Heparin-binding epidermal growth factor-like growth factor (HB-EGF) activates p38 to affect pulmonary fibrosis.

Objective: We aimed to examine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) affects the lung fibrosis process through the activation of p38 protein in mitogen-activated protein kinases (MAPK) signaling pathway, as well as the expression of downstream inflammatory factors. Methods: The expression levels of HB-EGF, collagen type I (COL-I), and hexokinase 2 (HK2) in peripheral blood mononuclear cells (PBMCs) of patients with connective tissue disease-related interstitial lung disease (CTD-ILD) were examined by qPCR, Western blotting and ELISA. Results: In vitro experiments showed that HB-EGF was increased in almost all subtypes [rheumatoid arthritis (RA), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIMs)] as well as in all groups (P < 0.05). For embryonic lung fibroblast (A549) cells, the expression levels of HK2 and α-smooth muscle actin (α-SMA) genes were elevated during 0-4 h and then plateaued. Transforming growth factor-ß1 (TGF-ß1) induced fibrosis in human embryonic lung fibroblasts (MRC-5) cells and A549 for a certain period of time, but the degree of induction varied, which may be related to the redifferentiability of cells at different spatial locations. Moreover, HB-EGF at concentrations above 1 ng/ml stimulation increased COL-I expression (P < 0.05), and for α-SMA gene, even 1 ng/ml concentration of HB-EGF had a stimulatory effect, and different concentrations of HB-EGF did activate the expression of p38 in a concentration-dependent manner within a certain concentration range, and by The qPCR results showed that for interleukin 6 (IL-6), an inflammatory factor regulated downstream of p38, the expression was significantly increased in A549 cells compared to control (P < 0.05), but tumor necrosis factor-α (TNF-α) expression was downregulated (P < 0.05), but for interleukin-1ß (IL-1ß) gene, there was no significant difference in A549 cells, and expression was downregulated in MRC-5 cells. Therefore, it is suggested that HB-EGF regulates the expression of inflammatory factors through p38 will be differential across cells. Conclusion: Our study shows that HB-EGF can suppress pulmonary fibrosis through downstream activation of p38/MAPK pathway activity, as well as the expression of various inflammatory factors downstream of it.

Long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha treatment for patients with Behcet's uveitis: A systematic review and meta-analysis.

AIM: This study aims to evaluate the long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha (anti-TNF-α) therapy for patients with Behcet's uveitis (BU) using meta-analysis. METHODS: We searched the Web of Science and PubMed databases for eligible studies up to December 1, 2022. The quality of each identified study was assessed using the Joanna Briggs Institute's case series literature quality assessment tool. Statistical analysis was conducted using Stata 16.0 software with a random-effects model. RESULTS: Twelve studies comprising 1156 patients with BU were included in our analysis. We found that 85.0% of patients achieved ocular inflammation remission after receiving anti-TNF-α treatment, with a 95% confidence interval (CI) ranging from 78.7% to 90.5%. Additionally, 77.4% (95% CI: 57.5%-92.5%) experienced an improvement in visual acuity (VA). Moreover, the pooled dose reduction of glucocorticoids (GCs) was 11.08 mg (95% CI: -13.34 mg to -8.83 mg). Throughout the follow-up period, the cumulative retention rate of the medication was 67.3% (95% CI: 53.7%-79.6%). Serious adverse events occurred in 5.8% (95% CI: 3.1%-8.9%) of cases, with the three most common types being severe infusion or injection reactions (2.7%; 95% CI: 0.8%-5.4%), tuberculosis (1.3%; 95% CI: 0.0%-3.9%), and bacterial pneumonia (1.3%; 95% CI: 0.1%-3.4%). Subgroup analysis revealed that ocular inflammation remission rates were 89.3% (95% CI: 81.2%-95.5%) for adalimumab treatment and 83.7% (95% CI: 75.3%-90.8%) for infliximab treatment. The drug retention rate after adalimumab therapy was 70.3% (95% CI: 62.0%-78.0%) compared to 66.4% (95% CI: 48.6%-82.2%) for infliximab treatment. Furthermore, the incidence of severe infusion or injection reactions was 2.2% (95% CI: 0.1%-5.8%) following adalimumab treatment and 3.5% (95% CI: 0.7%-7.7%) following infliximab treatment. CONCLUSIONS: Anti-TNF-α therapy represents an effective treatment for BU patients with favorable safety profile and high drug retention rate and a potential advantage of adalimumab over infliximab in terms of ocular inflammation remission, drug retention, and the incidence of severe infusion or injection reactions.

Predictors of rapidly progressive interstitial lung disease and prognosis in Chinese patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis.

Background: Rapidly progressive interstitial lung disease (RP-ILD) is the most serious complication of anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM). This study was performed to assess the prognostic factors of patients with anti-MDA5+ DM and the clinical characteristics and predictors of anti-MDA5+ DM in combination with RP-ILD. Methods: In total, 73 MDA5+ DM patients were enrolled in this study from March 2017 to December 2021. They were divided into survival and non-survival subgroups and non-RP-ILD and RP-ILD subgroups. Results: The lactate dehydrogenase (LDH) concentration and prognostic nutritional index (PNI) were independent prognostic factors in patients with anti-MDA5+ DM: the elevated LDH was associated with increased mortality (p = 0.01), whereas the elevated PNI was associated with reduced mortality (p < 0.001). The elevated LDH was independent risk prognostic factor for patients with anti-MDA5+ DM (HR 2.42, 95% CI: 1.02-4.83, p = 0.039), and the elevated PNI was independent protective prognostic factor (HR, 0.27; 95% CI, 0.08 - 0.94; p = 0.039). Patients who had anti-MDA5+ DM with RP-ILD had a significantly higher white blood cell count and LDH concentration than those without RP-ILD (p = 0.007 and p = 0.019, respectively). In contrast, PNI was significantly lower in patients with RP-ILD than those without RP-ILD (p < 0.001). The white blood cell count and elevated LDH were independent and significant risk factors for RP-ILD (OR 1.54, 95% CI: 1.12 - 2.13, p = 0.009 and OR 8.68, 95% CI: 1.28 - 58.83, p = 0.027, respectively), whereas the lymphocyte was an independent protective factor (OR, 0.11; 95% CI, 0.01 - 0.81; p = 0.03). Conclusion: The elevated LDH and elevated PNI were independent prognostic factors for patients with anti-MDA5+ DM. The elevated LDH was independent risk factor for RP-ILD. Patients with anti-MDA5+ DM could benefit from the measurement of LDH and PNI, which are inexpensive and simple parameters that could be used for diagnosis as well as prediction of the extent of lung involvement and prognosis.

Association Between SPARC Polymorphisms and Ankylosing Spondylitis and Its mRNA and Protein Expression in a Chinese Han Population: A Case-Control Study.

Objective: We explore the association of polymorphisms in Secreted protein acidic and rich in cysteine (SPARC) with ankylosing spondylitis (AS) and detect SPARC mRNA and protein expression in a Chinese Han population. Methods: Nine single-nucleotide polymorphisms (SNPs) of SPARC were genotyped in 768 AS patients and 768 controls by TaqMan genotyping assay. mRNA expression of SPARC was detected by real-time polymerase chain reaction (RT-PCR), and serum level of SPARC protein was detected by ELISA. Results: The frequency of A allele of rs171121187 was significantly higher in AS patients than in controls (Pc=0.003, odds ratio [OR]=1.45, 95% confidence interval [95% CI] = 1.18-1.77), the AA and AC genotypes increased the risk of AS when compared with CC genotype (Pc=0.003, OR=3.96, 95% CI=1.80-8.75, and Pc=0.003, OR=1.27, 95% CI=1.01-1.61, respectively). The frequency of G allele of rs4958487 was significantly lower in AS than in controls (Pc=0.001, OR=0.60, 95% CI=0.47-0.68), the GG and GA genotypes reduced the risk of AS when compared with AA genotype (Pc=0.005, OR=0.46, 95% CI 0.18-1.14, and Pc=0.005, OR=0.60, 95% CI=0.45-0.79, respectively). The haplotype AA of rs17112187/rs4958487 significantly increased the risk of AS (P=2.31E-5, OR=1.60, 95% CI=1.28-1.98), while haplotype CG decreased the risk of AS (P=5.42E-5, OR=0.55, 95% CI=0.41-0.74). Expression levels of SPARC mRNA were significantly lower in both Peripheral blood mononuclear cells (PBMC) and granulocytes in AS patients than in controls (P=0.008 and P=0.005, respectively). SPARC protein levels were also reduced in AS patients versus the controls (P=0.002). Conclusion: This study indicates that polymorphisms in SPARC are associated with AS susceptibility, and both mRNA and protein levels of SPARC are decreased in AS patients in a Chinese Han population.

Distribution and clinical significance of anti-carbamylation protein antibodies in rheumatological diseases among the Chinese Han population.

Objective: Several studies have demonstrated that anti-carbamylation protein antibodies (Anti-CarPA) are persistent in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSC), primary Sjögren's syndrome (pSS), and interstitial lung disease associated with RA (RA-ILD). However, the relationship between anti-CarPA and other rheumatic diseases (RDs) and non-RA-ILD is not known till now. This study sought to examine the presence of anti-CarPA in Chinese Han patients with RDs and its clinical significance. Methods: The study included 90 healthy controls (HCs) and 300 patients with RDs, including RA, SLE, polymyositis/dermatomyositis (PM/DM), pSS, SSC, spondyloarthritis (SpA), anti-neutrophil cytoplasmic autoantibodies associated with vasculitis (AAV), undifferentiated connective tissue disease (UCTD), and Behcet's disease (BD). Antibodies against carbamylated human serum albumin were detected using commercial enzyme-linked immunosorbent assay kits. Correlations between clinical and laboratory parameters were analyzed. Result: Serum levels of anti-CarPA in RA (34.43 ± 33.34 ng/ml), SLE (21.12 ± 22.23 ng/ml), pSS (16.32 ± 13.54 ng/ml), PM/DM (30.85 ± 17.34 ng/ml), SSC (23.53 ± 10.70 ng/ml), and UCTD (28.35 ± 21.91 ng/ml) were higher than those of anti-CarPA in the HCs (7.30 ± 5.05 ng/ml). The concentration of serum anti-CarPA was higher in patients with rheumatic disease-related interstitial lung disease (RD-ILD), especially RA-ILD, PM/DM-ILD, and pSS-ILD. Patients with RD-ILD who tested positive for anti-CarPA were more likely to have a more severe radiographic classification (grades II, p = 0.045; grades III, p = 0.003). Binary logistic regression analysis suggested that anti-CarPA had an association with ILD in RA (p = 0.033), PM/DM (p = 0.039), and pSS (p = 0.048). Based on receiver operating characteristics (ROC) analysis, anti-CarPA cutoffs best discriminated ILD in RA (>32.59 ng/ml, p = 0.050), PM/DM (>23.46 ng/ml, p = 0.038), and pSS (>37.08 ng/ml, p = 0.040). Moreover, serum levels of anti-CarPA were correlated with antibodies against transcription intermediary factor 1 complex (anti-TIF1) (R = -0.28, p = 0.044), antibodies against glycyl-transfer ribonucleic acid synthetase (anti-EJ) (R = 0.30, p = 0.031), and antibodies against melanoma differentiation-associated gene 5 (anti-MDA5) (R = 0.35, p = 0.011). Conclusion: Serum anti-CarPA could be detected in patients with RA, PM/DM, pSS, SSC, and UCTD among the Chinese Han population. And it may also assist in identifying ILD in patients with RA, PM/DM, and pSS, which emphasized attention to the lung involvement in anti-CarPA-positive patients.

Elevated platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with polymyositis/dermatomyositis: a retrospective study.

OBJECTIVES: This study aimed to examine the diagnostic and prognostic value of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in patients with polymyositis/dermatomyositis (PM/DM). METHOD: Clinical data of 200 patients with PM/DM and 204 healthy controls were retrospectively reviewed. We examined whether the PLR and NLR were associated with PM/DM. RESULTS: The PLR and NLR were higher in patients with PM/DM than in controls (both P < 0.001). The PLR and NLR were higher in patients with DM than in those with PM (both P < 0.01). The PLR was higher in the anti-melanoma differentiation-associated protein-5 (anti-MDA5) + PM/DM group than in the anti-MDA5- PM/DM group (P = 0.002). The NLR in non-survivors was higher than that in survivors (P = 0.01). The NLR was positively correlated with the occurrence of interstitial lung disease (ILD). The PLR and NLR were independent predictors of PM/DM, as well as risk factors (both P < 0.001). Moreover, the NLR had a predictive value for PM/DM-ILD and was closely related to mortality (P = 0.033, P = 0.003, respectively). CONCLUSIONS: Patients with PM/DM have a higher NLR and PLR than healthy controls, especially in those with anti-MDA5+. The PLR and NLR are independent risk factors for PM/DM and have some predictive value. The NLR is correlated with ILD and associated with an increased risk of mortality in patients with PM/DM. The NLR and PLR may be simple, economical, and accurate diagnostic and prognostic markers for patients with PM/DM. Key points • The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been studied in numerous inflammatory diseases as potential markers, but their clinical significance in polymyositis/dermatomyositis (PM/DM) remains unclear. • We examined the changes in the NLR and PLR between patients with PM/DM and healthy controls, as well as their association with mortality, interstitial lung disease, and anti-melanoma differentiation-associated protein-5. • Patients with PM/DM may benefit from using the NLR and PLR as simple, economical, and accurate diagnostic and prognostic markers.

CENPF knockdown inhibits adriamycin chemoresistance in triple-negative breast cancer via the Rb-E2F1 axis.

Drug resistance occurs frequently in triple-negative breast cancer (TNBC) and leads to early relapse and short survival. Targeting the DNA damage response (DDR) has become an effective strategy for overcoming TNBC chemoresistance. CENPF (centromere protein) is a key regulator of cell cycle progression, but its role in TNBC chemotherapy resistance remains unclear. Here, we found that CENPF, which is highly expressed in TNBC, is associated with a poor prognosis in patients receiving chemotherapy. In addition, in vitro CENPF knockdown significantly increased adriamycin (ADR)-induced cytotoxicity in MDA-MB-231 cells and ADR-resistant cells (MDA-MB-231/ADR). Then, we demonstrated that CENPF targets Chk1-mediated G2/M phase arrest and binds to Rb to compete with E2F1 in TNBC. Considering the crucial role of E2F1 in the DNA damage response and DNA repair, a novel mechanism by which CENPF regulates the Rb-E2F1 axis will provide new horizons to overcome chemotherapy resistance in TNBC.

Efficacy and Safety of Anti-Tumor Necrosis Factor-Alpha Agents for Patients with Intestinal Behcet's Disease: A Systematic Review and Meta-Analysis.

PURPOSE: Intestinal Behcet's disease (BD) is a systemic autoimmune disease for which treatment options are limited. As a prospective therapeutic strategy for intestinal BD, anti-tumor necrosis factor-alpha (anti-TNF-α) agents have received increasing attention. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of anti-TNF-α agents for patients with intestinal BD. MATERIALS AND METHODS: We searched PubMed, Embase, and Cochrane Library databases up to July 1, 2021 and articles that met the eligibility criteria were further assessed. Pooled rates were synthesized by a randomized effects model using Stata software. RESULTS: Eleven clinical trials covering 671 patients with intestinal BD were included. According to compositive data, the pooled rate for remission was 39% [95% confidence interval (CI) 26-52] in patients receiving anti-TNF-α agents. Intestinal symptoms were cured in 70% (95% CI 53-84) of the patients, and the rate for endoscopic healing was 65% (95% CI 52-78). Corticosteroid discontinuation was achieved in 43% (95% CI 28-58) of the patients, and the dose reduction of corticosteroid was 20.43 mg (95% CI 13.4-27.46). There were 239 adverse events and 80 serious adverse events during follow-up. CONCLUSION: Our study indicated that anti-TNF-α agents may serve as an effective treatment with acceptable safety for patients with intestinal BD. However, more robust evidence from randomized controlled trials is urgently needed to assess the long-term efficacy and safety of anti-TNF-α agents for those patients.

Role of CXCL16 in BLM-induced epithelial-mesenchymal transition in human A549 cells.

Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial-mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-ß1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-ß1/Smad3 signaling pathway.

Gene testing for osteonecrosis of the femoral head in systemic lupus erythematosus using targeted next-generation sequencing: A pilot study.

BACKGROUND: Previous publications indicated that genetic predisposition might play important roles in the onset of osteonecrosis of the femoral head (ONFH) in systemic lupus erythematosus (SLE). Some gene loci such as complement C3d receptor 2 (CR2), nitric oxide synthase 3 (NOS3), collagen type II alpha 1 chain (COL2A1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), and transient receptor potential cation channel subfamily V member 4 (TRPV4) were reported to be involved in this process. AIM: To investigate whether the risk of ONFH in SLE is associated with single nucleotide variations (SNVs) in these five genes. METHODS: SNVs in the CR2, NOS3, COL2A1, PTPN22, and TRPV4 genes were examined by using FastTarget and Illumina Miseq sequencing technologies in 49 cases of SLE with ONFH. Burrows-wheeler aligner was used to align the sequencing reads to hg19, and GATK and Varscan programs were used to perform SNV calling. PolyPhen-2, SIFT, and MutationTaster were used to assess the functional effects of non-synonymous SNVs. RESULTS: Six of the 49 patients were confirmed to have low frequency SNVs, including one patient with SNVs in NOS3 (exon 6: c.814G>A: p.E272K and exon 7: c.814G>A: p.E272K.), four in COL2A1 (rs41263847: exon 29: c.1913C>T: p.T638I, exon 28: c.1706C>T: p.T569I, and rs371445823: exon 8: c.580G>A: p.A194T, exon 7: c.373G>A: p.A125T), and one in CR2 (rs45573035: exon 2: c.200C>G: p.T67S). CONCLUSION: The onset of ONFH in SLE might be associated with the identified SNVs in NOS3, COL2A1, and CR2.

The contribution of macrophages to systemic lupus erythematosus.

As a heterogeneous autoimmune disease associated with severe organ damage, the precise mechanisms of systemic lupus erythematosus (SLE) remain to be clarified. Recent research indicates that innate immunity plays vital roles in SLE. Defects in the phagocytosis of apoptotic cells, aberrant activation and imbalanced polarization of macrophages, have been shown to participate in the pathogenesis of SLE. Treatments targeting these processes may ameliorate the disease activity in lupus models as well as in patients with SLE. Macrophages participate in the initiation of autoimmunity and the development of SLE in multiple levels. Better understanding of this complex disease is the prerequisite for exploring more effective therapies of SLE.

Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials.

BACKGROUND: Programmed death 1 protein (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are promising cancer immunotherapy. Their dermatologic safety profiles are still poorly understood. The purpose of this article is to evaluate the incidence of selected dermatologic and mucosal adverse effects (AEs) and determine the risk of developing these adverse events associated with PD-1/PD-L1 inhibitors, compared with chemotherapy or ipilimumab. METHODS: PubMed was searched for eligible studies (up to February 21, 2019). Only phase II and phase III randomized controlled trials (RCTs) compared with chemotherapy or ipilimumab monotherapy were included in this meta-analysis. RESULTS: A total 11,465 patients from 18 clinical trials were included in this meta-analysis. Rash and pruritus were the most frequently reported dermatologic AE, with incidence 11.8% and 12.2% respectively. Compared with patients receiving chemotherapy, PD-1/PD-L1 inhibitor treated patients had higher risk of developing rash (RR = 1.84), pruritus (RR = 3.74) and vitiligo (RR = 9.54), and also lower risk in developing mucosal inflammation (RR = 0.26), stomatitis (RR = 0.26), and alopecia (RR = 0.03). Additionally, anti-PD1/PD-L1 drugs had similar risk of developing rash and lower risk of inducing pruritus compared to ipilimumab. In the subgroup analysis, PD-L1 inhibitor demonstrated better safety than PD-1 inhibitor in developing rash, with RR = 1.38 and RR = 2.11, respectively. CONCLUSION: Our meta-analysis concluded that anti PD-1/PD-L1 drugs have different dermatological and mucosal safety profile compared to conventional therapy, and differences of dermatological toxicity between PD-1 and PD-L1 inhibitor warrant further investigation.

Association of polymorphisms in TNF and GRN genes with ankylosing spondylitis in a Chinese Han population.

The aim of this study is to investigate the association of the polymorphisms in tumor necrosis factor (TNF) and granulin (GRN) with ankylosing spondylitis (AS) in a Chinese Han population. Five single nucleotide polymorphisms (SNPs) covering TNF and six SNPs covering GRN were investigated in 861 Chinese Han AS patients and 864 healthy controls. For rs1799964, the C allele was linked to reduced risk of AS (p < 0.0001, OR = 0.60, 95% CI = 0.50-0.71). The carriers of the C/C homozygote showed a significantly lower risk of AS compared with the TT homozygote and the C/T heterozygote under the recessive model (p < 0.0001, OR = 0.23, 95% CI = 0.12-0.45). For rs1800629, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.54, 95% CI = 0.39-0.74). For rs1800630, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.59, 95% CI = 0.48-0.72). The carriers of the A/A homozygote showed a significantly lower risk of AS compared with the C/C homozygote and the A/C heterozygote under the recessive model (p < 0.0001, OR = 0.18, 95% CI = 0.07-0.47). For rs769178, the T allele was linked to increased risk of AS (p < 0.0001, OR = 2.59, 95% CI = 2.18-3.09). The carriers of the T/T homozygote showed a significantly higher risk of AS compared with the GG homozygote and the G/T heterozygote under the recessive model (p < 0.0001, OR = 3.34, 95 %CI = 1.95-5.72). There was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs361525. For GRN, there was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs25646, rs3760365, rs3785817, rs4792939, rs5848, rs850713 (p > 0.05). This study indicates that polymorphisms in TNF are related to AS, but polymorphisms in GRN are not related to AS susceptibility in a Chinese Han population.

Role of collagen triple helix repeat containing-1 in tumor and inflammatory diseases.

Initially, collagen triple helix repeat containing-1 (CTHRC1) is expressed mainly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels, and increases cell migration, promotes tissue repair in response to injury. A variety of studies demonstrated that over-expression of CTHRC1 in solid tumors results in enhancement of migration and invasion of tumor cells, and is associated with decreased overall survival and disease-free survival. CTHRC1 expression is elevated in hepatitis B virus-infected patients and highly correlated with hepatocellular carcinoma progression as well. Furthermore, CTHRC1 plays a pivotal role in a great many fields, including increases bone mass, prevents myelination, reverses collagen synthesis in keloid fibroblasts, and increases fibroblast-like synoviocytes migration speed and abundant production of arthritic pannus in rheumatoid arthritis. Therefore, it will provide new insight into the pathogenesis of tumor and autoimmune diseases, and will shed new light on the therapy of related clinical diseases.

Novel Gas Sensor Arrays Based on High-Q SAM-Modified Piezotransduced Single-Crystal Silicon Bulk Acoustic Resonators.

This paper demonstrates a novel micro-size (120 µm × 200 µm) piezoelectric gas sensor based on a piezotransduced single-crystal silicon bulk acoustic resonator (PSBAR). The PSBARs operate at 102 MHz and possess high Q values (about 2000), ensuring the stability of the measurement. A corresponding gas sensor array is fabricated by integrating three different self-assembled monolayers (SAMs) modified PSBARs. The limit of detection (LOD) for ethanol vapor is demonstrated to be as low as 25 ppm with a sensitivity of about 1.5 Hz/ppm. Two sets of identification code bars based on the sensitivities and the adsorption energy constants are utilized to successfully discriminate isopropanol (IPA), ethanol, hexane and heptane vapors at low and high gas partial pressures, respectively. The proposed sensor array shows the potential to form a portable electronic nose system for volatile organic compound (VOC) differentiation.

Biomolecular stiffness detection based on positive frequency shift of CMOS compatible gigahertz solidly mounted resonators.

In this work, gigahertz solidly mounted resonators (SMRs) (2.5GHz) were designed and fabricated to construct a novel particle-resonator system to achieve the biomolecular stiffness sensing in real time. The positive frequency shift of the system was used to estimate the stiffness of biomolecules connecting between the SMR and attached particles. The working principle was revealed by the mathematical analysis of the general block-spring model of the system. Further interpretations about the mechanism of such elastic interaction from the perspective of acoustic resonant modes of SMRs were given by finite element method. Biotin-streptavidin, antibody and antigen binding system were used as model molecular linkers to study the frequency shift varied with different particle diameters and particle densities. Different linker stiffness was realized by adjusting the concentrations of antigens connected with particles which form specific binding with antibodies immobilized on the SMR. The results fairly agree with the simulation results demonstrating the proposed particle-resonator system as an effective method to realize the real-time biomolecular stiffness detection.

Cyclocurcumin, a curcumin derivative, exhibits immune-modulating ability and is a potential compound for the treatment of rheumatoid arthritis as predicted by the MM-PBSA method.

The control and treatment of rheumatoid arthritis is a challenge in today's world. Therefore, the pursuit of natural disease-modifying antirheumatic drugs (DMRDs) remains a top priority in rheumatology. The present study focused on curcumin and its derivatives in the search for new DMRDs. We focused on prominent p38 mitogen-activated protein (MAP) kinase p38α which is a prime regulator of tumor necrosis factor-α (TNF-α), a key mediator of rheumatoid arthritis. In the present study, we used the X-ray crystallographic structure of p38α for molecular docking simulations and molecular dynamic simulations to study the binding modes of curcumin and its derivatives with the active site of p38α. The ATP-binding domain was used for evaluating curcumin and its derivatives. Molecular docking simulation results were used to select 4 out of 8 compounds. These 4 compounds were simulated using GROMACS molecular simulation platform; the results generated were subjected to molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) calculations. The results showed cyclocurcumin as a potential natural compound for development of a potent DMRD. These data were further supported by inhibition of TNF-α release from lipopolysaccharide (LPS)-stimulated human macrophages following cyclocurcumin treatment.

NLRP3 p.Q705K and CARD8 p.C10X single nucleotide polymorphisms are not associated with susceptibility to rheumatoid arthritis: a meta-analysis.

AIM: Genetic factors have a substantial contribution to the pathogenesis of rheumatoid arthritis (RA). Single nucleotide polymorphisms of NLRP3 p.Q705K and CARD8 p.C10X are two gene mutations that have been linked to many diseases. Here we carried out a meta-analysis to identify their association with susceptibility to RA. METHOD: Relevant studies were identified from databases, including PubMed, Cochrane Library, EMBase, Elsevier Science Direct, Web of Science, SpringerLink, and so on. Data extracted from selected studies were analyzed using the Version 12.0 STATA software. Pooled odds ratios (ORs) were calculated as the effect sizes for comparisons. RESULTS: In total, six case-control studies from five articles that contained 2705 RA patients and 2711 healthy controls were included. (i) The NLRP3 p.Q705K polymorphism in allelic model (OR = 0.908), genotypic models (OR1 = 0.786; OR2 = 0.916; OR3 = 0.729), dominant (OR = 0.909) and recessive models (OR = 0.778) were not associated with the risk of RA (all P > 0.05). (ii) The CARD8 p.C10X polymorphism in allelic model (OR = 0.995,), genotypic models (OR1 = 0.997; OR2 = 1.052; OR3 = 0.950), dominant (OR = 1.033) and recessive models (OR = 0.963) were not associated with the risk of RA (all P > 0.05). (iii) When compared with combined genotype CARD8/NLRP3 AA/CC, none of the other combined genotypes had significant pooled ORs (all P > 0.05). (iv) Individuals carrying at least one variant allele at each of the two loci showed no more susceptibility to RA than those carrying only wild-type alleles at both the NLRP3 p.Q705K and CARD8 p.C10X loci (OR = 1.056, P > 0.05). CONCLUSION: NLRP3 p.Q705K and CARD8 p.C10X polymorphisms were not associated with the susceptibility to RA, separately or in combined forms.

99Tc-MDP treatment for the therapy of rheumatoid arthritis, choroidal neovascularisation and Graves' ophthalmopathy.

Technetium 99 conjugated with methylene diphosphonate, which is an anti-inflammatory drug, can inhibit macrophage infiltration and downregulate a number of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1ß. Recently, numerous studies have indicated that it could improve rheumatoid arthritis (RA) activity by upregulating the frequency of peripheral γδ T cells and cluster of differentiation CD4+CD25+Foxp3+ Tregs, affecting the serum cytokine environment, inhibiting osteoclast formation and reducing the concentrations of rheumatoid factor-immunoglobulin M (IgM)/IgG/IgA. As well, it may have a therapeutic role for choroidal neovascularisation (CNV) and Graves' ophthalmopathy (GO). Therefore, it will be a valuable choice in the treatment of RA, CNV and GO.

A standardized method for quantifying proliferation by Ki-67 and cyclin A immunohistochemistry in breast cancer.

Immunohistochemical analysis of proliferation markers such as Ki-67 and cyclin A is widely used in clinical evaluation as a prognostic factor in breast cancer. The proliferation status of tumors is guiding the decision of whether or not a patient should be treated with chemotherapy because low-proliferative tumors are less sensitive by such treatment. However, the lack of optimal cutoff points and selection of tumor areas hamper its use in clinical practice. This study was performed to compare the Ki-67 and cyclin A expression counted in hot-spot vs average counting based on 5 to 14 random tumor areas in 613 breast carcinomas. We correlated the findings with 10-year follow-up in order to standardize the evaluation of proliferation markers in clinical practice. A significant correlation was found between the percentage of positive cells estimated by Ki-67 and cyclin A both by hot-spot and by average counting. Both methods showed that high expression of Ki-67 and cyclin A is associated with more adverse tumor stage. The cutoff value for Ki-67 for distant metastases was set to 22% and to 15%, using hot-spot and average counting, respectively. For cyclin A, the values were set to 14% and 8% using the respective methods. Survival curves revealed that patients with a high hot-spot proliferation index had a significantly greater risk of shorter tumor-free survival. Our findings suggest that the determination of proliferation markers in breast cancer should be standardized to hot-spot counting and that specific cutoff values for proliferation could be useful as prognostic markers in clinical practice. Moreover, we suggest that expression levels of cyclin A could be used as a complementary marker to estimate the proliferation status in tumors, especially those with "borderline" expression levels of Ki-67, in order to more accurately estimate the proliferations status of the tumors.