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Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.

During 2018-2020, we isolated 32 Eurasian avian-like swine influenza A(H1N1) viruses and their reassortant viruses from pigs in China. Genomic testing identified a novel reassortant H3N1 virus, which emerged in late 2020. Derived from G4 Eurasian H1N1 and H3N2 swine influenza viruses. This virus poses a risk for zoonotic infection.

Intervertebral disc degeneration (IDD) is the most common chronic skeletal muscle degeneration disease. Although the underlying mechanisms remain unclear, nucleus pulposus (NP) autophagy, senescence, and apoptosis are known to play a critical role in this process. Previous studies suggest that bromodomain-containing protein 4 (BRD4) promotes senescent and apoptotic effects in several age-related degenerative diseases. It is not known, however, if BRD4 inhibition is protective in IDD. In this study, we explored whether BRD4 influenced IDD. In human clinical specimens, the BRD4 level was markedly increased with the increasing Pfirrmann grade. At the cellular level, BRD4 inhibition prevented IL-1β-induced senescence and apoptosis of NP cells and activated autophagy via the AMPK/mTOR/ULK1 signaling pathway. Inhibition of autophagy by 3-methyladenine (3-MA) partially reversed the antisenescence and antiapoptotic effects of BRD4. In vivo, BRD4 inhibition attenuated IDD. Taken together, the results of this study showed that BRD4 inhibition reduced NP cell senescence and apoptosis by induced autophagy, which ultimately alleviated IDD. Therefore, BRD4 may serve as a novel potential therapeutic target for the treatment of IDD.

SynopsisNF-κB signaling has been reported to play a key regulatory role in the pathogenesis of Alzheimer’s disease (AD). The purpose of this study is to investigate the effects of ginkgolide on cell viability in an AD cellular model involving an APP/PS1 double gene-transfected HEK293 cell line (APP/PS1-HEK293) and further explore the mechanisms of action related to NF-κB signaling. The optimal time point and concentration of ginkgolide for cell proliferation were screened using a cell counting kit-8 assay. Based on the results, an in vitro study was performed by co-culture of APP/PS1-HEK293 with different dosages of ginkgolide, followed by an enzyme-linked immunosorbent assay to measure the levels of supernatant tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, as well as western blotting and real-time polymerase chain reaction to detect intracellular protein and mRNA expression of NF-κB p65, IκBa, Bcl-2, and Bax. APP/PS1-HEK293 cells exhibited the highest cell viability at a concentration of 100 µg/ml after 48 h of treatment with ginkgolide. The supernatant levels of TNF-α, IL-1β, and IL-6 in the high-dosage ginkgolide-treated groups were lower than those in the control group. Compared with the control group, there were decreased intracellular protein and mRNA expression of NF-κB p65 and Bax, but increased protein and mRNA expression of IκBa in both high-dosage and low-dosage groups. Ginkgolide may enhance cell viability, indicative of its neuroprotective effects on AD, at least partially via suppression of the NF-κB signaling pathway involving anti-apoptosis and anti-inflammation mechanisms. Therefore, ginkgolide might be a promising therapeutic agent against AD. Graphical abstract

Intervertebral disc degeneration (IDD), an important cause of chronic low back pain (LBP), is considered the pathological basis for various spinal degenerative diseases. A series of factors, including inflammatory response, oxidative stress, autophagy, abnormal mechanical stress, nutritional deficiency, and genetics, lead to reduced extracellular matrix (ECM) synthesis by intervertebral disc (IVD) cells and accelerate IDD progression. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a vital role in diverse degenerative diseases. Recent studies have shown that mTOR signalling is involved in the regulation of autophagy, oxidative stress, inflammatory responses, ECM homeostasis, cellular senescence, and apoptosis in IVD cells. Accordingly, we reviewed the mechanism of mTOR signalling in the pathogenesis of IDD to provide innovative ideas for future research and IDD treatment.

Supplemental Digital Content is available in the text., Phosphoglycerate mutase (PGAM) is a critical enzyme in glycolysis. PGAM2 is abundant in several types of tissues and malignant tumours. However, there is limited information regarding their clinicopathological significance in dysplastic nodules and hepatocellular carcinoma (HCC). This study aims to investigate the prognostic value of PGAM2 as a new biomarker for HCC. The PGAM2 expression level was evaluated by immunohistochemistry in liver cirrhosis (n = 10), low-grade dysplastic nodules (n = 15), high-grade dysplastic nodules (n = 15) and HCCs (n = 20) and 178 pairs of HCC and adjacent peritumoral liver tissues. We selected X-tile software for counting cut-point based on the outcomes for prognosis analysis, and used Kaplan–Meier analysis and Cox regression analysis can assess the prognosis of clinicopathologic parameters. Nuclear PGAM2 was significantly overexpressed in peritumoral liver tissues compared with HCC tissues (P = 0.0010). Kaplan–Meier analyses of 178 HCC samples revealed that nuclear PGAM2’s high expression level, but not cytoplasmic PGAM2, was significantly related to good overall survival rate (OS). In addition, univariate and multivariate Cox analyses indicated nuclear PGAM2 expression could be regarded as valuable predictors for OS in HCC. PGAM2 was highly expressed in HCC tissues than liver cirrhosis tissues, and nuclear PGAM2’s high expression might demonstrate HCC patients have poor postoperative results. Thus, nuclear PGAM2 can be regarded as valuable predictors for OS in HCC patients after surgery.

Intervertebral disc degeneration (IDD) is a common age-related disease with clinical manifestations of lumbar and leg pain and limited mobility. The pathogenesis of IDD is mainly mediated by the death of intervertebral disc (IVD) cells and the imbalance of extracellular matrix (ECM) synthesis and degradation. Oxidative stress and inflammatory reactions are the important factors causing this pathological change. Therefore, the regulation of reactive oxygen species and production of inflammatory factors may be an effective strategy to delay the progression of IDD. In recent years, nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream regulated protein heme oxygenase-1 (HO-1) have received special attention due to their antioxidant, anti-inflammatory and anti-apoptotic protective effects. Recent studies have elucidated the important role of these two proteins in the treatment of IDD disease. However, Nrf2 and HO-1 have not been systematically reported in IDD-related diseases. Therefore, this review describes the biological characteristics of Nrf2 and HO-1, the relationship between Nrf2- and HO-1-regulated oxidative stress and the inflammatory response and IDD, and the progress in research on some extracts targeting Nrf2 and HO-1 to improve IDD. Understanding the role and mechanism of Nrf2 and HO-1 in IDD may provide novel ideas for the clinical treatment and development of Nrf2- and HO-1-targeted drugs.

Low back pain is a common symptom of intervertebral disc degeneration (IDD), which seriously affects the quality of life of patients. The abnormal apoptosis and senescence of nucleus pulposus (NP) cells play important roles in the pathogenesis of IDD. Proanthocyanidins (PACs) are polyphenolic compounds with anti-apoptosis and anti-aging effects. However, their functions in NP cells are not yet clear. Therefore, this study was performed to explore the effects of PACs on NP cell apoptosis and aging and the underlying mechanisms of action. Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The apoptosis rate was determined TUNEL assays. Levels of apoptosis-associated molecules (Bcl-2, Bax, C-caspase-3 and Caspase-9) were evaluated via western blot. The senescence was observed through SA-β-gal staining and western blotting analysis was performed to observe the expression of senescence-related molecules (p-P53, P53, P21 and P16). Pretreatment with PACs exhibited protective effects against IL-1β-induced NP cell apoptosis including apoptosis rate, expressions of proapoptosis and antiapoptosis related genes and protein. PACs could also alleviate the increase of p-p53, P21, and P16 in IL-1β-treated NP cells. SA-β-gal staining showed that IL-1β-induced senescence of NP cells was prevented by PACs pertreatment. In addition, PACs activated PI3K/Akt pathway in IL-1β-stimulated NP cells. However, these protected effects were inhibited after LY294002 treatment. The results of the present study showed that PACs inhibit IL-1β-induced apoptosis and aging of NP cells by activating the PI3K/Akt pathway, and suggested that PACs have therapeutic potential for IDD.

To evaluate the clinical efficacy of microwave ablation (MWA) of benign breast lesions (BBLs) and compare the learning curves of international radiologists (IRs) and surgeons. In total, 440 patients with 755 clinicopathologically confirmed BBLs from 5 centers were prospectively enrolled from February 2014 to July 2018. Technical success, complications, volume reduction ratio (VRR), palpability, and cosmetic satisfaction after ablation were analyzed. In addition, the ablation time (AT) and energy (AE) with the number of procedures were analyzed for learning curve evaluation. The mean maximum diameter was 1.7 ± 0.6 cm. The complete ablation rate reached 100%, including 45.8% lesions adjacent to the skin, pectoralis, or areola. After a median follow-up of 13.7 months, the 12-month VRR of all lesions was 97.9%, and that for 1.0- to 2.0-cm and ≥ 2.0-cm lesions was 98.6% and 96.9%, respectively. A total of 55.9% of BBLs became nonpalpable (palpable in 85.7% of cases before MWA) by both the clinician and patient. The cosmetic and minimally invasive satisfaction rates were good or excellent in 98.4% and 94.5% of patients, respectively. The median AT/cm3 and AE/cm3 decreased as experience increased. The AE/cm3 of the IR with 5 years of experience was lower than that of the IR with 1 year of experience and the surgeons, while the AT/cm3 of surgeons was comparable with that of the IR with 5 years of experience at relatively mature phase. Ultrasound-guided percutaneous MWA is a valuable technique for the treatment of BBLs. Trial registration: ClinicalTrials.gov (NCT02860104) • Ultrasound-guided percutaneous microwave ablation has the potential to become a valuable technique for the treatment of benign breast lesions. • A skilled interventional radiologist shows a rapid improvement in mastering the technique.

Long non-coding RNAs (lncRNAs) have emerged as important biological tuners. Here, we reveal the role of an uncharacterized lncRNA we call SENEBLOC that is expressed by both normal and transformed cells under homeostatic conditions. SENEBLOC was shown to block the induction of cellular senescence through dual mechanisms that converge to repress the expression of p21. SENEBLOC facilitates the association of p53 with MDM2 by acting as a scaffold to promote p53 turnover and decrease p21 transactivation. Alternatively, SENEBLOC was shown to affect epigenetic silencing of the p21 gene promoter through regulation of HDAC5. Thus SENEBLOC drives both p53-dependent and p53-independent mechanisms that contribute to p21 repression. Moreover, SENEBLOC was shown to be involved in both oncogenic and replicative senescence, and from the perspective of senolytic agents we show that the antagonistic actions of rapamycin on senescence are dependent on SENEBLOC expression.

Posthepatectomy liver failure (PHLF) is a serious complication after hepatectomy, and its effective methods for preoperative prediction are lacking. Here, we aim to identify predictive factors and build a nomogram to evaluate patients' risk of developing PHLF.A retrospective review of a training cohort, including 199 patients who underwent hepatectomy at the Shanghai Eastern Hepatobiliary Surgery Hospital, was conducted. Independent risk variables for PHLF were identified using multivariate analysis of perioperative variables, and a nomogram was used to build a predictive model. To test the predictive power, a prospective study in which a validation cohort of 71 patients was evaluated using the nomogram. The prognostic value of this nomogram was evaluated by the C-index.Independent risk variables for PHLF were identified from perioperative variables. In multivariate analysis of the training cohort, tumor number, Pringle maneuver, blood loss, preoperative platelet count, postoperative ascites and use of anticoagulant medications were determined to be key risk factors for the development of PHLF, and they were selected for inclusion in our nomogram. The nomogram showed a 0.911 C-index for the training cohort. In the validation cohort, the nomogram also showed good prognostic value for predicting PHLF. The validation cohort was used with similarly successful results to evaluate risk in two previously published study models with calculated C-indexes of 0.718 and 0.711.Our study establishes for the first time a novel nomogram that can be used to identify patients at risk of developing PHLF.

Five compounds were isolated from the methanolic extract of

This study aimed to determine the effects of SKI on interleukin (IL)-1β-induced apoptosis of nucleus pulposus (NP) cells, intervertebral disc degeneration (IDD), and the Wnt signaling pathway. NP tissue specimens of different Pfirrmann grades (II-V) were collected from patients with different grades of IDD. Real-time polymerase chain reaction and western blotting were used to compare SKI mRNA and protein expression in NP tissues from patients. Using the IL-1β-induced IDD model, NP cells were infected with lentivirus-coated si-SKI to downregulate the expression of SKI and treated with LiCl to evaluate the involvement of the Wnt/β-catenin signaling pathway. Western blotting, immunofluorescence, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect NP cell apoptosis, extracellular matrix (ECM) metabolism, and related protein expression changes in the Wnt/β-catenin signaling pathway. To investigate the role of SKI in vivo, a rat IDD model was established by needle puncture of the intervertebral disc. Rats were injected with lentivirus-coated si-SKI and evaluated by magnetic resonance imaging (MRI), and hematoxylin and eosin (HE) and safranin O staining. SKI expression positively correlated with the severity of human IDD. In the IL-1β-induced NP cell degeneration model, SKI expression increased significantly and reached a peak at 24 h. SKI knockdown protected against IL-1β-induced NP cell apoptosis and ECM degradation. LiCl treatment reversed the protective effects of si-SKI on NP cells. Furthermore, lentivirus-coated si-SKI injection partially reversed the NP tissue damage in the IDD model in vivo. SKI knockdown reduced NP cell apoptosis and ECM degradation by inhibiting the Wnt/β-catenin signaling pathway, ultimately protecting against IDD. Therefore, SKI may be an effective target for IDD treatment.

Background: Chronic pain is a common postsurgery symptom. It has an adverse impact on patients’ overall wellbeing. Chronic pain after an operation is caused by intricate mechanisms that have not been well understood. The predictability of most surgical methods has enabled scholars to conduct randomized controlled trials (RCTs) involving pharmacological interventions to prevent chronic pain after a surgery. Therefore, the present study aims to evaluate the curative effects of gabapentin to prevent chronic pain in adults after surgery. Methods: The authors will collect RCTs related to the use of gabapentin to prevent chronic pain in adults following surgery. Accordingly, a comprehensive search will be performed in 4 online databases to find English language articles, including Cochrane Library, EMBASE, Web of Science, and PubMed. In addition, the search also includes 3 Chinese language databases: VIP data, WanFang database, and China National Knowledge Infrastructure. Each of the RCT published from their inception to September 2021 will be considered. The authors will carry out a meta-analysis of RCTs after screening the studies. Subsequently, the authors will use RevMan (v 5.3) to perform an assessment of bias risk, data synthesis, and subgroup analysis, provided inclusion criteria are met. Results: The results will provide clinical evidence for the curative effects of gabapentin to prevent chronic pain in adults after surgery. Conclusion: The summary provided in this systematic review will judge whether gabapentin intervention is effective and feasible to prevent chronic pain in adults following surgery. Registration number: 10.17605/OSF.IO/XG4CK

Currently, there is no effective treatment for Burkitt's lymphoma in patients aged above 60 years, and thus research on effective treatment options for Burkitt's lymphoma has been gaining increasing attention. Artesunate has been identified as a novel effective growth suppressor in Burkitt's lymphoma. Here, we utilized molecular biology, transcriptome analysis, and other techniques to study artesunate-induced death of the Burkitt's lymphoma cells DAUDI and CA-46, the effect of artesunate on gene expression in DAUDI and CA-46 cells, and the effect of artesunate-induced ATF4-CHOP-CHAC1 pathway on ferroptosis. We also studied the inhibitory effects and ferroptosis induction of artesunate on CA-46 cells in mouse xenografts. Results showed that artesunate induced ferroptosis in DAUDI and CA-46 cells, as evidenced by the protective effect of liproxstatin-1, ferrostatin-1, and desferoxamine, resulting in an endoplasmic reticulum stress response, a ctivation of the ATF4-CHOP-CHAC1 pathway enhanced ferroptosis in DAUDI and CA-46 cells. A mouse-transplanted tumor model showed that artesunate can inhibit the proliferation and induce ferroptosis of CA-46 cells in vivo. This study provides a novel perspective for the development of drugs against different types of Burkitt's lymphomas.

Multimode tumour ablation therapy is a treatment method that combines cryoablation with radiofrequency ablation, guided by medical imaging technology and based on precise planning, targeting, monitoring, and control of the thermal energy delivered, with the aim of achieving a whole-body antitumour immune response to malignant tumours. To develop standardized criteria for the application of multimode tumour ablation therapy to malignant hepatic tumours, to facilitate actualization of the criteria in various hospitals, and to ensure therapeutic efficacy and safety, the Society of Interventional Therapy of the Chinese Anti-Cancer Association and the Solid Tumor Theranostics Committee of the Shanghai Anti-Cancer Association assembled experts who specialize in oncology to discuss this treatment method and to arrive at a clinical practice consensus guideline for the indications, contraindications, and techniques of multimode tumour ablation therapy for malignant hepatic tumours.

Purpose To perform the Manchester-Oxford Foot Questionnaire Chinese Version (MOXFQ-Ch) through a cross-cultural adaptation and validation of the original questionnaire. Material and methods Three hundred and sixty nine patients (241 women/128 men, 48.75 ± 8.17 years old) with a diagnosis of hallux valgus foot (237 both feet; 74 right foot; 58 left foot) participated in this observational study. A translation and cross-cultural adaptation of the Manchester-Oxford Foot Questionnaire to Chinese was developed. Each participant completed twice the Manchester-Oxford Foot Questionnaire. In addition, the psychometric characteristics of Manchester-Oxford Foot Questionnaire Chinese Version were analyzed for internal consistency, construct validity and criterion validity (EuroQoL-5D; Short-Form 12v2; Foot Functional Index were used). Results The internal consistency of the different sub-scales and total value of the Manchester-Oxford Foot Questionnaire Chinese Version ranged between 0.976 (walking/standing) and 0.991 (pain). Moreover, in the item response analysis, the results ranged between 0.973 (walking/standing) and 0.998 (pain). The standard error of the measurement scores ranged between 1.071 (social interaction) and 1.864 (Manchester-Oxford Foot Questionnaire Chinese Version total value). The values of Minimal Detectible Change 90 were 4342. In addition, values of the root mean square error of approximation and Goodness-of-fit index were: 0.076 and 0.916 respectively. For criterion validity, were used the questionnaires: Short-Form 12v2, Foot Function Index (Chinese Version), and EuroQol-5D. Correlations with the three factors show a "r" value ranged between 0.104 (Factor 1 - SF12v2-Sub-scale) to 0.819 (FFI-Ch). Conclusions The Manchester-Oxford Foot Questionnaire has been translated and culturally adapted from the original version into Chinese. Manchester-Oxford Foot Questionnaire Chinese Version has shown excellent internal consistency, external validity ranges from moderate to excellent (depending on the questionnaire used) and, demonstrated a structure of one factor psychometrically supported. Consequently, the Manchester-Oxford Foot Questionnaire Chinese Version could be introduced into Chinese-speaking clinical and research settings to assess and monitor patients with hallux valgus Implications for rehabilitation Manchester-Oxford Foot Questionnaire has been cross-cultural adapted from the original version to Chinese. Manchester-Oxford Foot Questionnaire Chinese Version have been reported satisfactory psychometric properties and consistent results. Chinese speaking clinician and researcher, could use the Manchester-Oxford Foot Questionnaire Chinese Version to assess and follow up patients with food and ankle disease.

Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. TrxR has become an attractive target for anticancer agents. In this work, three Ru(II) complexes with salicylate as ligand, [Ru(phen)2(SA)] (phen = 1,10-phenanthroline, SA = salicylate, 1), [Ru(dmb)2(SA)] (dmb = 4,4′-dimethyl-2,2′-bipyridine, 2) and [Ru(bpy)2(SA)] (bpy = 2,2′-bipyridine, 3), were synthesized and characterized. The anticancer effect exerted by them was evaluated. Complex 1 was found to exhibit obvious anticancer activity, in comparison with cisplatin, against cancer cell lines, while displaying low toxicity to the normal cell line BEAS-2B. The mechanism of complex 1 cancer cell growth suppress was investigated in A549 cells. Complex 1 exerted its anticancer through inducing apoptosis and triggering cell cycle arrest at the G0/G1 phase. Complex 1 can selectively inhibit TrxR activity and thus promote the generation and accumulation of reactive oxygen species (ROS), which subsequently trigger mitochondrial dysfunction and DNA damage, activate oxidative stress-sensitive mitogen activated protein kinase (MAPK), and suppress the protein kinase B (PKB or AKT) signal pathway, resulting in apoptosis in A549 cells.

The aim of present study is to investigate the feasibility of patient-specific ankle-foot orthoses fabricated using additive manufacturing (AM) techniques. Then, clinical performance of the AFOs manufactured using material PA12 was evaluated in stroke survivors based on gait analysis data. The ankle and foot were scanned by EinScan-Pro 3D scanner. The software Geomagic Studio was used for modifying the AFO model. After processing the original AFO model into the final required model, material PA12 were used to fabricate the AFOs by Multi Jet Fusion (MJF) technique. Finally, gait analysis of 12 stroke patients was conducted to compare the effects with and without AFO. It took 2 hours from processing the initial AFO model to the completion of final model, and the printing time was 8 hours. The printing thickness of the AFO was 1.2 mm. With respect to the temporal-spatial parameters, the velocity and stride length in the gait with AFO increased significantly as compared to the gait without AFO (P=0.001, P=0.002). The cadence increased, double limb support phase decreased, and the step length difference decreased in the gait with AFO; however, the difference was not statistically significant (P=0.117, P=0.075, P=0.051).This study confirmed the feasibility of patient-specific AFO fabricated by AM techniques, and demonstrated the process of modifying AFO models successfully. The specific ankle-foot orthoses fabricated by material PA12 have a significant effect on the improvement of velocity and stride length in people with stroke.

Cancer cells in quiescence (G0 phase) are resistant to death, and re-entry of quiescent cancer cells into the cell-cycle plays an important role in cancer recurrence. Here we show that two p53-responsive miRNAs utilize distinct but complementary mechanisms to promote cancer cell quiescence by facilitating stabilization of p27. Purified quiescent B16 mouse melanoma cells expressed higher levels of miRNA-27b-3p and miRNA-455-3p relative to their proliferating counterparts. Induction of quiescence resulted in increased levels of these miRNAs in diverse types of human cancer cell lines. Inhibition of miRNA-27b-3p or miRNA-455-3p reduced, whereas its overexpression increased, the proportion of quiescent cells in the population, indicating that these miRNAs promote cancer cell quiescence. Accordingly, cancer xenografts bearing miRNA-27b-3p or miRNA-455-3p mimics were retarded in growth. miRNA-27b-3p targeted cyclin-dependent kinase regulatory subunit 1 (CKS1B), leading to reduction in p27 polyubiquitination mediated by S-phase kinase-associated protein 2 (Skp2). miRNA-455-3p targeted CDK2-associated cullin domain 1 (CAC1), which enhanced CDK2-mediated phosphorylation of p27 necessary for its polyubiquitination. Of note, the gene encoding miRNA-27b-3p was embedded in the intron of the chromosome 9 open reading frame 3 gene that was transcriptionally activated by p53. Similarly, the host gene of miRNA-455-3p, collagen alpha-1 (XXVII) chain, was also a p53 transcriptional target. Collectively, our results identify miRNA-27b-3p and miRNA-455-3p as important regulators of cancer cell quiescence in response to p53 and suggest that manipulating miRNA-27b-3p and miRNA-455-3p may constitute novel therapeutic avenues for improving outcomes of cancer treatment. Significance: Two novel p53-responsive microRNAs whose distinct mechanisms of action both stabilize p27 to promote cell quiescence and may serve as therapeutic avenues for improving outcomes of cancer treatment.

As one of the natural triterpenoids isolated from Anemone Raddeana Regel, Raddeanin A (RA) has been confirmed to possess therapeutic effects against multiple tumorigeneses, especially for the onset of glioblastoma and growth in human brains. However, the mechanism by which this happens remains poorly understood in terms of the vascular endothelium trafficking routine of RA through the brain-blood barrier (BBB). To seek such answers, human brain microenvironment endothelial cells (HBMECs) were used to stimulate the microenvironment in vitro, and to explore the intracellular accumulation of RA. The results of this experiment illustrated that RA has a relative moderate transport affinity for such cells. The kinetic parameter Km was 37.01 ± 2.116 μM and Vmax was 9.412 ± 0.1375 nM/min/mg of protein. Interestingly, protein downregulation of P-glycoprotein (P-gp, ABCB1/MDR1) significantly activated RA transmembrane activity, which proves that P-gp is responsible for RA cellular trafficking. In addition, the selective non-specific inhibitor, LY335979 increased either RA or the classical substrate of P-gp, digoxin, intracellular accumulation by restricting the transporter's function but without jeopardizing cytomembrane proteins. Moreover, a decrease in the expression or activity of P-gp triggered RA drug resistance to HBMECs. In summary, our data showed that both the expression and function of P-gp are all necessary for RA transmembrane trafficking through cerebrovascular endothelial cells. This study provides significant evidence for the presence of a connection between RA transport and P-gp variation during drug BBB penetration. It is also suggesting some vital guidance on the RA pharmacodynamic effect in human brains.

Backgrounds Diabetic nephropathy (DN) is one of the most important clinical complications of diabetes mellitus (DM) and is the most common cause of end-stage renal disease. Currently, there is no highly effective medicine that can prevent, halt, or reverse the progressive course of DN. Initial clinical data showed that Tripterygium glycosides (TGs), a traditional Chinese medicine, can decrease proteinuria in patients with DN. Objectives The objective of the present study is to investigate the efficacy and safety of TGs for the treatment of DN through meta-analysis of randomized controlled trials (RCTs). Methods All RCTs of TGs for DN were collected from The China National Knowledge Infrastructure (CNKI), PubMed, Web of Science, Wanfang Data, Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP) by setting the study inclusion and elimination standards. Two reviewers evaluated the quality of the trials and extracted the data independently. RevMan 5.4 software was used for meta-analyses. The primary outcome was a change in 24-hours urinary total protein (24 h TUP). Results 26 RCTs with 1824 participants were identified. Studies were assessed using the Cochrane risk of bias tool. The overall effects showed that TGs was compared with the controls, TGs showed significant effects in reducing 24 h TUP [WMD = -0.84, 95 % CI (-1.09, -0.59)], elevating serum albumin [WMD = 2.88, 95 % CI (1.87, 3.90)], and the total efficiency [OR = 4.08, 95 % CI (2.37, 7.04)]. This effect was consistent across the subgroups of period of intervention. Conclusions The present research showed that TGs was significantly associated with improvement of renal function in patients with DN. TGs offers a novel approach to the treatment of DN, more high-quality RCTs are needed for a better understanding of the role of TGs in DN therapy.

Type 2 diabetes mellitus (T2DM) is a pandemic metabolic disease worldwide. Multiple types of cancer, particularly liver cancer, are closely associated with T2DM. As a result, there is growing interest in investigating whether anti-diabetic medications could lower cancer risks in the population and even prolong patient survival among those with concurrent cancer. There are many types of anti-diabetic medications available in the clinic. The present study reviewed how different anti-diabetic drugs affect cancer risk and patient survival. On the one hand, multiple retrospective studies have shown that the different anti-diabetic medications have distinct effects on cancer risks. Insulin-raising drugs, including exogenous insulin, increased cancer risks, while drugs potentiating insulin sensitivity like metformin reduced cancer risks. On the other hand, the effects of anti-diabetic medications on patient survival are relatively less studied, except limited reports in liver cancer and pancreatic cancer. It seems that metformin could extend overall survival in patients of early-stage cancer. In contrast in the advanced cancer with metastasis, metformin has no effect or even worsens cancer mortality. It is yet unknown whether these distinct effects of metformin are attributable to the severity of the cancer staging or to the drug interactions between metformin and other medications. This question warrants reconsideration of the current clinical practice in the control of T2DM. Future large-scale prospective studies are needed to resolve this.

We updated the experience on percutaneous microwave ablation for renal cell carcinoma with five-center data and long-term follow-up.This retrospective study reviewed the T1N0M0 renal cell carcinoma patients who underwent microwave ablation between April 2006 and December 2019. Clinicopathological and procedural data were collected. Technical effectiveness and complications were assessed, and the Kaplan-Meier method was used for cancer-specific survival, disease-free survival, overall survival, and local neoplastic process analyses.A total of 323 consecutive patients (mean age, 62.9 years ± 14.0) with 371 biopsy-proved tumors (mean diameter, 2.9 cm ± 1.2) were enrolled, and 42.6% of the tumors were located adjacent to collecting system/bowel and technical effectiveness was achieved in 360 (97.0%) tumors. For 275 cT1a patients, during median follow-up time of 66.0 months (IQR, 58.4-73.6), 10-year local neoplastic processes, cancer-specific survival, disease-free survival, and overall survival rates were 1.9%, 87.4%, 71.8, and 67.5%, respectively. For 48 cT1b patients, during the median follow-up time of 30.4 months (IQR, 17.7-44.8), 5-year local tumor progression, cancer-specific survival, disease-free survival, and overall survival rates were 11.3%, 91.4%, 69.1, and 89.2%, respectively. Major complications showed no differences between cT1a (3.5%) and cT1b (6.9%) patients (p = 0.28). A clinical risk stratification system was developed based on multivariable model to predict DFS and CSS with c-indexes of 0.78 (95% CI: 0.71-0.85) and 0.77 (95% CI: 0.65-0.90), respectively.With matured follow-up at five institutions, ultrasound-guided percutaneous microwave ablation is a reliable treatment option for cT1a renal cell carcinoma even in dangerous location and appears to be promising for cT1b tumors.• To our knowledge, this is the first multicenter cohort of long-term oncologic outcomes with percutaneous MWA of cT1 RCC. • The predicting model we developed is accurate to predict the long-term DFS and CSS, which can help to provide a better MWA prognostication over routinely available clinical information. • The available evidence shows that microwave ablation of clinical stage T1 RCC is safe and reliable with promising long-term oncologic outcomes, especially for cT1a RCC with excellent 10-year results.

Various studies have revealed an association between cigarette smoking and increased risk for multiple sclerosis (MS). However, its role in neuromyelitis optica spectrum disorder (NMOSD) remains elusive. Therefore, in the present case-control study, we aimed to assess the association of active and passive cigarette smoking with the risk of MS and NMOSD. Thirty-six patients with NMOSD, 46 patients with MS, and 122 healthy individuals were included in this study. Standardized questionnaires and telephone interviews were used to collect information regarding the active and passive cigarette smoking behaviors of the patients and normal controls. The risk of MS was significantly higher among smokers than among nonsmokers (odds ratio = 2.166, 95% confidence interval: 1.109–4.170; P = .027). Further analysis of the risk between active and passive smokers, male smokers and nonsmokers showed no statistical difference. However, neither smokers nor active smokers had a greater or lower risk of NMOSD than their nonsmoking counterparts. Our preliminary study showed no significant association between cigarette smoking and the risk of NMOSD, strongly suggesting that, unlike MS, cigarette smoking might not confer NMOSD susceptibility, at least in the Northern Han Chinese population.

Ewing sarcoma (ES) is one of the most common malignant bone tumors in children and adolescents. The immune microenvironment plays an important role in the development of ES. Here, we developed an optimal signature for determining ES patient prognosis based on immune-related genes (IRGs).We analyzed the ES gene expression profile dataset, GSE17679, from the GEO database and extracted differential expressed IRGs (DEIRGs). Then, we conducted functional correlation and protein-protein interaction (PPI) analyses of the DEIRGs and used the machine learning algorithm-iterative Lasso Cox regression analysis to build an optimal DEIRG signature. In addition, we applied ES samples from the ICGC database to test the optimal gene signature. We performed univariate and multivariate Cox regressions on clinicopathological characteristics and optimal gene signature to evaluate whether signature is an important prognostic factor. Finally, we calculated the infiltration of 24 immune cells in ES using the ssGSEA algorithm, and analyzed the correlation between the DEIRGs in the optimal gene signature and immune cells.A total of 249 DEIRGs were screened and an 11-gene signature with the strongest correlation with patient prognoses was analyzed using a machine learning algorithm. The 11-gene signature also had a high prognostic value in the ES external verification set. Univariate and multivariate Cox regression analyses showed that 11-gene signature is an independent prognostic factor. We found that macrophages and cytotoxic, CD8 T, NK, mast, B, NK CD56bright, TEM, TCM, and Th2 cells were significantly related to patient prognoses; the infiltration of cytotoxic and CD8 T cells in ES was significantly different. By correlating prognostic biomarkers with immune cell infiltration, we found that FABP4 and macrophages, and NDRG1 and Th2 cells had the strongest correlation.Overall, the IRG-related 11-gene signature can be used as a reliable ES prognostic biomarker and can provide guidance for personalized ES therapy.

This study aimed to explore the prognostic role of dipeptidyl peptidase 4 (DPP4) expression in hepatocellular carcinoma (HCC). DPP4 expression was measured in formalin-fixed paraffin-embedded specimens that were gathered from 327 HCC patients. Immunohistochemistry analyses were utilized to examine DPP4 expression characteristics and prognostic values (overall survival (OS) and time to recurrence) of DDP4 in HCC tissues. In addition, a patient-derived xenograft (PDX) model was used to assess the correlation between DPP4 expression and tumor growth in vivo. DPP4 was expressed in low levels in HCC tissues in contrast to paired peritumoral tissues (38 cases were down-regulated in a total of 59 cases, 64.4%. P=0.0202). DPP4 expression was significantly correlated with TNM stage (P=0.038), tumor number (P=0.035), and vascular invasion (P=0.024), and significantly reduced in patients who were in TNM stages II and III-V, with multiple tumors, and with microvascular invasion compared to patients with TNM stage I, single tumor, and no microvascular invasion. Notably, HCC tissues with low expression of DPP4 had poor OS (P=0.016) compared with HCC tissues with high expression of DPP4, and results from PDX model showed that tumor growth was significantly faster in HCC patients that lowly expressed DPP4 compared to those with highly expressed DPP4. Our findings suggested that low levels of DPP4 could impact the aggressiveness of HCC and contribute to a poor prognosis.

Intrahepatic cholangiocarcinoma (ICC) is the second most common tumor in primary liver cancer, but the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. This study aimed to develop a novel prognostic classifier for patients with ICC after surgery. Using a proteomics approach, we screened tumor markers that up-regulated in ICC tissues, and narrowed down by bioinformatics analysis, western blot and immunohistochemistry. Prognostic markers were identified using Cox regression analyses in primary training cohort and the predictive models for time to recurrence (TTR) were established. The predictive accuracy of predictive model was validated in external validation cohort and prospective validation cohort. MTT assay, clonal formation assay and trans-well assays were used to verify the effect on the proliferation and migration in ICC cell line. Triosephosphate isomerise (TPI1) was significantly up-regulated in ICC tissues and Kaplan–Meier analysis reveals that higher TPI1 expression was strongly correlated with higher recurrence rate of ICC patients. In the primary training cohort, mean TTR was significantly longer (p

ObjectivesTo define the core competencies essential for specialist training in neurocritical care in China.DesignModified Delphi method and nominal group (NG) technique.SettingNational.ParticipantsA total of 1094 respondents from 33 provinces in China participated in the online survey. A NG of 11 members was organised by the Neuro-Critical Care Committee affiliated with the Chinese Association of Critical Care Physicians and the National Center for Healthcare Quality Management in Neurological Diseases.Results1094 respondents from 33 provinces in China participated in the online survey. A formal list containing 329 statements was generated for the rating by a NG. After five rounds of NG meetings and one round of comments and iterative review, 198 core competencies (54 on neurological diseases, 64 on general medical diseases, 42 on monitoring of practical procedures, 20 on professionalism and system management, five on ethical and legal aspects, three on the principles of research and certification and 10 on scoring systems) formed the final list.ConclusionBy using consensus techniques, we have developed a list of core competencies for neurocritical care training, which may serve as a reference for future specialist training programmes in China.

Hypoxia is associated with the progression of hepatocellular carcinoma through promotion of spontaneous metastasis but the mechanism remains unclear. Here, we hypothesis that tumor cell-derived HMGB1 orchestrates macrophages infiltration and promotes metastasis of HCC via enhancing macrophage-secreted IL-6 under hypoxia. HMGB1 expression was robustly exacerbated in tumors of HCC patients with PVTT. Meanwhile, hypoxia exposure gave rise to HMGB1 expression in hepatoma cells of human and mouse in a HIF-1α-dependent manner and subsequently induced the infiltration and reprogramming of macrophages to augment the expression of Il-6. Further study demonstrated macrophage-derived IL-6 enhanced the invasiveness and metastasis of murine HCC cells. Therefore, our study provides a novel understanding of the relationship between tumor cells and tumor associated macrophages (TAMs) in the context of hypoxia.

Rubiaceae-type cyclopeptides (RAs) are a type of plant cyclopeptides from the Rubia that have garnered significant attention owing to their unique bicyclic structures and amazing antitumour activities. Our recent work has shown that RAs suppress inflammation and angiogenesis and induce apoptosis. However, the underlying mechanism and targets remained unknown. Nuclear factor κB (NF-κB) signaling pathway plays a critical role in these biological processes, prompting us to investigate whether and how RAs affect this pathway. By screening compound libraries using NF-κB-dependent luciferase reporter, we observed that RA-V is the best NF-κB inhibitor. Further experiments demonstrated that RA-V interrupted the TAK1–TAB2 interaction and targeted TAK1 in this pathway. Moreover, RA-V prevented endotoxin shock and inhibited NF-κB activation and tumor growth in vivo. These findings clarify the mechanism of RA-V on NF-κB pathway and might account for the majority of known bioactivities of RA-V, which will help RA-V develop as new antiinflammatory and antitumour therapies.

As a proinflammatory cytokine, CD137 (4‐1BB, TNFRSF9) is present in membrane‐bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2.7 pg/ml) and CD137 expression on CD4+ T cells (4.9 ± 3.2%) compared with normal controls (1.1 pg/ml, P < 0.01; 1.3 ± 1.0%, P < 0.01). Alterations in CD137 expression may enhance ischemia‐induced inflammatory responses via bidirectional signaling and, consequently, aggravate brain injury in early stages of this disorder.

Background Recently, researchers have emphasised on the clinical therapeutic effects of pulsed-radiofrequency combined with blockade to treat chronic migraine (CM) patients. However, there are controversial results. Therefore, the authors conduct the proposed research to assess the efficacy of pulsed-radiofrequency combined with blockade to teat CM patients. Methods The authors will perform a comprehensive literature search on the following online-based databases from establishment till October 2021: Web of Science, EMBASE, PubMed, China National Knowledge Infrastructure, the Cochrane library, and WanFang database. We will consider all randomized controlled trials of pulsed-radiofrequency combined with blockade for CM for inclusion. There won't be any language constraints. Following the search, a pair of reviewers will independently screen and choose related articles to include in the meta-analysis. The Cochrane risk of bias tool will be used to assess the systematic value of all included randomized controlled trials. The study will utilize the risk ratio, mean differences, or standardized mean differences and their 95% confidence intervals to perform an estimation of the pooled mean effect size. Lastly, the authors will employ funnel plot, Egger test, and sensitivity analysis to determine and describe possible heterogeneity. Results The authors will publish the results in a peer-reviewed journal. Conclusion The proposed study will be the first to evaluate the effectiveness of pulsed-radiofrequency combined with blockade in the treatment of patients with CM. Ethics and dissemination Since the proposed study is a systematic review of published studies, an ethics approval is not needed. Registration number Oct 12, 2021.osf.io/d2wx3. (https://osf.io/d2wx3/).

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA; however, there is little understanding of how MTH1 itself is regulated. Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. Cancer Res; 77(22); 6226–39. ©2017 AACR.

Objectives Lung ultrasound detection of B-lines has become a simple, semiquantitative, noninvasive tool for evaluating pulmonary congestion in heart failure (HF) patients. This study compared the correlation of B-lines with E/eʹ, NT-proBNP, and ejection fraction (EF) in acute decompensated heart failure (ADHF). Methods Eighty-two consecutive patients who were diagnosed with acute decompensated HF were divided into two groups: preserved ejection fraction heart failure (HFpEF, EF≥50%, n=32) and reduced ejection fraction heart failure (HFrEF, EF

Fibulin-4 is an extracellular matrix (ECM) protein implicated in connective tissue development and elastic fiber formation. However, little is known about the underlying function of Fibulin-4 in cartilage development. The aim of this study was to investigate the role and probable mechanism of Fibulin-4 stimulation in ECM production and chondrocyte differentiation. Fibulin-4 has been observed to be abnormally elevated and matrix metalloproteinases 13 (MMP13) level was highly expressed in human osteoarthritis (OA) chondrocytes. In the chondrogenic cell line ATDC5, Fibulin-4 stimulation profoundly inhibited the expression of ECM gene type II collagen (Col2a1), aggrecan (Acan), and type X collagen (Col10a1). Overexpression of Fibulin-4 attenuated the expression of master transcription factors Sox6, Sox9 and Runx2, but had no effect on the expression of Sox5. Additionally, Fibulin-4 stimulation activated canonical Wnt pathway by reducing the expression of Wnt inhibitor DKK1 but not Sost. Moreover, Fibulin-4 augmented the expression of Wnt/β-catenin signaling target genes like β-catenin and Wnt-3a as well as diminished GSK-3β activation, and DKK1 abolished the effect of Fibulin-4 on chondrocyte differentiation, suggesting that Fibulin-4 is an important regulator of ECM production and chondrocyte differentiation through DKK1-mediated Wnt/β-catenin signaling. Our study provides evidence of a previously unknown link between Fibulin-4 and the canonical Wnt/β-catenin pathway that may contribute to our understanding of the molecular mechanisms of OA.

Background/Aims: Hepatocellular carcinoma (HCC) is a common malignant tumor with a high rate of recurrence. Immunohistochemical analysis of the marker of proliferation Ki-67 (MKI67) is used to assess proliferation activity of HCC The regulation of MKI67 expression remains unclear in HCC This study aims to explore the association between MKI67 expression and gene variants. Methods: A total of 195 hepatitis B virus (HBV)-related HCC patients were genotyped using Illumina HumanExome BeadChip-12-1_A (242,901 markers). An independent cohort (97 subjects) validated the association of polymorphism determinants and candidate genes with MKI67 expression. The relationships between MKI67 with p53 and variants of candidate genes in the clinical outcomes of HCC patients were analyzed. Results: We found that MKI67 combined with p53 was associated with a 3-year recurrence-free survival and five variants near TTN and CCDC8 were associated with MKI67 expression. TTN harboring rs2288563-TT and rs2562832-AA+CA indicated a favorable outcome for HCC patients. Conclusion: Variants near TTN and CCDC8 were associated with MKI67 expression, and rs2288563 and rs2562832 in TTN are potential biomarkers for the prediction of clinical outcomes in HBV-related HCC patients.

Background: Lhasa is the main residence of Tibetans and one of the highest cities in the world. Its unique geography and ethnic population provide the chance to investigate the interactions among high altitude, ethnicity, and cardiac adaptation. Meanwhile, echocardiographic data about healthy Tibetans on a large scale are not available. This study aimed to analyze physiological factors related to ventricular size and valvular function in healthy Tibetans in Lhasa. Methods: A representative sample of residents in Tibet was recruited using a multistage cluster random sampling method. Two-dimensional echocardiographic measurements and Doppler evaluation for valvular function were performed. Healthy Tibetans in Lhasa constituted the study population. Associations between physiological parameters and ventricular dimensions in healthy Tibetans were analyzed by canonical correlation analysis. Factors related to valvular regurgitations were determined by logistic regression analysis. Results: The 454 healthy Tibetans (340 females and 114 male) in Lhasa were included in the final analysis. Canonical correlation analysis revealed that weight was positively correlated with the proximal right ventricular outflow diameter and the basal left ventricular linear dimension in both genders. Weight and pulse were negatively related to mild tricuspid regurgitation. Age was a positive factor for pulmonary and aortic regurgitations. The same was found between systolic blood pressure and mitral regurgitation. Conclusions: Weight is associated with ventricular size and valvular regurgitation in healthy Tibetans. It should be of more concern in research of high altitude population.

Protein products of the regenerating islet-derived (REG) gene family are important regulators of many cellular processes. Here we functionally characterise a non-protein coding product of the family, the long noncoding RNA (lncRNA) REG1CP that is transcribed from a DNA fragment at the family locus previously thought to be a pseudogene. REG1CP forms an RNA–DNA triplex with a homopurine stretch at the distal promoter of the REG3A gene, through which the DNA helicase FANCJ is tethered to the core promoter of REG3A where it unwinds double stranded DNA and facilitates a permissive state for glucocorticoid receptor α (GRα)-mediated REG3A transcription. As such, REG1CP promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. REG1CP is also transcriptionally inducible by GRα, indicative of feedforward regulation. These results reveal the function and regulation of REG1CP and suggest that REG1CP may constitute a target for cancer treatment., The regenerating islet-derived (REG) protein family suppresses cell death and promotes cell proliferation. Here the authors report that the lncRNA REG1CP forms an RNA–DNA triplex at the promoter of REG3A gene to increase its expression.

The diagnostic and prognostic mechanisms of C-X-C motif chemokine ligand 3 (CXCL3) in colon cancer (CC) have not yet been reported. Therefore, the objective of the present study was to use cohorts of patients from Guangxi Medical University and the Gene Expression Omnibus (GEO) database to investigate and validate CXCL3 for the diagnosis and prognosis of CC, and to explore its prospective molecular mechanism. Reverse transcription-quantitative PCR (RT-qPCR) analysis of 38 paired tumor and non-tumor tissues, and immunohistochemistry (IHC) of 212 tumor and 46 non-tumor tissues was conducted to explore the expression of CXCL3 and its diagnostic and prognostic significance in the Guangxi Medical University CC cohort. A GEO dataset, {"type":"entrez-geo","attrs":{"text":"GSE40967","term_id":"40967"}}GSE40967, was used to validate the prognostic significance of CXCL3. Gene set enrichment analysis (GSEA) was also conducted to explore the potential molecular mechanisms underlying the effects of CXCL3 in CC. The RT-qPCR results indicated that CXCL3 expression was significantly higher in cancer tissues compared with adjacent normal tissues, suggesting that it may have high diagnostic value for CC. Multivariate Cox analysis based on the IHC results suggested that there was no appreciable association between CXCL3 positivity and the overall survival (OS) time of CC. However, a stratified analysis revealed that high expression of CXCL3 was associated with considerably increased mortality in the subgroup of CC patients with tumor size

Background:Improving patients’ perception of social support is significant not only for their re-adaptation to life but also for alleviating caregivers’ burden.Aim:This study aims to examine an integrated model regarding social support, psychotic symptoms and caregiver burden.Methods:Persons with schizophrenia ( N1 = 300) and their family caregivers ( N2 = 300) in Xinjin County, Chengdu, China, completed the survey to report their demographics, patients’ perception of social support (Duke Social Support Index), psychotic symptoms (Positive and Negative Syndrome Scale) and caregiver burden (Burden Scale for Family Caregivers, Short Version). Structural equation modelling was utilised to test the proposed model.Results:The degree of caregiver burden differed significantly within subgroups of patients’ gender and education, as well as caregivers’ gender, education and employment. Caregiver burden was negatively related to patients’ age and household income. Social interaction partially mediated the relationship between instrumental and subjective social support (total effect = 0.451, p Conclusion:This study shows the associations of patients’ social support with psychotic symptoms and caregiver burden. Culture-specific psychosocial interventions should be provided for both patients and caregivers to enrich external support and reduce psychotic symptoms and caregivers’ burden within the health care environment.

Kidney diseases are important causes of mortality world widely. Renal microvascular dysfunction plays a pivotal role in the development of kidney diseases. Pharmacological and biochemical tools have been used to conduct detailed studies on the metabolization of arachidonic acid by cytochrome P450 (CYP450) in renal microvasculature. CYP450 epoxygenase metabolites epoxyeicosatrienoic acids (EETs) are mainly produced in renal microvessels. EETs exhibit renoprotective effects through vasodilation, anti-hypertension, anti-apoptosis and anti-inflammation, and were reported as therapeutic targets of renal diseases. However, the ability of the kidney in generating EETs is reduced in renal diseases. Recently, the studies from transgenic animal overexpressing CYP450 epoxygenases and application of soluble epoxide hydrolase inhibitors revealed that increasing of EETs exhibits renoprotective effects in vivo. The present review focuses on the protective mechanisms of EETs in kidney physiology and diseases.

We aimed to evaluate the diagnostic efficacy of layered velocity vector imaging (VVI)-derived left ventricular (LV) mechanical parameters in the differential diagnosis of primary light-chain cardiac amyloidosis (AL-CA) and hypertrophic cardiomyopathy (HCM). We recruited 35 subjects with histologically-diagnosed AL-CA, 35 subjects with HCM, and 30 age-matched healthy controls. We used conventional echocardiography and electrocardiogram to evaluate general heart function and electrophysiology properties. Furthermore, we applied two-dimensional VVI echocardiography to assess the layered mechanical parameters during systole, including endocardial and epicardial longitudinal strain (ENDO and EPI LSsys), circumferential strain (CSsys), radial strain (RSsys), rotation (ROT) and twist (TWI), in different LV walls and levels. Two groups of patients had similarly elevated LV wall thickness and mild diastolic dysfunction, but normal ejection fraction. ENDO LSsys of three circular LV levels and six LV walls was markedly decreased in AL-CA patients, with the most prominent reduction in the basal level. The reduction of ENDO and EPI LSsys in HCM subjects was less profound, and was restricted to certain LV wall and levels. AL-CA patients had significantly reduced RSsys in the LV basal level compared with control or HCM patients. Two groups of patients exhibited similar reduction in layered regional CSsys, ROT and TWI. ROC analysis revealed that the sensitivity and specificity of basal ENDO LSsys for predicting AL-CA was 86 and 89%. Assessment of layered LSsys of LV walls and levels by VVI appeared to provide a more sensitive and specific diagnostic index for the differential diagnosis of AL-CA from HCM than conventional echocardiography. Future studies are warranted to evaluate its diagnostic efficacy for AL-CA diagnosis in the large population.

Purpose To perform a cultural adaptation and validation study (internal and external) of the FAAM questionnaire to create the Chinese version of the questionnaire (FAAM-Ch). Materials and methods Two independent professional native translators performed a translation from English to Chinese and reverse translation. Psychometric properties analysis: Internal consistency of measure was analysed through the Cronbach’s α coefficients. After extraction by maximum likelihood (EML), the structure factor and construct validity was analysed; to extract a factor, it was necessary to complete the following three requirements: ≥10% of variance, Eigenvalue >1.0 and scree plot inflection point. Standard error measurement (SEM) and minimal detectable change 90 (MDC90) were calculated. FFI-Taiwan version, SF12v2, and EuroQol5D were used for criterion validity analysis. Results The internal consistency (Cronbach’s α) for specific FAAM-Ch subscales was 0.879 (ADL) and 0.901 (Sport); test–retest analysis (interclass correlation) item ranging between 0.758 and 0.970 (ADL: 0758–0946; Sport: 0.911–0.970). Measures error: 3.449% (MDC90) and 1.478% (SEM). Chi-squared value =15228.74 and gl 406) (p

Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy.

Transcutaneous electrical nerve stimulation (TENS) has been reported to relieve pain and improve function in patients with knee osteoarthritis. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of TENS for the management of knee osteoarthritis.We searched Embase, PubMed, CENTRAL, SIGLE, PEDro, and clinicaltrials.gov, up to June 2014 for literature related to TENS used for the treatment of knee osteoarthritis. Two authors independently screened the searched records based on the title and abstract. Information including the authors, study design, mean age, sex, study population, stimulation frequency (of TENS), outcome measures, and follow-up periods were extracted by the 2 authors.Eighteen trials were included in the qualitative systematic review, and 14 were included in the meta-analysis. TENS significantly decreased pain (standard mean difference, -0.79; 95% confidence interval [CI], -1.31 to -0.27; P0.00001) compared with control groups. There was no significant difference in the Western Ontario and McMaster Universities Osteoarthritis Index (standard mean differences, -0.13; 95% CI, -0.35 to 0.1; P=0.09) or the rate of all-cause discontinuation (risk ratio, 0.77; 95% CI, 0.48 to 1.22; P=0.94) between the TENS and control groups.TENS might relieve pain due to knee osteoarthritis. Further randomized-controlled trials should focus on large-scale studies and a longer duration of follow-up.

Three-dimensional (3D) speckle-tracking echocardiography (STE) for myocardial strain imaging may be superior to two-dimensional STE, especially with respect to rotational mechanics. Automated strain measurements from nonstitched 3D STE may improve work flow and clinical utility. The aim of this study was to test the feasibility of model-based 3D STE for the automated measurement of voxel circumferential strain (Ecc) and myocardial rotation.Thirty-five individuals (12 healthy volunteers, 12 patients with dilated cardiomyopathy, and 11 patients with hypertensive left ventricular [LV] hypertrophy) were prospectively studied. The latter two groups did not have significant coronary artery disease on coronary arteriography. Tagged cardiovascular magnetic resonance (CMR) and feature-tracking CMR were used as reference standards. Regional (apex and mid left ventricle) and slice (within a region) Ecc and rotation were measured by real-time volume transthoracic echocardiography (nonstitched) using an automated algorithm.Compared with both CMR techniques, apical and mid-LV Ecc (concordance correlation coefficients [CCCs], 0.84-0.95 and 0.48-0.68) and rotation (CCCs, 0.70-0.95 and 0.42-0.68) showed excellent, good, and moderate agreement, respectively. At the LV base, rotation showed poor agreement with CMR methods (CCC, 0.04-0.21), consistent with previous descriptions, but calculated LV twist showed moderate to good correlation with CMR techniques (CCC, 0.61-0.84). However, the 95% CI for measurements between techniques was wide, emphasizing the challenges in comparing voxel deformation by 3D echocardiography with CMR, compounded by differences in approaches to measuring deformation, and matching regional and slice measurements between techniques. Reproducibility (n = 10, including test-retest variability) of automated 3D strain and rotation measurements was good to excellent (coefficient of variation10%) and was comparable with that of CMR methods (coefficient of variation10%) in the same patients.The data from this study show that automated measurements of voxel rotational mechanics by real-time volume transthoracic echocardiography is feasible and comparable with tagged CMR and feature-tracking CMR strain measurements, albeit with wide limits of agreement, emphasizing the differences between the modalities. Furthermore, this automated 3D speckle-tracking echocardiographic approach shows excellent reproducibility, including test-retest variability, comparable with that of the CMR methods.

To describe the epidemiological characteristics and trends of traumatic spinal cord injury in Chongqing, China.Hospital-based retrospective research.Xinqiao Hospital, Chongqing.We reviewed medical records of 554 patients with traumatic spinal cord injury (TSCI) admitted to Xinqiao Hospital from 2009 to 2013. Variables included gender, age, marital status, etiology, occupation, time of injury, level of injury, and severity of injury, the length of hospital stay, and treatment.The mean age of patients with TSCI was 45.6 ± 13.8 years, and the male/female ratio was 4.33:1. 94.2% (522 patients) of all patients with TSCI were married. Falls, comprising low falls and high falls (10.8% and 50.9%, respectively), were the leading reason for a hospital visit. And the second reason was MVCs (21.8%). The most common injury site was the cervical spinal cord, accounting for nearly more than 54%. The length of hospital stay ranged between 1 and 219 days (mean: 28.3 days). The proportions of complete tetraplegia, incomplete tetraplegia, complete paraplegia and incomplete paraplegia were 17.1%, 37.8%, 22.2%, and 22.9%, respectively.The result revealed that the proportion of males was higher, as well as falls and MVCs were the first two main reasons, with older mean age of patients with TSCI than other countries. The occupations with highest risk for TSCI were peasants and laborers. All of these results prompted that preventive methods should be based on the characteristics of different type of patients with TSCI.