Hyperactive lateral habenula mediates the comorbidity between rheumatoid arthritis and depression-like behaviors.

Rheumatoid arthritis (RA) patients have a high prevalence for depression. On the other hand, comorbid with depression is associated with worse prognosis for RA. However, little is known about the underlying mechanisms for the comorbidity between RA and depression. It remains to be elucidated which brain region is critically involved in the development of depression in RA, and whether alterations in the brain may affect pathological development of RA symptoms. Here, by combining clinical and animal model studies, we show that in RA patients, the level of depression is significantly correlated with the severity of RA disease activity and affects patients' quality of life. The collagen antibody-induced arthritis (CAIA) mouse model of RA also develops depression-like behaviors, accompanied by hyperactivity and alterations in gene expression reflecting cerebrovascular disruption in the lateral habenula (LHb), a brain region critical for processing negative valence. Importantly, inhibition of the LHb not only alleviates depression-like behaviors, but also results in rapid remission of RA symptoms and amelioration of RA-related pathological changes. Together, our study highlights a critical but previously overlooked contribution of hyperactive LHb to the comorbidity between RA and depression, suggesting that targeting LHb in conjunction with RA treatments may be a promising strategy for RA patients comorbid with depression.

Adipose derived mesenchymal stem cells alleviated osteoarthritis and chondrocyte apoptosis through autophagy inducing.

OBJECTIVE: We aim to explore the effect of adipose derived mesenchymal stem cells (ADMSCs) on a knee osteoarthritis rat model and analyze how ADMSCs affect chondrocyte apoptosis. MATERIALS AND METHODS: A surgically induced rat knee osteoarthritis (OA) model was constructed. ADMSCs were engrafted into the right knee cavity. Hematoxylin and eosin (H&E), Masson, and Safranin O were used to compare the histopathology of synovial membrane and cartilage. Immunohistochemical (IHC) was used to measure MMP-13, Collagen 2 (Col-2), Caspase-3 (Cas-3), PARP, p62, LC3b, DDR-2, FGFR-1, Wnt, P-AKT/AKT, p-CAMKII/CAMKII, and p-Smad1/Smad1 expression in the articular cartilage. qPCR and Western blot analysis were used to detect mRNA and protein levels of markers in chondrocytes. TUNEL and Annexin-V were used to assess apoptosis. RESULTS: Histological analysis showed that ADMSCs alleviated the deterioration of cartilage and osteoarthritis. ADMSCs coculture increase the expression of Col2 and Sox-9, while down regulated MMP-13 in IL-1ß stimulated chondrocytes. ADMSCs decreased proinflammatory cytokines IL-1ß, IL-6, and TNF-α. ADMSCs enhanced the viability of IL-1ß stimulated chondrocytes. ADMSC attenuated chondrocyte apoptosis. The pretreatment of 3-methyladenine (3-MA) reversed the reduction of Caspase-3 caused by ADMSCs, showing that the antiapoptotic effect was associated with autophagy inducing. ADMSCs significantly reduced the expression of FGFR-1, DDR-2, and Wnt in IL-1ß stimulated chondrocytes. ADMSCs reduced the ratio of p-Smad1/Smad1 and p-CAMK II/CAMKII, and increased the ratio of p-AKT/AKT. CONCLUSIONS: ADMSCs treatment alleviate osteoarthritis in rat OA models. AMDSCs reduced the secretion of proinflammatory cytokines and protected against apoptosis through autophagy inducing. ADMSCs' function could be related to multiple signaling pathway.

Efficiency of dose reduction strategy of etanercept in patients with axial spondyloarthritis.

OBJECTIVES: To evaluate the efficacy of different tapering or discontinuation strategies of etanercept in a cohort of axial spondyloarthritis from South China. METHODS: We performed a retrospective cohort study. Axial SpA patients who achieved clinical remission for at least 6 months after receiving a standard dose of etanercept therapy were enrolled. Different tapering or discontinuation strategies were compared. RESULTS: Altogether, 258 cases were enrolled. No differences were found in baseline characteristics among the three groups. Significantly more patients on discontinuation group (19%) than tapering group (5.4%, p<0.001) relapsed as early as 6 months. Almost all of the patients (103/107, 96.3%) in taper 25% group and more than 80% (71/88, 80.7%) of the patients in taper 50% group maintained low disease activity (LDA) or clinical remission during the first year. At the end of the 2-year follow-up, the percentage of patients maintaining LDA or remission were 28.6% (discontinuation), 55.7% (taper 50%), 84.1% (taper 25%), respectively. Activity indexes were significantly lower in taper 25% group compared to the other two groups. Patients in discontinuation group and tapering 50% group, with longer SpA duration were more likely to relapse, and remission>12 months before discontinuation/tapering helped to reduce relapse. CONCLUSIONS: It is feasible to slowly increase the dosing interval and transit to the lowest effective dosing interval for some patients in remission/LDA. Prolonging the time under remission before tapering help to improve the outcome. Tapering 25% of the etanercept dose every 3 months may be a pragmatic approach for more cost-effective use of the drug.

Incidence and predictive factors for malignancies with dermatomyositis: a cohort from southern China.

OBJECTIVES: We aimed to explore the incidence of malignancy in dermatomyositis and assess the potential risk factors of occurrence of malignancy in DM from southern China. METHODS: A retrospective cohort study of patients admitted in the 1st affiliated university hospital between 2003 and 2012 was performed. Demographic information, clinical symptoms, laboratory findings, medications were documented. The endpoint of the study was defined as occurrence of malignancy or death. RESULTS: For this approximately 10-year retrospective study, 60 out of 246 dermatomyositis patients developed malignancies with the overall incidence of 24.4%. Nasopharyngeal carcinoma (NPC) and ovarian carcinoma were the most common malignant disease, accounting for 35% (21/60) and 15% (9/60) of malignancies, respectively. Lung and colon were followed as the third most common carcinoma (5 out of 60, 8.3%). Among these 60 patients with malignancies, 39 (65.0%, 39/60) cases occurred within 1 year after DM diagnosis. Subsequently, malignancies were detected in 13 (21.7%, 13/60) patients during the second year and 8 (13.3%, 8/60) during the third year. One patient developed cancer at the 35th month after DM as the latest. The logistic regression multivariate analysis indicated that male gender [odds ratio (OR) = 3.76, 95% confidence interval (CI ) 1.86~7.61, p<0.01], dysphagia (OR= 2.21, 95%CI 1.10~4.48, p=0.03) and elevated erythrocyte sedimentation rate (ESR) (OR= 2.37, 95% CI 1.18~4.75, p=0.02) were risk factors for the occurrence of malignancies, while interstitial lung disease (ILD) acted as a protective factor (OR=0.13, 95%CI 0.06~0.28, p<0.01). CONCLUSIONS: It was necessary to carry out routine malignancy screening for Chinese DM patients due to its high incidence. Nasopharyngeal carcinoma and ovarian cancer were the most common malignant disease. The risk of malignancy was highest in the first year after DM diagnosis and reduced thereafter. Extensive work-ups for malignancy screening should be carried out at the first year. Male gender, dysphagia and elevated ESR were risk factors for occurrence of malignancy. The presence of ILD could diminish the risk of coexisting of malignancy.

Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA.

To investigate the effect of simvastatin on the migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and its cellular signal mechanisms, FLS from active RA patients were stimulated with 3 % FBS or GM-CSF in the presence or absence of simvastatin. Cells migration and invasion in vitro were measured by the Boyden chamber method. RhoA activity was assessed by a pull-down assay. Matrix metalloproteinases-2 (MMP-2) activity was evaluated by zymography. Simvastatin inhibits FBS- or GM-CSF-induced migration in a dose-dependent manner by RA FLS, and this inhibitory effect is independent of cell apoptosis. We also found that simvastatin suppressed in vitro invasion, adhesion, MMP-2 activity, cytoskeletal reorganization and RhoA activation. Furthermore, mevalonate or GGPP treatment reversed the inhibitory effect of simvastatin not only on migration and invasion in vitro but also on RhoA activation, and inhibition of RhoA by specific siRNA transfection reduced migration, adhesion and invasion of RA FLS. This study shows that simvastatin reduces RA FLS migration and invasion through the prevention of protein geranylgeranylation and RhoA activation. These findings provide a novel evidence that statin may be benefit for preventing RA arthritic destruction, and also indicate that RhoA may be a new target for the modulation of RA FLS migration and invasion.

Clinical features and independent predictors in the further development of rheumatoid arthritis in undifferentiated arthritis.

This study aims to investigate the prognosis of undifferentiated arthritis (UA) and to estimate the putative predictors contributing to predict the development of UA into rheumatoid arthritis (RA); thus, it could improve appropriate medical intervention. A retrospective cohort study of 218 patients with an initial diagnosis of UA and 2-year follow-up monitoring was carried out. The baseline information including demographic variables, clinical features, and laboratory data was collected. A logistic regression model was used for the statistical analysis. After 2 years of follow-up, 20.18% of UA patients evolved into RA, but 33.03% remained undifferentiated. Meanwhile, 25.23% went into remission, and 21.56% developed into other connective tissue diseases. Univariate and multivariate analysis showed that the titer of antibodies to cyclic citrullinated peptide (anti-CCP), tender joint count and duration of morning stiffness were independent predictors for the development of RA. The area under the curve (AUC) of duration of morning stiffness (0.81) was largest, followed by tender joint count (0.74). The AUC of anti-CCP antibodies (0.68) was higher than that of rheumatoid factor of IgM type (IgM-RF) (0.60), and the combination of these two antibodies was significantly higher than each alone (P < 0.001). In conclusion, UA patients had variable clinical outcomes and prognosis. Only the titer of anti-CCP antibodies, tender joint count, and duration of morning stiffness, instead of IgM-RF, could predict the development of RA. Although the anti-CCP antibody was better than the IgM-RF in predicting RA, a combined detection of them still improved the diagnostic performance.

[Associated factors for the occurrence of lupus enteritis].

OBJECTIVE: To explore the clinical and laboratory characteristics of patients with lupus enteritis to provide rationales for clinical diagnosis and treatment. METHODS: A retrospective group control study was conducted for systemic lupus erythematosus (SLE) patients with complaints of acute abdominal pain from 2004 to 2011. They were divided into 2 groups: lupus enteritis (n = 66) and non-lupus related abdominal pain (n = 73). The associated factors included demographic, laboratory, clinical and radiographic data. RESULTS: Lupus enteritis (39.3%) was the most common cause of lupus patients with acute abdominal pain. There were no differences in autoantibody profiles, complement, erythrocyte sedimentation rate, C reactive protein and SLE disease activity index (SLEDAI) score between two groups. The level of D-dimer and European consensus lupus activity measurement (ECLAM) score were significantly higher in the group of lupus enteritis than those in non-lupus related gastrointestinal injury. Lupus enteritis had significantly higher percentage of complications with multiple serous cavity effusions and ascites. But after adjusting with logistic regression multivariate analysis, only the level of D-dimer, ECLAM and volume of ascites were associated with occurrence of lupus enteritis. CONCLUSION: Lupus enteritis is the most common cause of acute abdominal pain. D-dimer is an excellent predictor for lupus abdominal pain. As compared with SLEDAI, ECLAM may be more suitable for assessment in SLE patients with alimentary tract injury.

Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats.

INTRODUCTION: Adipose derived mesenchymal stem cells (ADMSCs), carrying the similar characteristics to bone marrow mesenchymal stem cells, only much more abundant and easier to obtain, may be a promising treatment for liver fibrosis. We aim to investigate the therapeutic potential of ADMSCs transplantation in liver fibrosis caused by carbon tetrachloride (CCl4) in rats as well as its underlying mechanism, and to further explore the appropriate infusion pathway. METHODS: ADMSCs were isolated, cultured and identified. Placebo and ADMSCs were transplanted via portal vein and tail vein respectively into carbon tetrachloride (CCl4)-induced liver fibrosis rats. Computed tomography (CT) perfusion scan and microvessel counts were performed to measure the alteration of liver microcirculation after therapy. Liver function tests and histological findings were estimated. RESULTS: CT perfusion scan shown significant decrease of hepatic arterial perfusion index, significant increased portal vein perfusion, total liver perfusion in rats receiving ADMSCs from portal vein, and Factor VIII (FVIII) immunohistochemical staining shown significant decrease of microvessels in rats receiving ADMSCs from portal vein, indicating microcirculation improvement in portal vein group. Vascular endothelial growth Factor (VEGF) was significantly up-regulated in fibrosis models, and decreased after ADMSCs intraportal transplantation. A significant improvement of liver functional test and histological findings in portal vein group were observed. No significance was found in rats receiving ADMSCs from tail vein. CONCLUSIONS: ADMSCs have a therapeutic effect against CCl4-mediated liver fibrosis. ADMSCs may benefit the fibrotic liver through alteration of microcirculation, evidenced by CT perfusion scan and down-regulation of VEGF. Intraportal transplantation is a better pathway than tail vein transplantation.

Farnesoid X receptor protects human and murine gastric epithelial cells against inflammation-induced damage.

Bile acids from duodenogastric reflux promote inflammation and increase the risk for gastro-oesophageal cancers. FXR (farnesoid X receptor/NR1H4) is a transcription factor regulated by bile acids such as CDCA (chenodeoxycholic acid). FXR protects the liver and the intestinal tract against bile acid overload; however, a functional role for FXR in the stomach has not been described. We detected FXR expression in the normal human stomach and in GC (gastric cancer). FXR mRNA and protein were also present in the human GC cell lines MKN45 and SNU5, but not in the AGS cell line. Transfection of FXR into AGS cells protected against TNFα (tumour necrosis factor α)-induced cell damage. We identified K13 (keratin 13), an anti-apoptotic protein of desmosomes, as a novel CDCA-regulated FXR-target gene. FXR bound to a conserved regulatory element in the proximal human K13 promoter. Gastric expression of K13 mRNA was increased in an FXR-dependent manner by a chow diet enriched with 1% (w/w) CDCA and by indomethacin (35 mg/kg of body weight intraperitoneal) in C57BL/6 mice. FXR-deficient mice were more susceptible to indomethacin-induced gastric ulceration than their WT (wild-type) littermates. These results suggest that FXR increases the resistance of human and murine gastric epithelial cells to inflammation-mediated damage and may thus participate in the development of GC.

Clinical features and hyperferritinemia diagnostic cutoff points for AOSD based on ROC curve: a Chinese experience.

Hyperferritinemia has been reported in adult-onset Still's disease (AOSD). This study aims to investigate clinical features of AOSD in Chinese population and diagnostic value of different hyperferritinemia cutoff points based on ROC curve. A total of 48 patients from October 2002 to February 2007 diagnosed AOSD in the department of rheumatology, the first affiliated hospital of Sun Yat-set University were enrolled. A total of 86 patients mainly complaining fever >39°C for over one week and meeting Yamaguchi criteria but confirmed as non-AOSD by other serological or pathological tests were obtained from the same department as controls. Total serum ferritin levels were determined at the time of admission. Clinical features of AOSD in Chinese population were similar to previous studies. Significantly higher levels of total serum ferritin were presented in patients with AOSD (8100.7 ± 13678.5) compared with non-AOSD controls (448.3 ± 539.4) (P < 0.01). No differences were found in serum ferritin level between different categories of non-AOSD patients (P > 0.05). High value of area under receiver operating characteristic curve (ROC curve) suggested that ferritin was very predictive in AOSD diagnosis. Three cutoff points were picked based on clinical practice and ROC curve. Ferritin level ≥2,500 µg/L appeared to be highly specific for a diagnosis of AOSD, yet the low sensitivity may falsely ruled out patients with true AOSD. Hyperferritinemia ≥750 µg/L was seldom observed in inflammatory diseases or solid tumor. Hyperferritinemia ≥1,250 µg/L could mostly rule out other autoimmune diseases and hematologic diseases. Combined Yamaguchi criteria and hyperferritinemia gave better prediction for AOSD. In conclusion, different hyperferritinemia cutoff points observed in ROC curve help to optimize diagnostic and therapeutic strategy.

Treatment efficacy of etanercept and MTX combination therapy for ankylosing spondylitis hip joint lesion in Chinese population.

To investigate the efficacy of etanercept and MTX (methotrexate) combination therapy in Chinese patients with ankylosing spondylitis hip joint lesion, the possible courses and maintenance protocol, altogether 97 ankylosing spondylitis patients fulfilling the modified New York criteria with hip joint lesion were enrolled in a 12-month trial treated with combined etanercept and MTX. All these patients were required to be poor responders to SSZ (Sulfasalazine) or MTX therapy for 6 consecutive months or the longer. Etanercept was administered subcutaneously twice a week at a fixed dosage of 25 mg for the first six months, followed by 25 mg once a week in patients with good control of both symptoms and radiological progression, or twice a week for another six months in patients with BASDAI > or = 4. Combined MTX was administered intravenously once a week at the dosage of 15 mg. Demographics, clinical and laboratory features, physical function and quality of life using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), Harris hip score, and radiological assessment using the BASRI-hip index were recorded. Most patients achieved pain release at the end point of assessment. Significant improvement in Bath AS Disease Activity Index (BASDAI) (P < 0.05), Bath AS Functional Activity Index (BASFI) (P < 0.05), and Harris hip score (P < 0.05) was demonstrated. Radiographic progression was recorded as no exacerbation or alleviated. Larger interval between two etanercept administrations would provide similar advantages to standard method and possibly less adverse events if MTX was combined. Etanercept and MTX combination therapy was beneficial to ankylosing spondylitis patients with hip joint lesion, and staged dosage deduction in the long term proved to be effective as well as adverse event preventing.

Activation of farnesoid X receptor attenuates liver injury in systemic lupus erythematosus.

To investigate the expression and effect of farnesoid X receptor (FXR) on systemic lupus erythematosus (SLE) liver dysfunction and indicate its hepatoprotective role and the immunomodulatory property. mRNA and protein levels of FXR were determined on the liver specimens of SLE patients with liver injury as well as MRL/lpr rodent models. The FXR agonist chenodeoxycholic acid (CDCA) was administrated to MRL/lpr mice and the control BALB/C with concanavalin A (ConA)-induced liver injury. Blood samples were taken 0, 4, 8, 12, 16, and 24 h after ConA injection for the detection of serum ALT, AST, IFN-γ, TNF-α, and IL-6. FXR was down-regulated at both mRNA and protein levels in the liver specimens of SLE patients with liver injury as well as MRL/lpr mice. MRL/lpr was more susceptible to ConA than BALB/C indicated by significantly higher levels of aminotransferase and inflammatory cytokines. Activation of FXR by CDCA significantly reduced aminotransferase and inflammatory cytokines IFN-γ, TNF-α, and IL-6 caused by ConA injection in MRL/lpr mice. FXR was down-regulated in SLE patients as well as MRL/lpr lupus models with liver dysfunction. FXR activation ameliorated liver injury and suppressed inflammatory cytokines, thereby showing its protective function in SLE. Our findings raised the promising potential target for the treatment of SLE liver injury.

Clinical features and independent predictors of pulmonary arterial hypertension in systemic lupus erythematosus.

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic lupus erythematosus (SLE). We aim to estimate the putative predictors contributing to early identification of PAH, thus improve appropriate medical intervention and a better prognosis. A retrospective case-control study was conducted. Forty-one SLE patients with PAH and 106 SLE patients without PAH were enrolled. Demographic variables, clinical features, and laboratory data were compared between the two groups. Univariate and multivariate logistic regression models were used to examine the predictors contributing to PAH in SLE. Serositis, Raynaud's phenomenon, high disease activity, anticardiolipin antibodies, and anti-U1RNP were significantly associated with SLE-PAH. Univariate and multivariate analysis showed that Raynaud's phenomenon, anticardiolipin antibodies, and anti-U1RNP were independent predictors of PAH in SLE. This study highlighted the clinical pattern of SLE-PAH patients, and underlined the leading predictors of PAH development among patients with SLE. Routine echocardiography is recommended in SLE patients with the independent predictors mentioned above.

Polymorphisms in the ASAP1 and SP110 Genes and Its Association with the Susceptibility to Pulmonary Tuberculosis in a Mongolian Population.

Tuberculosis (TB) remains one of the deadliest infectious diseases in the world. Previous genome-wide association studies suggested that single-nucleotide polymorphisms (SNPs) in some genes could indicate the susceptibility to TB in some populations. Herein, we studied the association of SNPs in the immunity-related genes, i.e., ASAP1 and SP110 genes with the susceptibility to TB in a Mongolian population in China. A case-control study was performed with 197 TB patients and 217 healthy controls. Six SNPs in ASAP1 and six SNPs in SP110 were selected for genotyping test by second-generation sequencing technique. A SNP in SP110 gene (rs722555) was identified to be associated with susceptibility to TB in the Mongolian population (p < 0.05). The T allele of rs722555 in SP110 gene was associated with a 36% increase of risk at TB (OR 1.36, 95% CI 1.03-1.81), and the CT+TT genotype of rs722555 was associated with a 74% increase of risk at TB (OR 1.74, 95% CI 1.16-2.60) in the dominant genetic model. None of SNPs in ASAP1 gene tested in this study were significantly associated with TB susceptibility, while some individuals with SNPs (rs10956514, rs4733781, rs2033059, rs12680942, rs1017281, rs1469288, and rs17285138) in the ASAP1 gene tended to have a reduced risk at TB. In conclusion, this study suggested that the rs722555 SNP in SP110 gene might be a risk factor for TB in a Mongolian population.

[Radiological progression and life quality analysis in ankylosing spondylitis patients using etanercept/methotrexate combination therapy].

OBJECTIVE: To analyze the relationship between the radiological progression and quality of life in ankylosing spondylitis (AS) patients using etanercept/methotrexate (MTX) combination therapy. METHODS: A total of 153 AS cases fulfilling the 1984 modified New York diagnostic criteria were reviewed. All patients received radiological evolution at baseline and during a follow-up period. Radiological progression, clinical remission and life quality were recorded and analyzed for their relations. RESULTS: The radiological assessments of mSASSS (modified Stoke ankylosing spondylitis spine score) were recorded at baseline, 3, 6 & 12 months after treatment. Life quality assessments were recorded with SF (short-form)-36 simultaneously. No significant radiological improvement was observed at the end points. However, most patients reported a significant improvement of life quality after a combination therapy of etanercept/MTX. BASDAI (Bath ankylosing spondylitis disease activity index), C-reactive protein and erythrocyte sedimentation rate demonstrated similar trends. With no relevance with mSASSS, life quality was significantly correlated with disease activity and pain control. CONCLUSION: The combination therapy of etanercept/MTX greatly improves life quality in AS patients. Yet clinical remission and pain control offer no hint of a suspension of radiological progression. Routine radiological assessment is required throughout the follow-up period of AS even if life quality index reaches a high level.

Budd-Chiari syndrome in Behcet's disease: A report of two cases.

Budd-Chiari syndrome (BCS) is a rare but severe venous form of Behcet's disease (BD) that is caused by the obstruction of the venous outflow tract that transports blood from hepatic veins into the inferior vena cava. In countries where BD is prevalent, including the Middle East and Far East, BCS awareness is important. In the present study, two cases of BCS are presented in two male Chinese patients with BD. The clinical characteristics, treatment and outcomes were recorded and compared with previous studies, and the features of BD-BCS were summarized. The clinical characteristics of the two patients documented were similar. Each patient presented with insidious onset, abdominal symptoms and recurrent aphthous ulcers. Accurate diagnosis was delayed as other symptoms of BD were overlooked. Each patient responded well to TNF-α inhibitor treatment in combination with cyclophosphamide (CYC). One patient with good compliance was removed from CYC and corticosteroid therapy. Unfortunately, the other patient with poor compliance faced a poor outcome. It was concluded that multiple vessel lesions in ≥2 sites are common in vasculo-BD and that misdiagnosis may occur if other symptoms of BD are not noticed. BD-BCS is associated with a high mortality rate, but appropriate treatment may result in a favorable outcome.

Biomodal Tumor-Targeted and Redox-Responsive Bi2 Se3 Hollow Nanocubes for MSOT/CT Imaging Guided Synergistic Low-Temperature Photothermal Radiotherapy.

Hyperthemia (>50 °C) induced heating damage of nearby normal organs and inflammatory diseases are the main challenges for photothermal therapy (PTT) of cancers. To overcome this limitation, a redox-responsive biomodal tumor-targeted nanoplatform is synthesized, which can achieve multispectral optoacoustic tomography/X-ray computed tomography imaging-guided low-temperature photothermal-radio combined therapy (PTT RT). In this study, Bi2 Se3 hollow nanocubes (HNCs) are first fabricated based on a mild cation exchange way and Kirkendall effect and then modified with hyaluronic acid (HA) through redox-cleavable linkage (-s-s-), thus enabling the HNC to target cancer cells overexpressing CD-44 and control the cargo release profile. Finally, gambogic acid (GA), a type of heat-shock protein (HSP) inhibitor, which is vital to cells resisting heating-caused damage is loaded, into Bi2 Se3 HNC. Such HNC-s-s-HA/GA under a mild NIR laser irradiation can induce efficient cancer cell apoptosis, achieving PTT under relatively low temperature (≈43 °C) with remarkable cancer cell damage efficiency. Furthermore, enhanced radiotherapy (RT) can also be experienced without depth limitation based on RT sensitizer Bi2 Se3 HNC. This research designs a facile way to synthesize Bi2 Se3 HNC-s-s-HA/GA possessing theranostic functionality and cancer cells-specific GSH, but also shows a low-temperature PTT RT method to cure tumors in a minimally invasive and highly efficient way.

Intra-arterial chemotherapy combined with intravesical chemotherapy is effective in preventing recurrence in non-muscle invasive bladder cancer.

OBJECTIVE: To evaluate the efficacy and safety of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IC) in non-muscle invasive bladder cancer (NMIBC) and identify the risk factors for recurrence and progression. METHODS: This is a retrospective cohort study of NMIBC patients in south China. Ninety-nine patients underwent IAC combined with transurethral resection of bladder tumor (TURBT) and IC, and 50 patients underwent TURBT plus IC without IAC. The 5-year outcomes of the two groups were compared. Cox regression was used to evaluate risk factors. Kaplan-Meier curves were used to assess the significant differences of recurrence-free survival and progression-free survival. RESULTS: At 5 years, IAC significantly reduced the recurrence of high-grade NMIBC, 54.5% (18/33) in the non-IAC group vs 30.5% (18/59) in the IAC group (p = 0.028). IAC significantly reduced the recurrence of high-risk NMIBC, 56.3% (18/32) in the non-IAC group vs 26.1% (18/69) in the IAC group (p = 0.007). IAC significantly reduced the recurrence of intermediate-risk NMIBC, 44.4% (8/18) in the non-IAC group vs 22.2% (6/27) in the IAC group (p = 0.030). Tumors numbering from 2 to 7 had the highest recurrence rate (18.1%, 27/149). In this aspect, there was a significantly lower recurrence rate in the IAC group (30.8%, 12/30) than in the non-IAC group (68.2%, 15/22) (p = 0.007). No significant difference was found in the progression rate between the two groups. Only two cases (2/99, 2.0%) in the IAC group showed progression. The results of univariate and multivariate analyses suggested that the number of tumors, grade and risk level were risk factors for recurrence. No difference was found with respect to gender, age, tumor diameter, and T category. In the Kaplan-Meier plot, recurrence-free survival was significantly associated with treatment strategies (p < 0.01). Recurrence-free survival was shorter in the non-IAC group (12.73 ± 7.56 months) than in the IAC group (17.88 ± 12.26 months). CONCLUSIONS: Combined IAC is a promising procedure to prevent recurrence and may be useful to suppress progression in NMIBC patients. The independent risk factors for the recurrence of NMIBC were multifocal tumors, grade and risk level. Intra-arterial chemotherapy is an effective and safe procedure and may be a promising choice in areas where BCG is not available or for patients who are intolerant to BCG.

Amplification of SMYD3 promotes tumorigenicity and intrahepatic metastasis of hepatocellular carcinoma via upregulation of CDK2 and MMP2.

SMYD3, a member that belongs to the SET and MYND-domain (SMYD) family, has also been proven to largely participate in gene transcription regulation and progression of several human cancers as a histone lysine methyltransferase. However, the role and significance of SMYD3 in both the clinic and progression of hepatocellular carcinoma (HCC) remain unclear. Herein, we find that SMYD3 is increased in cirrhotic livers, and strikingly upregulated in hepatocellular carcinoma (HCC) tissues and cell lines. Subsequent analyses suggest that high expression level of SMYD3 significantly correlates with the malignant characteristics of HCC, and predicts poor prognosis in patients. Our results show that overexpression of SMYD3 increases, while silencing of SMYD3 inhibits, cell proliferation, invasiveness and tumorigenicity both in vitro and in vivo. SMYD3 also promotes intrahepatic metastasis of HCC cells. For the mechanisms, we identify that SMYD3 bound to CDK2 and MMP2 promoter and increased H3K4me3 modification at the corresponding promoters to promote gene transcription. Importantly, pharmacological targeting of SMYD3 with BCI-121 inhibitor effectively repressed the tumorigenicity of HCC cells. Finally, our results show that gene locus amplification is a cause for SMYD3 overexpression in HCC. These findings not only uncover that SMYD3 overexpression promotes the tumorigenicity and intrahepatic metastasis of HCC cell via upregulation of CDK2 and MMP2, but also suggest SMYD3 could be a practical prognosis marker or therapeutic target against the disease.

[Abnormal signaling activity of phosphatidylinositol 3-kinase pathway in peripheral blood T cells from patients with systemic lupus erythematosus].

OBJECTIVE: To investigate the activity of phosphatidylinositol 3-kinase (PI3K) signal pathway, a cytoplasmic signaling pathway known to play an important role in T cell activation, in peripheral blood T cells from systemic lupus erythematosus (SLE) patients. METHODS: T cells were isolated from the peripheral blood samples of 28 SLE patients, 5 males and 23 females, with RosettSep T cell purification kit. PI3K activity was determined by immunoprecipitation and ELISA, and Western blotting was used to measure the Akt and phosphorylated Akt protein expression. T cell proliferation and cytokine production was examined by MTT test and ELISA respectively. Fifteen healthy adults and 8 active rheumatoid arthritis patients were used as controls. The T cells from the SLE patients and normal controls were treated with 10% normal control serum of SLE serum for 24 h ("rest") and then to detect the P13K and Akt activity. Some T cells from the SLE patients were stimulated with CD3/CD28 mono-antibodies or CD3/CD28 mono-antibodies + LY294002, a specific P13K inhibitor, and then the proliferation and secretion of IL-6 and IL-10 were analyzed. RESULTS: Compared with the healthy controls and rheumatoid arthritis patients, the activity levels of PI3K and Akt in the T cells of peripheral blood from the SLE patients were significantly increased. T cells allowed to "rest" for 24 hours in culture medium showed a reversal of the changes in activity of PI3K and Akt. The activity of PI3K pathway was increased in the T cells from healthy controls when cultured with SLE serum. The proliferation and IL-6 and IL-10 secretion of the T cells from SLE patients cultured with LY294002 were inhibited. The P13K and Akt activity levels of the T cells from SLE patients were not related to SLE disease activity index (SLEDAI). CONCLUSION: The T cells from SLE patients show an abnormal activation of PI3K pathway which may be due, at least in part, to their exposure to relevant serum factors.