Search

It remains unknown for decades how some of the therapeutic fusion proteins positive in a small percentage of cancer cells account for patient outcome. Here, we report that osteosarcoma Rab22a-NeoF1 fusion protein, together with its binding partner PYK2, is sorted into exosomes by HSP90 via its KFERQ-like motif (RVLFLN142). The exosomal Rab22a-NeoF1 fusion protein facilitates the pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages. The exosomal PYK2 activates RhoA in its negative recipient osteosarcoma cells and induces signal transducer and activator of transcription 3 activation in its recipient macrophages to increase M2 phenotype. Consequently, lung metastases of its recipient osteosarcoma cells are promoted by this exosomal Rab22a-NeoF1 fusion protein, and this event can be targeted by disrupting its interaction with PYK2 using a designed internalizing RGD peptide.

Background Gastric cancer is the second leading cancer-related mortality worldwide and more effective treatment strategies are urgently needed to combat the disease. Using lipoteichoic acid (LTA) and miR-27b-3p agomir, we aimed to assess the efficacy of this combination of therapies in treating gastric cancer. Methods The RNA levels of miR-27b-3p, FOXO3, MET, KRAS, vascular endothelial growth factor C (VEGFC), TSC1, and P65 were analyzed by quantified-PCR (Q-PCR) and the cell viability of AGS cells was analyzed by MTT. Confirm Luciferase reporter assays were used to explore the putative miR-27b-3p binding sites and Western blot analyzed the protein level of GAPDH, VEGFC, P65, AKT, and phosphorylated-AKT (p-AKT). The level of P65 in both the cytoplasm and nucleus of AGS cells was visualized by immunofluorescence assay. Subcutaneous xenograft models of gastric cancer were established, and mice were treated with miR-27b-3p agomir, LTA, or both. Hematoxylin-eosin staining and Ki-67 immunohistochemistry analysis of tumor tissues were then performed. Results The results showed that the decreased expression of miR-27b-3p in gastric cancer cell lines inhibited the viability of AGS cells, and VEGFC was confirmed as the target of miR-27b-3p. In addition, ectopic expression of miR-27b-3p significantly inhibited the AKT pathway in AGS and N87 cells, and LTA suppressed the proliferation of gastric cancer cells by inhibiting the NF-κB pathway. In an established xenograft model, both miR-27b-3p agomir alone and LTA treatment alone inhibited tumor growth and treatment which combined the two showed an even stronger inhibitory effect. Conclusions Taken together, the combined use of LTA and miR-27b-3p agomir exhibited a synergistic effect in the treatment of gastric cancer.

Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon-intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1-38 of Rab22a (Rab22a1-38) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a1-38 moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP-GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.

Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis., Osteosarcoma is an aggressive tumour and little is known the mechanisms underpinning its highly metastatic nature. Here, the authors highlight a role for the CK1α/CBX4 axis in driving metastasis, suggesting that this pathway might be targeted for therapeutic benefit.

The endocannabinoid (eCB) signaling system plays an important role in the regulation of the central nervous system (CNS). α/β-Hydrolase domain-containing 6 (ABHD6) is a transmembrane serine hydrolase that can hydrolyze monoacylglycerol (MAG) lipids such as endocannabinoid 2-arachidonic acid glycerol (2-AG); participate in neurotransmission, inflammation, glucose and lipid metabolism, tumorigenesis and other biological processes; and be a potential therapeutic target for various neurological diseases, such as traumatic brain injury (TBI), multiple sclerosis (MS), epilepsy, mental illness and pain. This review summarizes the molecular mechanisms of action and biological functions of ABHD6, particularly its mechanism of action in the pathogenesis of neurological diseases, and provides a theoretical basis for finding new pharmacological intervention targets by targeting ABHD6.

Background: Rab22a-NeoF1 fusion gene containing the 1-38aa of Rab22a (Rab22a1-38) plays a decisive role in driving tumor metastasis by activating RhoA via binding to SmgGDS607. However, its intercellular regulation remains unknown. Methods: The Lys7 (K7) acetylation of Rab22a-NeoF1 was initially identified by mass spectrum. Co-transfection, immunoprecipitation and Western blotting were used to characterize the acetyltransferases and deacetylases responsible for the K7 acetylation of Rab22a-NeoF1, and to define the interaction of proteins. The specificity of K7 acetylation of Rab22a-NeoF1 was determined by its specific anti-K7ac-Rab22a-NeoF1 antibody and its K7R mutant. RhoA-GTP was measured by RhoA activation assay. The migration and invasion were assessed by Transwell assay without and with Matrigel matrix, respectively. The orthotopic osteosarcoma metastasis model in vivo was used to monitor the lung metastases of U2OS/MTX300-Luc stably expressing Vector, Rab22a-NeoF1 or its K7R mutant with or without C646, a relatively specific inhibitor of p300/CBP. The unpaired Student t test was used for the statistical significance. Results: The K7 of Rab22a-NeoF1 is acetylated by p300/CBP while is de-acetylated by both HDAC6 and SIRT1. The K7R mutant of Rab22a-NeoF1 lacks its binding to SmgGDS607 and subsequently lost its promoting functions, such as activation of RhoA, cell migration, invasion and lung metastasis in osteosarcoma in vitro and in vivo, which are also diminished by p300/CBP inhibitor C646. Conclusion:The promoting function of Rab22a-NeoF1 is dependent on its K7 acetylation in osteosarcoma, and targeting this acetylation (e.g., C646) may benefit cancer patients, in particular osteosarcoma patients, who are positive for the Rab22a1-38.

Truncating variants in TTN (TTNtv), coding for the largest structural protein in the sarcomere, contribute to the largest portion of familial and ambulatory dilated cardiomyopathy (DCM). TTN haploinsufficiency caused by TTNtv is suggested as the disease mechanism. However, it is unclear whether TTN insufficiency causes DCM. Moreover, it is unknown whether modulation of downstream pathways serves as a therapeutic strategy for DCM caused by TTN insufficiency. Here, we show that reduction of cardiac Ttn expression by adeno-associated virus mediated shRNA (Ttn shRNA) generated DCM in mouse, demonstrating impaired cardiac performance, enlarged left ventricle (LV) and reduced LV wall thickness. A screen of 10 dysregulated and selected genes identified that Yin Yang 1 (Yy1) significantly suppressed DCM caused by Ttn shRNA. Gene profiling by RNAseq showed Yy1 modulated cell growth related genes. Ttn insufficiency activated cardiomyocyte cell cycle reentry by upregulating of Ccnd1 and Ccnd2. Cardiomyocytes activated by Ttn insufficiency did not advance to S phase by EdU incorporation assay. Yy1 promoted cardiomyocyte cell cycle by further enhancing Ccnd1 and Ccnd2 and increasing DNA replication without undergoing cell division. Importantly, upregulation of Ccnd1 and Ccnd2 suppressed DCM caused by Ttn insufficiency. Our findings demonstrate that DCM caused by Ttn insufficiency can be treated by therapeutically promoting cardiac cell cycle.

Rationale: Pathogenic variations in the lamin gene ( LMNA ) cause familial dilated cardiomyopathy (DCM). LMNA insufficiency caused by LMNA pathogenic variants is believed to be the basic mechanism underpinning LMNA -related DCM. Objective: To assess whether silencing of cardiac Lmna causes DCM and investigate the role of Yin Yang 1 ( Yy1 ) in suppressing Lmna DCM. Methods and Results: We developed a Lmna DCM mouse model induced by cardiac-specific Lmna short hairpin RNA. Silencing of cardiac Lmna induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of Yy1 suppressed Lmna DCM and cardiac fibrosis by inducing Bmp7 expression and preventing upregulation of Ctgf . Knockdown of upregulated Bmp7 attenuated the suppressive effect of Yy1 on DCM and cardiac fibrosis. However, upregulation of Bmp7 alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of Bmp7 together with Ctgf silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, upregulation of Yy1 regulated Bmp7 and Ctgf reporter activities and modulated Bmp7 and Ctgf gene expression in cardiomyocytes. Downregulation of Ctgf inhibited TGF-β (transforming growth factor-β)/Smad signaling in DCM hearts. Regulation of both Bmp7 and Ctgf further suppressed TGFβ/Smad signaling. In addition, co-modulation of Bmp7 and Ctgf reduced CD3+ T cell numbers in DCM hearts. Conclusions: Our findings demonstrate that upregulation of Yy1 or co-modulation of Bmp7 and Ctgf offer novel therapeutic strategies for the treatment of DCM caused by LMNA insufficiency.

Procollagen C-proteinase enhancer protein (PCOLCE) was originally identified as an enhancer to facilitate the catalysis of procollagens by BMP1. PCOLCE participates in the reconstitution of extracellular and corneal repair. The elevation of PCOLCE in blood indicates that breast cancer has metastasized into the bones. However, direct research on PCOLCE has not been reported. Methods: ECM candidates were identified by RNA-seq analysis from 4 normal and 16 osteosarcoma tissues. The in vitro migration and invasion abilities of osteosarcoma cells were determined by a Transwell assay. A spontaneous metastatic osteosarcoma model was established to assess osteosarcoma metastasis in vivo. The N-linked glycosylated amino acids were identified by PNGase F treatment combined with Western blotting. The mechanism of TWIST1 regulating PCOLCE transcription was elucidated by luciferase, qPCR and ChIP assays. Results: PCOLCE was markedly up-regulated in human osteosarcoma tissues compared to its expression in noncancerous adjacent tissues; high PCOLCE expression in tissues correlated with a poor patient prognosis, and the knockdown of PCOLCE by shRNAs impaired the migration, invasion and lung metastasis of osteosarcoma cells. The overexpression of wild-type PCOLCE, but not its N29Q mutant, promoted migration, invasion and metastasis, indicating that the glycosylation of PCOLCE at Asn29 is necessary for its functions in osteosarcoma. TWIST1, a key transcription factor in metastasis, was also overexpressed in osteosarcoma tissues and positively correlated with either PCOLCE or its potential procollagen substrates, such as COL1A1, COL1A2, COL5A1, COL8A2 and COL10A1. Conclusion: Our findings are the first to provide evidence that PCOLCE plays a critical role in promoting the lung metastasis of osteosarcoma, and this up-regulation of PCOLCE by TWIST1 may lead to a new therapeutic strategy to treat patients with metastatic osteosarcoma.

Although several clinical trials studied the efficacy of chitosan on weight loss, controversial results have been found. Herein, we evaluated randomized controlled trials (RCTs) of chitosan consumption in adult participants on body weight and body composition through a meta-analysis with trial sequential analysis (TSA). We searched EMBASE, MEDLINE, Web of Science, and CENTRAL databases. The primary body composition indices including body weight, body mass index (BMI), waist circumference, body fat, and hip circumference were extracted. The quality of included articles was assessed according to the Cochrane risk of bias tool. Data were pooled using the random-effects models and calculated as weighted mean difference (WMD) with 95% confidence intervals (CI). Heterogeneity investigated using I2 statistics. TSA, subgroup analyses, sensitivity analysis, meta-regression and publication bias were also evaluated. Overall, 15 eligible trials (18 treatment arms) with 1130 subjects were included. The pooled analyses revealed a significant reduction in body weight (WMD, −0.89 kg; 95% CI, −1.41 to −0.38; P = 0.0006), BMI (WMD, −0.39 kg/m2; 95% CI, −0.64 to −0.14; P = 0.002) and body fat (WMD, −0.69%; 95% CI, −1.02 to −0.35; P = 0.0001) receiving chitosan supplementation. Subgroup analyses also showed that consuming chitosan in dose (>2.4 g/d), shorter-term (

Background Chinese blood centers use Hepatitis B surface antigen (HBsAg) rapid test (RT) in pre-donation and two rounds of screening with different enzyme-linked immunosorbent assays in post-donation. Nucleic acid testing (NAT) on screening non-reactive (SC-) donations has been gradually implemented since 2010. Yet RT+ and SC-/NAT+ donors are seldom included in hepatitis B virus (HBV) positive rate estimates in Chinese blood donors. Methods We performed HBsAg neutralization test (NT) on whole blood (WB) with pre-donation RT+ results and post-donation screening reactive (SC+) samples from Mianyang and Chongqing in 2015. The annual totals of pre- and post-donation NT+ donors were combined with the annual totals of SC-/NAT+ donors to derive the estimated HBV positive rates. Result In Mianyang and Chongqing, 59.4% and 68.2% of RT+ donors in Jan-Aug 2015 contributed for NT, 95.5% and 97.2% of which were NT+ respectively. In 2015, 422 and 667 donors from Mianyang and Chongqing respectively were HBsAg RT+, yielding estimated 403 and 648 pre-donation RT+/NT+ deferrals. 411 and 668 post-donation SC+ samples were NT tested from Mianyang and Chongqing, of which 249 and 323 were NT+ respectively. An estimated 63 donors in Mianyang and 88 donors in Chongqing were SC-/NAT+. The estimated HBV confirmed positive rate in blood donors are 1.59% in Mianyang and 1.01% in Chongqing. Conclusion Pre-donation HBsAg RT effectively intercepts donations from HBV infected donors. Using NT confirmatory results from RT+, SC+ and SC-/NAT+ donors, this study provides a model for more accurate estimation for HBV positive rates in China.

N6-methyladenosin (m6A) is one of the most pervasive modification of mRNA in eukaryotes and the m6A methyltransferases and demethylases play critical roles in many types of cancer. However the role of m6A-binding proteins in cancer remains elusive. Here we report that the down-regulation of YTHDF2 was specifically induced by hypoxia in hepatocellular carcinoma (HCC) cells, and that overexpression of YTHDF2 suppressed cell proliferation, tumor growth and activation of MEK and ERK in HCC cells. Mechanistically, YTHDF2 directly bound the m6A modification site of EGFR 3’-UTR to promote the degradation of EGFR mRNA in HCC cells. This is the first report showing that YTHDF2 may act as a tumor suppressor to repress cell proliferation and growth via destabilizing the EGFR mRNA in HCC.

Summary Intracranial aneurysm (IA) is an enormous threat to human health, which often results in nontraumatic subarachnoid hemorrhage or dismal prognosis. Diagnosing IAs on commonly used computed tomographic angiography (CTA) examinations remains laborious and time consuming, leading to error-prone results in clinical practice, especially for small targets. In this study, we propose a fully automatic deep-learning model for IA segmentation that can be applied to CTA images. Our model, called Global Localization-based IA Network (GLIA-Net), can incorporate the global localization prior and generates the fine-grain three-dimensional segmentation. GLIA-Net is trained and evaluated on a big internal dataset (1,338 scans from six institutions) and two external datasets. Evaluations show that our model exhibits good tolerance to different settings and achieves superior performance to other models. A clinical experiment further demonstrates the clinical utility of our technique, which helps radiologists in the diagnosis of IAs., Highlights • GLIA-Net is a deep learning method for the clinical diagnosis of IAs • It can be applied directly to CTA images without any laborious preprocessing • A clinical study demonstrates its effectiveness in assisting diagnosis • An IA dataset of 1,338 CTA cases from six institutions is publicly released, The bigger picture Intracranial aneurysms (IAs) are enormous threats to human health with a prevalence of approximately 4%. The rupture of IAs usually causes death or severe damage to the patients. To enhance the clinical diagnosis of IAs, we present a deep learning model (GLIA-Net) for IA detection and segmentation without laborious human intervention, which achieves superior diagnostic performance validated by quantitative evaluations as well as a sophisticated clinical study. We anticipate that the publicly released data and the artificial intelligence technique would help to transform the clinical diagnostics and precision treatments of cerebrovascular diseases. They may also revolutionize the landscape of healthcare and biomedical research in the future., Intracranial aneurysm (IA) diagnosis on CTA images is laborious and time consuming in clinical routine. By combining global risk prediction with local IA recognition, the proposed GLIA-Net can robustly and efficiently assist radiologists in clinical practice without any pre- or postprocessing. The state-of-the-art performance has been validated via a multi-cohort dataset, which has been publicly released to democratize deep learning algorithms for biomedical research.

Background Spasticity and impaired hand function are common complication in patients with stroke, and it pose negative impact on quality of life. Aim We aimed to assess the effect of the combined administration of kinesio taping (KT) and modified constraint-induced movement therapy (mCIMT) on upper extremity function and spasticity in hemiplegic patients with stroke. Design A randomized controlled pilot study. Setting A hospital center. Population Patient of stroke with hemiplegia for 3-12 months. Methods Thirty-five patients were enrolled and allocated into three groups, including the sham KT and mCIMT group, KT group, or KT and mCIMT group. The KT, sham KT, and mCIMT serve as additional therapies (5 days/week for 3 weeks) besides regular rehabilitation (5 days/week for 6 weeks). KT was applied over the dorsal side of the affected hand, while mCIMT was applied to restrain the unaffected upper extremity. The outcomes included the modified Tardieu scale (mTS), Brunnstrom stage, Box and Block Test (BBT), Fugl-Meyer assessment for the upper extremity (FMA-UE), and Stroke Impact Scale version 3.0. Measurements were taken at baseline, immediately after intervention (third week), and 3 weeks later (sixth week). Results Between baseline and the third week, within-group comparisons yielded significant improvement in the wrist and hand parts of the FMA and BBT of the Sham KT and mCIMT group (P=0.007-0.035); in the hand part of the FMA, BBT, and mTS degree (P=0.005-0.024) of the KT group; and in the Brunnstrom stage of the wrist, FMA-UE, BBT, and mTS degrees (P=0.005-0.032) of the KT and mCIMT group. Between baseline and the sixth week, there was significant difference in the proximal part of the FMA and mTS degree in groups with KT, but an additional improvement on the Brunnstrom stage of the wrist was noted in the KT and mCIMT group. Conclusions KT benefits patients with stroke in spasticity reduction and upper extremity function. The combination of KT and mCIMT provides extra benefit in motor performance with a more long-lasting effect. Clinical rehabilitation impact Kinesio taping could act as potential adjuvant therapy in patient of stroke with hemiplegia.

Background: Procalcitonin (PCT) was used for predicting the development of acute kidney injury (AKI) in several studies recently. We aimed to investigate the accuracy of PCT for predicting AKI in this study. Methods: Studies that assessed the predictive performance of PCT for the development of AKI in adult patients were searched from Medline, Embase, and the Cochrane Library from inception to June 2020. We calculated the pooled sensitivities and specificities and the area under the summary receiver-operating characteristic (SROC) curves. I2 was used to test the heterogeneity and the potential heterogeneity was investigated by meta-regression. Results: In total, 9 of 119 studies with 4852 patients were included, 1272 were diagnosed with AKI. In the overall analysis, the area under the SROC curve was 0.82 (95% CI, 0.79–0.85) and the pooled sensitivity and specificity were 0.76 (95% confidence interval [CI], 0.64–0.85) and 0.75 (95% CI, 0.61–0.86), respectively. In the subgroup analysis among septic patients, the pooled sensitivity and specificity were 0.59 (95% CI, 0.29–0.84) and 0.53 (95% CI, 0.31–0.74), and the area under the SROC was 0.57 (95% CI, 0.53–0.62). Conclusion: PCT may be a potential predictor for the development of AKI.

Long non-coding RNAs serve as key components of competing endogenous RNA (ceRNA) networks that underlie tumorigenesis. We investigated the pathogenic roles of lncRNA FAM230B and its molecular mechanism in gastric cancer (GC). The levels of FAM230B expression in five gastric cancer cell lines and in human gastric mucosal cells were compared by quantitative RT-PCR. To analyze the function of FAM230B in GC, we overexpressed FAM230B in AGS cells, silenced FAM230B in MGC-803 cells, and tested the effect of FAM230B on tumor growth in nude mice. The interaction between miR-27a-5p and FAM230B was predicted by a bioinformatics analysis and then verified with a dual-luciferase reporter assay. We also further investigated the role and mechanism of FAM230B by forcing overexpression of miR-27a-5p in MGC-803 gastric cancer cells. We found that FAM230B was highly expressed in gastric cancer cell lines and mainly located in the cytoplasm. FAM230B overexpression promoted the proliferation, migration, and invasion of AGS cells and repressed their apoptosis; it also facilitated tumor growth in vivo. In contrast, FAM230B knockdown suppressed the proliferation, migration, and invasion of MGC0803 cells, but enhanced their apoptosis and inhibited tumor growth in vivo. MiR-27a-5p expression was suppressed by FAM230B overexpression in AGS cells. MiR-27a-5p inhibited the proliferation, migration, and invasion of gastric cancer cells, and promoted the apoptosis of gastric cancer cells by reducing TOP2A (topoisomerase 2 alpha) expression. Our study showed that lncRNA FAM230B might function to promote GC. FAM230B functioned as a ceRNA by sponging miR-27a-5p and enhancing TOP2A expression.

Background The potential effects of coenzyme Q10 (CoQ10) supplementation in overweight/obese patients with type 2 diabetes mellitus are not fully established. In this article, we aimed to perform a pooled analysis to investigate the effects of CoQ10 intervention on cardiovascular disease (CVD) risk factors in overweight/obese patients with type 2 diabetes mellitus (T2DM). Methods MEDLINE, Embase, and Cochrane databases were searched for randomized controlled trials that evaluated the changes in CVD risk factors among overweight and obese patients with T2DM following CoQ10 supplementation. Two investigators independently assessed articles for inclusion, extracted data, and assessed risk of bias. Major endpoints were synthesized as weighted mean differences (WMDs) with 95% CIs. Subgroup analyses were performed to check the consistency of effect sizes across groups. Publication bias and sensitivity analysis were also performed. Results Fourteen eligible trials with 693 overweight/obese diabetic subjects were included for pooling. CoQ10 interventions significantly reduced fasting blood glucose (FBG; -0.59 mmol/L; 95% CI, -1.05 to -0.12; P=0.01), hemoglobin A1c (HbA1c; -0.28%; 95% CI-0.53 to -0.03; P=0.03), and triglyceride (TG) levels (0.17 mmol/L; 95% CI, -0.32 to -0.03; P=0.02). Subgroup analysis also showed that low-dose consumption of CoQ10 (

In the original version of [this article][1] ([1][2]), there were three errors in Fig. 6: in Fig. 6A, the GADPH blots were inadvertently duplicated from Fig. 5D; in Fig. 6B, the image for Aspirin/NC was a duplicate of DMSO/sh#2; and in Fig. 6B, the Aspirin/vector image was a duplicate of Aspirin/sh#

Osteosarcoma is the most common primary malignant bone tumor. However, our understanding of the molecular mechanism underlying its pathogenesis is incomplete. Studies have shown that aberrant expression of NK homeobox (NKX) genes may be involved in the oncogenesis of various cancers. Here, through migration screening assay, we found that a series of NKX genes inhibit the migration of osteosarcoma cells. Among these genes, NKX2-2 is a bona fide tumor suppressor for osteosarcoma. Overexpression of NKX2-2 decreases the migration, invasion, proliferation and colony formation of osteosarcoma cells in vitro and suppresses tumor growth and metastasis in vivo. Moreover, based on the results from both in vitro and in vivo studies, the transcriptional activation domain of NKX2-2 is important for its tumor suppressor function. Mechanistically, we revealed that NKX2-2 acts as a tumor suppressor partially by mediating the transcriptional downregulation of COL5A2, PLAU, SEMA7A and S1PR1 genes. In summary, our studies of NKX2-2 revealed new molecular mechanisms underlying osteosarcoma proliferation and metastasis and may provide a series of potential therapeutic targets for osteosarcoma.

Acute myeloid leukemia(AML)is a form of cancer originated from malignant clonal stem cells in bone marrow marked by heterogenous clinical outcome due to the complexity of its molecular and cytogenetic architecture. The longstanding standard regimen for AML treatment is induction therapy with 3 days of an anthracycline and 7 days of standard-dose cytarabine followed by consolidation chemotherapy or bone marrow transplantation. Despite the optimized induction regimen and progress in recognizing molecular heterogeneity of AML which helps to stratify patients, the outcome for older patients who represent the majority of the population remains dismal and the relapse of leukemia, particularly after transplantation, is challenging to manage. Novel therapeutic strategies are in desperate need. Immune checkpoint inhibitors(ICIs) as positive modulators of immune response have achieved impressive efficacy in melanoma and numerous solid tumor malignancies. For AML, the success of allogenic stem cell transplantation where graft-versus-leukemia effect significantly contributes to anti-neoplastic response makes it potential beneficiary for checkpoint inhibition treatment. Programmed-death 1(PD-1)and cytotoxic T-lymphocyte-associated protein 4(CTLA-4) are the two most actively investigated checkpoint receptors. Early data from ongoing clinical trials demonstrates therapeutic promise of checkpoint inhibitors for treating AML patients with improved overall response rate compared with traditional therapy as well as reversible side effects. Single anti-PD-1 monoclonal antibody(CT-011) infusion shows rather modest clinical efficacy. While combinations of PD-1 inhibitor nivolumab with hypomethylating agents(HMA) azacitidine represent encouraging outcome for relapsed/refractory(R/R) AML patients with higher overall response rate(ORR) compared with single agent HMA therapy. More rationally designed combinations are under investigation for better clinical response. CTLA-4 inhibitor ipilimumab exhibits specific potency in treating relapsed AML patients in later post-transplantation stage. Immune-related adverse events(irAEs) are of great concern to doctors. irAEs found in these trials can mostly be appropriately managed with steroids but are occasionally fatal. A good awareness of the inflammatory toxicities and early intervention with appropriate treatment are critical for outcome improvement. This article reviews data from several phase I、II clinical trials that evaluating PD-1 and CTLA-4 inhibitors on AML patients and discusses especially efficacy and adverse events as well as prospects of these drugs in treating acute myeloid leukemia.

BACKGROUND Hepatitis C virus (HCV) is an important transfusion-transmitted virus with global significance. The objective of this study was to evaluate the HCV prevalence and incidence among Chinese blood donors from 2013 to 2016. STUDY DESIGN AND METHODS Whole blood and apheresis platelet donations collected from five Chinese blood centers from June 1, 2013, to December 31, 2016, were screened in parallel by two different enzyme-linked immunosorbent assays for anti-HIV 1/2, hepatitis B surface antigen, anti-HCV, and syphilis. Screening-reactive samples were further confirmed by western blot. Confirmatory positive rates among first-time and repeat donors were used to estimate the prevalence and incidence rates. Multivariable logistic regression modeling was used to examine factors associated with HCV infection. RESULTS A total of 1,276,544 donations were collected from five Chinese blood centers, of which an estimated 1203 were confirmed HCV positive. The overall HCV prevalence among first-time donors was 166.56 per 100,000 donors (95% confidence interval, 156.04-177.08). The HCV incidence rate was estimated to be 15.21 (95% confidence interval, 11.83-19.56) per 100,000 person-years among repeat donors. Multivariable logistic regression results showed that increased age, lower educational levels, ethnicity, and occupation were all important factors associated with HCV confirmatory status among first-time donors (p

The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches, we explored how depletion of cMyBPC altered sarcomere function. We demonstrated that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM), normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation, enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in patients with DCM, whereas inhibiting myosin by MYK-461 should benefit the substantial proportion of patients with HCM with MYBPC3 mutations.

The present report showed the green synthesis of Silver nanoparticles (AgNPs) using Mulberry leaf extract via an environment friendly approach and investigated to know the probable ameliorative effect via biochemical assessment on retinopathy of rats that are maternally subjected to Al intoxication and diabetes. Mulberry leaf extract biomolecules act as capping and reducing agent for fabrication of AgNPs. Later, the fabricated AgNPs were characterized by using spectroscopic and microscopic instrumental techniques such as HR-TEM, UV–Vis, XRD and FT-IR. EDS, XRD and TEM have confirmed the synthesis of AgNPs. HRTEM results exhibited that the formed AgNPs are polydispersed and spherical in nature with mean particle size of 35 nm. Microscopic observation of retina in Al-intoxicated and diabetic mother rats showed abnormal changes in retinal cell layers. Yet, the retina of rats that are maternally received AgNPs plus diabetes or Al-intoxicated exhibited noticeable amelioration. However, lower ameliorations were found in rat's retina that are maternally undergone for combined exposure. Additionally, biochemical assessment revealed that the application of AgNPs caused the amelioration of the changes in Al concentration and maternal serum glucose. The present study revealed that AgNPs are active against diabetic and Aluminium-persuaded developmental retinopathy.

The poor clinical outcome and prognosis of esophageal squamous cell carcinoma (ESCC) is mainly attributed to its highly invasive and metastatic nature, making it urgent to further elicit the molecular mechanisms of the metastasis of ESCC. The function of each polycomb chromobox (CBX) protein in cancer is cell-type-dependent. Although CBX8 has been reported to promote the esophageal squamous cell carcinoma (ESCC) tumorigenesis, its role in ESCC metastasis has not been explored yet. In this study, we report that the inhibition of cell migration, invasion, and metastasis in ESCC requires CBX8-mediated repression of Snail, a key transcription factor that induces epithelial-to-mesenchymal transition (EMT), and that CBX8 inversely correlated with Snail in the ESCC tissues. Moreover, this novel function of CBX8 is dependent on its binding with the Snail promoter, which in turn suppresses the transcription of Snail. Collectively, CBX8 may play paradoxical roles in ESCC, inhibiting metastasis while promoting cell proliferation.

Background Potential effects of resveratrol consumption on cardiovascular disease risk factors and body weight in overweight/obese adults have not been fully elucidated. Our present analysis was to evaluate the effects of resveratrol consumption on risk markers related to cardiovascular health in overweight/obese Individuals. Methods Multiple literature databases were systematically searched, and 21 studies were included. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI), and heterogeneity was assessed with the I2 test. Publication bias and subgroup analyses were also performed. Results There were variations in reporting quality of included studies. Resveratrol intervention significantly lowered total cholesterol (WMD, –0.19 mmol/L; 95% CI, –0.32 to –0.06; P = 0.004), systolic blood pressure (WMD, –2.26 mmHg; 95% CI, –4.82 to –0.49; P = 0.02), and fasting glucose (WMD, –0.22 mmol/L; 95% CI, –0.42 to –0.03; P = 0.03). Heterogeneity was noted for these outcomes (35.6%, 38.7% and 71.4%, respectively). Our subgroup analysis showed significant reductions in total cholesterol, systolic blood pressure, diastolic blood pressure, glucose, and insulin in subjects ingesting higher dose of resveratrol (≥300 mg/day). Conclusion Our finding provides evidence that daily resveratrol consumption might be a candidate as an adjunct to pharmacological management to better prevent and control cardiovascular disease in overweight/obese individuals.

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD). Excessive uric acid (UA) level in the blood leads to hyperuricemic nephropathy (HN), which is characterized by glomerular hypertension, arteriolosclerosis and tubulointerstitial fibrosis. Fatty acid binding protein 4 (FABP4) is a potential mediator of inflammatory responses which contributes to renal interstitial fibrosis. However, the roles of FABP4 in HN remains unknown. In the study, a mouse model of HN induced by feeding a mixture of adenine and potassium oxonate, severe kidney injury and interstitial fibrosis, as well as the increased kidney-expressed FABP4 protein level were evident, accompanied by the activation of inflammatory responses. Oral administration of BMS309403, a highly selective FABP4 inhibitor, improved renal dysfunction, inhibited the mRNA level of KIM-1 and NGAL, as well as reduced the expression of proinflammatory cytokines and fibrotic proteins in the injured kidneys. BMS309403 treatment also inhibited the FABP4 activity and further suppressed the activation of JAK2-STAT3 and NF-kB P65 signaling pathways in the hyperuricemia-injured kidneys and UA-stimulated human tubular epithelial (HK-2) cells, respectively. In summary, our study for the first time demonstrated that FABP4 played a crucial role in kidney inflammation and fibrosis via the regulation of JAK2-STAT3 and NF-kB P65 pathways in HN mice. The results suggested that FABP4 inhibition might be a promising therapeutic strategy for HN.

Understanding the difference between malignant and benign pancreatic masses is critical in terms of diagnosis, although this is difficult to determine in clinical practice. The contrast-enhanced harmonic endoscopic ultrasound (CH-EUS) technique was introduced in 2010, although, to the best of the authors' knowledge, there has been no systematic review or meta-analysis to date evaluating its diagnostic performance for the differentiation of pancreatic masses. The aim of the present study was to systematically evaluate the diagnostic performance of CH-EUS for the differentiation of pancreatic masses. Search key words and inclusion and exclusion criteria were initially presented. Two independent authors read and extracted the relevant information from the included studies. Disagreements were resolved through discussion with another two experienced authors. Metadisc and Stata software were used for the meta-analysis and the evaluation of bias. A total of 16 studies comprising 1,325 patients were included in this meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of CH-EUS were used to distinguish between malignant and benign tumors, and the values obtained were 93% [95% confidence interval (CI): 91-94%], 84% (95% CI: 80-87%), 5.58 (95% CI: 3.90-7.97), 0.09 (95% CI: 0.07-0.11) and 72.56 (95% CI: 48.93-107.60), respectively. The area under the summary receiver operating characteristic curve was determined to be 0.96. No publication bias was identified in this meta-analysis. Taken together, these results confirm that CH-EUS has a high accuracy rate for distinguishing between benign and malignant pancreatic space-occupying lesions, and it may therefore be used as an effective diagnostic tool for pancreatic masses.

The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin binding protein-C; cMyBPC) or myosin missense mutations cause hyper-contractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches we explored how depletion of cMyBPC altered sarcomere function. We demonstrate that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM) normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation - enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across all phases of the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in DCM patients, while inhibiting myosin by MYK-461 should benefit the substantial proportion of HCM patients with MYBPC3 mutations.

The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin binding protein-C; cMyBPC) or myosin missense mutations cause hyper-contractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches we explored how depletion of cMyBPC altered sarcomere function. We demonstrate that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM) normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation - enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across all phases of the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in DCM patients, while inhibiting myosin by MYK-461 should benefit the substantial proportion of HCM patients with MYBPC3 mutations.One Sentence SummaryAnalyses of cardiomyocytes with hypertrophic cardiomyopathy mutations in MYBPC3 reveal that these directly activate myosin contraction by disrupting myosin states of relaxation, and that genetic or pharmacological manipulation of myosin therapeutically abates the effects of MYBPC3 mutations.

Purpose: Aspirin has recently been reported to reduce both the incidence and the risk of metastasis in colon cancer. However, there is no evidence at the cellular levels or in the animal models for such an effect of aspirin on cancer metastasis. Experimental Design: MTT assay, colony formation assay, and apoptosis assay were employed to analyze the effects of aspirin on the osteosarcoma cell viability in vitro. The NF-κB activity was measured by the NF-κB p65 luciferase reporter. Western blotting was used to analyze the proteins in cells. The migration and invasion abilities of osteosarcoma cells in vitro were measured by the Transwell assay. Xenograft-bearing mice were used to assess the roles of aspirin in both tumor growth and metastasis of osteosarcoma in vivo (n = 5–8 mice/group). An unpaired Student t test or ANOVA with the Bonferroni post hoc test were used for the statistical comparisons. Results: Aspirin reduced cell viability in a dose- and time-dependent manner in osteosarcoma cell lines, and aspirin synergistically sensitized osteosarcoma cells to cisplatin (DDP) in vitro and in vivo (P < 0.001). Moreover, aspirin markedly repressed the migration and invasion of osteosarcoma cells in vitro (P < 0.001), and dramatically diminished the occurrence of osteosarcoma xenograft metastases to the lungs in vivo (P < 0.001). Mechanistically, aspirin diminishes osteosarcoma migration, invasion, and metastasis through the NF-κB pathway. Conclusions: Aspirin suppresses both the growth and metastasis of osteosarcoma through the NF-κB pathway at the cellular level and in the animal models. Clin Cancer Res; 21(23); 5349–59. ©2015 AACR.

No previous study has investigated dietary pattern in association with obesity risk in a middle-aged Chinese population. The purpose of this study was to evaluate the associations between dietary patterns and the risk of obesity in the city of Hangzhou, the capital of Zhejiang Province, east China. In this cross-sectional study of 2560 subjects aged 45–60 years, dietary intakes were evaluated using a semi-quantitative food frequency questionnaire (FFQ). All anthropometric measurements were obtained using standardized procedures. The partial correlation analysis was performed to assess the associations between dietary patterns and body mass index (BMI), waist circumference (WC), and waist to hip ratio (WHR). Multivariate logistic regression analysis was used to examine the associations between dietary patterns and obesity, with adjustment for potential confounders. Four major dietary patterns were extracted by means of factor analysis: animal food, traditional Chinese, western fast-food, and high-salt patterns. The animal food pattern was positively associated with BMI (r = 0.082, 0.144, respectively, p &lt, 0.05) and WC (r = 0.102, 0.132, respectively, p &lt, 0.01), and the traditional Chinese pattern was inversely associated with BMI (r = −0.047, −0.116, respectively, p &lt, 0.05) and WC (r = −0.067, −0.113, respectively, p &lt, 0.05) in both genders. After controlling for potential confounders, subjects in the highest quartile of animal food pattern scores had a greater odds ratio for abdominal obesity (odds ratio (OR) = 1.67, 95% confidence interval (CI): 1.188–2.340, p &lt, 0.01), in comparison to those from the lowest quartile. Compared with the lowest quartile of the traditional Chinese pattern, the highest quartile had a lower odds ratio for abdominal obesity (OR = 0.63, 95% CI: 0.441–0.901, p &lt, 0.05). Conclusions: Our findings indicated that the animal food pattern was associated with a higher risk of abdominal obesity, while the traditional Chinese pattern was associated with a lower risk of abdominal obesity. Further prospective studies are warranted to confirm these findings.

Previous studies reported the potential associations between dietary patterns and the risk of coronary heart disease (CHD) in adulthood, however a consistent perspective has not been established to date. Herein, we carried out this meta-analysis to evaluate the associations between dietary patterns and the risk of CHD. MEDLINE and EBSCO were searched for relevant articles published up to April 2015. A total of 35 articles (reporting 37 original studies) met the inclusion criteria and were included in the present meta-analysis. The decreased risk of CHD was shown for the highest compared with the lowest categories of healthy/prudent dietary patterns (odds ratio (OR) = 0.67; 95% confidence interval (CI): 0.60, 0.75; p < 0.00001) and alcohol consumption (OR = 0.68; 95% CI: 0.59, 0.78; p < 0.00001). There was evidence of an increased risk of CHD in the highest compared with the lowest categories of the unhealthy/Western-type dietary patterns (OR = 1.45; 95% CI: 1.05, 2.01; p = 0.02). The results of this meta-analysis indicate that different dietary patterns may be associated with the risk of CHD.

Pancreatic glandular necrosis is rapid inflammation of the pancreas and contributes to severe acute pancreatitis in humans. The pathogenesis of pancreatic tissue inflammation during acute pancreatitis is still largely unknown. Recent studies suggest that 5-lipoxygenase (5-LOX) is an essential mediator in modulating cell death pathways in human diseases. In this study, we aimed to evaluate the effects of a 5-LOX inhibitor, zileuton, on tissue apoptosis and neutrophils activation in pancreatic tissues during acute necrotizing pancreatitis (ANP) in a rat model. In this present study, both mRNA and protein levels of 5-LOX are upregulated during ANP and zileuton treatment is shown to repress ANP-induced upregulation of 5-LOX levels. In addition, zileuton treatment is found to repress blood biomarkers of neutrophils activation such as soluble intercellular adhesive molecular 1 (ICAM-1), soluble E-selectin (E-selectin), soluble P-selectin (P-selectin), leukotriene B4 (LTB4), and myeloperoxidase (MPO). Also, zileuton treatment attenuates pancreatic tissue pathology, upregulates caspase-3, downregulates B-cell lymphoma 2 (Bcl-2), and activates tissue apoptosis evaluated by TUNEL staining. Our results show that 5-LOX plays an important role in activating apoptosis and repressing neutrophils activation during ANP. The current study suggests that 5-LOX can be used as a potential target for the treatment of ANP.

Accumulating evidence has suggested that the human leucocyte antigen-G (HLA-G) 14 bp ins/del polymorphism might be related to cancer susceptibility. However, epidemiologic findings have been inconsistent. Therefore, we performed a meta-analysis of case–control study to derive a more precise estimation of this association. Electronic databases were searched to identify all eligible studies of HLA-G 14 bp ins/del polymorphism and cancer risk. Odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to evaluate the strength of the association in fixed-effects model or random-effects model according to heterogeneity. Publication bias, sensitivity analysis and subgroup analyses based on cancer type, ethnicity, source of controls and sample size were also performed. A total of 14 case–control studies, involving 2,757 cases and 3,972 controls, were included in the present meta-analysis. The pooled analysis showed that there is no significant relationship between the HLA-G 14 bp ins/del polymorphism and cancer susceptibility under the genetic models (for the allele model del vs. ins: OR 1.13, 95 % CI 1.00–1.27; for the homozygote comparison model del/del vs. ins/ins: OR 1.22, 95 % CI 0.95–1.56; for the dominant model del/del + ins/del vs. ins/ins: OR 1.15, 95 % CI 0.94–1.42; for recessive model del/del vs. ins/del + ins/ins: OR 1.13, 95 % CI 0.96–1.34; respectively). Subgroup analyses indicated significant association among breast cancer, population based control and the large sample size group in some genetic models. Our investigations demonstrate that genotypes for the HLA-G 14 bp ins/del polymorphism may be not associated with overall cancer risk. In a subgroup meta-analysis, however, HLA-G 14-bp ins/del polymorphism might contribute to breast cancer susceptibility.

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild-type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1.

The main purpose of this study was to investigate the diagnostic value of dynamic contrast-enhanced MRI (DCE-MRI) in differentiating osteomyelitis from acute neuropathic arthropathy in the diabetic foot. This prospective study was carried out on 30 diabetic foot patients, with a mean age of 51 years. The patients all underwent clinical examinations, laboratory examinations and DCE-MRI. The DCE-MRI parameters (Ktrans, Kep and Ve) of the regions of acute neuropathic arthropathy and osteomyelitis were calculated. Receiver operating characteristic curves (ROCs) were used to identify the DCE-MRI parameters that showed the highest accuracy in differentiating the acute neuropathic arthropathy from the osteomyelitic regions. Pearson correlation coefficients were used to assess the correlations among the DCE-MRI parameters, the level of C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR). The Ktrans, Kep and Ve values of the osteomyelitic regions were higher than those of the acute neuropathic arthropathy regions, and significant differences were found between the two groups (P = 0.000, P = 0.000, P = 0.000). The ROC analysis showed that Ktrans and Ve performed best in differentiating osteomyelitis from acute neuropathic arthropathy, both with an area under the curve of 0.938. The Pearson correlation coefficients showed that the DCE-MRI parameters correlated significantly with the level of CRP and ESR (P = 0.000, P = 0.014, P = 0.000; P = 0.000, P = 0.000, P = 0.013). Our results showed that DCE-MRI may provide reproducible parameters that can reliably differentiate osteomyelitis from acute neuropathic arthropathy.

Background The potential glucose-lowering effects of pomegranate have been reported in animal and observational studies, but intervention studies in humans have generated mixed results. In this paper, we aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the precise effects of pomegranate supplementation on measures of glucose control, insulin levels and insulin sensitivity in humans. Methods Comprehensive electronic searches were conducted in PubMed, Embase, and the Cochrane Library. Studies included were RCTs that evaluated the changes in diabetes biomarkers among adults (≥18 years) following pomegranate interventions. The predefined outcomes included fasting blood glucose (FBG), fasting blood insulin (FBI), glycated haemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR). Endpoints were calculated as weighted mean differences (WMDs) with 95% confidence intervals (CIs) by using a random-effects model. Publication bias, subgroup analyses, sensitivity analysis and random-effects meta-regression were also performed to explore the influence of covariates on the net changes in fasting glucose and insulin concentrations. Results Sixteen eligible trials with 538 subjects were included. The pooled estimates suggested that pomegranate did not significantly affect the measures of FBG (WMD, −0.6 mg/dL; 95% CI, −2.79 to 1.58; P=0.59), FBI (WMD, 0.29 μIU/mL; 95% CI, −1.16 to 1.75; P=0.70), HOMA-IR (WMD, −0.04; 95% CI, −0.53 to 0.46; P=0.88) or HbA1c (WMD, −0.11%; 95% CI, −0.39 to −0.18; P=0.46). Overall, significant heterogeneity was detected for FBI and HOMA-IR, but subgroup analysis could not identify factors significantly influencing these parameters. These results were robust in sensitivity analysis, and no significant publication bias was found in the current meta-analysis. Conclusion Pomegranate intake did not show a notably favourable effect on improvements in glucose and insulin metabolism. The current evidence suggests that daily pomegranate supplementation is not recommended as a potential therapeutic strategy in glycemic management. Further large-scale RCTs with longer duration are required to confirm these results. Electronic supplementary material The online version of this article (10.1186/s12937-017-0290-1) contains supplementary material, which is available to authorized users.

// Jianjun Tang 1, * , Gang Wang 1, * , Meifang Zhang 1, * , Feng-yan Li 1 , Yi Sang 1 , Boqing Wang 1, 2 , Kaishun Hu 1 , Yuanzhong Wu 1 , Rongzhen Luo 1 , Dan Liao 1 , Jingying Cao 1 , Xin Wang 1 , Li Wang 1 , Ruhua Zhang 1 , Xiaoshi Zhang 1 , Wu-Guo Deng 1 , Dan Xie 1 , Rui-hua Xu 1 , Tiebang Kang 1 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China 2 Department of Hepatobiliarypancreatic Surgery, Affiliated Tumor Hospital, Xinjiang Medical University, Urumqi 830000, China * These authors contributed equally to this work Correspondence to: Tiebang Kang, e-mail: kangtb@mail.sysu.edu.cn Keywords: CBX8, Polycomb Group protein, colorectal cancer, metastasis, proliferation, p53, integrin Received: July 23, 2014 Accepted: September 13, 2014 Published: October 24, 2014 ABSTRACT The effect of polycomb chromobox (Cbx) proteins in cancer is context-dependent. The Chromobox homolog 8 (CBX8) was originally characterized as a transcriptional repressor, which inhibits cell proliferation in Ink4a-Arf-dependent and -independent manner. However, the role of CBX8 in colorectal cancer remains unknown. Here, we found that high CBX8 expression was associated with a low rate of distant metastasis and good prognosis in CRC patients, even though CBX8 was up-regulated in CRC cell lines and clinical samples. Knockdown of CBX8 inhibited CRC proliferation in vitro and in vivo, mostly by increasing p53 and its downstream effectors. However, knockdown of CBX8 enhanced CRC migration, invasion and metastasis in vitro and in vivo, in part through direct up-regulation of integrin β4 (ITGB4) that in turn decreased RhoA activity. Collectively, the knockdown of CBX8 inhibited CRC proliferation, while promoting its metastasis, thus exerting paradoxical effects in CRC progression.

Objective Complement component C4 copy number variations are associated with various inflammatory diseases. This study was undertaken to investigate whether copy number variations of C4 are also involved in the pathogenesis of Behcet's disease (BD). Methods Gene expression was examined by enzyme-linked immunosorbent assay (ELISA) or real-time polymerase chain reaction (PCR). Copy number variations of C4 isotypes (C4A and C4B) were detected by real-time PCR in 905 patients with BD, 205 patients with ankylosing spondylitis (AS) and acute anterior uveitis, and 1,238 controls. The activation of CD4+ T cells was analyzed by flow cytometry, and cytokine production was detected by ELISA. Results Protein expression of total C4 in serum was significantly increased in patients with active BD compared with those with inactive BD or controls (Bonferroni corrected P [Pcorr] = 1.64 × 10−4 and Pcorr = 0.037, respectively), but not in patients with AS and acute anterior uveitis. Copy number variation analysis identified a significantly increased frequency of more than 2 copies of C4A in BD patients (P = 1.65 × 10−7, odds ratio [OR] 2.84). HLA–B51, which is located on the same chromosome as C4, showed a strong association with BD in the Han Chinese population (P = 8.90 × 10−65, OR 5.05), but logistic regression showed that C4A copy number variation was an independent risk factor for BD. A significantly increased expression of C4A was observed in the high copy number groups (>2 copies or 2 copies) versus the low copy number group (Pcorr = 0.019 and Pcorr = 0.044, respectively). Increased production of interleukin-6 (IL-6) was also observed in the high C4A copy number group (Pcorr = 0.037). No effect of C4 copy number variation on the expression of T cell activation markers was detected. Conclusion Our findings indicate that a high copy number of C4A confers risk for BD by modulating the expression of C4A and enhancing IL-6 production.

This study aimed to investigate the predisposition of common pre-miRNA SNPs with Behcet's disease (BD), Vogt-Koyanagi-Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS). A two-stage association study was carried out in 859 BD, 400 VKH syndrome, 209 AAU(+)AS(+) patients and 1,685 controls all belonging to a Chinese Han population. Genotyping, the expression of miR-196a and Bach1 (the target gene of miR-196a), cell proliferation, cytokine production were examined by PCR-RFLP, real-time PCR, CCK8 and ELISA. In the first stage study, the results showed significantly increased frequencies of the miR-196a2/rs11614913 TT genotype and T allele in BD patients (adjusted P (c) = 0.024, OR = 1.63; adjusted P (c) = 5.4 x 10(-3), OR = 1.45, respectively). However, no significant association of the tested SNPs with VKH and AAU(+)AS(+) patients was observed. The second stage and combined studies confirmed the association of rs11614913 with BD (TT genotype: adjusted P (c) = 6x10(-5), OR = 1.53; T allele: adjusted P (c) = 8x10(-6), OR = 1.35; CC genotype: adjusted P (c) = 0.024, OR = 0.68). A stratified analysis showed an association of the rs11614913 TT genotype and T allele with the arthritis subgroup of BD (P (c) = 5.3 x 10(-3), OR = 1.89; P (c) = 0.015, OR = 1.56, respectively). Functional experiments showed a decreased miR-196a expression, an increased Bach1 expression and an increased production of IL-1 beta and MCP-1 in TT cases compared to CC cases (P = 0.023, P = 0.0073, P = 0.012, P = 0.002, respectively). This study shows that a functional variant of miR-196a2 confers risk for BD but not for VKH syndrome or AAU(+)AS(+) by modulating the miR-196a gene expression and by regulating pro-inflammatory IL-1 beta and MCP-1 production.

Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type–dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4–HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. Cancer Res; 76(24); 7277–89. ©2016 AACR.

PURPOSE. Acute anterior uveitis (AAU) is the most common form of uveitis and is a frequent ocular manifestation of ankylosing spondylitis (AS). Thymocyte CD4(+) cells have been reported to play an important role in the pathogenesis of both AAU and AS. To test whether the copy number variations (CNVs) of CD4(+) T cell transcription factor genes including T-bet, GATA binding protein 3 (GATA)-3, related orphan receptor C (RORC) and forkhead box protein 3 (FOXP3) are associated with acute anterior uveitis either in the presence or absence of ankylosing spondylitis (AAU(+)AS(+); AAU(+)AS(-)). METHODS. The study included 676 patients with AAU, including 298 patients with AAU(+)AS(+), 378 patients with AAU(+)AS(-), and 596 unrelated healthy controls in a Chinese Han population. Copy number variations were examined by real-time PCR. RESULTS. The frequency of a high copy number (CN) of T-bet was increased in AAU(+)AS(+) as well as AAU(+)AS(-) patients when compared with controls (P value after Bonferroni correction [P-corr] = 4.3 x 10(-5); odds ratio [OR] = 2.0 and P-corr = 1.2 x 10(-8); OR = 2.3, respectively). The frequency of a high CN of GATA-3 was significantly higher in AAU(+)AS(+) patients than in controls (P-corr = 1.8 x 10(-7); OR = 4.9). A higher frequency of CN of FOXP3 was found in female AAU(+)AS(+) patients and female AAU(+)AS(-) patients (P-corr = 0.005, OR = 5.9 and (Pcorr) = 0.004, OR = 4.9, respectively). No association was found between CNVs of RORC and AAU(+)AS(-) or AAU(+)AS(+) patients. CONCLUSIONS. A high copy number of T-bet and GATA-3 confers susceptibility to AAU and AS, and a high copy number of FOXP3 confers susceptibility to female patients with AAU either with or without AS.

The relationships between polymorphisms of the trans-membrane(TM) region located in the major histocompatibility complex (MHC) class I chain–related gene A (MICA) and Behcet’s disease (BD) have been discussed previously, however, the results were contradictory. In this study, we thoroughly assess whether MICA-TM gene variants are associated with BD by means of a systematic review and meta-analysis. Our study focused on the effects of polymorphisms of MICA-A4, A5, A5.1, A6 and A9 from the included articles. Sixteen previous original publications representing 1,555 BD patients and 2,086 unrelated healthy controls analyzed the association of BD with MICA-TM gene polymorphisms. For the five alleles, MICA-A6 showed a strongly positive correlation with BD patients and could be viewed as an increased risk factor of BD (OR = 2.34, 95%CI: 2.02–2.70). Furthermore, MICA-A4, A5, A5.1 and A9 exhibited negative associations with BD (OR = 0.71, 95%CI: 0.58–0.86; OR = 0.75, 95%CI: 0.63–0.90; OR = 0.63, 95%CI: 0.44–0.91; OR = 0.70, 95%CI: 0.58–0.84, respectively). Our meta-analysis confirmed MICA-A6 could be responsible for BD in three ethnic regions and should probably be treated as a risk factor for BD. MICA-A4, A5, A5.1 and A9 could be regarded as protective factors, especially in the Middle East and East Asia.

The objective of this study was to evaluate the usefulness of covariates in identifying birth records with implausible values of gestational age. Birthweight distributions for births with early reported gestational ages are markedly bimodal, suggesting a mixture of two distributions. Most births form a normal-shaped left-hand (primary) distribution and a smaller number form the right-hand (secondary) distribution. The births in the secondary distribution are thought to have gestational age mistakenly reported. Prior work has found that births in the secondary distribution are at higher risk of poor outcomes than those in the primary distribution. Using 2002 US Natality data for gestational ages 26-35 weeks, we fit normal mixture models to birthweight with and without covariates (maternal race, education, parity, age, region of the country, prenatal care initiation) by reported gestational age. Additional models were stratified by infant sex. This approach allowed for the relationship between the covariates and birthweight to differ between the components. Mixture models fit reasonably well for reported gestational ages

Scope We performed a pooled analysis with trial sequential analysis (TSA) to evaluate the efficacy and safety of chitosan supplementation on serum lipids in humans. Methods and results Medline, EMBASE, and CENTRAL databases were queried. Impact was expressed as a weighted mean difference (WMD) and 95% confidence interval (CI). Sensitivity analysis was conducted using the leave-one-out method. Statistical heterogeneity, publication bias, TSA, and subgroup analyses were also assessed. Fourteen trials (21 treatment arms) encompassing 1108 participants were suitable for statistical pooling. Chitosan supplementation significantly improved the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations in all patients. The WMDs were -0.20 mmol L-1 (95% CI, -0.35 to -0.05; p = 0.009) for TC, and -0.20 mol L-1 (95% CI, -0.26 to -0.15; p = 0.0001) for LDL-C, respectively. TSA demonstrated that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit providing conclusive evidence for the benefit of chitosan. However, no significant changes were seen with high-density lipoprotein cholesterol (HDL-C) and triglycerides. Our findings were robust after sensitivity analyses, and no serious adverse events were reported with chitosan intake. Conclusion Supplementation with chitosan effectively reduces plasma concentrations of TC and LDL-C. Current evidence indicates daily chitosan supplementation as a candidate for therapeutic lipid management strategies.

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.