膀胱尿路上皮癌患者外周血CK20、CD105及CD146表达的临床意义

目的检测膀胱尿路上皮癌患者外周血中血清肿瘤标志物CK20、CD105和CD146的表达,探讨CK20、CD105和CD146作为膀胱尿路上皮癌微转移指标的应用价值。方法采用流式细胞仪检测50例膀胱尿路上皮癌患者、30例健康志愿者外周血中CK20及CD105/CD146的表达情况。分析膀胱尿路上皮癌患者外周血中CK20及CD105/CD146的阳性表达率及其与临床病理学指标的关系;CK20及CD105/CD146在膀胱尿路上皮癌患者外周血中表达的相关性及联合检测的意义。结果CK20和CD105/CD146在膀胱癌组中的阳性表达率分别为28.0%和48.0%,其表达与肿瘤分期、病理分级、有无远处转移、肿瘤直径、病灶数量等相关(P<0.05),而与患者性别、年龄无相关性(P>0.05)。患者中有10例同时出现CK20及CD105/CD146阳性表达,两者的表达有相关性(χ2=4.276,r=0.281,P<0.05)。联合检测与单独检测CK20相比,阳性率有所提高,差异有统计学意义(P=0.005);联合检测与单独检测CD105/CD146相比,阳性率差异无统计学意义(P=0.423),但阳性率仍有提高。结论CK20及CD105/CD146对于预测膀胱尿路上皮癌微转移具有较高的敏感性。联合检测CK20及CD105/CD146与单项检测相比,具有更高的敏感性。CK20及CD105/CD146可以作为膀胱尿路上皮癌微转移早期诊断、早期治疗和预后判断的生物学指标。     

CD146与前列腺癌微血管生成关系的研究

目的探讨前列腺癌(PCa)组织中CD146(Mel-CAM,MUC18)的表达与其微血管形成的关系。方法采用免疫组化(EnVision+TM)方法检测45例PCa、24例良性前列腺增生(BPH)组织中CD146蛋白的表达和CD34标记的肿瘤微血管数目和密度(MVD)值。结果CD146蛋白在BPH和PCa组织阳性表达率分别为12.5%和82.2%;BPH与PCa组织的MVD值分别为20.40±10.25和36.10±9.94;两者均较对照组(BPH)差异有统计学意义(P<0.01)。CD146阳性组与CD146阴性组间的MVD值存在显著性差异(P<0.01)。CD146的表达与PCa分化程度、临床病理分期无统计学意义(P>0.05)。结论CD146表达是PCa形成的早期事件,CD146可能参与了前列腺癌浸润和转移过程;CD146在前列腺癌微血管形成过程中发挥了重要作用;CD146可作为判断前列腺癌预后的指标和治疗的新靶点。     

miRNA 146a对软骨细胞MMP 13表达的影响

目的研究在正常软骨细胞及中期和晚期骨关节炎(osteoarthritis,OA)软骨细胞中上调或下调miRNA 146a后基质金属蛋白酶13(matrix metallopeptidase 13,MMP 13)的表达变化规律。探索miRNA 146a在骨关节炎发生、发展中的作用。方法收集正常人膝关节软骨4例,骨关节炎患者膝关节软骨12例。骨关节炎组又依据Kellgren-Lawrence的放射学诊断标准分为中期和晚期骨关节炎。通过化学转染的方法转染miRNA 146a mimic或miRNA 146a inhibitor于各组软骨细胞,测定上调或下调miRNA 146a后,MMP 13蛋白水平表达的变化。结果正常人软骨细胞中上调miRNA146a后,MMP13的蛋白水平较对照组及抑制组均出现明显的上升,结果具有统计学意义;下调miRNA146a后,MMP 13蛋白水平下降,结果没有统计学意义。中期OA软骨细胞表达MMP 13水平高于晚期OA软骨细胞,差异具有统计学意义。中期OA软骨细胞上调miRNA 146a后,MMP 13的蛋白水平上升,结果具有统计学意义;抑制miRNA 146a后,MMP 13的蛋白水平下降,结果具有统计学意义。晚期OA软骨细胞上调miRNA 146a后,MMP 13的蛋白水平上升,结果具有统计学意义;晚期OA软骨细胞抑制miRNA 146a后,MMP 13的蛋白水平下降,结果具有统计学意义。结论 miRNA 146a可调控软骨细胞MMP 13表达,从而参与骨关节炎的发生、发展。     

Articular cartilage surface roughness as an imaging‐based morphological indicator of osteoarthritis: A preliminary investigation of osteoarthritis initiative subjects

Current imaging‐based morphometric indicators of osteoarthritis (OA) using whole‐compartment mean cartilage thickness (MCT) and volume changes can be insensitive to mild degenerative changes of articular cartilage (AC) due to areas of adjacent thickening and thinning. The purpose of this preliminary study was to evaluate cartilage thickness‐based surface roughness as a morphometric indicator of OA. 3D magnetic resonance imaging (MRI) datasets were collected from osteoarthritis initiative (OAI) subjects with Kellgren–Lawrence (KL) OA grades of 0, 2, and 4 (n = 10/group). Femoral and tibial AC volumes were converted to two‐dimensional thickness maps, and MCT, arithmetic surface roughness (S_a), and anatomically normalized S_a (normS_a) were calculated. Thickness maps enabled visualization of degenerative changes with increasing KL grade, including adjacent thinning and thickening on the femoral condyles. No significant differences were observed in MCT between KL grades. S_a was significantly higher in KL4 compared to KL0 and KL2 in the whole femur (KL0: 0.55 ± 0.10 mm, KL2: 0.53 ± 0.09 mm, KL4: 0.79 ± 0.18 mm), medial femoral condyle (KL0: 0.42 ± 0.07 mm, KL2: 0.48 ± 0.07 mm, KL4: 0.76 ± 0.22 mm), and medial tibial plateau (KL0: 0.42 ± 0.07 mm, KL2: 0.43 ± 0.09 mm, KL4: 0.68 ± 0.27 mm). normS_a was significantly higher in KL4 compared to KL0 and KL2 in the whole femur (KL0: 0.22 ± 0.02, KL2: 0.22 ± 0.02, KL4: 0.30 ± 0.03), medial condyle (KL0: 0.17 ± 0.02, KL2: 0.20 ± 0.03, KL4: 0.29 ± 0.06), whole tibia (KL0: 0.34 ± 0.04, KL2: 0.33 ± 0.05, KL4: 0.48 ± 0.11) and medial plateau (KL0: 0.23 ± 0.03, KL2: 0.24 ± 0.04, KL4: 0.40 ± 0.10), and significantly higher in KL2 compared to KL0 in the medial femoral condyle. Surface roughness metrics were sensitive to degenerative morphologic changes, and may be useful in OA characterization and early diagnosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2755–2764, 2017.

     

Promoter polymorphism (T‐1486C) of TLR‐9 gene is associated with knee osteoarthritis in a Turkish population

In this study, we aimed to determine whether TLR‐9 T‐1486C SNP was associated with susceptibility to OA in the Turkish population. The study group comprised 272 patients with Grade 2‐3‐4 knee OA according to the Kellgren‐Lawrence scoring system and the control group was formed of 296 individuals with Grade 0–1. The TLR‐9 genotype were assessed by real‐time polymerase chain reaction. An analysis of TLR‐9 promoter −1486T/C polymorphism revealed that the −1486CC genotype appeared to have a higher risk for OA and −1486TT and −1486CT genotypes have a protective effect against the development of OA (crude OR = 0.473, 95% CI = 0.297–0.754, p = 0.002, adjusted OR = 0.531, 95% CI = 0.326–0.864, p = 0.011). This study indicate that there is a correlation of TLR‐9 T‐1486C gene polymorphism with advanced knee OA in a Turkish population. Changed in TLR expression due to different allelles may cause osteoarthrith development outcome cartilage degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2484–2489, 2017.

     

CD30, a marker to detect the high‐risk kidney transplant recipients

Abstract: Background: Sensitization of potential renal transplant recipients may impact the selection of donors and the outcome of transplant. Another element of the potential kidney transplant recipient immune system that provides useful information regarding the transplant outcome is the immunologic CD30 molecule. Methods and results: This study shows a significant correlation between the pre‐transplant high level of soluble CD30 and increased incidence of post‐transplant infection. Only 7/34 (20.6%) of the patients who had a low level of sCD30 (<90 U/mL) developed infection as compared with the 25/58 (43.1%) of the patients who had a high level (>90 U/mL) of sCD30 (p < 0.04). Higher level of sCD30 pre‐transplant was also correlated with the increased level of serum creatinine (p < 0.05) and pre‐transplant malignancy (p < 0.04). A significant higher level of sCD30 was also noted among females (74%), as compared with males (50%) with p < 0.03. In addition, significant effect of 3–6 human leukocyte antigen (HLA) mismatches on rejection was seen. Conclusions: These results show that higher pre‐transplant immunologic reactivity measured by sCD30 level was associated with post‐transplant outcome. The high level of sCD30 among females may indicate an active immunologic status, perhaps because of previous pregnancies.     

CD133 as a marker for regulation and potential for targeted therapies in glioblastoma multiforme

The CD133 epitope has been identified as a tumor marker for the purification of a subpopulation of glioblastoma multiforme (GBM) cells demonstrating cancer stem cell phenotypes. Isolated tumorsphere-forming CD133(+) GBM cells demonstrated heightened in?vitro proliferation, self-renewal, and invasive capacity. Orthotopic transplantation of CD133(+) cells led to the formation of heterogeneous tumors that were phenocopies of the original patient tumor. In this article, the authors discuss the complex regulation of CD133 expression in gliomas, its role in tumorigenesis, and its potential as a marker for targeted and personalized therapeutic intervention.     

The (−1486T/C) promoter polymorphism of the TLR‐9 gene is associated with end‐stage knee osteoarthritis in a Chinese population

Based on the recent observation that Toll‐like receptors (TLRs) may be involved in the pathogenesis of osteoarthritis (OA) we explored the possibility that human TLR gene polymorphisms are associated with OA. Two separate populations were studied in a two‐stage case–control study with a total of 503 OA patients and 428 healthy controls. The TLR‐2, TLR‐4, and TLR‐9 genotypes were assessed by real‐time polymerase chain reaction. Our data demonstrated a lack of association among TLR‐2, TLR‐4, and TLR‐9 (T‐1237C) polymorphisms and the risk of developing OA in both stages of the study. T‐1486C was significantly associated with OA in both populations with G1635A of TLR‐9 gene was found to be significantly associated with OA when the two populations were combined. Stratifying the samples by K‐L score there were significant differences in the genotype of the TLR‐9 T‐1486C and G1635A between OA of the knee grade 4 and controls. In haplotype analyses, the haplotype TTG and TTA revealed higher risk of OA and TCA confers a lower risk of OA in combined population. The present results demonstrate that TLR‐9 polymorphisms, in particular T‐1486C is significantly associated with OA. TLR‐9 gene polymorphisms may play a role in the etiology of knee OA. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:9–14, 2012     

CD146 gene expression in clear cell renal cell carcinoma: a potential marker for prediction of early recurrence after nephrectomy

Objectives

To investigate whether CD146 gene expression could provide useful information to predict early recurrence after nephrectomy.

Methods

This study included 84 patients with clear cell renal cell carcinoma (cRCC), and 44 subjects without tumor were used as controls. Quantitative RT-PCR was used to measure the CD146 gene expression.

Results

The mean value of CD146 expression in patients with metastatic cRCC (0.0438?±?0.0024) was significantly higher than in those with localized cRCC (0.0374?±?0.0012, P?=?0.018) or in controls (0.0344?±?0.0010, P?=?0.001). Of patients with localized cRCC, those with recurrence had a significantly higher CD146 expression than those without recurrence (P?=?0.029). The univariate analysis showed that CD146 was associated with early recurrence. The recurrence-free survival curve indicated that patients with a high CD146 expression had a significantly higher recurrence rate than those with a low CD146 expression (P?=?0.018).

Conclusions

CD146 gene expression can be useful for predicting early recurrence and stratifying the patients into risk groups for possible adjuvant treatment.     

N‐acetylcysteine prevents nitric oxide‐induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis

We investigated whether N‐acetylcysteine (NAC), a precursor of glutathione, could protect rabbit articular chondrocytes against nitric oxide (NO)‐induced apoptosis and could prevent cartilage destruction in an experimental model of osteoarthritis (OA) in rats. Isolated chondrocytes were treated with various concentrations of NAC (0–2 mM). Apoptosis was induced by 0.75 mM sodium nitroprusside (SNP) dehydrate, which produces NO. Cell viability was assessed by MTT assay, while apoptosis was evaluated by Hoechst 33342 and TUNEL staining. Intracellular reactive oxygen species (ROS) and glutathione levels were measured, and expression of p53 and caspase‐3 were determined by Western blotting. To determine whether intraarticular injection of NAC prevents cartilage destruction in vivo, cartilage samples of an OA model were subjected to H&E, Safranin O, and TUNEL staining. NAC prevented NO‐induced apoptosis, ROS overproduction, p53 up‐regulation, and caspase‐3 activation. The protective effects of NAC were significantly blocked by buthionine sulfoximine, a glutathione synthetase inhibitor, indicating that the apoptosis‐preventing activity of NAC was mediated by glutathione. Using a rat model of experimentally induced OA, we found that NAC also significantly prevented cartilage destruction and chondrocyte apoptosis in vivo. These results indicate that NAC inhibits NO‐induced apoptosis of chondrocytes through glutathione in vitro, and inhibits chondrocyte apoptosis and articular cartilage degeneration in vivo. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:156–163, 2010     

Meniscal extrusion and degeneration during the course of osteoarthritis in the Murine collagenase‐induced osteoarthritis model

Meniscal damage is, despite its major role in knee osteoarthritis (OA), often neglected in OA animal models. We evaluated structural meniscal degeneration during the course of OA in the murine collagenase‐induced OA (CIOA) model. To investigate this, OA was induced in the knee joints of 33 male C57BL/6 mice by an intra‐articular injection of 10U collagenase. The mice were sacrificed after 1, 3, 7, 14, 28, and 56 days, and the knees were harvested and processed for histological analysis. As control, six knees were obtained from 16‐week‐old mice in which no OA was induced. Meniscal damage, meniscal extrusion, and articular cartilage damage were evaluated on thionin‐stained sections. Associations between parameters of interest were evaluated with Spearman rho correlation tests. When compared to non‐OA knees, meniscal extrusion was visible from day 1 onwards and meniscal degeneration had a tendency to increase over time. The meniscus damage appeared around the same time as articular cartilage damage (day 14–28) and was statistically significantly more pronounced anterior than posterior, and no differences were seen between medial and lateral menisci. Meniscus and articular cartilage damage were moderately associated in the CIOA knees (ρ = 0.57; 95%CI [0.23–0.78]). Our findings suggest that the CIOA model is a valuable model to study the role of meniscal damage during OA progression and can support the development of future preventative treatment strategies. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:2416–2420, 2018.     

Intra‐articular delivery of glucosamine for treatment of experimental osteoarthritis created by a medial meniscectomy in a rat model

Glucosamine (GlcN) is a naturally occurring amino‐monosaccharide with putative chondroprotective activity. Optimum responses to GlcN are achieved at concentrations which are impractical with oral dosing. Intra‐articular delivery of a bolus dose of GlcN is one way to overcome these pharmacokinetic obstacles. In this study we report the effects of exposing primary human chondrocytes to a bolus dose of GlcN. We also locally administered GlcN in the context of a meniscal transection model of rat osteoarthritis (OA). The knees of male rats were subjected to medial meniscal transection and developed arthritic changes over 4 weeks. Treatment groups were then given thrice weekly 100 μL injections of 35 μg, 350 μg, 1.8 mg, or 3.5 mg of GlcN dissolved in normal saline. Gross images, modified Mankin scores, and histomorphometric measurements were used as outcome measures. The 350 μg dosage of GlcN had the most significant positive impact on all components of the modified Mankin score. Together, these findings suggest the local delivery of high concentrations of GlcN is well tolerated and can suppress experimental OA through influences on both bone and cartilage. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:302–309, 2014.     

CD4:CD8 ratio as a frontier marker for clinical outcome,immune dysfunction and viral reservoir size in virologically suppressed HIV-positive patients

Introduction

Absolute CD4 T cell count and plasma viral load have been established as predictors of HIV disease progression, and CD4 T cell count is used as an indicator for initiation of antiretroviral therapy. Following long-term therapy, patients generally present with significant CD4 T cell recovery contrasting with persistently elevated CD8 T cell counts, which leads to a partial restoration of CD4:CD8 ratio. This review focuses on the relevance of the CD4:CD8 ratio on clinical outcomes, immune dysfunction and HIV reservoir size in long-term treated patients.

Method

We conducted a comprehensive literature review of publications in English language using major electronic databases. Our search was focused on factors contributing to CD4:CD8 T cell ratio and clinical outcome in adult HIV-positive patients in the context of treated infection.

Discussion

Low CD4:CD8 ratio has been linked to ageing and acts as a predictor of mortality in the general population. This ratio may represent the combined effects of inflammation and immunological changes called “inflammaging.” Although the mechanisms underlying partial correction of the CD4:CD8 ratio and persistently elevated CD8 T cell count in long-term treated patients remain poorly understood, it has been recently indicated that patients with optimal CD4 T cell recovery and low CD4:CD8 ratio still harbour increased immune activation, an immune senescent phenotype and have a higher risk of non-AIDS morbidity and mortality. This review reconsiders CD4:CD8 ratio in the light of advances in the understanding of immune dysfunction and examines its pathophysiological features and implications on clinical outcome and HIV reservoir size in long-term treated HIV-positive adults.

Conclusion

The CD4:CD8 ratio can contribute to the immunological evaluation of treated patients in a long-term follow-up and may be applied for monitoring both immune dysfunction and viral reservoir size in immune-based clinical trials.     

Total joint arthroplasty in the treatment of advanced stages of thumb carpometacarpal joint osteoarthritis

PURPOSE: Osteoarthritis of the thumb basal joint is a very common and disabling condition that frequently affects middle-aged women. Many different surgical techniques have been proposed for extensive degenerative arthritis of the first carpometacarpal (CMC) joint. Joint replacement has been an effective treatment of this condition. The purpose of this article is to present the outcome of a total cemented trapeziometacarpal implant in the treatment of more advanced stages of this disease. METHODS: Total joint arthroplasty of the trapeziometacarpal joint was performed on 26 thumbs in 25 patients to treat advanced osteoarthritis (Eaton and Littler stages III and IV) between 1998 and 2003. Indications for surgery after failure of conservative treatment were severe pain, loss of pinch strength, and diminished thumb motion that limited activities of daily living. A trapeziometacarpal joint prosthesis was the implant used in this series. The average follow-up time was 59 months. RESULTS: At the final follow-up evaluation, thumb abduction averaged 60 degrees and thumb opposition to the base of the small finger was present. The average pinch strength was 5.5 kg (85% of nonaffected side). One patient had posttraumatic loosening, which was revised with satisfactory results. Radiographic studies at the final follow-up evaluations did not show signs of atraumatic implant loosening. One patient complained of minimal pain, and the remaining 24 patients were pain free. CONCLUSIONS: In our series, total joint arthroplasty of the thumb CMC joint has proven to be efficacious with improved motion, strength, and pain relief. We currently recommend this technique for the treatment of stage III and early stage IV osteoarthritis of the CMC joint in older patients with low activity demands. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.     

CD74 expression is increased in high‐grade,invasive urothelial carcinoma of the bladder

This study aimed to identify the clinicopathological features of bladder cancer patients with high CD74 expression, as milatuzumab humanized anti‐CD74 antibody is being evaluated in clinical trials for hematological malignancies. Expression of CD74 was examined in 342 urothelial carcinomas of the bladder, and two urothelial carcinoma cell lines by immunohistochemistry and western blotting, respectively. CD74 was overexpressed in 192 (56.1%) of the 342 cancer tissues, although it was not expressed in the cancer cell lines. CD74 staining was intense in tumor cells and inflammatory cells in the tumor stroma, but not in normal urothelium. CD74 expression was significantly associated with older age at diagnosis (≥68 years, P = 0.048), high World Health Organization grade (P = 0.019), advanced stages (P = 0.001) and non‐papillary growth pattern (P = 0.040). CD74 expression was also correlated with the absence of tumor‐infiltrating inflammatory cells (P < 0.001) and the presence of tumor‐associated inflammatory cells (P = 0.017). However, CD74 expression was not related to recurrence‐free and overall survivals in primary and subgroup analyses. In conclusion, urothelial bladder carcinomas with high CD74 expression are characterized by older age, high World Health Organization grade, non‐papillary growth and advanced stages.     

Association of a functional polymorphism in the promoter region of TLR‐3 with osteoarthritis: A two‐stage case–control study

Recent studies have suggested that polymorphisms in toll‐like receptor 9 (TLR‐9), an endosomal TLR, are associated with knee osteoarthritis (OA). TLR‐3, ‐7, and ‐8 are also found on the surface of endosomes and to investigate whether similar associations exist with polymorphisms in these TLR genes we performed a two‐stage case–control study and genotyped 11 TLR single nucleotide polymorphisms (SNPs) in 823 OA cases and 594 healthy controls by polymerase chain reaction restriction fragment length polymorphism assays. Real‐time PCR was performed to assess the functional expression of an identified promoter polymorphism in TLR‐3 following dexamethasone stimulation of articular chondrocytes. An association between TLR‐3 SNPs at rs3775296 and rs3775290 and OA was identified in both populations. In males the allelic frequencies of TLR‐7 rs179010 and TLR‐8 rs5744080 were significantly different between OA cases and healthy controls. The ATCA, CTCA, and CCTA haplotypes of TLR‐3 were associated with OA susceptibility. A significant difference in TLR‐3 gene expression following dexamethasone treatment was seen among the various genotypes of rs3775296 (p = 0.004). Our findings indicate that a SNP in the promoter region of TLR‐3 is associated with elevated TLR‐3 gene expression and susceptibility to knee OA in a Chinese Han population. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 680–685, 2013     

New surgical model of post‐traumatic osteoarthritis: Isolated intra‐articular bone injury in the rabbit

Osteoarthritis (OA) is a leading cause of disability worldwide. We hypothesized that inflammation following isolated intra‐articular bone injury can stimulate post‐traumatic OA and developed a rabbit model to test that concept. Sixty female New Zealand White Rabbits were used. Twenty‐six experimental animals had two holes drilled into their right femoral‐notch, 18 rabbits had sham surgery, and 16 were un‐operated controls. Rabbits were euthanized in subgroups at 72 h, 3, 6, 9, and 52 weeks. Knees were assessed grossly and tissues collected. Cartilage and synovium were analyzed with histology and qPCR and subgroups compared statistically. All surgical joints showed gross and histological (modified Mankin score) cartilage damage after surgery, with experimentals worsening with time (p < 0.05). Cartilage qPCR showed fivefold increases in TGFβ (p < 0.05) expression at 72 h and 3 weeks with sixfold increases in MMP13 (p < 0.025) expression at 72 h. By 6 weeks, expression of these markers was similar to baseline levels. Synovial membrane thickening with increased cellularity was seen at both 9 and 52 weeks (p < 0.05). Short‐term synovial inflammatory marker (IL‐1β, IL‐Ra, IL‐6, and IL‐8) expression was three‐ to fourfold increase in experimentals at 72 h (p < 0.01) returning to baseline levels by 3 weeks. Intra‐articular bone injury creates early joint inflammation with some chronic synovial changes and progressive cartilage damage consistent with OA in adult rabbits. This model provides an exciting new avenue to potentially explore some relevant inflammatory drivers of OA without major mechanical variables. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 914–920, 2013