Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

Granulomas in Pediatric Liver Biopsies: Single Center Experience.

BACKGROUND: Granulomas in pediatric liver biopsies (GPLB) are rare with the largest pediatric cohort reported over 25 years ago. METHODS: Single-center retrospective study of GPLB. RESULTS: Seventeen liver biopsies from 16 patients with granulomas were identified (9 boys, 56%) with a median age of 13 years (range: 1-18) for which the most common indication was the presence of a nodule/mass (47%). Significant comorbidities were seen in 13 patients (81%) and included: liver transplant (25%), history of a neoplasm (25%), autoimmune hepatitis (6%), Crohn disease (6%), bipolar disorder (6%), severe combined immunodeficiency (6%), and sickle cell disease (6%). Eleven patients were taking multiple medications at the time of biopsy. Granulomas were more commonly pan-acinar (11 cases) followed by subcapsular (4 cases), portal (1 case), and periportal (1 case). Necrosis was seen in 10 cases (59%). GMS stain was positive in 2 cases for Histoplasma-like yeast; microbiological cultures were negative in all cases (no: 4). A 18S and 16S rRNA gene sequencing performed in 15 cases revealed only 1 with a pathogenic microorganism, Mycobacterium angelicum. CONCLUSION: In our experience, GPLB are heterogenous with only 3 cases having an identifiable infectious etiology and many of the remaining cases being associated to multiple medications, suggesting drug-induced liver injury as possible etiology.

mTORC1 and ferroptosis: Regulatory mechanisms and therapeutic potential.

Ferroptosis, a form of regulated cell death triggered by lipid hydroperoxide accumulation, has an important role in a variety of diseases and pathological conditions, such as cancer. Targeting ferroptosis is emerging as a promising means of therapeutic intervention in cancer treatment. Polyunsaturated fatty acids, reactive oxygen species, and labile iron constitute the major underlying triggers for ferroptosis. Other regulators of ferroptosis have also been discovered recently, among them the mechanistic target of rapamycin complex 1 (mTORC1), a central controller of cell growth and metabolism. Inhibitors of mTORC1 have been used in treating diverse diseases, including cancer. In this review, we discuss recent findings linking mTORC1 to ferroptosis, dissect mechanisms underlying the establishment of mTORC1 as a key ferroptosis modulator, and highlight the potential of co-targeting mTORC1 and ferroptosis in cancer treatment. This review will provide valuable insights for future investigations of ferroptosis and mTORC1 in fundamental biology and cancer therapy.

Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis.

OBJECTIVES: Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage homeostasis has been extensively explored, whereas far less effort has been invested toward enhancing chondrocyte anabolism. This study aimed to repurpose clinically approved drugs as potential stimulators of chondrocyte anabolism in treating OA. METHODS: Screening of a Food and Drug Administration-approved drug library; Assays for examining the chondroprotective effects of digoxin in vitro; Assays for defining the therapeutic effects of digoxin using a surgically-induced OA model; A propensity-score matched cohort study using The Health Improvement Network to examine the relationship between digoxin use and the risk of joint OA-associated replacement among patients with atrial fibrillation; identification and characterisation of the binding of digoxin to low-density lipoprotein receptor-related protein 4 (LRP4); various assays, including use of CRISPR-Cas9 genome editing to delete LRP4 in human chondrocytes, for examining the dependence on LRP4 of digoxin regulation of chondrocytes. RESULTS: Serial screenings led to the identification of ouabain and digoxin as stimulators of chondrocyte differentiation and anabolism. Ouabain and digoxin protected against OA and relieved OA-associated pain. The cohort study of 56 794 patients revealed that digoxin use was associated with reduced risk of OA-associated joint replacement. LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin's regulations of chondrocytes. CONCLUSIONS: These findings not only provide new insights into the understanding of digoxin's chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for OA.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.

OBJECTIVE: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial. METHODS: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation. RESULTS: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity. CONCLUSIONS: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

A recombinant influenza virus with a CTLA4-specific scFv inhibits tumor growth in a mouse model.

Oncolytic viruses (OV) have shown excellent safety and efficacy in preclinical and clinical studies. Influenza A virus (IAV) is considered a promising oncolytic virus. In this report, we generated a recombinant influenza virus expressing an immune checkpoint blockade agent targeting CTLA4. Using reverse genetics, a recombinant influenza virus, termed rFlu-CTLA4, encoding the heavy chain of a CTLA4 antibody on the PB1 segment and the light chain of the CTLA4 antibody on the PA segment was produced. RFlu-CTLA4 could replicate to high titers, and antibodies were produced in the allantoic fluid of infected eggs. Furthermore, the selective cytotoxicity of the virus was higher in various hepatocellular carcinoma cancer cell lines than in the normal cell line L02 in vitro, as indicated by MTS assays. More importantly, in a subcutaneous H22 mouse hepatocarcinoma model, intratumoral injections of rFlu-CTLA4 inhibited the growth of treated tumors and increased the overall survival of mice compared with injections of the PR8 virus. Taken together, these results warrant further exploration of this novel recombinant influenza virus for its potential use as a single or combination agent for cancer immunotherapy.

Long noncoding RNA FAM66C promotes tumor progression and glycolysis in intrahepatic cholangiocarcinoma by regulating hsa-miR-23b-3p/KCND2 axis.

Long noncoding RNAs (lncRNAs) are known to be the important regulators in cancer progression. However, the role of lncRNA FAM66C (FAM66C) is yet to be investigated in intrahepatic cholangiocarcinoma (ICC). This study aimed to investigate the effects and related mechanisms of FAM66C in ICC. Human ICC tissues and cell lines were collected. The expression levels of FAM66C, hsa-miR-23b-3p (miR-23b-3p), and KCND2 were detected by qRT-RCR. The transfection experiments were employed to measure the effect of FAM66C on cell viabilities, migration, and invasion in ICC cells by CCK-8, transwell assays. Glycolysis was investigated by glucose consumption, lactate production and ATP levels. The dual-luciferase reporter and RNA pull down assays were conducted as a means of confirming the interactions between FAM66C, miR-23b-3p, and KCND2. Furthermore, the levels of the EMT-associated proteins (KCND2, GLUT1, PKM2, and LDHA) in ICC cells were detected by western blot. FAM66C was increased in ICC tissues and cells, increased cell viability, glycolysis, migration and invasion, and decreased apoptosis were shown in FAM66C overexpressing cells. Mechanistic analyses revealed that FAM66C regulated the downstream target gene KCND2 by sponging miR-23b-3p. FAM66C effect on ICC was further validated in murine xenograft assays. FAM66C knockdown cells gave rise to tumors that were smaller in size, consistent with the role of FAM66C as a promoter of in vivo tumor growth. These data revealed that FAM66C was able to drive ICC tumor progression and glycolytic activity via the miR-23b-3p/KCND2 axis, indicating FAM66C may be a viable target for treating ICC.

Association Between Magnetic Resonance Imaging-Measured Intercondylar Notch Dimensions and Anterior Cruciate Ligament Injury: A Meta-analysis.

PURPOSE: To explore the association between the magnetic resonance imaging (MRI)-measured intercondylar notch dimensions, including the intercondylar notch width (NW) and intercondylar notch width index (NWI), and the risk of anterior cruciate ligament (ACL) injury by performing a meta-analysis of studies that relied on the multiplanar imaging and soft-tissue visualization strengths of MRI. METHODS: The MEDLINE, Embase, and SportDiscus databases were searched from inception to March 2017. Observational studies reporting on the associations of the NWI and NW with ACL injury were retrieved. A random-effects model was used to calculate the overall weighted mean difference (WMD) between the ACL injury group and control group. RESULTS: A total of 20 studies were included in this meta-analysis. The combined data showed that subjects with ACL injury, as compared with the control group, had a significantly decreased NW (pooled WMD, -1.53 [95% confidence interval, -1.81 to -1.25]; P < .00001) and NWI (pooled WMD, -0.02 [95% confidence interval, -0.03 to -0.01]; P < .00001). Similar findings were observed in subgroup analyses in terms of different injury mechanisms. No significant difference in NWI was found in the axial view. A significantly decreased NW and NWI were found in other plane views. The sensitivity analyses after the exclusion of studies enrolling only athletes or skeletally immature subjects reached similar outcomes. The Begg rank correlation test showed no publication bias. CONCLUSIONS: With the accumulation of evidence, this meta-analysis concluded that the NW and/or NWI measured by MRI was significantly lower in ACL-injured patients than in control subjects. For persons with a narrow intercondylar notch, preventive measures can be prepared for the prevention of ACL injuries. LEVEL OF EVIDENCE: Level III, meta-analysis of Level II and III studies.

Mechanisms of Action of Vitamin D as Supplemental Therapy for Pneumocystis Pneumonia.

The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is the most effective regimen for therapy of Pneumocystis pneumonia (PCP). As many patients with PCP are allergic or do not respond to it, efforts have been devoted to develop alternative therapies for PCP. We have found that the combination of vitamin D3 (VitD3) (300 IU/kg/day) and primaquine (PMQ) (5 mg/kg/day) was as effective as TMP-SMX for therapy of PCP. In this study, we investigated the mechanisms by which vitamin D enhances the efficacy of PMQ. C57BL/6 mice were immunosuppressed by CD4+ cell depletion, infected with Pneumocystismurina for 8 weeks, and then treated for 9 days with the combination of VitD3 and PMQ (VitD3-PMQ) or with TMP-SMX or PMQ to serve as controls. The results showed that vitamin D supplementation increased the number of CD11c+ cells, suppressed the production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], and interleukin-6 [IL-6]) and inducible nitric oxide synthase (iNOS), and enhanced the expression of genes related to antioxidation (glutathione reductase and glutamate-cysteine ligase modifier subunit), antimicrobial peptides (cathelicidin), and autophagy (ATG5 and beclin-1). These results suggest that the main action of vitamin D is enhancing the ability of the host to defend against Pneumocystis infection.

Regulation of Collagen V Expression and Epithelial-Mesenchymal Transition by miR-185 and miR-186 during Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a devastating disease, with no good diagnostic biomarker and limited treatment options. Previous studies suggest that collagen V overexpression and collagen V-mediated immune response play roles in the pathogenesis of idiopathic pulmonary fibrosis. This study aimed to identify dysregulated miRNA-related collagen V overexpression during idiopathic pulmonary fibrosis. We found that the expression levels of miR-185 and miR-186 were decreased in the lungs of idiopathic pulmonary fibrosis patients. The levels of miR-185 and miR-186 were not correlated with disease severity of idiopathic pulmonary fibrosis. The direct regulation of COL5A1 by miR-185 and miR-186 was confirmed by a luciferase reporter assay. Furthermore, mimics of miR-185 and miR-186 blocked transforming growth factor-ß-induced collagen V overexpression and alleviated transforming growth factor-ß-induced epithelial-mesenchymal transition in A549 cells and HCC827 cells. Our findings suggest that attenuated expression of miR-185 and miR-186 may be responsible for collagen V overexpression during idiopathic pulmonary fibrosis, and these miRNAs may serve as pathogenesis-related biomarkers and treatment targets.

Relationship between cigarette smoking and hyperuricemia in middle-aged and elderly population: a cross-sectional study.

The aim of the study was to estimate the cross-sectional association between cigarette smoking and the prevalence of hyperuricemia (HU) in the middle-aged and elderly males and females. A total of 3415 males and 2932 females were included in this study. HU was defined as SUA≥ 416 mmol/L for males and ≥360 mmol/L for females. The smoking status was classified into four categories based on daily smoking habit: (1) 0/day; (2) 1-10/day; (3) 11-20/day; and (4) >20/day. Multivariable logistic regressions were conducted to examine the aforementioned association. The prevalence of HU in the male and female sample was 25.0 and 10.0 %, respectively. In male subjects, the prevalence of HU in smokers (22.8 %) was significantly lower than that in non-smokers (26.5 %) (p = 0.016). Meanwhile, with adjustment for potential confounding factors, the prevalence of HU in smokers was still lower (OR = 0.83, 95 % CI 0.70-0.98, P = 0.033). Furthermore, a significantly inverse association between smoking status and HU was observed in the multivariable model. The multivariable-adjusted OR (95 % CI) for HU in the second, third and fourth category of smoking status was 0.84 (95 % CI 0.66-1.06), 0.90 (95 % CI 0.69-1.18) and 0.76 (95 % CI 0.58-0.99), respectively, compared with that in the first category. A clear trend (P for trend was 0.036) was observed. However, there was no significant association between cigarette smoking and HU in female subjects (P for trend was 0.739). This study indicated an inverse association between cigarette smoking and the prevalence of HU in the middle-aged and elderly male population, independent of some major confounding factors. The findings of this study expect further prospective studies to confirm the causal relationship.

Is tea consumption associated with the serum uric acid level, hyperuricemia or the risk of gout? A systematic review and meta-analysis.

BACKGROUND: The aim of this study was to examine the associations of tea consumption with the serum uric acid (SUA) level, hyperuricemia (HU) and the risk of gout. METHODS: A comprehensive literature search up to June 2016, using PUBMED and EMBASE databases, was conducted to identify the relevant observational studies that examined the associations of tea consumption with the SUA level, HU and the risk of gout. RESULTS: A total of fifteen observational studies were included in this study, and nine studies were extracted for meta-analysis. For the SUA level, seven studies were included. According to the combined weighted mean difference (WMD), there was no significant difference between the highest and the lowest tea intake category in terms of the SUA level (WMD = 7.41 µmol/L, 95%CI: -2.34 to 17.15; P = 0.136). In subgroup analysis including three studies, green tea consumption was positively associated with the SUA level (WMD = 17.20 µmol/L, 95%CI: 7.00 to 27.40; P = 0.01). For the prevalence of HU, five studies were included. The overall multi-variable adjusted odds ratio (OR) for the highest versus the lowest category of tea consumption was 0.98 (95%CI: 0.77 to 1.24; P = 0.839). For the risk of gout, two prospective cohort studies showed that there was no relationship between tea consumption and the risk of gout in males and females, respectively. CONCLUSION: The current evidences suggest that tea consumption does not seem to be associated with the SUA level, HU and the risk of gout. However, due to the limited number of studies, green tea consumption might be positively associated with the SUA level. More well-designed prospective cohort studies are needed to elaborate these issues further.

Association between metabolic syndrome and knee osteoarthritis: a cross-sectional study.

BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic joint disease in China. The aim of this study was to examine the association between metabolic syndrome (MetS) and knee OA in a population-based Chinese study. METHODS: Data included in this analysis is from a cross-sectional study, i.e., the Xiangya Hospital Health Management Center Study. MetS was diagnosed according to the criteria defined by the Chinese Diabetes Society. Radiographic knee OA was defined as changes equivalent to Kellgren-Lawrence (K-L) grade 2 or above at least one side. Associations between MetS and its components with OA were evaluated by conducting multivariable adjusted logistic regression. RESULTS: A total of 5764 participants were included in the present study. The unadjusted OR (1.27, 95%CI: 1.10-1.47, P = 0.001), age-sex adjusted OR (1.17, 95%CI: 1.01-1.36, P = 0.041) and multivariable adjusted OR (1.17, 95%CI: 1.01-1.36, P = 0.043) all suggested a positive association between MetS and knee OA. Besides, its components (e.g., overweight, hypertension and dyslipidemia) were also associated with the prevalence of radiographic knee OA respectively, after adjusting for some confounding factors. In addition, with the accumulation of MetS components, the prevalence of knee OA increased. Furthermore, MetS as a whole was associated with the prevalence of knee osteophyte (OSP) (OR = 1.72, 95%CI: 1.42-2.09, P < 0.001), but not joint space narrowing (JSN) (OR = 1.06, 95%CI: 0.91-1.23, P = 0.449). CONCLUSIONS: The findings of the present study indicated that there was a positive association between the prevalence of MetS and knee OA. However, MetS as a whole was associated with the higher prevalence of knee OSP, but not JSN, which should shed light on our understanding the association between MetS and OA.

Association Between Tibial Plateau Slopes and Anterior Cruciate Ligament Injury: A Meta-analysis.

PURPOSE: To investigate the associations of medial tibial plateau slope (MTPS), lateral tibial plateau slope (LTPS), and coronal tibial plateau slope (CTPS) with anterior cruciate ligament (ACL) injury both in the general population and in different gender subgroups. METHODS: PubMed, Ovid, Embase, and Scopus databases were searched through from inception to August 31, 2016. Observational studies reporting associations of MTPS/LTPS/CTPS with ACL injury were retrieved for analysis. Either a fixed- or random-effects model was used to calculate the overall standardized mean difference (SMD). Reviews, meeting abstracts, cadaver or animal studies, and other studies without disclosing full text were excluded in this study. RESULTS: A total of 29 studies were included. Subjects with ACL injury exhibited a significant increase in MTPS (SMD: 0.34 [95% confidence interval (CI): 0.18, 0.49]; P < .0001) and LTPS (SMD: 0.49 [95% CI: 0.30, 0.68]; P < .00001), but not in the CTPS (SMD: 0.09 [95% CI: -0.10, 0.27]; P = .36), compared with controls. Meanwhile, significant differences in MTPS and LTPS were observed in the male subgroup (SMD: 0.41 [95% CI: 0.20, 0.62]; P = .0001 and SMD: 0.55 [95% CI: 0.26, 0.85]; P = .0002, respectively) but not in the female (SMD: 0.31 [95% CI: -0.02, 0.64]; P = .06 and SMD: 0.26 [95% CI: -0.04, 0.56]; P = .09, respectively). CONCLUSIONS: The present meta-analysis showed that the increases in MTPS and LTPS were overall risk factors of ACL injury. However, these slopes would only be considered as "at risk" for males, but not for females. In addition, it was also proved that CTPS was not a risk factor of ACL injury. LEVEL OF EVIDENCE: Level III, meta-analysis of Level II and III studies.

Single-dose intra-articular bupivacaine plus morphine versus bupivacaine alone after arthroscopic knee surgery: a meta-analysis of randomized controlled trials.

PURPOSE: The purpose of this meta-analysis was to compare the efficacy and safety of single-dose intra-articular bupivacaine plus morphine versus bupivacaine alone for pain management following arthroscopic knee surgery. METHOD: A comprehensive literature search was conducted to identify randomized controlled trials that used single-dose intra-articular bupivacaine plus morphine and bupivacaine alone for post-operative pain, using MEDLINE (1966-2014), Cochrane Library and EMBASE databases. The weighted mean difference (WMD), relative risk (RR) and their corresponding 95 % confidence intervals (CIs) were calculated using RevMan statistical software. RESULT: A total of twenty-nine trials (n = 1167) were included. The post-operative visual analog scale (VAS) pain score of the bupivacaine plus morphine group compared with the bupivacaine alone group was significantly lower (WMD -1.15, 95 % CI -1.67 to -0.63, p < 0.0001). As far as safety, there was no significant difference in side effects between the two groups (RR 1.10, 95 % CI 0.59-2.04, n.s.). Sensitivity analyses suggested that the results of these two primary outcomes were stable and reliable. However, the current evidence did not suggest a superior effect with respect to the time to first analgesic request (WMD 51.33, 95 % CI -110.99 to 213.65, n.s.) and the number of patients requiring supplementary analgesia (RR 1.13, 95 % CI 0.92-1.39, n.s.). CONCLUSIONS: On the basis of the currently available literature, this study is the first to suggest that single-dose intra-articular bupivacaine plus morphine was shown to be significantly better than bupivacaine alone at relieving post-operative pain after arthroscopic knee surgery without increasing the short-term side effects. Routine use of single-dose intra-articular bupivacaine plus morphine is an effective way for pain management after arthroscopic knee surgery. LEVEL OF EVIDENCE: II.

Associations of dietary and serum magnesium with serum high-sensitivity C-reactive protein in early radiographic knee osteoarthritis patients.

INTRODUCTION: This study aimed to examine the associations of dietary magnesium (Mg) intake and serum Mg concentration with the high-sensitivity C-reactive protein (hsCRP) level in early radiographic knee osteoarthritis (OA) patients. METHODS: Multivariable logistic regression was used to test the associations of dietary and serum Mg with the serum hsCRP in early radiographic knee OA patients after adjustment of a number of potential confounding factors. RESULTS: A total of 936 early radiographic knee OA patients were included. A significant association between dietary Mg intake and hsCRP was observed. The multivariable-adjusted odds ratio (OR) (95% CI) for elevated hsCRP (≥3.0 mg/l) in the second, third, fourth, and fifth dietary Mg intake quintile were 0.44 (95% CI: 0.24-0.82), 0.58 (95% CI: 0.31-1.10), 0.34 (95% CI: 0.15-0.77), and 0.19 (95% CI: 0.06-0.57), respectively, compared with the lowest (first) quintile, and p for trend was 0.01. A significant association between serum Mg concentration and hsCRP was observed. The multivariable-adjusted OR (95% CI) for elevated hsCRP in the second, third, fourth, and fifth serum Mg concentration quintile were 0.63 (95% CI: 0.35-1.12), 0.83 (95% CI: 0.50-1.39), 0.53 (95% CI: 0.31-0.91), and 0.46 (95% CI: 0.25-0.85), respectively, compared with the lowest quintile, and p for trend was 0.01. CONCLUSION: The present study indicated that both dietary and serum Mg were inversely associated with serum hsCRP in early radiographic knee OA patients.

Preparation and Properties of Novel Polymer Blue Fluorescent Materials.

The pyrazoline was chosen as the luminescent functional group, and then four kinds of new polyamide polymer blue fluorescent materials were designed and synthesized. The structures of them were confirmed by using NMR (H 1NMR) and gel permeation chromatography (GPC). Furthermore, liquid and solid film fluorescence excitation and emission spectra of the compounds were measured, and three polymers J1, J2 and J3 showed good fluorescence properties. The polymeric materials showed good film capacity, low cost and good thermal stability, and are expected to be widely applied in electroluminescent devices.

JNK pathway in osteosarcoma: pathogenesis and therapeutics.

CONTEXT: The c-Jun NH2-terminal kinase (JNK) is a member of the mitogen-activated protein kinase super family. JNK can phosphorylate a number of activator protein-1 components, activating several transcription factors, and thus, JNK signaling pathway is being involved in several carcinogenic mechanisms. OBJECTIVE: In this study, we have reviewed the recent updates of the association of JNK pathway with osteosarcoma (OS), which is one of the most common and aggressive bone malignancies. METHODS: In this review, we have explored the databases like PubMed, Google Scholar, MEDLINE, etc., and collected the most relevant papers of JNK signaling pathway involved in the pathogenesis and therapeutics of OS. RESULTS: Evidence showed that JNK is a master protein kinase that plays an important role in osteoblast proliferation, differentiation and apoptosis. Interesting reports showed that chemical JNK inhibitors reduce OS cell proliferation and metastasis. Many of the components of this pathway have now been identified and the application of JNK inhibitors has been proven to work in vivo in human and in animal models; however, JNK pathway has not been translated into clinical use. CONCLUSION: Therapeutic interventions of potent and selective inhibitors of JNK might provide promising therapeutic approaches for the treatment of OS, and could improve the survival rate and quality of life of OS patients.