Search

The study aimed to establish a population pharmacokinetic (PPK) model of tacrolimus for Chinese patients with nephrotic syndrome using the patient's genotype and Wuzhi capsule dosage as the main test factors.Ninety-six adult patients with nephrotic syndrome, who were receiving tacrolimus treatment, were enrolled. A nonlinear mixed-effects model was used to determine the influencing factors of interindividual tacrolimus metabolism variation and establish a PPK model. To optimize the tacrolimus dosage, 10,000 Monte Carlo simulations were performed.The 1-chamber model of first-order absorption and elimination was the most suitable model for the data in this study. The typical population tacrolimus clearance (CL/F) value was 16.9 L/h. The percent relative standard error (RSE%) of CL/F was 12%. Increased Wuzhi capsule and albumin doses both decreased the tacrolimus CL/F. In CYP3A5 homozygous mutation carriers, the CL/F was 39% lower than that of carriers of the wild-type and heterozygous mutation. The tacrolimus CL/F in patients who were coadministered glucocorticoids was 1.23-fold higher than that of the control. According to the patient genotype and combined use of glucocorticoids, 26 combinations of Wuzhi capsule and tacrolimus doses were matched. The Monte Carlo simulation identified the most suitable combination scheme.An improved tacrolimus PPK model for patients with nephrotic syndrome was established, and the most suitable combination of Wuzhi capsule and tacrolimus doses was identified, thus, facilitating the selection of a more economical and safe administration regimen.

This study aims to investigate the dosage pattern, efficacy, and safety of sacubitril/valsartan (Sac/Val) in Chinese heart failure with reduced ejection fraction (HFrEF) patients regarding real-world settings. Patients from 27 centers with a confirmed diagnosis of HFrEF and initiated Sac/Val treatment were enrolled. The primary objective was to evaluate the dosage pattern and change of heart failure status. In a final cohort of 983 patients, outpatient Sac/Val treatment demonstrated a similar beneficial effect in NT-proBNP and cardiac function. After initiating the treatment, overall and sub-population showed similar safety and efficacy. Patients who received a higher dose of Sac/Val (> 200 mg/d) demonstrated better improvement in LV function and reduction of NT-proBNP regardless of adjustment. Among Chinese HFrEF patients, Sac/Val showed a comparable reduction in NT-proBNP and improvement in cardiac function. Data further support guideline recommendations of Sac/Val in Chinese population. Optimal up-titration might provide further benefits. Further long-term and prognostic studies are needed. Graphical abstract

Aim: We investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors (TKIs) for advanced hepatocellular carcinoma (HCC). Method: This retrospective study included HCC patients treated with HAIC, TKIs and anti-PD-1 antibodies between May 2019 and November 2020 in our hospital. Primary end points were progression-free survival and safety. Results: Twenty-seven advanced HCC patients were analyzed. The median follow-up was 12.9 months (range: 4.0–24.0 months) and the median progression-free survival was 10.6 months. The objective response rate and disease control rate were 63.0 and 92.6%, respectively. No treatment-related deaths occurred. Conclusion: In patients with advanced HCC, treatment with HAIC, anti-PD-1 antibodies and oral TKIs was effective and safe.

This study aimed to expand our understanding of metformin (Met) in inhibiting hepatocellular carcinoma (HCC) progression and to investigate its underlying mechanism. Met was administrated to HCC cells at 5, 10, and 20 μM, after which the cell phenotype was evaluated. RNA-seq cluster analysis was used to screen for target genes modulated by Met. Luciferase activity and ChIP assays were performed to detect the effect of FOXO3 on the transcriptional activation of NLRP3. We evaluated the effect of Met and FOXO3 and on the growth of HCC cells in vivo. Met inhibited HCC cell proliferation and promoted apoptosis. Met also induced pyroptosis of HCC cells. FOXO3 was significantly upregulated by Met treatment, and FOXO3 activated transcription of NLRP3. Cells after Met treatment together with FOXO3 knockdown have a stronger colony formation and migration ability but a lower apoptosis rate compared to the Met treatment alone group. In vivo, Met inhibited HCC tumor growth. The tumors in Met treatment and FOXO3 knockdown group grew faster than in Met treatment group. Thus, Met attenuates HCC cell development by inducing apoptosis and pyroptosis. This effect of metformin is partially dependent on FOXO3 which can activate the transcription of NLRP3.

Antibiotic residues in the environment and in foods pose a serious threat to ecosystems and human health. Developing sensitive and on-site detection methods is therefore in high demand. In this work, a portable paper-based colorimetric sensor with a smartphone platform with an ultrahigh sensitivity has been designed for on-site and quantitative analysis of antibiotic residues based on aptamer-regulated nanozyme activity. The developed excellent peroxidase-like nanozymes, carbon-protected NiCo bimetal oxides with a unique hollow nanocage structure (NiCo@C HCs), could effectively catalyze the oxidation of chromogenic substrates by H

BackgroundEpidemiological evidence of the associations between metal exposure and gout-related outcomes (including serum uric acid [SUA], hyperuricemia and gout) is scarce. The aim of the study is to investigate the associations of metal exposure with SUA, hyperuricemia and gout in general adults.MethodsIn this study, the exposure to five blood metals (mercury, manganese, lead, cadmium and selenium) of general adults was analyzed based on the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 (n = 14,871). Linear, logistic and weighted quantile sum (WQS) regression models were applied to examine the associations of blood metals with gout-related outcomes. Possible dose-response relationships were analyzed through restricted cubic spline regression.ResultsCompared with the lowest quartile of blood metals, mercury (quartile 2 and 4), lead (quartile 2, 3, and 4) and selenium (quartile 2 and 4) were found to be positively correlated with SUA and hyperuricemia. Higher levels of mercury and lead were associated with gout, but only those in the fourth quartile had statistical significance (OR [95%CI]: 1.39 [1.10-1.75] and 1.905 [1.41-2.57]) respectively). The WQS index of the blood metals was independently correlated with SUA (β [95%CI]: 0.17 [0.13-0.20]), hyperuricemia (OR [95%CI]: 1.29 [1.16-1.42]) and gout (OR [95%CI]: 1.35 [1.15-1.58]). Among them, lead was the most heavily weighted component (weight = 0.589 for SUA, 0.482 for hyperuricemia, and 0.527 for gout). In addition, restricted cubic spline regression models showed a linear association of lead with the prevalence of hyperuricemia and gout.ConclusionOur results suggested that blood metal mixtures were positively associated with gout-related outcomes, with the greatest effect coming from lead.

ObjectiveSystemic inflammation is associated with a poor prognosis in acute heart failure (AHF). This study was to assess the long-term prognostic value of combining the accessible inflammatory markers in relation to all-cause mortality in patients with AHF.MethodsConsecutive patients with AHF who were hospitalized between March 2012 and April 2016 at the Department of Cardiology of the First Affiliated Hospital of Nanjing Medical University were enrolled in this prospective study. The LASSO regression model was used to select the most valuable inflammatory biomarkers to develop an inflammatory prognostic scoring (IPS) system. Kaplan-Meier method, multivariate COX regression and time-dependent ROC analysis were used to assess the relationship between inflammatory markers and AHF prognosis. A randomized survival forest model was used to estimate the relative importance of each inflammatory marker in the prognostic risks of AHF.ResultsA total of 538 patients with AHF were included in the analysis (mean age, 61.1 ± 16.0 years; 357 [66.4%] men). During a median follow-up of 34 months, there were 227 all-cause deaths (42.2%). C-reactive protein (CRP), red blood cell distribution width (RDW) and neutrophil-to-lymphocyte ratio (NLR) were incorporated into the IPS system (IPS = 0.301×CRP + 0.263×RDW + 0.091×NLR). A higher IPS meant a significantly worse long-term prognosis in Kaplan-Meier analysis, with 0.301 points as the optimal cut-off value (P log-rank ConclusionsInflammatory biomarkers were associated with the risk of all-cause mortality in patients with AHF, while IPS significantly improved the predictive power of the model and could be used as a practical tool for individualized risk stratification of patients with AHF.

Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism remain elusive. Here we report that amino acid biosynthesis is reprogrammed in Pkd2-knockout mouse kidneys via a defective PERK-eIF2ɑ-ATF4 pathway. Transcriptomic analysis revealed that the amino acid biosynthesis pathways such as serine, arginine and cysteine were impaired, and associated critical enzymes were downregulated in Pkd2-knockout mouse kidneys. ATF4 and CHOP, transcription factors downstream of the endoplasmic reticulum (ER) stress sensor PERK, were identified as master regulators of these enzymes' expression. PKD2 deficiency impaired the expression of ATF4 and amino acid synthesis enzymes in RCTEC cells under ER stress. Mechanistically, as an ER-resident protein, PKD2 interacts with TBL2, which functions as an adaptor bridging eIF2ɑ to PERK. PKD2 depletion impaired the recruitment of eIF2ɑ to TBL2, thus impeding activation of the PERK-eIF2ɑ-ATF4 pathway and downstream amino acid biosynthesis. These findings illuminate a molecular mechanism linking the PKD2-mediated PERK-eIF2ɑ-ATF4 pathway and amino acid metabolic reprogramming in ADPKD.

Summary Background Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma. Methods AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov , NCT02329860 . Findings Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in the placebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand–foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators. Interpretation Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile. Funding Jiangsu Hengrui Medicine.

In this study we aimed to assess the anti-tumor effect of co-inhibition of Aurora kinase A (AURKA) and heat shock transcription factor 1 (HSF1) on hepatocellular carcinoma (HCC), as well as to explore the mechanism involved. Expression of AURKA and HSF1 in primary HCC tissues and cell lines was detected by immunohistochemistry (IHC), qRT-PCR and Western blotting. AURKA was knocked down in HepG2 and BEL-7402 HCC cells using lentivirus-mediated RNA interference. Next, CCK-8, clone formation, transwell and flow cytometry assays were used to assess their viability, migration, invasion and apoptosis, respectively. The expression of proteins related to cell cycle progression, apoptosis and endoplasmic reticulum stress (ERS) was analyzed using Western blotting. In addition, in vivo tumor growth of HCC cells was assessed using a nude mouse xenograft model, and the resulting tumors were evaluated using HE staining and IHC. Both AURKA and HSF1 were highly expressed in HCC tissues and cells, while being negatively related to HCC prognosis. Knockdown of AURKA significantly inhibited the colony forming and migrating capacities of HCC cells. In addition, we found that treatment with an AURKA inhibitor (Danusertib) led to marked reductions in the proliferation and migration capacities of the HCC cells, and promoted their apoptosis. Notably, combined inhibition of AURKA and HSF1 induced HCC cell apoptosis, while increasing the expression of ERS-associated proteins, including p-eIF2α, ATF4 and CHOP. Finally, we found that co-inhibition of AURKA and HSF1 elicited an excellent in vivo antitumor effect in a HCC mouse model with a relatively low cytotoxicity. Combined inhibition of AURKA and HSF1 shows an excellent anti-tumor effect on HCC cells in vitro and in vivo, which may be mediated by ERS. These findings suggest that both AURKA and HSF1 may serve as targets for HCC treatment.

BackgroundThe United States Centers for Disease Control and Prevention (CDC)-sanctioned prevention strategies have included frequent handwashing with soap and water, covering the mouth and nose with a mask when around others, cleaning and disinfecting maintaining a distance of at least 6 feet from others, etc. Although many of these recommendations are based upon observation and past infection control practices, it is important to combine and explore public data sets to identify predictors of infection, morbidity and mortality to develop more finely honed interventions, based on sociodemographic factors.MethodCross-sectional study of both states in the US and counties in NY state.ResultsPopulation density was found to be significantly associated with state-level coronavirus infection and mortality rate (b = 0.49, 95% confidence interval (CI): 0.34, 0.64, P ConclusionPopulation density was the only significant predictor of mortality across states in the USA. Lower mean age, lower median household incomes and more densely populated states were at higher risk of COVID-19 infection. Population density was not found to be a significant independent variable compared to minority status and socioeconomic factors in the New York epicenter. Meanwhile, public ridership was found to be a significant factor associated with incidence in New York counties.

To explore the clinical effect of warming-needle moxibustion with different lengths of moxa stick for asthenospermia with kidney deficiency and liver depression.A total of 240 patients with asthenospermia of kidney deficiency and liver depression were randomly divided into a 4-cm group (moxibustion with 4-cm moxa stick, 60 cases, 3 cases dropped off), a 3-cm group (moxibustion with 3-cm moxa stick, 60 cases, 4 cases dropped off), a 2-cm group (moxibustion with 2-cm moxa stick, 60 cases, 2 cases dropped off) and an acupuncture group (60 cases, 3 cases dropped off). All patients were treated with warming-needle moxibustion with different lengths of moxa stick or conventicnal acupuncture at Zhongwan (CV 12), Guanyuan (CV 4), Zhongji (CV 3), Guilai (ST 29), Yaoyangguan (GV 3), Guanyuanshu (BL 26), etc., once a day, five times a week; 4-week treatment was taken as one course, a total of two courses of treatment were given. The semen routine indexes, seminal plasma biochemical indexes, sex hormone levels and TCM syndrome score were compared before and after treatment among the 4 groups.After treatment, the sperm density, sperm viability, ratio of grade A sperm, ratio of grade A and B sperm, seminal plasma fructose and neutral α-glucosidase were higher than those before treatment (The warming-needle moxibustion with 4-cm moxa stick could effectively improve quality and motility of sperm and clinical symptoms in patients with asthenospermia of kidney deficiency and liver depression, which is superior to moxibustion with 3-cm, 2-cm moxa sticks and conventional acupuncture.

Background Hepatic arterial infusion chemotherapy delivers the drug directly to the liver. We aim to explore the benefits and tolerability of Hepatic arterial infusion chemotherapy plus regorafenib in advanced colorectal liver metastasis refractory to standard systemic chemotherapy. Methods This study analyzed 47 patients treated with hepatic arterial infusion chemotherapy plus regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with bevacizumab or cetuximab between Jan 2017 and Jun 2020. Regorafenib was given for only 3 weeks in a 4-week cycle. Results Among 47 patients, 32 (68%) were males. The median age was 61 (29–75). With a median follow-up of 22.2 months (3.7–50.7 months). Before Hepatic arterial infusion chemotherapy administration in combination with regorafenib, 34 (72.3%) patients previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%)patients previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both). The initial doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%), while for 24.6% (n = 14) dose was unknown. Median Overall Survival was 22.2 months. Median Progression-Free Survival was 10.8 (95% CI: 9.0–13.7) months. Common Adverse Events were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). Only 2 patients discontinued regorafenib due to Adverse Events. Conclusions Regorafenib combined with Hepatic arterial infusion was effective and tolerable in patients with liver predominant metastasis of colorectal cancer. Hence, this therapy can be considered as an alternative for second- or subsequent lines of therapy in patients refractory to standard systemic chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with extremely poor prognosis. Gemcitabine resistance is a major challenge in the treatment of PDAC. Here, we showed that LINC00460 was associated with the response to gemcitabine both in PDAC patients and PDAC-PDX. After knocking down LINC00460 in PDAC tumor cells, results of RNA sequencing followed by gene ontology analysis indicated that LINC00460 influenced the activity of growth factors and modified the extracellular matrix. FISH showed that LINC00460 is mostly located in the cytoplasm. Results of RNA pull-down, LC-MS/MS, RIP, and immunoblotting confirmed that LINC00460 could directly bind to PDAP1. Furthermore, we demonstrated that LINC00460 mediated the cellular communication of PDAC tumor cells and CAFs by PDAP1/PDGFA/PDGFR signaling pathway and regulated the gemcitabine-resistance function of CAFs, which could be reversed by treatment with a PDGFR inhibitor (crenolanib). PDAC-PDX tumors with lower expression of LINC00460 showed a better response to gemcitabine plus crenolanib treatment. Our finding supported the application of LINC00460 in precision medicine that uses gemcitabine plus crenolanib to treat PDAC with low expression of LINC00460.

Accurate on-site analysis of food quality, environmental pollutants, and disease biomarkers is of great significance for safeguarding public health. In this work, based on the novel nanozymes, MnCo oxides@carbon yolk-shell nanocages (MnCo@C NCs), a portable colorimetric sensor with smartphone platform has been developed for rapid, on-site and quantitative analysis of total antioxidant capacity (TAC) and phenolic compounds. The MnCo@C NCs are synthesized via one-step calcination of polydopamine-coated MnCo Prussian blue analogs (MnCo-PBA@PDA). The PDA-derived carbon shell is found to be able to protect the nanocages from collapsing, thus increasing their specific surface areas and porosity. Benefiting from the unique structure and multivalent MnCo bimetallic oxides, the MnCo@C NCs perform outstanding catalytic performance and multiple enzyme-mimicking activities including oxidase, laccase and catalase. Hence, a multifunctional application platform integrated smartphone has been constructed for rapid and sensitive colorimetric detection of three model analytes (i.e., ascorbic acid (AA), 2,4-dichlorophenol (2,4-DP), and epinephrine) with extremely low detection limits of 0.29 μM, 0.76 μM, and 0.70 μM, respectively. This sensor device is successfully applied in TAC analysis in vegetables, fruits, and beverages, as well as epinephrine determination in human serum samples. This work provides new insights into designing multifunctional nanozymes to advance the instant detection technology in the field of food supervision, environment monitoring, and human health.

Purpose: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). Experimental Design: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. Results: Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. Conclusions: Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution.

Background Restrictive cardiomyopathy (RCM) presents a high risk for sudden cardiac death in pediatric patients. Constrictive pericarditis (CP) exhibits a similar clinical presentation to RCM and requires differential diagnosis. While mutations of genes that encode sarcomeric and cytoskeletal proteins may lead to RCM, infection, rather than gene mutation, is the main cause of CP. Genetic testing may be helpful in the clinical diagnosis of RCM. Methods In this case series study, we screened for TNNI3, TNNT2, and DES gene mutations that are known to be etiologically linked to RCM in four pediatric patients with suspected RCM. Results We identified one novel heterozygous mutation, c.517C>T (substitution, position 517 C → T) (amino acid conversion, p.Leu173Phe), and two already known heterozygous mutations, c.508C>T (substitution, position 508, C → T) (amino acid conversion, p.Arg170Trp) and c.575G>A (substitution, position 575, G → A) (amino acid conversion, p.Arg192His), in the TNNI3 gene in three of the four patients. Conclusion Our findings support the notion that genetic testing may be helpful in the clinical diagnosis of RCM.

Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V

Objective The effect of the serum chloride (Cl) level on mortality in critically ill patients with acute kidney injury (AKI) remains unknown. We sought an association between mortality and serum Cl. Methods We identified AKI patients in the eICU Collaborative Research Database from 2014 to 2015 at 208 US hospitals. The outcomes included in-hospital and intensive care unit (ICU) mortality. Time-varying covariates Cox regression models and the Kaplan-Meier (K-M) curves were used to assess the association between serum Cl levels and mortality. Multivariable adjusted restricted cubic spline models were used to analyze the potential nonlinear relationship between mortality and serum Cl. Results In total, 4,234 AKI patients were included in the study. Compared with normochloremia (98≤chloride Conclusions Lower serum Cl levels after ICU admission was associated with increased in-hospital and ICU mortality in critically ill patients with AKI. The results should be verified in well-designed prospective studies.

BackgroundEthylene oxide (EO) has been shown to associate with increased cardiovascular risk. This study aimed to explore the relationship and its meditating factors between EO exposure and the major cardiovascular risk factor of obesity among the general adult population.MethodsCross-sectional data of 3,220 participants from National Health and Nutritional Examination Survey (NHANES) 2013–2016 were enrolled. Obesity was defined as body mass index (BMI) ≥30 kg/m2, and abdominal obesity was defined as waist circumference (WC) ≥102 cm in men and ≥88 cm in women. The association among hemoglobin adduct of EO (HbEO), inflammatory biomarkers, and obesity was evaluated using restricted cubic splines and the multivariable linear regression model. Mediation analysis was used to further assess their association.ResultsThe increased quartiles of HbEO were inversely associated with BMI and WC [Q1 vs. Q4, BMI: β = −2.98 (−3.74, −2.22), WC: β = −6.50 (−8.60, −4.39); all p for trend < 0.05], and were inversely associated with obesity after full adjustment [obesity: OR = 0.43 (0.31, 0.58), abdominal obesity: OR = 0.42 (0.27, 0.65); all p for trend < 0.05]. The levels of alkaline phosphatase, white blood cells, lymphocytes, and neutrophils were also positively associated with BMI and WC (all p < 0.05). Mediation analysis showed that exposure of EO not only had a negative direct effect on BMI and WC, but also generated an inverse indirect effect.ConclusionsCurrent findings showed an inverse association between HbEO and obesity, and suggested that systemic inflammation may not be their only mediator. Additional research is required to explore the underlying link of EO and system metabolism.

Background Sinus of Valsalva aneurysm (SVA) is a rare congenital disease that can cause severe clinical presentations when the aneurysm ruptures. Here, we report a rare case of a noncoronary sinus of Valsalva aneurysm with rupture into the right atrium. Case presentation A 14-year-old Chinese female patient presented viral myocarditis with acute heart failure at the local hospital, and she was finally diagnosed with a noncoronary sinus Valsalva aneurysm with rupture into the right atrium by digital subtraction angiography with cardiac catheterization angiography and echocardiography at our hospital (Children’s Hospital of Chongqing Medical University). Percutaneous closure intervention was performed shortly after her diagnosis, and the patient showed good functional recovery. Conclusions We report a case of ruptured sinus of Valsalva aneurysm successfully treated by percutaneous closure, which is an excellent alternative treatment.

Background Soft tissue sarcoma (STS) is a malignant tumor of highly heterogeneous mesenchymal origin. STS has a biological pattern and clinical transformation with localized invasive growth and is susceptible to hematogenous metastasis. Local therapeutic strategies may treat recurrent and oligometastatic STS, including surgery and radiation therapy. This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for recurrent and oligometastatic STS. Methods We retrospectively analyzed 37 recurrent and oligometastatic STS patients with 58 lesions treated with SBRT from 2009 to 2019 at our institution. Oligometastatic is defined as metastatic lesions less than or equal to 3. The primary endpoint was local control (LC); secondary endpoints were survival and toxicity. Results The median follow-up was 21.0 months (3.0 to 125.0 months). Among 37 patients, 18 were recurrent patients, and 19 were oligometastatic patients. Median LC was 25.0 months (95% CI 20.0–45.0). The 1-, 2-, and 3-year LC rates were 80.2%, 58.3%, and 46.6%, respectively. Median overall survival (OS) was 24.0 months (95% CI 13.0–28.0), and the survival rates after SBRT were 71.5%, 40.0%, and 29.1% at 1, 2, and 3-year, respectively. Median progression-free survival (PFS) was 10.0 months (95% CI 8.0–15.0 months), PFS rate after SBRT was 43.6%, 26.8%, and 18.4% at 1, 2, and 3 years, respectively. Late grade 3 radiation dermatitis was observed in one patient (2.7%). Using univariate and multivariate COX analysis, better OS, PFS, and LC were obtained in the histologic grade 1(G1) group, and tumor size and a number of lesions influenced LC. Conclusions SBRT is a safe and effective treatment for patients with recurrent and oligometastatic STS. Histological grade influences local control and survival. SBRT may be a promising treatment option for recurrent and oligometastatic STS.

Prostate cancer (PCa) has become the second leading cause of cancer-related mortality in males worldwide. Although the long noncoding RNA DLX6-AS1 has been recognized to be an oncogene in multiple cancers, the biological function and regulatory mechanism of DLX6-AS1 in prostate cancer are still obscure. In the present study, we observed that DLX6-AS1 was significantly upregulated in PCa tissues and cells. Knockdown of DLX6-AS1 inhibited PCa progression by suppressing cell proliferation and accelerating cell apoptosis. Molecular mechanism exploration indicated that DLX6-AS1 acted as a sponge for miR-497-5p and synuclein gamma (SNCG) was a downstream target gene of miR-497-5p. In addition, there was a negative correlation between DLX6-AS1 and miR-497-5p in PCa tissues. Rescue assays showed that SNCG overexpression could partially recover DLX6-AS1 knockdown-mediated inhibition of progression in PCa. Furthermore, xenograft tumor model was established to determine the role of DLX6-AS1 in PCa tumor growth and the results suggested that DLX6-AS1 could facilitate tumor growth by regulating SNCG in vivo. In conclusion, our study investigated the biological function and underlying mechanism of DLX6-AS1 in PCa and validated that DLX6-AS1 functioned as an oncogene through miR-497-5p/SNCG axis.

BACKGROUND Transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have shown promising local benefits for advanced hepatocellular carcinoma (HCC). S-1, a composite preparation of a 5-fluorouracil prodrug, has proven to be a convenient oral chemotherapeutic agent with definite efficacy against advanced HCC. AIM To evaluate the efficacy and safety of TACE followed by HAIC with or without oral S-1 for treating advanced HCC. METHODS In this single-center, open-label, prospective, randomized controlled trial, 117 participants with advanced HCC were randomized to receive TACE followed by oxaliplatin-based HAIC either with (TACE/HAIC + S-1, n = 56) or without (TACE/HAIC, n = 61) oral S-1 between December 2013 and September 2017. Two participants were excluded from final analysis for withdrawing consent. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate, disease control rate and safety. RESULTS In total, 115 participants (100 males and 15 females; mean age, 57.7 years ± 11.9) were analyzed. The median PFS and OS were 5.0 mo (0.4–58.6 mo) (95% confidence interval (CI): 3.82 to 6.18) vs 4.4 mo (1.1–54.4 mo) (95%CI: 2.54 to 6.26; P = 0.585) and 8.4 mo (0.4–58.6 mo) (95%CI: 6.88 to 9.92) vs 8.3 mo (1.4–54.4 m) (95%CI: 5.71 to 10.96; P = 0.985) in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. The objective response rate and disease control rate were 30.9% vs 18.4% and 72.7% vs 56.7% in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. Grade 3/4 adverse events had a similar frequency in both treatment groups. CONCLUSION No improvements in tumor response rates, PFS or OS were observed with the addition of S-1 to TACE/HAIC in advanced HCC. Both treatment regimens had a similar safety profile.

We investigated therapist interpretations (Ints) and probes for insight (PIs) in relation to changes in client collaboration and insight for 1 male client paired with 3 successive doctoral student therapists in psychodynamic psychotherapy for 192 sessions over 5 years. Judges coded client collaboration and insight in the antecedent and subsequent 3 min for all Ints and PIs in each of 6 middle sessions for each treatment. Qualitative analyses showed that PIs were more helpful than Ints for this defended client. More gains in collaboration were found when antecedent client collaboration was high, antecedent client insight was low, and therapists gave PIs instead of Ints, but no differences were found among therapists. More gains in insight were found when antecedent insight in a given session was higher than in other sessions with the same therapist, with Therapist 3 facilitating more insight than Therapist 1; no differences were found between Ints and PIs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective: To further explore the relationship between the blood urea nitrogen to creatinine (BUN/Cr) ratio and the prognosis of patients with acute heart failure (AHF), a two-part study consisting of a prospective cohort study and meta-analysis were conducted. Methods: A total of 509 hospitalized patients with AHF were enrolled and followed up. Cox proportional hazards regression was used to analyze the relationship between the BUN/Cr ratio and the long-term prognosis of patients with AHF. Meta-analysis was also conducted regarding the topic by searching PubMed and Embase for relevant studies published up to October 2019. Results: During a median follow-up of 2.8 years, 197 (42.6%) deaths occurred. The cumulative survival rate of patients with a BUN/Cr ratio in the bottom quartile was significantly lower than in the other 3 groups (log-rank test: p = 0.003). In multivariate Cox regression models, the mortality rate of AHF patients with a BUN/Cr ratio in the bottom quartile was significantly higher than in the top quartile (adjusted HR 1.52; 95% CI 1.03–2.24). For the meta-analysis, we included 8 studies with 4,700 patients, consisting of 7 studies from the database and our cohort study. The pooled analysis showed that the highest BUN/Cr ratio category was associated with an 77% higher all-cause mortality than the lowest category (pooled HR 1.77; 95% CI 1.52–2.07). Conclusions: Elevated BUN/Cr ratio is associated with poor prognosis in patients with AFH and is an independent predictor of all-cause mortality.

The tumor microenvironment (TME) profoundly influences tumor progression and affects immunotherapy responses and resistance. Understanding its heterogeneity is the key for developing immunotherapy. However, the available methods can only partially portray the TME heterogeneity with a small number of cell types. Here, we developed a deep learning-based frame with a design visible, DCNet, that embeds the relationships between cells and their marker genes in the neural network, and can infer the cell landscape with more than 400 cell types based on bulk RNA-seq data. DCNet accurately recapitulated the cell landscape of multiple single cell RNA-seq datasets, which showed better robustness and stability. Based on the cell landscape of TCGA patients, which was built with DCNet, the patients were divided into two groups with significant differences in survival time and distinct cell-type populations. DCNet provides a foundation for decoding TME heterogeneity. The source code of DCNet can be found on GitHub: https://github.com/xindd/DCNet.

The chromosomal t(4;14) (p16;q32) translocation drives high expression of histone methyltransferase nuclear SET domain-containing 2 (NSD2) and plays vital roles in multiple myeloma (MM) evolution and progression. However, the mechanisms of NSD2-driven epigenomic alterations in chemoresistance to proteasome inhibitors (PIs) are not fully understood. Using a CRISPR/Cas9 sgRNA library in a bone marrow-bearing MM model, we found that hepatoma-derived growth factor 2 (HRP2) was a suppressor of chemoresistance to PIs and that its downregulation correlated with a poor response and worse outcomes in the clinic. We observed suppression of HRP2 in bortezomib-resistant MM cells, and knockdown of HRP2 induced a marked tolerance to PIs. Moreover, knockdown of HRP2 augmented H3K27me3 levels, consequentially intensifying transcriptome alterations promoting cell survival and restriction of ER stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylase MYC-induced nuclear antigen (MINA) to remove H3K27me3. Tazemetostat, a highly selective epigenetic inhibitor that reduces H3K27me3 levels, synergistically sensitized the anti-MM effects of bortezomib both in vitro and in vivo. Collectively, these results provide a better understanding of the origin of chemoresistance in patients with MM with the t(4;14) translocation and a rationale for managing patients with MM who have different genomic backgrounds.

Background The prognosis of hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (PVTT) is dismal after standard treatment with sorafenib. Hepatic arterial infusion chemotherapy (HAIC) has been suggested for patients with HCC and major PVTT. Purpose To compare the efficacy and safety of sorafenib plus 3cir-OFF HAIC versus sorafenib alone for advanced HCC with major PVTT. Materials and Methods This phase II trial recruited systemic treatment-naïve patients with HCC and major PVTT (portal vein invasion grade Vp3 [first branch] and Vp4 [main trunk]) between June 2017 and November 2019. Patients were randomly assigned (1:1 ratio) to receive sorafenib (400 mg twice daily) plus 3cir-OFF HAIC (35 mg/m

Background Aseptic Loosening (AL) following periprosthetic osteolysis is the main long-term complication after total joint arthroplasty (TJA). However, there is rare effective treatment except for revision surgery, which is costly and painful to the patients. In recent years, the ketone body β-hydroxybutyrate (BHB) has attracted much attention and has been proved to be beneficial in many chronic diseases. With respect to the studies on the ketone body β-hydroxybutyrate (BHB), its anti-inflammatory ability has been widely investigated. Although the ketone body β-hydroxybutyrate has been applied in many inflammatory diseases and has achieved considerable therapeutic efficacy, its effect on wear particles induced osteolysis is still unknown. Results In this work, we confirmed that the anti-inflammatory action of β-hydroxybutyrate (BHB) could be reappeared in CoCrMo alloy particles induced osteolysis. Mechanistically, the ketone body β-hydroxybutyrate (BHB) deactivated the activation of NLRP3 inflammasome triggered by CoCrMo alloy particles. Of note, this inhibitory action was independent of Gpr109a receptor as well as histone deacetylase (HDAC) suppression. Furthermore, given that butyrate, one kind of short chain fatty acid (SCFA) structurally related to β-hydroxybutyrate (BHB), has been reported to be an inhibitor of osteoclast, thus we also investigate the effect of β-hydroxybutyrate (BHB) on osteoclast, which was contributed to bone resorption. It was found that β-hydroxybutyrate (BHB) did not only affect osteoclast differentiation, but also inhibit its function. Unlike the inflammasome, the effect of β-hydroxybutyrate (BHB) on osteoclast may mainly rely on histone deacetylase (HDAC) suppression. Conclusions In general, our study showed that the alleviation of osteolysis may owe to the effect of β-hydroxybutyrate (BHB) on inflammasome deactivation and osteoclast. Graphical Abstract

Background Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis. Methods A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by Micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, Enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis. Results C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits (P P P P P P P P Conclusion Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.

Depressive symptoms and abnormal glycolipid metabolisms are common in patients with Parkinson's disease (PD), but their relationship has not been fully reported. It is not clear whether glycolipid impairments lead to poor cognitive and motor function, and aggravate depressive symptoms. Therefore, we aimed to explore the relationships between glycolipid variables, cognition, motor and depressive symptoms in PD patients cross-sectionally. Two hundred ten PD patients were recruited. Glycolipid parameters and Uric acid (UA) were measured. Depressive symptoms, cognitive function and motor symptoms were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MOCA) and the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III). Depressive PD patients had significantly worse motor symptoms and higher levels of fasting plasma glucose (FPG) than those in non-depressive patients (F = 24.145, P 0.001). Further, logistic regression analysis indicated that UPDRS-III (OR = 1.039, 95% CI 1.019-1.057, P = 0.044), FPG (OR = 1.447, 95% CI 1.050-1.994, P = 0.024) were independently associated with depression. In PD patients without depression, UA (β = - 0.068, t = - 2.913, P = 0.005) and cholesterol (CHOL) (β = - 3.941, t = - 2.518, P = 0.014) were independent predictors of the UPDRS-III score; in addition, UPDRS-III score was negatively associated with MOCA score (β = - 0.092, t = - 2.791, P = 0.007). FPG levels and motor symptoms were related to depressive symptoms in PD patients. Further, in non-depressive PD patients, UA and CHOL showed putative biomarkers of motor symptoms.

Few studies have compared serum BDNF and glycolipid profiles in patients with deficit schizophrenia (DS) and non-deficit schizophrenia (NDS). We aimed to compare BDNF and glycolipid profiles between DS and NDS patients and healthy controls, and to investigate the relationship between BDNF, glycolipid profiles in DS and NDS patients.A total of 591 patients with chronic schizophrenia (SZ) and 238 healthy controls participated in this study. According to Proxy for the Deficit Syndrome Scale, SZ patients were divided into DS (n = 158) and NDS (n = 273) patients. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Serum BDNF levels were measured using enzyme-linked immunosorbent assay (ELISA).BDNF levels were significantly lower in SZ patients than those in healthy controls (7.81 ± 2.98 ng/ml vs. 11.96 ± 2.29 ng/ml, P 0.01). Furthermore, BDNF levels were lower in DS group than those in NDS group (P = 0.007, OR = 0.846, 95% CI = 0.750-0.955). Lower triglyceride levels were also an independent predictor for DS patients (P = 0.007, OR = 0.846, 95% CI = 0.750-0.955). Serum BDNF levels were negatively associated with the severity of deficit syndrome in SZ patients (β = -1.151, t = -2.559, P = 0.011). In DS group, triglycerides were associated with PANSS negative subscore (β = -0.262, t = -2.994, P = 0.003) and depressive factor subscore (β = 0.282, t = 2.146, P = 0.035).Serum BDNF and triglycerides may be informative biomarkers of DS in SZ patients. The differences in glycolipid metabolism patterns between DS and NDS patients indicate that deficit syndrome is an independent endophenotype of SZ patients.

The purpose of this study was to examine the relationship between N,N-diethyl-m-toluamide (DEET) exposure and obesity-related outcomes in the general adult population using the data from the National Health and Nutrition Examination Survey (NHANES).This cross-sectional study examined the data from the NHANES from 2007 to 2016 and totally evaluated 8,770 individuals. DEET's primary oxidative metabolite, 3-(diethylcarbamoyl) benzoic acid (DCBA), is a sensitive and specific indicator of DEET exposure. DCBA was divided into three groups based on the interquartile range. Body mass index (BMI) and waist circumference (WC) were used to define obesity and abdominal obesity, respectively. The association among DCBA and obesity-related outcomes was evaluated using a multivariable linear and logistic regression model.Overall, median age of participants was 46.0 (IQR 31.0, 59.0) years, with 4295 (49.2%) men, while median BMI and WC were 27.8 (24.0, 32.0) and 29.6 (86.6, 108.1) kg/mThese findings suggested that higher DCBA concentrations are positively associated with the prevalence of obesity and abdominal obesity in the general adult population.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis. Its fibrotic tumor microenvironment (TME) plays a crucial role in promoting tumor invasion and metastasis, which eventually leads to a dismal 5-year survival rate in PDAC patients. Aortic carboxypeptidase-like protein (ACLP) promotes tissue fibrosis in benign diseases. However, its role in cancer-associated fibrosis remains unelucidated. Here, we show that ACLP was mainly expressed in cancer-associated fibroblasts (CAFs) but not in cancer cells and highly expressed in PDAC tissues. High ACLP expression was correlated with poor overall survival. Moreover, ACLP expression in PDAC patients with liver metastases was higher than that in PDAC patients without liver metastases. By detecting activation marker expression and CAF contractility and motility, we found that ACLP promoted CAF activation in PDAC, leading to TME fibrosis. Furthermore, ACLP-activated CAFs could promote cancer cell invasion in vitro and tumor metastasis in vivo. Mechanistically, ACLP promotes the expressions of MMP1 and MMP3 in CAFs, thus promoting PDAC invasion and metastasis. Intriguingly, we identified an ACLP-PPARγ-ACLP feedback loop in PDAC CAFs. Abatement of this feedback loop might be a promising approach in CAF-targeting PDAC treatment.

Alzheimer's disease (AD) is a serious neurodegenerative disease. It is widely believed that the accumulation of amyloid beta (A

Aldehydes have been shown to be potentially carcinogenic, mutagenic, and cardiotoxic to humans. Dietary fiber reduces exposure to certain environmental pollutants and has been widely used to improve various metabolic disorders. However, the effects of dietary fiber on serum concentrations of aldehydes remain unexplored. Data was collected from the National Health and Nutrition Examination Survey (NHANES) 2013–2014. Generalized linear regression and restricted cubic spline models were performed to elucidate the association of dietary fiber intake with the serum concentration of aldehydes. After fully adjusting for age, sex, education level, race, smoking status, alcohol use, diabetes, hypertension, body mass index, energy intake, poverty-income ratio, and physical activity, dietary fiber intake had a strong negative association with serum levels of isopentanaldehyde and propanaldehyde and a positive association with serum levels of benzaldehyde. The estimated increases in the mean log2-unit (ng/mL) of aldehydes for each fold increase in dietary fiber were −0.140 (95% confidence interval [CI]: −0.195 to −0.085) for isopentanaldehyde, −0.060 (95% CI: −0.099 to −0.015) for propanaldehyde, and 0.084 (95% CI: 0.017 to 0.150) for benzaldehyde, respectively. No significant association was observed between dietary fiber intake and the concentration of any other aldehydes. These results demonstrate that dietary fiber reduces the concentration of certain aldehydes in serum.

Background Elderly patients with COVID-19 were shown to have a high case-fatality rate. We aimed to explore the risk factors associated with death in patients over 70 years old (yr). Methods In this retrospective study, we enrolled consecutively hospitalized patients over 70 yr with COVID-19 between January 20 and February 15, 2020 in Renmin Hospital of Wuhan University. Epidemiological, demographic, and clinical data were collected. Clinical subtypes, including mild, moderate, severe, and critical types, were used to evaluate the severity of disease. Patients were classified into two groups: survivor and non-survivor groups. Clinical data were compared between the two groups. Univariable and multivariable Cox regression methods were used to explore the risk factors. Results A total of 147 patients were enrolled. The case-fatality rate was 28.6%. Multivariable Cox proportional hazard regression showed that clinical subtypes, including the severe type (HR = 2.983, 95% CI: 1.231–7.226, P = 0.016) and the critical type (HR = 3.267, 95%CI: 1.009–10.576, P = 0.048), were associated with increasing risk of death when compared with the general type. Blood urea nitrogen greater than 9.5 mmol/L (HR = 2.805, 95% CI: 1.141–6.892, P = 0.025) on admission was an independent risk factor for death among laboratory findings. Conclusion The patients over 70 yr with COVID-19 had a high case-fatality rate. The risk factors, including clinical subtypes and blood urea nitrogen greater than 9.5 mmol/L, could help physicians to identify elderly patients with poor clinical outcomes at an early stage.

Circular RNA migration and invasion inhibitory protein (circMIIP) is reported to be upregulated in non-small cell lung cancer (NSCLC) tissues compared with normal tissues. However, the role and working mechanism of circMIIP in NSCLC progression remain largely unclear.Cell proliferation ability was analyzed by colony formation assay, cell counting kit-8 (CCK-8) assay, and 5-ethynyl-2'-deoxyuridine assay. Cell apoptosis was assessed by flow cytometry. Transwell assays were performed to analyze the migration and invasion abilities of NSCLC cells. The interaction between microRNA-766-5p (miR-766-5p) and circMIIP or family with sequence similarity 83A (FAM83A) was validated by dual-luciferase reporter assay and RNA immunoprecipitation assay. Xenograft tumor model was established to analyze the role of circMIIP on tumor growth in vivo.CircMIIP was highly expressed in NSCLC tissues and cell lines. CircMIIP knockdown restrained the proliferation, migration and invasion and induced the apoptosis of NSCLC cells. CircMIIP acted as a molecular sponge for miR-766-5p, and circMIIP silencing-mediated anti-tumor effects were largely overturned by the knockdown of miR-766-5p in NSCLC cells. miR-766-5p interacted with the 3' untranslated region (3'UTR) of FAM83A, and FAM83A overexpression largely reversed miR-766-5p accumulation-induced anti-tumor effects in NSCLC cells. CircMIIP competitively bound to miR-766-5p to elevate the expression of FAM83A in NSCLC cells. CircMIIP knockdown significantly restrained xenograft tumor growth in vivo.CircMIIP promoted cell proliferation, migration and invasion and suppressed cell apoptosis in NSCLC cells through mediating miR-766-5p/FAM83A axis.

This study aimed to evaluate the clinical outcomes, toxicity, and prognostic factors of SBRT combined with gemcitabine plus capecitabine (GEM-CAP) in treating locally advanced pancreatic cancer (LAPC). A total of 56 patients with LAPC treated with SBRT combined with GEM-CAP were reviewed from October 2010 to October 2016. The median total prescription dose at five fractions was 40 Gy (30–50 Gy). The patients were subjected to two cycles of GEM-CAP before SBRT. GEM-CAP chemotherapy was then offered for four cycles or until disease tolerance or progression. The primary endpoints included overall survival (OS) and progression-free survival (PFS). The median OS and PFS from the date of diagnosis was 19 (95% CI 14.6–23.4) and 12 months (95% CI 8.34–15.66), respectively. The 1-year and 2-year survival rates were 82.1% and 35.7%, whereas the 1-year and 2-year PFS rates were 48.2% and 14.3%, respectively. The median carbohydrate antigen 19-9-determined PFS time was 11 months (95% CI 5.77–16.24). Multivariate analysis demonstrated that tumor diameter, lymph node metastasis, pre-treatment CA19-9 level, and post-treatment CA19-9 decline were independent prognostic factors (p

BACKGROUND Growth arrest-specific gene 2 (GAS2) plays a role in modulating in reversible growth arrest cell cycle, apoptosis, and cell survival. GAS2 protein is universally expressed in most normal tissues, particularly in the liver, but is depleted in some tumor tissues. However, the functional mechanisms of GAS2 in hepatocellular carcinoma (HCC) are not fully defined. AIM To investigate the function and mechanism of GAS2 in HCC. METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting. Cell proliferation was analyzed by counting, MTS, and colony formation assays. Cell cycle analysis was performed by flow cytometry. Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting. RESULTS GAS2 protein expression was lower in HCC than in normal tissues. Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53, while knockdown of GAS2 promoted the proliferation of hepatocytes (P < 0.05). Furthermore, GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells, particularly the elevation of sub G1 (P < 0.01). Apoptosis induced by GAS2 was dependent on p53, which was increased by etoposide addition. The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated, but became diminished upon downregulation of GAS2. In the clinic specimen, GAS2 was downregulated in more than 60% of HCCs. The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues (P < 0.05). CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis, possibly by regulating the cell cycle and p53-dependent apoptosis pathway.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fourth leading cause of cancer‐related death worldwide. Our previous study showed that EYA4 functioned by suppressing growth of HCC tumor cells, but its molecular mechanism is still not elucidated. Based on the results of gene microassay, EYA4 was inversely correlated with MYCBP and was verified in human HCC tissues by immunohistochemistry and western blot. Overexpressed and KO EYA4 in human HCC cell lines confirmed the negative correlation between EYA4 and MYCBP by qRT‐PCR and western blot. Transfected siRNA of MYCBP in EYA4 overexpressed cells and overexpressed MYCBP in EYA4 KO cells could efficiently rescue the proliferation and G2/M arrest effects of EYA4 on HCC cells. Mechanistically, armed with serine/threonine‐specific protein phosphatase activity, EYA4 reduced nuclear translocation of β‐catenin by dephosphorylating β‐catenin at Ser552, thereby suppressing the transcription of MYCBP which was induced by β‐catenin/LEF1 binding to the promoter of MYCBP. Clinically, HCC patients with highly expressed EYA4 and poorly expressed MYCBP had significantly longer disease‐free survival and overall survival than HCC patients with poorly expressed EYA4 and highly expressed MYCBP. In conclusion, EYA4 suppressed HCC tumor cell growth by repressing MYCBP by dephosphorylating β‐catenin S552. EYA4 combined with MYCBP could be potential prognostic biomarkers in HCC.

Elemicin, an alkenylbenzene constituent of natural oils of several plant species, is widely distributed in food, dietary supplements, and medicinal plants. 1′-Hydroxylation is known to cause metabolic activation of alkenylbenzenes leading to their potential toxicity. The aim of this study was to explore the relationship between elemicin metabolism and its toxicity through comparing the metabolic maps between elemicin and 1′-hydroxyelemicin. Elemicin was transformed into a reactive metabolite of 1′-hydroxyelemicin, which was subsequently conjugated with cysteine (Cys) and N-acetylcysteine (NAC). Administration of NAC could significantly ameliorate the elemicin- and 1′-hydroxyelemicin-induced cytotoxicity of HepG2 cells, while depletion of Cys with diethyl maleate (DEM) increased cytotoxicity. Recombinant human CYP screening and CYP inhibition experiments revealed that multiple CYPs, notably CYP1A1, CYP1A2, and CYP3A4, were responsible for the metabolic activation of elemicin. This study revealed that metabolic activation plays a critical role in elemicin cytotoxicity.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Sorafenib is the standard first-line treatment for advanced HCC, but its efficacy is limited. Apatinib is a small-molecule tyrosine kinase inhibitor that has shown promising antitumor effects in gastric and non-small cell lung cancers in clinical trials, but there have been only a few studies reporting its anti-HCC effects in vitro and in HCC xenograft models. Hence, our present study systemically investigated and compared the antitumorigenic and antiangiogenic efficacy of apatinib and sorafenib in HCC in vitro and in vivo using multimodality molecular imaging, including bioluminescence imaging (BLI), bioluminescence tomography (BLT), fluorescence molecular imaging (FMI), and computed tomography angiography (CTA). Moreover, the safety and side effects of the two drugs were systemically evaluated. We found that apatinib showed a comparable therapeutic efficacy to sorafenib for the inhibition of HCC. The drug safety evaluation revealed that both of these drugs caused hypertension and mild liver and kidney damage. Sorafenib caused diarrhea, rash, and weight loss in mice, but these effects were not observed in mice treated with apatinib. In conclusion, apatinib has similar antitumorigenic and antiangiogenic efficacy as sorafenib in HCC with less toxicity. These findings may provide preclinical evidence supporting the potential application of apatinib for the treatment of HCC patients., Atherosclerosis: halting plaque in its tracks Researchers have combined different sophisticated imaging techniques to assess the safety and efficacy of liver cancer therapy in animal models. Many hepatocellular carcinoma (HCC) patients respond to sorafenib, but this drug is expensive and may cause severe side-effects. Qian Liang at China’s Institute of Automation, Beijing, and colleagues have employed cutting-edge imaging technologies to study an alternative drug, apatinib, which has shown promise for stomach and lung cancer and has an excellent safety profile. Using bioluminescence imaging, the researchers could directly visualize apatanib-mediated inhibition of tumor growth in live mice much earlier than would be possible with other methods. The researchers subsequently used additional imaging techniques to demonstrate that apatanib inhibits tumor blood vessel growth. These findings reveal a promising alternative treatment for HCC, as well as a powerful strategy for drug testing in animals.

Creating access to DNA double-strand break (DSB) sites in the chromatin context is an essential step during the repair process, but much remains to be determined about its regulatory mechanisms. Here, using a novel reporter cassette for simultaneous detection of homologous recombination (HR) and nonhomologous end joining (NHEJ) at the same chromosomal site, we report that the efficiency of HR but not NHEJ negatively correlates with nucleosome density. We demonstrate that PARP1 is required for HR by modulating nucleosome density at damage sites. Mechanistic studies indicate that the ATPase domain of BRG1 and the ZnF domain of SIRT1 interact with poly-ADP ribose (PAR) in response to DNA damage, and are responsible for bringing the two factors to broken DNA ends. At DNA damage sites, BRG1 and SIRT1 physically interact, whereupon SIRT1 deacetylates BRG1 at lysine residues 1029 and 1033, stimulating its ATPase activity to remodel chromatin and promote HR.

Microvascular invasion (MVI) is a powerful predictor of recurrence in patients who undergo liver resection for hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy of postoperative adjuvant transarterial chemoembolization (PA-TACE) in HCC patients with MVI, and further select potential patients benefitting from PA-TACE.Patients who had HCC with MVI and underwent liver resection between September 2004 and December 2015 were identified for further analysis. Overall survival (OS) and disease-free survival (DFS) were compared between patients treated with and without PA-TACE. Propensity score matching analysis was used to minimize inter-group differences.A total of 176 patients with HCC and MVI were included. In both the entire and propensity-matched cohorts, OS and DFS were higher in PA-TACE group than non-TACE group (all P 0.05). In subgroup analyses, PA-TACE showed efficacy in improving OS and DFS in HCC patients at early stage beyond Milan criteria and intermediate stage, but not in patients within Milan criteria. Multivariable analysis identified PA-TACE as a significantly favorable factor of OS and DFS for patients beyond Milan criteria, but not for those within Milan criteria.PA-TACE could be beneficial for patients who have HCC with MVI beyond Milan criteria, but not for those within Milan criteria.

Background Use of Haemophilus influenzae type b conjugate vaccine is effective in reducing the disease burden, but its coverage in China is unclear. The aim of this meta-analysis is to assess the coverage of Hib conjugate vaccines in children in Mainland China. Methods We systematically searched Pubmed, Web of Science, Medline, CNKI and Wanfang to identify studies assessing the coverage of Hib vaccine in Chinese children. Random-effects models were used to obtain pooled estimates for Hib vaccine coverage and analyzed heterogeneity with meta-regression and subgroup analyses. Results Thirty-three studies that included 7,227,480 subjects in 12 provinces met our inclusion criteria. The pooled overall coverage of Hib conjugate vaccine was 54.9% [95% confidence interval (CI): 52.9-57.0]. The pooled coverage for the nonlocal population (54.3%; 95% CI: 52.4-56.3) was lower than that for the local residents (62.0%; 95% CI: 58.4-65.6). The region-pooled coverage was higher in the east of China (59.7%; 95% CI: 57.3-62.1) than in the central and west parts of the country (48.5%; 95% CI: 40.6-56.4). Overall, 26.7% (95% CI: 20.1-33.2) had 1 dose only, 14.8% (95% CI: 10.0-19.6%) had 2 doses, 13.5% (95% CI: 9.1-17.8) had 3 doses and 14.3% (95% CI: 9.7-18.9) had 4 doses. Conclusions We found a low coverage of Hib conjugate vaccine, particularly for the nonlocal children and those living in the central and west parts of China. Including Hib vaccine into the national immunization program is recommended to reduce disparities in vaccination coverage.

Hyperlipidemia, characterized by high serum lipids, is a risk factor for cardiovascular disease. Recent studies have identified an important role for celastrol, a proteasome inhibitor isolated from Tripterygium wilfordii Hook. F., in obesity-related metabolic disorders. However, the exact influences of celastrol on lipid metabolism remain largely unknown. Celastrol inhibited the terminal differentiation of 3T3-L1 adipocytes and decreased the levels of triglycerides in wild-type mice. Lipidomics analysis revealed that celastrol increased the metabolism of lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), sphingomyelins (SMs), and phosphatidylethanolamines (PEs). Further, celastrol reversed the tyloxapol-induced hyperlipidemia induced associated with increased plasma LPCs, PCs, SMs, and ceramides (CMs). Among these lipids, LPC(16:0), LPC(18:1), PC(22:2/15:0), and SM(d18:1/22:0) were also decreased by celastrol in cultured 3T3-L1 adipocytes, mice, and tyloxapol-treated mice. The mRNAs encoded by hepatic genes associated with lipid synthesis and catabolism, including Lpcat1, Pld1, Smpd3, and Sptc2, were altered in tyloxapol-induced hyperlipidemia, and significantly recovered by celastrol treatment. The effect of celastrol on lipid metabolism was significantly reduced in Fxr-null mice, resulting in decreased Cers6 and Acer2 mRNAs compared to wild-type mice. These results establish that FXR was responsible in part for the effects of celastrol in controlling lipid metabolism and contributing to the recovery of aberrant lipid metabolism in obesity-related metabolic disorders.