controls, and investigated the functional capacity of Treg cells from these subjects. In AS patients, the frequency of CD4+CD25+Foxp3+CD127− Treg cells was slightly increased compared to healthy controls, but the level of Foxp3 MFI in AS patient CD4+CD25+Foxp3+CD127− Treg cells was significantly lower than that in healthy control CD4+CD25+Foxp3+CD127− Treg cells. Tim-3+ Treg cells were previously shown to present stronger suppressive capacity than Tim-3− Treg cells. Here, we discovered that the Tim-3+ cell frequency in CD4+CD25+Foxp3+CD127− Treg cells was significantly lower in AS patients. In both healthy volunteers and AS patients, Tim-3+ Treg cells demonstrated higher transcription of Foxp3, IL-10 and TGF-β, higher secretion of IL-10 and TGF-β, and stronger inhibition of conventional T cell inflammation, than Tim-3− Treg cells. In some but not all functional aspects, the Tim-3+ Treg cells from healthy controls were more potent than the Tim-3+ Treg cells from AS patients. Collectively, these results demonstrated two Treg-related impairments in AS patients. First, the frequency of the more potent Tim-3+ Treg cells was lower in AS patients, and second, some of Tim-3+ Treg-mediated functions were less potent in AS patients. Interestingly, the ratio of Tim-3−/Tim-3+ Treg cells in AS patients was directly correlated with the Bath ankylosing spondylitis disease activity index (BASDAI) score, the C-reactive protein (CRP) level, and the erythrocyte sedimentation rate (ESR). Given the fact that Tim-3+ Treg cells presented potent suppressive functions, Tim-3+ Treg cells and Tim-3+ Treg-mediated mechanisms might be potential candidates for immunotherapies in AS patients.

Abstract Purpose: Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism. Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance. Results: High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model. Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. Clin Cancer Res; 24(3); 708–23. ©2017 AACR.

Abstract Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612–26. ©2018 AACR.

AbstractPurpose:Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer.Experimental Design:The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6− bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in bladder cancer.Results:Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6− cells, OV6+ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ bladder cancer CSCs in an orthotopic bladder cancer model.Conclusions:OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.

Objective To study the therapeutic effects and possible mechanism of tin caulis densrobii in patients with Sjogren's syndrome.Methods Twenty patients with Sjogren's syndrome were randomly divided into two groups(treated group and non-treated group),every group had 10 cases.And 10 healthy people were selected as control group.Treated group was given tin caulis dendrobii,three times a day,5 mL per day.Non treated group and control group were given normal saline instead.After one week treatment,salivary flow,pathological grade of labial gland,and the expression of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),aquaporin-5(AQP5) in peripheral blood were detected.Results The salivary flow in treated group was significantly higher than that of the non-treated group and control group(P＜0.05).The expression of TNF-α and IL 1β3 in treated group were significantly lower than those in non treated group and control group(P＜0.05),while the expression of AQP5 in treated group was significantly higher when compared to the patients without treatment(P＜0.05).Besides,correlation analysis showed that the expressions of TNF-α,IL-1β3 and AQP5 had a linear correlation with pathological grade of the labial gland(P＜0.05).Conclusion Tin caulis dendrobii could improve the pathological status of the labial gland by regulating the expression of TNF-α,IL-1β and AQP-5 mRNA,and thus it has a therapeutic effect on the patients with Sjogren's syndrome.

Objective:To establish optimal extraction procedure of polysaccharides from tin caulis dendrobii and observe its curative effects on patients with primary Sjgren's syndrome.Methods:Orthogonal design was adopted,and time and times of boiling,solid-fluid ratio were selected as variable factors.The effects of patients with primary Sjgren's syndrome were observed by measuring the total curative effect,saliva flow and routine blood.Results:The most favorable extraction conditions were as follows,boiling 8 times and 0.5 hours each time with solid-fluid ratio of 1:20.Compared with before treatment,the static flow was increased in the two groups after treatment,and the polysaccharides groups increased more than the hydroxychloroquine sulfate group.The treatment efficiency of the polysaccharides group was 80%,and the efficiency of the hydroxychloroquine sulfate group was 73.33%.Conclusion:Polysaccharides from tin caulis dendrobii could improve the symptoms of patients with primary Sjgren's syndrome.