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Dong Xu,1 Xu Zhu,2 Junyu Huo,2 Xupin Xie,1 Changpin Huang,1 Xin Fang,1 Ting Yin3 1Department of Vascular Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Cardiology, Jiangsu Province Hospital and Nanjing Medical University, First Affiliated Hospital, Nanjing, Jiangsu, People’s Republic of China; 3Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Ting Yin, Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China, Tel +86 13777879077, Fax +86 56005600, Email ameliyt@163.com Xin Fang, Department of Vascular, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China, Tel +86 13867478324, Fax +86 56005600, Email fangxin324@hotmail.comPurpose: Peripheral arterial disease (PAD) presenting with underlying hypertension (HTN) poses a higher risk of bilateral lower limb amputation than PAD patients without HTN. While the role of HTN management of PAD patients has received limited attention. We analyzed the clinical characteristics of PAD in adults with HTN and explored risk factors for PAD to construct a nomogram for evaluating critical limb ischemia (CLI) and lesion severity.Methods Patients and Methods: Between January 2014 and December 2019, we retrospectively evaluated 1886 patients with peripheral artery disease with coexisting HTN. Patients were randomly divided into training (n = 1320, 70%) and validation cohorts (n = 566, 30%), and according to the subjective experience of PAD [Fontaine classification (I–II vs III–IV)], patients were further classified into intermittent claudication (IC) and CLI groups. LASSO regression and multivariate Cox proportional hazard analyses were used to construct a nomogram using variables defined in the training cohort, which was validated in the validation cohort. The evaluation of the predictive discriminative, accuracy and clinical application are further analyzed.Results: In the training cohort, optimal independent factors included age, male sex, body mass index, diabetes mellitus, heart rate, triglyceride, and uric acid (AM-BDHTU), which were included in the nomogram predicting the CLI risk (all P < 0.05). The C-index values for CLI risk in PAD with HTN patients were 0.729 (95% CI: 0.704– 0.807) and 0.728 (95% CI: 0.652– 0.744) in the training and validation sets, respectively. Calibration curves indicated good consistency between predicted and actual outcomes. DCA confirmed the clinical utility of the diagnostic model.Conclusion: The AM-BDHTU nomogram, constructed and validated using simple to obtain clinical variables, when combined with the Fontaine classification, effectively predicts the risk of CLI among PAD patients with HTN.Keywords: peripheral arterial disease, hypertension, vascular-related complications, LASSO regression, nomogram, predictive diagnosis

The aim of this study was to assess the associations of urinary thiocyanate, nitrate, and perchlorate concentrations with dyslipidemia, individually and in combination, which has not previously been studied. Data from the 2001–2002 and 2005–2016 National Health and Nutrition Examination Surveys (NHANES) were analyzed in this cross-sectional study. The dependent variables were continuous serum lipid variables (triglycerides [TG], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and apolipoprotein B [Apo B]) and binary serum lipid variables, with the latter reflecting dyslipidemia (elevated TG, ≥ 150 mg/dL; elevated TC, ≥ 200 mg/dL; elevated LDL-C, ≥ 130 mg/dL; lowered HDL-C

Recently, the use of ligament advanced reinforcement system (LARS) artificial ligament, a new graft which has several unique advantages such as no donor-site morbidity, early recovery and no risk of disease transmission which has been a significant breakthrough for anatomical ligament reconstruction. Growing studies suggested that the special design of the LARS ligament with open fibers in its intra-articular part was believed to be more resistant to torsional fatigue and wearing. However, the safety and efficacy of LARS artificial ligament for ankle joint lateral collateral ankle ligament reconstruction has not been defined to date.To evaluate the clinical results of all-arthroscopic anatomical reconstruction of ankle joint lateral collateral ligaments with the LARS artificial ligament for chronic ankle instability.Twenty-two patients with chronic lateral instability underwent anatomical reconstruction of the lateral collateral ligaments of ankle with LARS artificial ligament. The visual analogue score (VAS), American Orthopaedic Foot and Ankle Society score (AOFAS score) and Karlsson score were used to evaluate the clinical results before and after surgery.A total of 22 patients (22 ankles) were followed up for a mean of 12 mo. All patients reported significant improvement compared to their preoperative status. The mean AOFAS score improved from 42.3 ± 4.9 preoperatively to 90.4 ± 6.7 postoperatively. The mean Karlsson score improved from 38.5 ± 3.2 preoperatively to 90.1 ± 7.8 postoperatively. The mean VAS score improved from 1.9 ± 2.5 preoperatively to 0.8 ± 1.7 postoperatively.All-arthroscopic anatomical reconstruction of the lateral collateral ligaments with LARS artificial ligament achieved a satisfactory surgical outcome for chronic ankle instability.

Introduction: Hepatocellular carcinoma (HCC) may occur with several simultaneous tumor foci in the liver (multifocal HCC). Molecular biology indicated that the larger the distance between two tumor nodules, the more those two nodules differed in their genetic composition. Therefore, we explored whether the overall survival (OS) of patients with HCC depends on the mutual distance of the HCC nodules. Methods: In a retrospective study of 92 patients, CT/MRI images and survival data of the patients were collected. Based on the CT or MRI images at the time of diagnosis, the size of each tumor, the distance between the centers (center distance), and adjacent edges (edge distance) of the tumor nodules were measured, respectively. These data, combined with the number of tumor nodules and clinical characteristics, were compared with the patient’s OS data. Results: As expected, the average tumor diameter was significantly associated with patient survival in univariate Cox regression analysis (p = 0.00028, hazard ratio [HR] = 1.2). However, in multivariate analysis, the average center distance (p = 0.036, HR = 1.18) and average edge distance (p = 0.033, HR = 0.84) were also significantly associated with survival. Conclusion: Thus, not only the size of multiple HCC lesions but also their distance is important for the prognosis of patients with HCC. This may be of particular interest in patients with two nodules and BCLC B and C stages for the selection of therapeutic modalities and/or procedures.

The field of environmental health has begun to examine the effects of higher-order chemical combinations. The current literature lacks studies exploring associations between multiple organic chemical mixtures and cardiometabolic diseases (CVDs). This study aimed to evaluate associations between urinary phenols, parabens metabolites, and total and individual CVDs among a nationally representative sample of adults in the US. This cross-sectional study analyzed 7 urinary chemicals detected among the general population from the 2005–2016 National Health and Nutrition Examination Survey (NHANES, n=10,428). Multivariate logistic regression and weighted quantile sum (WQS) regression were applied to examine relationships between phenols and parabens metabolites, alone and in combination, and total and individual CVDs prevalence. Compared with the lowest quartile, URBPA (OR: 1.52; 95% CI: 1.20–1.91; P=0.001) levels in the highest quartile were independently associated with increased total CVD. The WQS index of phenols and parabens mixtures were independently correlated with total CVD (adjusted odds ratios [OR]: 1.16; 95% confidence interval [CI]:1.06–1.28; P=0.002), angina (adjusted OR: 1.30; 95% CI: 1.07–1.59; P=0.009), and heart attack (adjusted OR: 1.30; 95% CI: 1.12–1.51, P

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.

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.

We aimed to comprehensively evaluate the association of urinary nitrate, thiocyanate, and perchlorate metabolites with hypertension among a nationally representative sample of the US adult population. This cross-sectional study investigated data from 15,717 adults aged more than 20 years obtained from the National Health and Nutritional Examination Survey (NHANES) for the years 2005-2016. In the survey, urinary levels of nitrate, thiocyanate, and perchlorate were measured using ion chromatography combined with electrospray tandem mass spectrometry. Blood pressure was calculated as the mean of three measurements. Hypertension was defined as (a) systolic BP ≥130 and/or diastolic BP ≥80 mmHg and/or (b) self-report. Multivariate logistic regression and weighted quantile sum (WQS) regression models were applied to estimate the association between exposure to multiple inorganic anions and hypertension. Restricted cubic spline (RCS) regressions were fitted to discern the potential relationship between the anion exposure and hypertension. These innovation methods used to support our results. Overall, 7533 (49.95%) people with and 7638 (50.35%) without hypertension were included in this study. In the multivariable-adjusted logistic regression models, urinary nitrate (P0.001) and perchlorate (P0.001) were independently negatively associated with increased occurrence of hypertension, while urinary thiocyanate was insignificantly associated with hypertension (P = 0.664). The WQS regression index showed that, in combination, the three inorganic anions mixture were negatively correlated with hypertension (adjusted OR 0.89; 95% CI 0.83-0.95, P0.001). Urinary nitrate was the most heavily weighted component in the hypertension model (weight = 0.784). RCS regression demonstrated that nitrate (nonlinearity P = 0.205) and perchlorate (nonlinearity P = 0.701) were linearly associated with decreased occurrence of hypertension. Concurrent exposure to nitrate, thiocyanate, and perchlorate is associated with a decreased risk of hypertension, with the greatest influence coming from nitrate probably; urinary specific thiocyanate alone had an insignificant association with hypertension.

Rapid, simple, accurate and highly sensitive detection of enzymes is essential for early screening and clinical diagnosis of many diseases. In this study, we report the fabrication of a turn-on ratiometric electrochemical sensor for the in situ determination of β-Galactosidase (β-Gal) based on surface engineering and the design of a molecular probe (Pygal) specific for β-Gal recognition. First, Pygal probe was synthesized and characterized, and then co-assembled with the methylene blue (MB) internal reference probe on the surface of single-wall carbon nanotubes (SWCNT)-modified carbon fiber microelectrode (CFME). The resulting CFME/SWCNT/MB + Pygal sensor is activated in the presence of β-Gal giving one peak at 0.33 V originating from the oxidation of the product of Pygal enzymatic hydrolysis (PyOH). Another oxidation peak attributed to MB appears simultaneously at -0.28 V allowing the construction of a ratiometric electrochemical sensor for β-Gal detection with improved sensitivity and accuracy. The sensor showed a linear response to β-Gal in a wide concentration range from 1.5 to 30 U L

Hepatic steatosis plays a detrimental role in the onset and progression of alcohol-associated liver disease (ALD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved protein related to the unfolded protein response. Recent studies have demonstrated that MANF plays an important role in liver diseases. In this study, we investigated the role of MANF in ethanol-induced steatosis and the underlying mechanisms. We showed that the hepatic MANF expression was markedly upregulated in mouse model of ALD by chronic-plus-single-binge ethanol feeding. Moreover, after chronic-plus-binge ethanol feeding, hepatocyte-specific MANF knockout (HKO) mice displayed more severe hepatic steatosis and liver injury than wild-type (WT) control mice. Immunoprecipitation-coupled MS proteomic analysis revealed that arginosuccinate synthase 1 (ASS1), a rate-limiting enzyme in the urea cycle, resided in the same immunoprecipitated complex with MANF. Hepatocyte-specific MANF knockout led to decreased ASS1 activity, whereas overexpression of MANF contributed to enhanced ASS1 activity in vitro. In addition, HKO mice displayed unique urea cycle metabolite patterns in the liver with elevated ammonia accumulation after ethanol feeding. ASS1 is known to activate AMPK by generating an intracellular pool of AMP from the urea cycle. We also found that MANF supplementation significantly ameliorated ethanol-induced steatosis in vivo and in vitro by activating the AMPK signaling pathway, which was partly ASS1 dependent. This study demonstrates a new mechanism in which MANF acts as a key molecule in maintaining hepatic lipid homeostasis by enhancing ASS1 activity and uncovers an interesting link between lipid metabolism and the hepatic urea cycle under excessive alcohol exposure.

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.

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.

Alzheimer’s disease (AD) is a serious neurodegenerative disease. It is widely believed that the accumulation of amyloid beta (Aβ) in neurons around neurofibrillary plaques is the main pathological characteristic of AD; however, the molecular mechanism underlying these pathological changes is not clear. Baicalin is a flavonoid extracted from the dry root of Scutellaria baicalensis Georgi. Studies have shown that baicalin exerts excellent anti-inflammatory and neuroprotective effects. In this study, an AD cell model was established by exposing SH-SY5Y cells to Aβ1-42 and treating them with baicalin. Cell survival, cell cycle progression, and apoptosis were measured by MTT, flow cytometry, and immunofluorescence assays, respectively. The expression levels of Ras, ERK/ERK phosphorylation (p-ERK), and cyclin D1 were measured by Western blotting. In addition, whether the MEK activator could reverse the regulatory effect of baicalin on Ras-ERK signaling was investigated using Western blotting. We found that baicalin improved the survival, promoted the proliferation, and inhibited the apoptosis of SH-SY5Y cells after Aβ1-42 treatment. Baicalin also ameliorated Aβ1-42-induced cell cycle arrest at the S phase and induced apoptosis. Furthermore, baicalin inhibited the levels of Ras, p-ERK, and cyclin D1 induced by Aβ, and this effect could be reversed by the MEK activator. Therefore, we suggest that baicalin may regulate neuronal cell cycle progression and apoptosis in Aβ1-42-treated SH-SY5Y cells by inhibiting the Ras-ERK signaling pathway. This study suggested that baicalin might be a useful therapeutic agent for senile dementia, especially AD.

Xu Zhu,1 Jing Xue,2 Zheng Liu,3 Wenjie Dai,4 Hui Xu,5 Qiaoling Zhou,5 Shuangping Zhao,6 Quan Zhou,7 Wenhang Chen5 1Department of Epidemiology and Health Statistics, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 2Department of Scientific Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 3Department of Anesthesiology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Ji’nan, Shandong, 250014, People’s Republic of China; 4Xiangya School of Public Health, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 5Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 6Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 7Department of Science and Education, The First People’s Hospital of Changde City, Changde, Hunan, 415000, People’s Republic of ChinaCorrespondence: Wenhang ChenDepartment of Nephrology, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Kaifu District, Changsha, 410008, People’s Republic of ChinaFax +86 731 84327348Email wenhangchen@csu.edu.cnObjective: The serum lactate/albumin ratio (LAR) can be used to independently predict mortality due to sepsis. However, whether the LAR predicts the outcomes of critically ill patients with acute kidney injury (AKI) remains unclear. This study was performed to assess the prognostic value of the LAR in critically ill AKI patients.Methods: This retrospective observational study enrolled AKI patients, and all data were collected through the eICU Collaborative Research Database. Outcomes included in-hospital and intensive care unit (ICU) death. Multivariate Cox regression analysis was used to determine independent risk factors. Forest plots and smoothing curves were generated. A series of subgroup analyses were performed to further validate the robustness of the findings.Results: A total of 4666 eligible patients were enrolled. We divided the participants into four groups according to the LAR: quartile (Q)1 (LAR < 0.46, n = 1167), Q2 (0.46 ≤ LAR < 0.79, n = 1162), Q3 (0.79 ≤ LAR < 1.49, n = 1170), and Q4 (LAR ≥ 1.49, n = 1167). The LAR, when analyzed as a continuous variable, was associated with hospital and ICU mortality (adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.18– 1.26, P < 0.0001 for both). The risk of in-hospital and ICU mortality increased with increasing LAR Q relative to Q1. The smoothing curves revealed a continuous linear association after adjusting for all covariates. By the Kaplan–Meier analysis, patients in the higher LAR group showed significantly shorter survival time. By the receiver operating characteristic analysis, LAR was efficient in predicting in-hospital mortality (area under the curve [AUC]: 0.717) and ICU mortality (AUC: 0.733). A positive and consistent effect of the LAR was seen in all subgroups analyses after adjusting for all covariates.Conclusion: A high LAR is an independent risk factor for in-hospital and ICU mortality in critically ill patients with AKI. Further prospective studies are needed to validate these result.Keywords: lactate/albumin ratio, acute kidney injury, mortality, critical care

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.

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.

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.

Cerebral aneurysm (CA) is a common brain disease, and the development of cerebral aneurysm is driven by inflammation and hemodynamic stress. MicroRNA (miR)-124-5p is reported to be associated with inflammatory response in brain disease such as cerebral ischemia-reperfusion injury. However, the function and molecular mechanism of miR-124-5p in CA are not clear, thus, the effects of miR-124-5p on inflammatory response in CA were explored. Firstly, the expression of miR-124-5p in the peripheral blood of patients with CA and the control group was detected by reverse transcription-quantitative PCR. Then, the human umbilical vein endothelial cells (HUVECs) were used as an in vitro model system and stimulated with interleukin (IL)-1β to simulate the inflammatory environment of CA, and the expression of miR-124-5p was detected. Next, the effect of miR-124-5p on the migration and invasion of HUVECs was detected using Transwell assays. Meanwhile, the function of miR-124-5p on various inflammatory factors was determined by western blotting and enzyme-linked immunosorbent assay (ELISA). Next, the TargetScan website was used to predict FoxO1 as a target gene of miR-124-5p, and this target association was validated by double luciferase reporter assay and western blotting. Finally, the interaction of miR-124-5p with FoxO1 in CA was measured by Transwell western blotting and ELISA assays. The results showed that the expression level of miR-124-5p in the peripheral blood of patients with CA was lower compared with that of control group, and the miR-124-5p in HUVECs stimulated by IL-1β was less compared with that in normal HUVECs. Besides, miR-124-5p could inhibit the migration and invasion abilities of HUVECs and the release of inflammatory factors. Additionally, the overexpression of miR-124-5p was able to inhibit the expression of FoxO1. miR-124-5p-inhibitor promoted the migration and invasion of HUVECs, as well as inflammatory response, which was weakened following the introduction of FoxO1 small interfering RNA. Overall, the present study demonstrated that miR-124-5p could prevent the occurrence and development of cerebral aneurysm by downregulating the expression of FoxO1.

Ting Yin,1 Iokfai Cheang,1 Xu Zhu,1 Shengen Liao,1 Haifeng Zhang,2 Xinli Li1 1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People’s Republic of China; 2Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, People’s Republic of ChinaCorrespondence: Haifeng ZhangDepartment of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, People’s Republic of ChinaEmail haifeng_zhang@163.comShengen LiaoDepartment of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People’s Republic of ChinaEmail shengenliao@163.comPurpose: The optimal blood pressure (BP) targets in terms of mortality risk after stroke remain unclear. This study aimed to assess the relationship between BP and mortality in stroke survivors.Patients and Methods: We included 1696 participants with self-reported history of stroke aged 18 years and older from the National Health and Nutrition Examination Survey (NHANES) 1999– 2014 and NHANES III with public-use linked mortality files from 2015. Baseline systolic BP (SBP) and diastolic BP (DBP) levels were obtained by taking the average of 3 measures. Cox proportional hazard models and restricted cubic splines were conducted to explore the relationship between BP and all-cause mortality.Results: During a median follow-up period of 5.6 years, 888 deaths occurred. After fully adjusting for confounding factors, SBP displayed a J-curve relationship (nadir 135 mm Hg), while DBP exhibited a reverse J-curve relationship (nadir 73 mm Hg) with the risk of all-cause mortality. However, the J-curve or reverse J-curve pattern between blood pressure and mortality appeared to be limited to individuals with an age > 65 years, identifying a nadir of SBP/DBP of 142/73 mm Hg. The risk of mortality followed a linear relationship for SBP and DBP in stroke survivors aged ≤ 65 years, with risks increasing with higher SBP and lower DBP.Conclusion: In this cross-sectional study that used national survey data, these data suggest a strong J-curve or reverse J-curve relationship between blood pressure and risk of all-cause mortality, whereas the pattern appears to be limited to individuals with an age > 65 years, with a nadir at 142/73 mmHg. However, missing data on stroke type and stroke treatment limits the generalizability. Future prospective studies are needed to determine preferential blood pressure target in patients after stroke.Keywords: blood pressure, J-curve, stroke, age, mortality

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.

Dilated cardiomyopathy (DCM) is one of the main causes of systolic heart failure and frequently has a genetic component. The molecular mechanisms underlying the onset and progression of DCM remain unclear. This study aimed to identify novel diagnostic biomarkers to aid in the treatment and diagnosis of DCM.The Gene Expression Omnibus (GEO) database was explored to extract two microarray datasets, GSE120895 and GSE17800, which were subsequently merged into a single cohort. Differentially expressed genes were analyzed in the DCM and control groups, followed by weighted gene coexpression network analysis to determine the core modules. Core nodes were identified by gene significance (GS) and module membership (MM) values, and four hub genes were predicted by the Lasso regression model. The expression levels and diagnostic values of the four hub genes were further validated in the datasets GSE19303. Finally, potential therapeutic drugs and upstream molecules regulating genes were identified.The turquoise module is the core module of DCM. Four hub genes were identified: GYPC (glycophorin C), MLF2 (myeloid leukemia factor 2), COPS7A (COP9 signalosome subunit 7A) and ARL2 (ADP ribosylation factor like GTPase 2). Subsequently, Hub genes showed significant differences in expression in both the dataset and the validation model by real-time quantitative PCR (qPCR). Four potential modulators and seven chemicals were also identified. Finally, molecular docking simulations of the gene-encoded proteins with small-molecule drugs were successfully performed.The results suggested that ARL2, MLF2, GYPC and COPS7A could be potential gene biomarkers for DCM.

Using data from the National Health and Nutrition Examination Survey (NHANES), this study aimed to explore the relationship between ethylene oxide (EO) exposure and serum lipid profiles as well as the mediation effect of systemic inflammation among the general adult population.This cross-sectional study analyzed NHANES data from 2013 to 2016, examining a total of 2721 participants. The EO biomarker (hemoglobin adduct of EO [HbEO]) was quantified in blood using a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The association among HbEO levels, inflammatory biomarkers, and four serum lipids was evaluated using a multivariable linear regression model. Mediating analysis was performed to examine the effect of inflammatory biomarkers on the relationship between HbEO levels and serum lipid profiles.As the quartiles of HbEO increased, high-density lipoprotein cholesterol (HDL-C) monotonically decreased (p for trend0.001). Using the lowest quartile of HbEO as a reference, the percent change for HDL-C was 6.30% (95% CI: 3.89%, 8.71%) in the highest quartile of HbEO. HbEO levels were dose-dependently associated with triglycerides (TG) (p for trend = 0.001). The percent change in TG in the fourth quartile of HbEO was 17.24% (95% CI: 2.01%, 32.48%) compared to the first quartile. Overall, inflammatory biomarkers (hs-CRP, alkaline phosphatase, white blood cell count, neutrophil count, and lymphocyte count) increased monotonically in correlation with increasing HbEO levels (all p for trend0.01); were positively correlated with total cholesterol (TC), TG, and low-density lipoprotein cholesterol (LDL-C); and were negatively associated with HDL-C. Additionally, inflammatory biomarkers strongly mediated the relationships between HbEO and HDL-C and TG with maximum mediated proportions of 21.40% and 33.40%, respectively.These findings suggest that HbEO is closely linked to serum lipid profiles and that systemic inflammation may be a key mediator of this association.

BACKGROUND: The role of thoracic consolidation radiotherapy in patients with extensive stage small cell lung cancer (ES-SCLC) remains controversial. This study aimed to evaluate the efficacy of thoracic radiotherapy (TRT) in these patients. METHODS: A systematic literature search was performed in PubMed, Embase, and the Cochrane library to identify qualified clinical studies. The hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS) and local recurrence-free survival (LRFS) were extracted, and toxicity of the TRT group versus non-TRT group was analyzed. RESULTS: A total of 12 studies were included in this meta-analysis, including 936 patients in the TRT group and 1,059 patients in the non-TRT group. The combined results showed that TRT significantly improved OS (HR =0.65; 95% CI: 0.55–0.77, P

Cobalt exposure has adverse health effects on the cardiovascular system in occupational and laboratory studies, but these effects have not been assessed in the general population. We aimed to determine whether serum cobalt levels had relationship with the prevalence of cardiovascular disease (CVD) in the general population. Using data from the National Health and Nutrition Examination Survey (NHANES) (2015–2016), we performed the cross-sectional study. We analyzed the baseline chrematistics of 3,389 participants (1623 men and 1766 women). Generalized linear models and restricted cubic spline plots curve were undertaken to elucidate the relationship. Stratified subgroup analysis was tested to exclude interaction between different variates and cobalt. Our results showed that the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for CVD prevalence across the quartiles of cobalt were 0.94 (0.68, 1.30), 1.58 (1.17, 2.13), and 1.84 (1.37, 2.48) compared with lowest quartile. The restricted cubic spline curve also suggested nonlinear and positive association between cobalt and CVD (P for nonlinearity = 0.005). In summary, our cross-sectional results verify that higher cobalt levels are associated with a higher prevalence of cardiovascular disease.

17β-Estradiol (E2), the strongest of the three major physiological estrogens in females, is an important factor in the female reproductive system. The abnormal level of E2 causes health issues, such as weak bones, urinary tract infections and even depression. Here, we present a novel, sensitive and selective, electrochemical aptasensor for detection of 17β-estradiol (E2). The E2 recognition aptamer was split into two fragments: the first fragment, functionalised with adamantane, is attached to poly(β-cyclodextrin) (poly(β-CD))-modified electrode surface through host-guest interactions between the adamantane and poly(β-CD). The second fragment, labelled with gold nanoparticles, forms the stem-loop structure with the first fragment only in the presence of E2. That specific recognition process triggers the change in the electrochemical signal (a change in the peak current from reduction of AuNPs), recorded by means of differential pulse voltammetry (DPV). The feasibility of the sensing design was firstly investigated on the commercially available glass carbon electrodes (GCE), with achieved a linear detection range of 1.0 × 10−13 to 1.0 × 10−8 M and a limit of detection (LoD) 0.7 fM. The sensing methodology was then translated onto single-use, disposable, laser-scribed graphene electrodes (LSGE) on a plastic substrate. The dynamic sensing range of E2 on LSGE was found to be 1.0 × 10−13 to 1.0 × 10−9 M, with a LoD of 63.1 fM, comparable to these of GCE. The successful translation of the developed E2 aptasensor from GCE to low-cost, disposable LSGE highlights a potential of this sensing platform in commercial, portable sensing detection systems for E2 and similar targets of biological interest.

Background. Survival of patients with portal vein tumor thrombosis (PVTT) is extremely poor; transarterial chemoembolization (TACE) is a treatment for patients with HCC and PVTT. Some studies showed that hepatic arterial infusion chemotherapy (HAIC) might improve the survival of HCC with PVTT. There were few researches of combining TACE with HAIC for patients with HCC and PVTT. Aim. This study was aimed at comparing overall survival (OS) and progression-free survival (PFS) following treatment with conventional transarterial chemoembolization plus hepatic arterial infusion chemotherapy (cTACE-HAIC) or conventional transarterial chemoembolization (cTACE) alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). Methods. From January 2011 to December 2016, 155 patients with HCC and PVTT who received cTACE-HAIC (cTACE-HAIC group) ( n = 86 ) or cTACE alone (cTACE group) ( n = 69 ) were retrospectively evaluated. Propensity score matching (PSM) reduced the confounding bias and yielded 60 matched patient pairs. The tumors’ responses were evaluated using the modified response evaluation criteria in solid tumors (mRECIST). OS and PFS of groups were compared using the Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models. Results. The median follow-up duration was 93 months (range: 1–93 months). The cTACE-HAIC group’s OS (9.0 months) and PFS (6.0 months) were significantly longer than the cTACE group’s OS (5.0 months) and PFS (2.0 months) ( p = 0.018 and p = 0.045 , respectively) in the matched cohort. Multivariate analyses showed that cTACE-HAIC was independently associated with OS (hazard ratio (HR) 0.602, p = 0.010 ) and PFS (HR 0.66, p = 0.038 ). The matched groups did not differ regarding grade 3 or 4 adverse events. Conclusion. cTACE-HAIC was superior to cTACE alone regarding OS and PFS in patients with HCC and PVTT. Treatment-associated toxicities were generally well tolerated.

As a common herbicide in farmland, there has been wide concern over quinclorac residue because of its potential risks to the environment and human health. For the detection and monitoring of quinclorac residue in the environment, enzyme-linked immunoassay (ELISA) and time-resolved fluoroimmunoassay (TRFIA) were established. The half-maximal inhibition concentrations (IC50) of ELISA and TRFIA were 0.169 mg/L and 0.087 mg/L with a linear range (IC20–IC80) of 0.020–1.389 mg/L and 0.004–1.861 mg/L, respectively. Compared with ELISA, the limit of detection (LOD, IC20) and IC50 of TRFIA improved approximately 5-fold and 2-fold. The cross-reaction rates for the quinclorac analogs were less than 2%. The average recoveries of quinclorac in river water, paddy water, paddy soil, and brown rice samples were 77.3–106.1%, with RSDs of 1.7–12.5%. More importantly, the results of the two methods were consistent with that of the referenced method of UPLC-MS/MS (R2 > 0.98). ELISA and TRFIA both showed good detection performance and could meet the requirements of the quantitative determination of quinclorac. Therefore, the proposed ELISA and TRFIA could be applied to the rapid and sensitive detection and monitoring of quinclorac residue in the environment.

Oxidative stress is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed redox homeostasis in cystic cells remain elusive. Here, we identified the impaired activity of the NRF2 (nuclear factor erythroid 2-related factor 2) antioxidant pathway as a driver of oxidative damage and ADPKD progression. Using a quantitative proteomic approach, together with biochemical analyses, we found that increased degradation of NRF2 protein suppressed the NRF2 antioxidant pathway in ADPKD mouse kidneys. In a cohort of patients with ADPKD, reactive oxygen species (ROS) frequently accumulated, and their production correlated negatively with NRF2 abundance and positively with disease severity. In an orthologous ADPKD mouse model, genetic deletion of Nrf2 further increased ROS generation and promoted cyst growth, whereas pharmacological induction of NRF2 reduced ROS production and slowed cystogenesis and disease progression. Mechanistically, pharmacological induction of NRF2 remodeled enhancer landscapes and activated NRF2-bound enhancer-associated genes in ADPKD cells. The activation domain of NRF2 formed phase-separated condensates with MEDIATOR complex subunit MED16 in vitro, and optimal Mediator recruitment to genomic loci depended on NRF2 in vivo. Together, these findings indicate that NRF2 remodels enhancer landscapes and activates its target genes through a phase separation mechanism and that activation of NRF2 represents a promising strategy for restoring redox homeostasis and combatting ADPKD.

The coronavirus disease 2019 (COVID-19) has become a global pandemic since its outbreak in December 2019, which posed a threat to the safety and well-being of people on a global scale. Cancer patients are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and their critical morbidity and case fatality rates are high. The ablation expert committee of the Chinese Society of Clinical Oncology compiled corresponding expert recommendations. These recommendations summarize the preventive measures and management of tumor ablation treatment in medical institutions, including outpatient clinics, oncology wards, ablation operation room, and postablation follow-ups in accordance with the guidelines and protocols imposed by the National Health Commission of the People's Republic of China and the experience in management and prevention according to various hospitals. This consensus aims to reduce and prevent the spread of SARS-CoV-2 and its cross-infection between cancer patients in hospitals and provide regulatory advice and guidelines for medical personnel.

To evaluate the utility of echocardiography (echo) in the diagnosis of persistent fifth aortic arch (PFAA), a very rare congenital aortic arch anomaly, and to compare echo and computed tomography angiography (CTA) imaging findings to improve our understanding of this anomaly. Data on the clinical diagnosis, imaging findings, and clinical management of PFAA were retrospectively analyzed in 10 suspected cases of PFAA admitted to our hospital between January 2012 and February 2017. We compared echo as a first line examination modality, and CTA and surgery results as the gold standard. Weinberg's classification was used to classify the type of PFAA. All patients (100%) received echo examination, eight patients (80%) received CTA examination, and four patients (40%) received sternotomy surgery; all recovered well after surgery. According to Weinberg's classification, 2, 6, and 2 cases (20%, 60%, and 20%) were classified as Type A, B, and C, respectively. Echo was able to diagnose 5 cases of PFAA (1 Type A case and 4 Type B cases) in the first instance. The diagnostic conformance rate of echo was 62.5% after comparisons with CTA and surgery results. The clinical manifestation of PFAA was atypical, and its diagnosis depended primarily on medical imaging. Echo has a relatively high diagnostic accuracy for PFAA, which is very valuable for its early detection.

Prostate cancer (PCa) is known as one of the most common cancers in men all over the world. Previous studies have identified that the pro-inflammatory mediator interleukin-17F (IL-17F) aggravates the progression of several diseases. However, whether IL-17F plays a role in PCa is still lack of enough exploration. In this study, IL-17F expression was strikingly upregulated in PCa tissues. Treatment of IL-17F promoted cell viability at a dose-dependent manner. Further, functional assays were implemented by treatment of 100 ng/ml of IL-17F. Cell viability, proliferation, migration, invasion and stemness were promoted by 100 ng/ml of IL-17F. IL-17F increased the expression of p-PI3K and p-AKT in PCa cells, indicating that IL-17F might activate the PI3K/AKT signalling pathway in PCa cells. LY294002 (the inhibitor of the PI3K/AKT signalling pathway) could reverse the facilitating effects of IL-17F treatment on PCa cell viability, proliferation, migration, invasion and stemness. Taken together, current study revealed that IL-17F facilitated PCa cell malignant phenotypes via activation of the PI3K/AKT signalling pathway, offering a potential therapeutic target for PCa.

The performance of photoelectrochemical (PEC) analysis system relies closely on the properties of the photoelectric electrodes. It is of great significance to integrate photoactive materials with flexible substrates to construct ultra-sensitive PEC sensors for practical application. This work reports a novel photoelectrode developed by immobilizing α-Fe2O3 nanoparticles (NPs)/defect-rich carbon nitride (d-C3N4), an excellent Z-scheme heterojunction photoelectric material, onto three-dimensional (3D) flexible carbon fiber textile. Specifically, 3D hierarchical structure of flexible carbon fiber textile provides larger specific surface area and higher mechanical strength than traditional electrodes, resulting in more reaction sites and faster reaction kinetics to achieve signal amplification. Simultaneously, α-Fe2O3/d-C3N4 Z-scheme heterojunction exhibits enhanced light absorption capability and high redox ability, thus dramatically improving the PEC performance. This photoelectrode was used to construct a flexible PEC aptasensor for ultrasensitive detection of penbritin, demonstrating excellent performance in terms of wide linear range (0.5 pM–50 nM), low detection limit (0.0125 pM) and high stability. The design principle is applicable to the manufacture of other photoelectric sensing systems, which provides an avenue for the development of portable environmental analysis and field diagnostics equipment.

Background With the prominent growth of power market, real-time electricity price has become a trend in smart grid as it enables moderation of power consumption of customers. Accurate forecast of real-time price (RTP) has much influence on customers’ behaviors, such as better scheduling operating time of domestic appliances in order to maximize benefit. In this paper, an innovative hybrid RTP forecasting model considering linear and non-linear behaviors within input data, is proposed to forecast the short-term electricity prices in smart grid. Results The effectiveness of the proposed hybrid forecasting model is verified by numerical results in terms of forecasting performance evaluations. The results clearly demonstrate that our approach is effective in RTP forecasting with a high accuracy. The mean absolute percentage error (MAPE) is approximate to 3.5% and it also significantly outperforms the existing models. Conclusion Based on the achieved results, we can conclude that the proposed hybrid model is an accurate and efficient tool in short-term RTP forecasting and it is potentially effective to a variety of forecasting tasks.

Farm animals raised under free-range (FR) systems are assumed to have improved welfare and higher-quality products that are better to eat than intensively reared animals. However, the modulations are limited in scientific investigations. In this study, we compared 2 rearing systems (FR and cage) and their effects on chickens, including production performance, product quality, body condition, physiological indicators, and gene expression. By using a match-mismatch design in which each treatment was transferred to the other treatment during the last period of the experiment, we aimed to understand the influence of current and former rearing conditions and the ability of individuals to adapt to the current environment. The results indicated that the FR system led to better chicken welfare (e.g., gait score, feather condition, and physiological indicators, P < 0.05) and contributed to higher product quality (P < 0.05), although it resulted in poorer production performance (P < 0.05) and foot pad condition (P < 0.05) than that of the cage rearing system. Additionally, the FR system triggered a series of inner changes and genetic responses in chickens, such as the upregulation of calcium and GnRH signaling, actin and cytoskeleton regulations, immune functions, and developmental processes, and the downregulation of pathological regulations (q-value < 0.05 for all gene ontology terms and P < 0.05 for all Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways). In conclusion, rearing systems alter chicken gene expression patterns, which provide a genetic basis for the adaptability to rearing environments and ultimately affects chicken welfare and products.

This study was aimed at identifying genetic and non-genetic risk factors for valproic acid (VPA)-induced hyperammonaemia in Chinese paediatric patients with epilepsy. A total of 210 epileptic patients, treated with VPA as monotherapy, were enrolled and classified into hyperammonaemia and control groups according to their blood ammonia level (cut-off value 50 μmol/L). Serum concentrations of VPA and its major metabolites were simultaneously determined by ultrahigh-performance liquid chromatography-tandem mass spectrometry. Six single nucleotide polymorphisms in the candidate genes, CYP2C9, CYP2A6, CYP2B6 and CPS1, were analysed by a matrix-assisted laser desorption ionization-time of flight mass spectrometry method or nested PCR. Significant differences in age, aspartate transaminase level and the incidence of liver injury were observed between patients of hyperammonaemia and control groups. Genotype distributions of CYP2C9*3, CYP2A6*4 and CPS1 4217C>A allelic variants were also significantly different between the two groups. According to multiple regression analysis, a significant negative correlation was detected between age and the blood ammonia level, while liver injury, the concentration-dose ratio (CDR) of VPA and 2-propyl-4-pentenoic acid (4-ene VPA), and the presence of CYP2A6*4 or CPS1 4217C>A showed positive correlations with the blood ammonia level. In addition, the risk factors for hyperammonaemia identified by logistic regression analysis were as follows: a younger age (odds ratio [OR] = 0.85; 95% confidence interval [CI] = 0.76-0.96; p = 0.007), occurrence of liver injury (OR = 4.60; 95% CI = 1.27-16.74; p = 0.021), higher CDR of 4-ene VPA (OR = 1.08; 95% CI = 1.03-1.14; p = 0.001), and carrying mutant alleles of CYP2C9*3 (OR = 3.42; 95% CI = 1.15-10.19; p = 0.028), CYP2A6*4 (OR = 3.23; 95% CI = 1.40-7.48; p = 0.006) and CPS1 4217C>A (OR = 3.25; 95% CI = 1.52-6.94; p = 0.002). Our findings indicated that multiple genetic and non-genetic risk factors that were identified can be used to predict the development of VPA-induced hyperammonaemia in Chinese paediatric patients with epilepsy.

Introduction: Brain metastasis (BM) is the commonest adult intracranial malignancy and many patients with brain metastases require two course radiotherapy. Re-irradiation is frequently performed in Radiotherapy (RT) departments for multiple brain metastases. Patient concerns: We present a case of a 55-year-old male patient suffering from brain metastases, who had previously received whole-brain radiotherapy (WBRT) and first CyberKnife Stereotactic Radiotherapy (CKSRT) for metastases, presented with a recurrence of metastasis and new lesions in the brain. Diagnoses: An enhanced computed tomography (CT) scan of the brain revealed abnormalities with double-dosing of intravenous contrast that identified >10 lesions scattered in the whole brain. Interventions: Re-irradiation was performed using CKSRT. The patient was treated with 30 Gy in 5 fractions for new lesions and 25 Gy in 5 fractions for lesion that were locally recurrent and close to brainstem lesions. Outcome: The lesions were well-controlled, and the headache of the patient was significantly relieved one month after radiotherapy. The total survival time of the patients was 17 months from the beginning of the Cyberknife treatment. Conclusion: The present case report demonstrates that CyberKnife therapy plays a significant role in the repeated radiotherapy for multiple metastatic brain tumors. CKSRT can be used as a salvage method in recurrent multiple brain metastases.

Numerical studies of buckling failure and debond propagation were carried out on composite sandwich columns with face/core debond. Nonlinear simulations with cohesive elements were carried out by Abaqus 6.14 to predict the buckling modes and debond propagation in sandwich composite columns. For specimens with embedded circular face/core debond, the debond propagated in the interface along the direction which was perpendicular to the compression direction until the through-the-width debond was formed. After that, the face/core debond propagated along the compression direction just as these specimens with through -the-width rectangle debond. Comparisons of the experimental and simulated ultimate loads associated with failure modes showed a good agreement. The maximum error of ultimate load was 10.61%, which proved that the model was capable of predicting accurate buckling loads and post-buckling behaviors.

Objective. miRNA has gained attention as a therapeutic target in various malignancies. The proposal of this study was to investigate the biological functions of key miRNAs and target genes in cancers of the digestive tract which include esophageal carcinoma (ESCA), gastric adenocarcinoma (GAC), colon adenocarcinoma (COAD), and rectal adenocarcinoma (READ). Materials and Methods. After screening differentially expressed miRNAs (DEMIs) and differentially expressed mRNAs (DEMs) in four digestive cancers from The Cancer Genome Atlas (TCGA) database, the diagnostic value of above DEMIs was evaluated by receiver-operating characteristic (ROC) curve analysis. Then, corresponding DEMIs’ target genes were predicted by miRWalk 2.0. Intersection of predicted target genes and DEMs was taken as the target genes of DEMIs, and miRNA-mRNA regulatory networks between DEMIs and target genes were constructed. Meanwhile, the univariate Cox risk regression model was used to screen miRNAs with distinct prognostic value, and Kaplan–Meier analysis was used to determine their significance of prognosis. Furthermore, we performed bioinformatics methods including protein-protein interaction (PPI) networks, gene ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene group RIDA analysis by Gene-Cloud of Biotechnology Information (GCBI) to explore the function and molecular mechanisms of DEMIs and predicted target genes in tumor development. Results. Eventually, 3 DEMIs (miR-7-3, miR-328, and miR-323a) with significant prognostic value were obtained. In addition, 3 DEMIs (miR-490-3p, miR-133a-3p, and miR-552-3p) and 281 target genes were identified, and the 3 DEMIs showed high diagnostic value in READ and moderate diagnostic value in ESCA, GAC, and COAD. Also, the miRNA-mRNA regulatory network with 3 DEMIs and 281 overlapping genes was successfully established. Functional enrichment analysis showed that 281 overlapping genes were mainly related to regulation of cell proliferation, cell migration, and PI3K-Akt signaling pathway. Conclusion. The diagnostic value and prognostic value of significant DEMIs in cancers of the digestive tract were identified, which may provide a novel direction for treatment and prognosis improvement of cancers of the digestive tract.

Enzalutamide and apalutamide are two androgen receptor inhibitors approved for the treatment of castration-resistant prostate cancer (CRPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC), respectively. Apalutamide is associated with an increased incidence of skin rash above the placebo groups in the SPARTAN trial in nmCRPC and in the TITAN trial in metastatic castration-sensitive prostate cancer patients. On the contrary, the rate of skin rash across all clinical trials (including PROSPER [nmCRPC]) for enzalutamide is similar to the placebo. We hypothesized that the apalutamide-associated increased skin rash in patients could be linked to a structural difference. The 2-cyanophenyl and dimethyl moieties in enzalutamide are substituted in apalutamide with 2-cyanopyridine and cyclobutyl, respectively. In our evaluations, the 2-cyanopyridine moiety of apalutamide was chemically reactive with the thiol nucleophile glutathione, resulting in rearranged thiazoline products. Radiolabeled apalutamide, but not radiolabeled enzalutamide, was shown to react with mouse and human plasma proteins. Thiol nucleophiles decreased the extent of covalent binding to the model protein bovine serum albumin, whereas amine and alcohol nucleophiles had no effect, suggesting reactivity with cysteine of proteins. Subcutaneous administration of apalutamide dose dependently increased lymphocyte cellularity in draining lymph nodes in a mouse drug allergy model (MDAM). Enzalutamide, and its known analogue RD162 in which the cyanophenyl was retained but the dimethyl was replaced by cyclobutyl, demonstrated substantially less covalent binding activity and negative results in the MDAM assay. Collectively, these data support the hypothesis that the 2-cyanopyridine moiety in apalutamide may react with cysteine in proteins forming haptens, which may trigger an immune response, as indicated by the activity of apalutamide in the MDAM assay, which in turn may be leading to increased potential for skin rash versus placebo in patients in the SPARTAN and TITAN clinical trials.

Elemicin is a constituent of natural aromatic phenylpropanoids present in many herbs and spices. However, its potential to cause toxicity remains unclear. To examine the potential toxicity and associated mechanism, elemicin was administered to mice for 3 weeks and serum metabolites were examined. Enlarged livers were observed in elemicin-treated mice, which were accompanied by lower ratios of unsaturated- and saturated-lysophosphatidylcholines in plasma, and inhibition of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in liver. Administration of the unsaturated fatty acid oleic acid reduced the toxicity of 1'-hydroxylelemicin, the primary oxidative metabolite of elemicin, while treatment with the SCD1 inhibitor A939572 potentiated its toxicity. Furthermore, the in vitro use of recombinant human CYPs and chemical inhibition of CYPs in human liver microsomes revealed that CYP1A1 and CYP1A2 were the primary CYPs responsible for elemicin bioactivation. Notably, the CYP1A2 inhibitor α-naphthoflavone could attenuate the susceptibility of mice to elemicin-induced hepatomegaly. This study revealed that metabolic activation of elemicin leads to SCD1 inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.