4-Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders.

OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene-1 (IRG1) and the IRG1-itaconic acid-NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4-octyl itaconate (4-OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute-onset NMOSD and to investigate the inhibitory effects of 4-OI on NLRP3 inflammasome activation via the IRG1-itaconic acid-NLRP3 pathway in monocytes and macrophages by using in vitro models. METHODS: Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3-related inflammatory factors. Subsequently, the effects of 4-OI on the IRG1-itaconic acid-NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP-1 cells) via in vitro experiments. RESULTS: Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4-OI inhibited the activation of the IRG1-itaconic acid-NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD. INTERPRETATION: 4-OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD-derived PBMCs and in a human macrophage model. Thus, 4-OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future.

DNA methylation of skeletal muscle function-related secretary factors identifies FGF2 as a potential biomarker for sarcopenia.

BACKGROUND: Sarcopenia is characterized by progressive loss of muscle mass and function due to aging. DNA methylation has been identified to play important roles in the dysfunction of skeletal muscle. The aim of our present study was to explore the whole blood sample-based methylation changes of skeletal muscle function-related factors in patients with sarcopenia. METHODS: The overall DNA methylation levels were analysed by using MethlTarget™ DNA Methylation Analysis platform in a discovery set consistent of 50 sarcopenic older adults (aged ≥65 years) and 50 age- and sex-matched non-sarcopenic individuals. The candidate differentially methylated regions (DMRs) were further validated by Methylation-specific PCR (MSP) in another two independent larger sets and confirmed by pyrosequencing. Receiver operating characteristic (ROC) curve analysis was used to determine the optimum cut-off levels of fibroblast growth factor 2 (FGF2)_30 methylation best predicting sarcopenia and area under the ROC curve (AUC) was measured. The correlation between candidate DMRs and the risk of sarcopenia was investigated by univariate analysis and multivariate logistic regression analysis. RESULTS: Among 1149 cytosine-phosphate-guanine (CpG) sites of 27 skeletal muscle function-related secretary factors, 17 differentially methylated CpG sites and 7 differentially methylated regions (DMRs) were detected between patients with sarcopenia and control subjects in the discovery set. Further methylation-specific PCR identified that methylation of fibroblast growth factor 2 (FGF2)_30 was lower in patients with sarcopenia and the level was decreased as the severity of sarcopenia increased, which was confirmed by pyrosequencing. Correlation analysis demonstrated that the methylation level of FGF2_30 was positively correlated to ASMI (r = 0.372, P < 0.001), grip strength (r = 0.334, P < 0.001), and gait speed (r = 0.411, P < 0.001). ROC curve analysis indicated that the optimal cut-off value of FGF2_30 methylation level that predicted sarcopenia was 0.15 with a sensitivity of 84.6% and a specificity of 70.1% (AUC = 0.807, 95% CI = 0.756-0.858, P < 0.001). Multivariate logistic regression analyses showed that lower FGF2_30 methylation level (<0.15) was significantly associated with increased risk of sarcopenia even after adjustment for potential confounders including age, sex, and BMI (adjusted OR = 9.223, 95% CI: 6.614-12.861, P < 0.001). CONCLUSIONS: Our results suggest that lower FGF2_30 methylation is correlated with the risk and severity of sarcopenia in the older adults, indicating that FGF2 methylation serve as a surrogate biomarker for the screening and evaluation of sarcopenia.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Expression of TRAF6 in peripheral blood B cells of patients with myasthenia gravis.

BACKGROUND: Tumor necrosis factor receptor-associated factor 6 (TRAF6) can regulate the activation of inflammatory signaling pathways by acting as an E3 ubiquitin ligase, which enhances B cell activation. This study aimed to evaluate the expression of TRAF6 in the peripheral blood B cells of myasthenia gravis (MG) patients and analyze the relationships between TRAF6 expression and clinical characteristics. METHOD: In our study, the expression level of TRAF6 in peripheral blood B cells of 89 patients was measured by flow cytometry compared with that of healthy subjects. The effects of disease severity, MG classification and immunotherapy on TRAF6 expression level were also analyzed. RESULTS: In our study, TRAF6 expression was elevated in CD19+ B cells and CD19+CD27+ memory B cells in generalized MG (GMG) patients compared with ocular MG (OMG) patients (p = 0.03 and p = 0.03, respectively). There was a significant positive correlation between the TRAF6 expression level and disease severity in both OMG patients and GMG patients (CD19+ B cells: OMG: p < 0.001, r = 0.89; GMG: p = 0.001, r = 0.59; CD29+CD27+ B cells: OMG: p = 0.001, r = 0.80; GMG: p = 0.048, r = 0.38). TRAF6 expression was significantly elevated in CD19+ B cells and CD19+CD27+ memory B cells in GMG with acute aggravation compared with GMG in MMS (p = 0.009 and p = 0.028, respectively). In the eleven MG patients who were followed, TRAF6 expression in B cells and memory B cells was significantly decreased after treatment (p = 0.03 and p < 0.01, respectively). CONCLUSION: TRAF6 is potentially a useful biomarker of inflammation in patients with MG, and might be used to evaluate the effectiveness of treatment.

Serum Meteorin-like is associated with weight loss in the elderly patients with chronic heart failure.

BACKGROUND: Unintentional weight loss (cachexia) has been associated with poor outcomes in chronic heart failure (CHF). Meteorin-like (Metrnl) is a novel myokine with protective effects on cardiovascular diseases. However, the change of Metrnl concentrations and its role in elderly patients with CHF remains unclear. The aim of this study was to evaluate the association of serum Metrnl with weight loss and outcomes in elderly patients with CHF. METHODS: A total of 931 consecutive elderly patients (aged 60 years and older) with CHF and 135 age-matched and sex-matched control subjects were enrolled. Serum Metrnl concentration was measured by enzyme-linked immunosorbent assay. Body weight was measured at baseline and 12 months. RESULTS: Median of serum Metrnl levels was lower in CHF patients when compared with controls [201.31 (184.95-261.16) pg/mL vs. 168.68 (103.15-197.54) pg/mL, P < 0.001]. Patients with the lowest levels of Metrnl had higher N-terminal pro brain natriuretic peptide (NT-proBNP) levels but lower left ventricular eject fraction (LVEF) and estimated glomerular filtration rate (P < 0.001). Lower serum Metrnl was associated with a higher risk of >5% weight loss from baseline to 12 months [odds ratio = 6.13, 95% confidence interval (CI) = 2.57-14.62 per log decrease; P < 0.001]. Serum Metrnl levels were decreased as LVEF decreased (P < 0.001) and were positively correlated with LVEF (r = 0.267, P < 0.001) but negatively correlated with NT-proBNP levels (r = -0.257, P < 0.001). Cox regression analysis suggested that lower serum Metrnl was associated with higher cardiovascular mortality [hazard ratio (HR) = 6.71, 95% CI = 3.41-13.18 per log decrease; P < 0.001], CHF rehospitalization (HR = 3.07, 95% CI = 1.82-5.17 per log decrease; P < 0.001), and the combined major adverse cardiac event(s) (MACEs) (HR = 5.38, 95% CI = 3.51-8.25 per log decrease; P < 0.001). The Kaplan-Meier survival curves showed that low concentration of Metrnl was a prognostic indicator of MACEs in patients with CHF. CONCLUSIONS: Our study suggests that lower serum Metrnl level is correlated with weight loss and the severity of cardiac dysfunction in elderly patients with CHF.

Significant Histologic Changes Are Not Rare in Treatment-naive Hepatitis B Patients with Normal Alanine Aminotransferase Level: A Meta-analysis.

BACKGROUND AND AIMS: Chronic hepatitis B is the main cause of liver cancer. However, the most neglected group has been treatment-naive chronic hepatitis B patients with normal alanine aminotransferase (ALT). People have tended to subjectively assume that the liver lesions of these patients are not serious and do not need antiviral treatment. However, the truth is not as optimistic as we thought. We aimed in this study to analyze the proportion of significant inflammation or fibrosis in aforementioned patients. METHODS: Medline, Embase, and Cochrane Library were searched up to January 10th 2020, to identify studies of these patients with liver biopsy. The double arcsine method was used with a random-effect model to combine the proportion of significant inflammation or fibrosis. Potential heterogeneity was explored by subgroup analysis and meta-regression. Outcome of interests included the proportion of significant inflammation or fibrosis and cirrhosis. The secondary outcome was to find the risk factors of significant histological changes. RESULTS: Nineteen eligible studies, with 2,771 participants, were included. The pooled proportion of significant inflammation or fibrosis was 35% [95% confidence interval (CI): 27 to 43] and 30% (95% CI: 25 to 36), respectively. The pooled proportion of cirrhosis was 3% [95% CI: 1 to 5, (12 studies; 1,755 participants)]. In subgroup analysis, old age [vs. young (<40 years-old), 44% vs. 26%, p=0.012] was significantly associated with higher fibrosis stage as well as cirrhosis [vs. young (<40 years-old), 4.8% vs. 1.8%, p<0.001]. CONCLUSIONS: About 1/3 of the treatment-naive chronic hepatitis B patients with normal ALT show significant histological changes, and some even have cirrhosis.

Discharge may not be the end of treatment: Pay attention to pulmonary fibrosis caused by severe COVID-19.

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- ß, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- ß signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.

Combination of quantitative hepatitis B core antibody (qHBcAb) and aspartate aminotransferase (AST) can accurately diagnose immune tolerance of chronic hepatitis B virus infection based on liver biopsy.

BACKGROUND AND AIMS: Immune tolerance is defined as HBeAg positive, high hepatitis B virus load (HBV), persistent normal alanine aminotransferase (ALT), no or slight inflammation or fibrosis in liver histology. However, it is still unclear the threshold of high hepatitis B virus load and how to predict histology without liver biopsy. The aim of this study was to predict immune tolerance in HBeAg positive, alanine aminotransferase -normal populations with non-invasive indicators. METHODS: Two multi-center prospective cohort study recruited 907 treatment-naïve chronic hepatitis B (CHB) patients who had undergone liver biopsy in mainland China from August 2013 to September 2016 and April 2018 to June2019. Quantitative hepatitis B core antibody, AST and HBV DNA were investigated using commercial diagnostic assays and histological grading and staging was assessed by the Ishak scoring system. RESULTS: One hundred and thirteen untreated CHB patients with HBeAg-positive, normal alanine aminotransferase (ALT) and high level of HBV DNA (≥5log10 IU/mL) were enrolled in this study. The area under the receiver operating characteristic curves (AUROCs) of qHBcAb, AST, HBV DNA and qHBcAb-AST index were 79.6%, 80.5%, 76.4% and 87.7%. Our novel qHBcAb-AST index, which combined qHBcAb and AST showed better performance with higher sensitivity (88.6% [95% confidence interval (CI) 72.3% - 96.3%]) and negative predictive value (NPV) (93.8% [95% CI 84.2% - 98.0%]). CONCLUSIONS: The combination of qHBcAb and AST can more accurately predict the immune tolerance of people with HBeAg-positive, normal alanine aminotransferase (ALT).

Biosafety of a 3D-printed intraocular lens made of a poly(acrylamide-co-sodium acrylate) hydrogel in vitro and in vivo.

AIM: To assess the biosafety of a poly(acrylamide-co-sodium acrylate) hydrogel (PAH) as a 3D-printed intraocular lens (IOL) material. METHODS: The biosafety of PAH was first evaluated in vitro using human lens epithelial cells (LECs) and the ARPE19 cell line, and a cell counting kit-8 (CCK-8) assay was performed to investigate alterations in cell proliferation. A thin film of PAH and a conventional IOL were intraocularly implanted into the eyes of New Zealand white rabbits respectively, and a sham surgery served as control group. The anterior segment photographs, intraocular pressure (IOP), blood parameters and electroretinograms (ERG) were recorded. Inflammatory cytokines in the aqueous humor, such as TNFα and IL-8, were examined by ELISA. Cell apoptosis of the retina was investigated by TUNEL assay, and macroPAHge activation was detected by immunostaining. RESULTS: PAH did not slow cell proliferation when cocultured with human LECs or ARPE19 cells. The implantation of a thin film of a 3D-printed IOL composed of PAH did not affect the IOP, blood parameters, ERG or optical structure in any of the three experimental groups (n=3 for each). Both TNFα and IL-8 in the aqueous humor of PAH group were transiently elevated 1wk post-operation and recovered to normal levels at 1 and 3mo post-operation. Iba1+ macroPAHges in the anterior chamber angle in PAH group were increased markedly compared to those of the control group; however, there was no significant difference compared to those in the IOL group. CONCLUSION: PAH is a safe material for 3D printing of personal IOLs that hold great potential for future clinical applications.

Construction of a comprehensive nutritional index and its correlation with quality of life and survival in patients with nasopharyngeal carcinoma undergoing IMRT: A prospective study.

OBJECTIVES: The aim of this study was to investigate the relationship between a comprehensive nutritional index (CNI) and QoL in patients with NPC who undergo IMRT and to explore the relationship between CNI and survival. METHODS: 359 patients with newly diagnosed NPC were enrolled. QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 and Quality of Life Questionnaire Head and Neck Cancer Module at three time points: before, immediately after, and 3 months after IMRT. The CNI comprised five values including body mass index, usual body weight percentage, hemoglobin, albumin, and total lymphocyte count, and was evaluated before and immediately after IMRT. The correlation between the CNI and QoL and the effect of CNI on prognosis were analysed. RESULTS: QoL and CNI scores decreased remarkably after IMRT (P < 0.05). The CNI was quite low in patients with III-IV clinical tumor stage and those undergoing induction chemotherapy plus concurrent chemotherapy. After IMRT, lower CNI score correlated worse QoL (P < 0.05). The Kaplan-Meier curve indicated that patients with lower CNI had significantly poorer survival outcomes (P = 0.02). In multivariate analysis, CNI remained an independent prognostic factor of overall survival (P = 0.046). CONCLUSIONS: CNI can be recommended as an appropriate indicator reflecting the integrated nutrition status of NPC patients. Low CNI was associated with poor QoL and predicted a poor survival outcome. More interventions should be taken to improve the nutrition status of NPC patients to improve QoL and enhance survival outcomes.

Extrauterine epithelioid trophoblastic tumors presenting as lung mass: A case report and literature review.

RATIONALE: Extrauterine epithelioid trophoblastic tumors (ETT) is a rare variant of gestational trophoblastic neoplasms. Here we aim to learn more clinical and pathological characteristics of ETT patient with an isolated pulmonary mass without uterine lesions, through a rare case of extra-uterine ETT and 7 cases published in English periodicals literature. PATIENT CONCERNS: A 31-year-old Chinese woman, presented with low-level elevation of serum human chorionic gonadotropin (HCG) for more than 2 years without abnormal symptoms. Dilation and curettage (D&C) was performed and histopathology revealed a secretory phase of endometrium. Chest computed tomography (CT) scan showed a 0.8 cm nodular lesion in the upper left lobe. Then a thoracotomy with left upper lobe segmentectomy was performed. DIAGNOSIS: After pathological and immunohistochemistry diagnosis, the case was confirmed as ETT (III). INTERVENTIONS: According to FIGO guideline, the patient took 3 cycles of multivalent chemotherapy consisting of cisplatin and etoposide, alternating with etoposid, methotrexate dactinomycin (EP-EMA). OUTCOMES: The patient had no obvious signs of recurrence after 13 months of follow-up. LESSONS: When a fertile age woman persistently shows abnormal low-level escalation of HCG, ETT should be taken into consideration, especially lung X-ray or CT showing lesions without apparent abnormality of the uterus.

(­)­Epicatechin protects against myocardial ischemia­induced cardiac injury via activation of the PTEN/PI3K/AKT pathway.

Flavonol (­)­epicatechin (EPI) is primarily contained in green tea (Camellia sinensis) and cocoa beans (Theobroma cacao), and has been demonstrated to be beneficial for the health of the cardiovascular system. However, the effect and the underlying mechanism of EPI on myocardial ischemia induced cardiac injury has not yet been determined. Therefore, the present study aimed to detect whether EPI inhibited myocardial ischemia injury. An in vivo mouse myocardial ischemia model was induced by the ligation of left descending coronary artery for 7 days. EPI (1 mg/kg/day) was administrated 10 days prior to myocardial ischemia operation. The in vitro mouse myocardial ischemia model was induced by cultivating neonatal mouse cardiomyocytes under anoxia condition for 12 h. Cardiomyocytes were treated with EPI (5 µM) for 1 h and then incubated under anoxia conditions. Mouse hearts and cultured cardiomyocytes were used for hematoxylin­eosin, masson, ultrasonography, terminal dUTP nick end­labeling, immunofluorescence, western blotting and MTT assays. Results revealed that myocardial ischemia­induced mouse cardiac injury was significantly inhibited by EPI, as evidenced by decreased myocardial apoptosis, cardiac fibrosis and myocardial hypertrophy and improved cardiac function. In addition, it was confirmed that EPI serves a protective effect against myocardial ischemia via the phosphatase and tensin homolog (PTEN)/phosphoinositide 3­kinase (PI3K)/protein kinase B (AKT) signaling pathway, which was reversed by the PI3K inhibitor, LY294002. The protective role of EPI in myocardial apoptosis was further confirmed on mouse cardiomyocytes following anoxia treatment in vitro. In conclusion, the data suggested that EPI protects against myocardial ischemia induced cardiac injury through the PTEN/PI3K/AKT signaling pathway in vivo and in vitro, which may provide clinical therapeutic approaches and targets for cardiac ischemia injury.

Pretreatment quality of life as a predictor of survival for patients with nasopharyngeal carcinoma treated with IMRT.

BACKGROUND: To evaluate the prognostic significance of pretreatment quality of life for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. METHODS: We performed a prospective, longitudinal study on 554 newly diagnosed patients with NPC from April 2011 to January 2015. A total of 501 consecutive NPC patients were included. Patients were asked to complete the EORTC QLQ-C30 (version 3.0) and QLQ-H&N35 questionnaires before treatment. RESULTS: Global health status among QLQ-C30 correlates with EBV DNA(P = 0.019). In addition, pretreatment appetite loss was significantly correlated with EBV DNA(P = 0.02). Pretreatment teeth, opening mouth, feeding tube was significantly correlated with EBV DNA, with P value of 0.003, < 0.0001, and 0.031, respectively. In multivariate analysis, pretreatment cognitive functioning of QLQ-C30 was significantly associated with LRFS, with HR of 0.971(95%CI 0.951-0.990), P = 0.004. Among scales of QLQ-H&N35 for multivariate analysis, pretreatment teeth (P = 0.026) and felt ill (P = 0.012) was significantly associated with PFS, with HR of 0.984 (95%CI 0.971-.998) and 1.004 (95%CI 1.001-1.007), respectively. Felt ill of QLQ-H&N35 was significantly associated with DMFS, with HR of 1.004(95%CI 1.000-1.007), P = 0.043. There is no QoL scale significantly associated with OS after multivariate analysis. CONCLUSIONS: In conclusion, our analysis confirms that pretreatment teeth and felt ill was significantly associated with PFS in NPC patients treated with IMRT. In addition, the posttreatment EBV DNA was significantly associated with OS.

Self-Sealed Bionic Long Microchannels with Thin Walls and Designable Nanoholes Prepared by Line-Contact Capillary-Force Assembly.

Long microchannels with thin walls, small width, and nanoholes or irregular shaped microgaps, which are similar to capillaries or cancerous vessels, are urgently needed to simulate the physiological activities in human body. However, the fabrication of such channels remains challenging. Here, microchannels with designable holes are manufactured by combining laser printing with line-contact capillary-force assembly. Two microwalls are first printed by femtosecond laser direct-writing, and subsequently driven to collapse into a channel by the capillary force that arises in the evaporation of developer. The channel can remain stable in solvent due to the enhanced Van der Waals' force caused by the line-contact of microwalls. Microchannels with controllable nanoholes and almost arbitrary patterns can be fabricated without any bonding or multistep processes. As-prepared microchannels, with wall thicknesses less than 1 µm, widths less than 3 µm, lengths more than 1 mm, are comparable with human capillaries. In addition, the prepared channels also exhibit the ability to steer the flow of liquid without any external pump.

Association of down-regulation of CD109 expression with up-expression of Smad7 in pathogenesis of psoriasis.

Transforming growth factor (TGF)-ß signaling plays an important role in the pathogenesis of psoriasis. CD109, a novel TGF-ß co-receptor, which inhibits TGF-ß signaling by enhancing Smad7-dependent degradation of TGF-ß type I receptor (TGF-ß RI), is abnormally expressed in psoriasis. To date, the expression of Smad7 and the correlation between CD109 and Smad7 expression in psoriasis have not been fully elucidated. This study was designed to investigate the expression and the correlation of CD109 and TGF-ß signaling associated proteins in psoriasis and their roles in the pathogenesis of psoriasis. Thirty-two psoriasis specimens were subjected to immunohistochemical staining for CD109, Smad7, TGF-ß RI and Ki67. Ten normal skin (NS) specimens served as controls. The positive expression rate (% positive cells) of Smad7 and Ki67 in psoriasis was significantly higher than in NS (62.6%±19.9% vs. 17.2%±4.4%, and 50.7%±14.3% vs. 19.5%±3.2%, respectively, P<0.001), and the expression levels of CD109 and TGF-ß RI were reduced significantly in psoriasis as compared with NS (8.1%±6.7% vs. 35.8%±6.7% and 27.3%±3.4% vs. 3.0%±3.4%, respectively, P<0.001). There were significantly negative correlations between CD109 and Smad7 (r=-0.831, P<0.01). These findings indicated that CD109 might play a certain role in the pathogenesis of psoriasis. Lower expression of CD109 and TGF-ß RI was highly correlated with higher expression of Smad7 and Ki67, suggesting that CD109 may induce the pathogenesis of psoriasis through Smad7-mediated degradation of TGF-ß RI, and lead to the termination of TGF-ß signaling.

High efficiency integration of three-dimensional functional microdevices inside a microfluidic chip by using femtosecond laser multifoci parallel microfabrication.

High efficiency fabrication and integration of three-dimension (3D) functional devices in Lab-on-a-chip systems are crucial for microfluidic applications. Here, a spatial light modulator (SLM)-based multifoci parallel femtosecond laser scanning technology was proposed to integrate microstructures inside a given 'Y' shape microchannel. The key novelty of our approach lies on rapidly integrating 3D microdevices inside a microchip for the first time, which significantly reduces the fabrication time. The high quality integration of various 2D-3D microstructures was ensured by quantitatively optimizing the experimental conditions including prebaking time, laser power and developing time. To verify the designable and versatile capability of this method for integrating functional 3D microdevices in microchannel, a series of microfilters with adjustable pore sizes from 12.2 µm to 6.7 µm were fabricated to demonstrate selective filtering of the polystyrene (PS) particles and cancer cells with different sizes. The filter can be cleaned by reversing the flow and reused for many times. This technology will advance the fabrication technique of 3D integrated microfluidic and optofluidic chips.

Expression of USP15, TßR-I and Smad7 in psoriasis.

The deubiquitinating enzyme ubiquitin specific peptidase 15 (USP15) is regarded as a regulator of TGFß signaling pathway. This process depends on Smad7, the inhibitory factor of the TGFß signal, and type I TGFß receptor (TßR-I), one of the receptors of TGFß. The expression level of USP15 seems to play vital roles in the pathogenesis of many neoplasms, but so far there has been no report about USP15 in psoriasis. In this study, immunohistochemical staining of USP15, TßR-I and Smad7 was performed in 30 paraffin-embedded psoriasis specimens and 10 normal specimens to investigate the expression of USP15, TßR-I and Smad7 in psoriasis and to explore the relevance among them. And USP15 small interfering RNA (USP15 siRNA) was used to transfect Hacat cells to detect the mRNA expression of TßR-I and Smad7. Of 30 cases of psoriasis in active stage, 28, 24 and 26 cases were positive for USP15, TßR-I and Smad7 staining, respectively. The positive rates of USP15 and Smad7 were significantly higher in psoriasis specimens than in normal skin specimens (44.1%±26.0% vs. 6.1%±6.6%, 47.2%±27.1% vs. 6.6%±7.1%), and positive rate of TßR-I (20.3%±22.2%) in psoriasis was lower than that in normal skin specimens (46.7%±18.2%). There was a significant positive correlation between USP15 and Smad7 expression, and significant negative correlations between USP15 and TßR-expression, an I d between TßR- and Smad7 expression I in psoriasis. After transfection of USP15 siRNA in Hacat cells, the expression of TßR-mRNA was up I -regulated and that of Smad7 was down-regulated. It is concluded that USP15 may play a role in the pathogenesis of psoriasis through regulating the TßR-I/Smad7 pathway and there may be other cell signaling pathways interacting with USP15 to take part in the development of psoriasis.

Olmsted syndrome: a case report and review of literature.

We report a case of an 18-month-old boy with slightly whitened fingernails and toenails since birth. At the age of 100 days, he progressively developed bilateral palmoplantar keratoderma which resulted in painful walking and disabled grasping. Perianal keratotic plaques and perioral hyperkeratotic erythema could also be observed. Both fingernails and toenails were dystrophic. Scalp hairs were sparse, but total alopecia was no present. The histopathologic changes of the biopsy from the inner side of the right foot showed nonspecific changes, which mainly showed highly hyperkeratosis and acanthosis with slight superficial perivascular inflammatory infiltration. A clinical diagnosis of Olmsted syndrome was established according to the typical feature of the lesions, which is the presence of symmetrical palmoplantar keratoderma with periorificial keratotic plaques. We review the literature and present a summary of all reported cases to date.

[Expression of neutral endopeptidase and motility-related protein-1 in cutaneous malignant melanoma].

OBJECTIVE: To study the expression of neutral endopeptidase (CD10) and motility-related protein-1 (CD9) in malignant melanoma and their clinical significance. METHODS: Immunohistochemical study for CD10 and CD9 using Streptavidin-biotin complex technique was carried out in 48 cases of primary cutaneous malignant melanoma (CMM), 23 cases of metastatic melanoma and 23 cases of benign nevus. RESULTS: The positivity rate of CD10 was highest in metastatic melanoma and lowest in benign nevus (P < 0.01). In contrast, the positivity rate of CD9 in metastatic melanoma was lower than that in CMM (P < 0.05). The expression of CD9 was inversely correlated with that of CD10 in malignant melanoma (CMM: r = -0.40, P = 0.005; metastatic MM: r = -0.44, P = 0.034). The expression of CD10 and CD9 in CMM also correlated with tumor histology, Clark's level of invasion and presence of nodal metastasis. A similar relationship was also observed for CD10 and CD9 expression in stromal fibroblasts of CMM (r = -0.43, P = 0.007). CONCLUSIONS: CD10 and CD9 expression correlates with the invasiveness and metastatic potential of malignant melanoma; both factors may demonstrate a counteracting effect. These two markers have potential implications in prognostic assessment of CMM. Stromal fibroblasts may also play an important role in the progression of CMM.