Search

Vascular calcification (VC) is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process, in which vascular smooth muscle cells (VSMCs) transform into osteoblast/chondrocyte-like cells as in bone formation. VC is associated with significant morbidity and mortality in chronic kidney disease (CKD) and cardiovascular disease, but the underlying mechanisms remain unclear. In this study we investigated the role of large-conductance calcium-activated potassium (BK) channels in 3 experimental VC models. VC was induced in vascular smooth muscle cells (VSMCs) by β-glycerophosphate (β-GP), or in rats by subtotal nephrectomy, or in mice by high-dosage vitamin D3. We showed that the expression of BK channels in the artery of CKD rats with VC and in β-GP-treated VSMCs was significantly decreased, which was functionally confirmed by patch-clamp recording. In β-GP-treated VSMCs, BK channel opener NS1619 (20 μM) significantly alleviated VC by decreasing calcium content and alkaline phosphatase activity. Furthermore, NS1619 decreased mRNA expression of ostoegenic genes OCN and OPN, as well as Runx2 (a key transcription factor involved in preosteoblast to osteoblast differentiation), and increased the expression of α-SMA protein, whereas BK channel inhibitor paxilline (10 μM) caused the opposite effects. In primary cultured VSMCs from BK(−/−) mice, BK deficiency aggravated calcification as did BK channel inhibitor in normal VSMCs. Moreover, calcification was more severe in thoracic aorta rings of BK(−/−) mice than in those of wild-type littermates. Administration of BK channel activator BMS191011 (10 mg· kg(−1) ·d(−1)) in high-dosage vitamin D3-treated mice significantly ameliorated calcification. Finally, co-treatment with Akt inhibitor MK2206 (1 μM) or FoxO1 inhibitor AS1842856 (3 μM) in calcified VSMCs abrogated the effects of BK channel opener NS1619. Taken together, activation of BK channels ameliorates VC via Akt/FoxO1 signaling pathways. Strategies to activate BK channels and/or enhance BK channel expression may offer therapeutic avenues to control VC.

Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer. Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol 3-kinase UPS: ubiquitin-proteasome system

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused millions of infections and deaths worldwide since its emergence in December 2019. As there is little or no natural immunity in the human population or specific anti-COVID-19 drugs, researchers from the government, academia and industry are developing vaccines at an unprecedented speed to halt the pandemic. In this review, the results of animal experiments and clinical trials on several vaccine technical platforms are summarized, and several challenges are also discussed to further promote the development, evaluation and application of vaccines during the challenging situation of the global pandemic.

This paper aimed to research the function and in-depth mechanism of GPR37 in lung adenocarcinoma (LUAD). Herein, based on TCGA and Oncomine databases, we revealed that GPR37 was expressed at high levels in LUAD, and upregulation of GPR37 was related to the poor outcomes. Furthermore, biological function experiments in vitro were utilized to assess whether GPR37 impacts malignant phenotype of LUAD cells. Gain- or loss-of-function assays indicated that the upregulation of GPR37 contributed to improving the proliferation, migration, and invasion of LUAD cells in vitro, while knockdown of GPR37 can inhibit the malignant biological behaviors. Then, we found that depletion of GPR37 resulted in a decrease in the expression of TGF-β1 as well as the extents of Smad2 and Smad3 phosphorylation, while overexpression of GPR37 presented opposite outcomes. Altogether, our findings indicated that GPR37 is a potential oncogene of LUAD, and its promoting effects on the malignant progression of LUAD may be realized via TGF-β/Smad pathway.

The phylogeny and systematics of cordycipitoid fungi have been extensively studied in the last two decades. However, systematic positions of some taxa in the family Cordycipitaceae have not yet been thoroughly resolved. In this study, a new phylogenetic framework of Cordycipitaceae is reconstructed using multigene (nrSSU, nrLSU, tef-1α, rpb1 and rpb2) sequence data with large-scale taxon sampling. In addition, ITS sequence data of species belonging to the Lecanicillium lineage in the family Cordycipitaceae are used to further determine their phylogenetic placements. Based on molecular phylogenetic data together with morphological evidence, two new genera (Flavocillium and Liangia), 16 new species and four new combinations are introduced. In the new genus Flavocillium, one new species F. bifurcatum and three new combinations previously described as Lecanicillium, namely F. acerosium, F. primulinium and F. subprimulinium, are proposed. The genus Liangia is built by the new species Lia. sinensis with Lecanicillium-like asexual morph, isolated from an entomopathogenic fungus Beauveria yunnanensis. Due to the absence of Paecilomyces hepiali, an economically and medically significant fungus, in the earlier phylogenetic analyses, its systematic position has been puzzling in both business and academic communities for a long time. Here, P. hepiali is recharacterized using the holotype material along with seven additional samples. It is assigned to the genus Samsoniella (Cordycipitaceae, Hypocreales) possessing Cordyceps-like sexual morph and Isaria-like asexual morph, and thus a new combination, namely S. hepiali is proposed. An additional nine new species in Samsoniella are described: S. alpina, S. antleroides, S. cardinalis, S. cristata, S. lanmaoa, S. kunmingensis, S. ramosa, S. tortricidae and S. yunnanensis. Four new species in Cordyceps are described: C. chaetoclavata, C. cocoonihabita, C. shuifuensis and C. subtenuipes. Simplicillium yunnanense, isolated from synnemata of Akanthomyces waltergamsii, is described as a new species.

Glycemic variability (GV) plays an important role in the pathogenesis of vascular complications associated with diabetes mellitus (DM). Paeoniflorin is an effective Chinese traditional medicine with anti-inflammatory and immune-regulatory effects. Previous studies implicated the beneficial effects of paeoniflorin in treatment for diabetic complications, such as type 2 diabetic nephropathy and diabetes with myocardial ischemic injury. Current evidence suggests that oxidative stress and platelet activation, as well as their interaction, are potentially associated with GV and involved in the pathogenesis of diabetes-associated vascular complications. This study aimed to explore the effects of paeoniflorin on oxidative stress and platelet activation, using human umbilical vein endothelial cells (HUVECs) cultured with different glucose concentrations, and streptozotocin-induced diabetic rats fed different glycemic index diets. Paeoniflorin treatment effectively improved the morphology and cell viability of HUVECs under glucose fluctuation. Moreover, the platelet aggregation rate, CD62p expression, and reactive oxygen species (ROS) concentration decreased, while glutathione peroxidase (GSH-px) levels increased in paeoniflorin-treated groups. In conclusion, our study found that paeoniflorin ameliorates oxidative stress and platelet activation induced by glycemic variability both in vivo and in vitro, suggesting a novel potential strategy for treatment of diabetic complications.

BackgroundImported malaria has been an important challenge for China. Fatality rates from malaria increased in China, particularly in Henan Province, primarily due to malpractice and misdiagnoses in healthcare institutions, and the level of imported malaria. This study aims to investigate the relationship between the state of diagnosis and subsequent complications among imported malaria cases at healthcare institutions, based on malaria surveillance data in Henan Province from 2012 to 2017.MethodsA retrospective descriptive analysis was performed using data from the Centre for Disease Control and Prevention, Zhengzhou City, the capital of Henan Province. A decision tree method was exploited to provide valuable insight into the correlation between imported malaria cases and healthcare institutions.ResultsFrom 2012 to 2017, there were 371 imported malaria cases, mostly in males aged between 20 and 50 years, including 319Plasmodium falciparumcases. First visits of 32.3%, 19.9% and 15.9% malaria cases for treatment were to provincial, municipal and county healthcare institutions, respectively. The time interval between onset and initial diagnosis of 284 cases (76.5%) and the time interval between initial diagnosis and final diagnosis of 197 cases (53.1%) was no more than 72 h. An apparent trend was found that there were notably fewer patients misdiagnosed at first visit to healthcare institutions of a higher administrative level; 12.5% of cases were misdiagnosed in provincial healthcare institutions compared to 98.2% in private clinics, leading to fewer complications at healthcare institutions of higher administrative level due to correct initial diagnosis. In the tree model, the rank of healthcare facilities for initial diagnosis, and number of days between onset and initial diagnosis, made a major contribution to the classification of initial diagnosis, which subsequently became the most significant factor influencing complications developed in the second tree model. The classification accuracy were 82.2 and 74.1%, respectively for the tree models of initial diagnosis and complications developed.ConclusionInadequate seeking medical care by imported malaria patients, and insufficient capacity to diagnose malaria by healthcare institutions of lower administrative level were identified as major factors influencing complications of imported malaria cases in Henan Province. The lack of connection between uncommon imported malaria cases and superior medical resources was found to be the crucial challenge. A web-based system combined with WeChat to target imported malaria cases was proposed to cope with the challenge.

Aim To evaluate the protective effects of lipoic acid-niacin (N2L) dimers against blue light (BL)-induced oxidative damage to human retinal pigment epithelium (hRPE) cells in vitro. Methods hRPE cells were divided into a control group (CG), a BL group, an N2L plus BL irradiation group, an α-lipoic acid (ALA) plus BL group, an ALA-only group, and an N2L-only group. hRPE cellular viability was detected by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide assays, and apoptosis was evaluated by annexin-V-PE/7-AAD staining followed by flow cytometry. Ultrastructural changes in subcellular organelles were observed by transmission electron microscopy. Reactive oxygen species formation was assayed by flow cytometry. The expression levels of the apoptosis-related proteins BCL-2 associated X protein (BAX), B-cell leukmia/lymphoma 2 (BCL-2), and caspase-3 were quantified by Western blot analysis. Results BL exposure with a light density of 4±0.5 mW/cm2 exceeding 6h caused hRPE toxicity, whereas treatment with a high dose of N2L (100 mol/L) or ALA (150 mol/L) maintained cell viability at control levels. BL exposure caused vacuole-like degeneration, mitochondrial swelling, and reduced microvillus formation; however, a high dose of N2L or ALA maintained the ultrastructure of hRPE cells and their organelles. High doses of N2L and ALA also protected hRPE cells from BL-induced apoptosis, which was confirmed by Western blot analysis: BCL-2 expression significantly increased, while BAX and caspase-3 expression slightly decreased compared to the CG. Conclusion High-dose N2L treatment (>100 mol/L) can reduce oxidative damage in degenerating hRPE cells exposed to BL with an efficacy similar to ALA.

ACOS5, OsACOS12 and PpACOS6 are all capable of fatty acyl-CoA synthetase activity but exhibit different substrate preferences. The transcriptional regulation of ACOS for sporopollenin synthesis appears to have been conserved in Physcomitrella, rice and Arabidopsis during evolution. Sporopollenin is the major constituent of spore and pollen exines. In Arabidopsis, acyl-CoA synthetase 5 (ACOS5) is an essential enzyme for sporopollenin synthesis, and its orthologues are PpACOS6 from the moss Physcomitrella and OsACOS12 from monocot rice. However, knowledge regarding the evolutionary conservation and divergence of the ACOS gene in sporopollenin synthesis remains limited. In this study, we analysed the function and regulation of PpACOS6 and OsACOS12. A complementation test showed that OsACOS12 driven by the ACOS5 promoter could partially restore the male fertility of the acos5 mutant in Arabidopsis, while PpACOS6 did not rescue the acos5 phenotype. ACOS5, PpACOS6 and OsACOS12 all complemented the acyl-CoA synthetase-deficient yeast strain (YB525) phenotype, although they exhibited different substrate preferences. To understand the conservation of sporopollenin synthesis regulation, we constructed two constructs with ACOS5 driven by the OsACOS12 or PpACOS6 promoter. Both constructs could restore the fertility of acos5 plants. The MYB transcription factor MS188 from Arabidopsis directly regulates ACOS5. We found that MS188 could also bind the promoters of OsACOS12 and PpACOS6 and activate the genes driven by the promoters, suggesting that the transcriptional regulation of these genes was similar to that of ACOS5. These results show that the ACOS gene promoter region from Physcomitrella, rice and Arabidopsis has been functionally conserved during evolution, while the chain lengths of fatty acid-derived monomers of sporopollenin vary in different plant species.

Objective: To investigate the expression of LncRNA MNX1-AS1 in NSCLC and its effect on NSCLC cell lines. Methods: In this experiment, the expression of LncRNA MNX1-AS1 was detected by qRT-PCR in 116 NSCLC samples, and the correlation between MNX1-AS1 and NSCLC patients was further analyzed by chi-square test. The prognostic value of MNX1-AS1 was assessed by Kaplan-Meier survival curve. The expression of MNX1-AS1 in NSCLC cell line A549 was knocked down, and the effects of MNX1-AS1 on proliferation, apoptosis, migration and invasion of NSCLC cells were evaluated. Results: Compared with normal lung tissue, the expression of MNX1-AS1 was significantly increased in lung cancer tissues (p

Non-small cell lung cancer (NSCLC) is one of the most common malignancies, and Taxol is a cornerstone in the treatment. However, taxol-resistance eventually limits the clinical effects and applications. Daurinoline could restore the sensitivity of resistant MCF-7/adr and KBv200 cells. Whereas, the effect of daurinoline on the chemo-resistant NSCLC cells and the mechanism has not been elucidated. In this study, daurinoline was firstly demonstrated that inhibited the proliferation, migration, invasion and EMT phenotype of chemo-resistant NSCLC cells. And these effects were associated with EMT and Notch-1 reversal. Moreover, daurinoline could significantly enhance the anti-tumor effect of Taxol rather than epirubicin, adriamycin and cisplatin. And the reverse fold (RF) value of daurinoline was greater than terfenadine reported before. There are little cytotoxic effects of daurinoline and its derivatives reported by L.W. Fu, et al. (2001). Therefore, daurinoline may be a potential anti-tumor agent or chemosensitizer for chemo-resistant NSCLC patients.

This retrospective study aimed to evaluate the combined effect of anti-PD-1 inhibitor and nanoparticle albumin-bound (nab)-paclitaxel for refractory melanoma among Chinese patients. Data from January 2018 to March 2021 were retrospectively collected and analyzed. Sixty-four patients were eligible for analysis from a single Chinese cancer center. The median follow-up was 16.0 months at data cutoff. The objective response rate (ORR) was 29.7%, and the disease control rate (DCR) was 67.2% in all patients. Treatment-naive patients had significantly higher ORR than pretreated patients (42.9% vs 13.8%, p = 0.011). Cutaneous melanoma patients with NRAS gene mutation benefited more than non-mutated patients (DCR of 100% vs. 54.5%) (p = 0.030). The median progression-free survival (mPFS) of all patients was 5.2 months and the duration of response was 10.8 months. Median duration of disease control was 7.7 months. Prior treatment-naive patients had significantly longer PFS than those who accepted prior treatments (7.2 vs. 5.1 months, p = 0.024). Patients with abnormally high LDH level had shorter mPFS (3.6 months vs. 6.6 months, p = 0.020). Median overall survival was not reached in this study. Most patients experienced adverse events (AEs), but only 17.2% of patients experienced grade 3 severe AEs. The most common AEs were alopecia (89.1%), neutropenia (18.8%), pruritus (15.6%), and arthralgia (14.1%). Some patients had immune related AEs (irAEs). No grade 4 or 5 AEs were observed. Patients with ≥ 3 AEs or with irAEs had longer mPFS (p

The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with BRAF V600E/K mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with BRAF V600E/K mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3–4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3–4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3–4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [p = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens (p = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, p = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.

Background Acral and mucosal melanomas are rarely seen in Caucasians but common in China. There are limited data on the recurrence characteristics for these patients. This study aimed to identify the recurrence pattern for localized melanoma in China, especially acral and mucosal subtypes. Methods Patients with localized melanoma who underwent radical resection between January 1999 and December 2014 in southern China were retrospectively reviewed. Survival and annual recurrence hazard were analyzed by Kaplan–Meier method and hazard function, respectively. Results Totally, 1012 patients were included (acral melanoma 400; chronic sun-induced damage (CSD)/non-CSD melanoma 314; mucosal melanoma 298). Recurrence was recorded in 808 patients (localized 14.1%; regional 29.6%, and distant 56.3%). Mucosal melanoma had local and M1c stage recurrence more frequently than cutaneous melanoma, but less frequent regional node relapse. There was no difference in recurrent site distribution between acral and CSD/non-CSD melanoma. The annual recurrence hazard curve for the entire cohort showed a double-peaked pattern with the first major peak in the second year after surgery and the second peak near the seventh year. Mucosal melanoma had a higher recurrence risk than cutaneous melanoma. Acral melanoma had a lower flat recurrence peak than CSD/non-CSD melanoma. Tumor thickness > 4.0 mm, ulceration, positive regional nodes, and wound infection were associated with a higher recurrence risk in cutaneous melanoma. Adjuvant therapy reduced the recurrence risk of cutaneous melanoma but not of mucosal melanoma. Conclusions This is a large cohort about the rule of recurrence risk in acral and mucosal melanoma and will provide an initial framework for development of surveillance and adjuvant strategy for Chinese melanoma patients.

The goal of this study was to clone and characterize complete cDNA sequences of three important development-relevant genes of yellow catfish Pelteobagrus fulvidraco, including lrp6, sox9a1 and fgfr2c, and explore their transcriptional responses in several tissues of P. fulvidraco to high fat diet. The predicted amino acid sequences of P. fulvidraco Lrp6, Sox9a1 and Fgfr2c contained all of the conserved structural features that were characteristic of these genes in other species, including YWTD domains, EGF-like repeats, LDLR ligand binding repeats, PPSP repeats motifs, HMG box, TA-binding functional domain, Ig I-III and PTK I-II. The mRNAs of the three genes were expressed in various tissues, but their mRNA levels varied among tissues. Compared to the control, high fat diet tended to down-regulate the mRNA expression of sox9a1 and fgfr2c in mesenteric fat, liver and ovary, and up-regulate their mRNA levels in muscle and kidney; in contrast, high fat diet down-regulated lrp6 mRNA levels in the ovary and muscle, but had no significant effects on lrp6 mRNA expression in mesenteric fat, liver and kidney. Our findings provide the first data about their expression responses to dietary lipid in teleosts and reinforce the multiple functions at the molecular level.

Excessive Zn in the aquatic environment can be toxic and causes dysfunction in Zn homeostasis for fish, which ultimately influences the function of various biological processes. Zn homeostasis is controlled by Zn transporters. This study cloned and characterized the full-length cDNA sequences of six Zn transport-relevant genes (ZnT1, ZnT5, ZnT7, ZIP4, ZIP5 and MTF-1) from yellow catfish Pelteobagrus fulvidraco. The six genes share similar domains to their corresponding members of mammals. Their mRNA amounts were widely existent across eight tissues (intestine, liver, brain, heart, gill, muscle, spleen and mesenteric fat), but relatively predominant in the liver and intestine. On day 28, Zn exposure tended to increase transcript levels of ZnT1, ZnT5 and MTF-1, decrease hepatic ZIP5 expression, but did not significantly affect the expression of ZnT7 and ZIP4. On day 56, Zn exposure tended to increase transcript levels of ZnT1 and MTF-1, down-regulate hepatic mRNA amounts of ZIP4 and ZIP5; among three Zn treatments, ZnT5 expression in the 0.5 mg Zn/L group and ZnT7 expression in the 0.25 mg Zn/L group were the highest. The mRNA abundances of these genes showed Zn concentration- and exposure time-dependent manners. For the first time, we characterized the full-length cDNA sequences of six Zn transport-relevant genes in fish, explored their tissue expression profiles and transcriptional responses to Zn exposure. Our study built good basis for further investigating their physiological functions of these genes and provided new insights into the regulatory mechanisms of Zn homeostasis in fish.

Background Recent studies demonstrated beneficial effects of zileuton, a 5-lipoxygenase (5LO) inhibitor, on some brain diseases in animal models, but the role of zileuton in the depression remains unknown. Methods We investigated the effects of zileuton on depressive behaviors using tail suspension test (TST), forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice injected with lipopolysaccharide (LPS). The 5LO level, activation of microglia, NF-κB p65, TNF-α, IL-1β, brain-derived neurotrophic factor (BDNF), and c-AMP response element-binding protein (CREB) were determined in the mouse hippocampus. Results We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and was reversed by fluoxetine administration. Zileuton significantly suppressed LPS-induced depressive behaviors, evidenced by the decreases in immobility time in TST and FST, as well as the latency to feed in NSFT. This treatment pronouncedly alleviated LPS-induced neuroinflammatory response, characterized by decreased 5LO, suppressed activation of microglia, decreased NF-κB p65, TNF-α and IL-1β, and significantly increased the ratio of p-CREB/CREB or mBDNF/proBDNF in the hippocampus of the LPS-challenged mice. Conclusions Zileuton abrogates LPS-induced depressive-like behaviors and neuroinflammation, and enhances CREB/BDNF signaling in the hippocampus, suggesting that zileuton could have potential therapeutic value for depression.

The overexpression of EGFR correlates with rapidly progressive disease, resistance to chemotherapy and poor prognosis. In certain human cancers, PI3K works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and PI3K has therapeutic advantage and was an attractive approach against tumors. In this work, based on the molecular docking and previous studies, a series of 4-aminoquinazolines derivatives containing 6-sulfonamide substituted pyridyl group were rationally designed and identified as potent EGFR and PI3K dual inhibitors. The cytotoxicity experiment results showed that this series of compounds could effectively inhibit cell growth. The kinase assay demonstrated that 6c and 6i had high inhibition for EGFR and selectivity for PI3Kα distinguished from other isoforms. Further experiments showed that 6c could induce cell cycle arrest in G1 phase and apoptosis in BT549 cells. The western blot assay indicated that 6c inhibited the proliferation of BT549 cell through EGFR and PI3Kα/Akt signaling pathway. Our study suggested that compound 6c was a potential dual inhibitors of EGFR and PI3Kα.

Cordyceps tenuipes is a worldwide entomopathogenic fungus and is famous as the edible and medical value in East Asian nations. In the present study, the high-quality whole-genome of C. tenuipes was...

Peroxisome proliferator-activated receptor (PPAR) expression has been implicated in pathological states such as cancer, inflammation, diabetes, and neurodegeneration. We isolated natural PPAR agonists—eight 2,5-diketopiperazines—from the jellyfish-derived fungus Aspergillus flavus. Cyclo-(L-Pro-L-Phe) was the most potent PPAR-γ activator among the eight 2,5-DKPs identified. Cyclo-(L-Pro-L-Phe) activated PPAR-γ in Ac2F rat liver cells and SH-SY5Y human neuroblastoma cells. The neuroprotective effect of this partial PPAR-γ agonist was examined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, lactate dehydrogenase release, and the Hoechst 33342 staining assay in SH-SY5Y cells. Our findings revealed that cyclo-(L-Pro-L-Phe) reduced hydrogen peroxide-induced apoptosis as well as the generation of reactive oxygen species. Rhodamine 123 staining and western blotting revealed that cyclo-(L-Pro-L-Phe) prevented the loss of mitochondrial membrane potential and inhibited the activation of mitochondria-related apoptotic proteins, such as caspase 3 and poly (ADP-ribose) polymerase. Moreover, cyclo-(L-Pro-L-Phe) inhibited the activation and translocation of nuclear factor-kappa B. Thus, the partial PPAR-γ agonist cyclo-(L-Pro-L-Phe) demonstrated potential neuroprotective activity against oxidative stress-induced neurodegeneration in SH-SY5Y cells.

DNA hypermethylation and the silencing of tumor suppressor genes caused by DNA hypermethylation is considered as a molecular hallmark of many kinds of cancers. Procaine, a local anesthetic, has been shown as a potential DNA methylation inhibitor in some types of cancers. However, the influence of procaine on DNA methylation regulation as well as the biological function in gastric cancer is still unknown. We report here that procaine represses the DNA-methylation level and promotes the proliferation arrest and apoptosis of gastric cancer cells. Global DNA methylation measurement demonstrates that procaine significantly reduces the global DNA methylation level. Analyses of the DNMTs expression and activity show procaine represses the activity, but not the expression, of DNMT1/DNMT3A. Further evidence on specific genes shows that procaine reduces the DNA methylation level in the promoter regions of CDKN2A and RARβ genes through abrogating the binding of DNMT1/DNMT3A toward these regions. This repression would not be reversed by the overexpression of DNMT1/DNMT3A. Moreover, RT-qPCR and luciferase report assays demonstrate that procaine leads to the upregulation of CDKN2A and RARβ due to the activation of the promoter of these genes. In the end, we test the function of procaine toward gastric cancer cells and find that procaine has the growth inhibitory and apoptosis inducement effect toward gastric cancer cells. Collectively, our data not only uncovers the regulation mechanisms of procaine to DNA methylation but also suggests an anti-tumor potential of procaine specific to the gastric carcinoma and provides a new therapeutic strategy for gastric carcinoma.

The acquired resistance of non-small cell lung cancer (NSCLC) to taxanes eventually leads to the recurrence and metastasis of tumours. Thus, the development of therapeutic strategies based on the mechanisms by which cells acquire resistance to prolong their survival rate in chemotherapy drug treatment failure patients are warranted. In this study, we found that the resistant cells acquired increased migratory and invasive capabilities, and this transformation was correlated with epithelial-mesenchymal transition (EMT) and Notch pathway deregulation in the resistant cells. Finally, we reported for the first time that terfenadine augmented the effect of epirubicin (EPI) better than Taxol and cisplatin (DDP) by inhibiting migration, invasion, and the EMT phenotype, and the combination therapy also reversed Notch signalling pathway and enhanced the accumulation of fluorescent P-gp substrate rhodamine 123 (Rh123). Similar activities of terfenadine on EPI were observed in xenografts. All of our results confirmed that terfenadine combined with EPI synergistically inhibits the growth and metastatic processes of resistant cells both in vitro and in vivo. Therefore, terfenadine or its derivatives are a promising approach for the clinical challenge of resistance in patients with advanced NSCLC.

Acral melanoma is a rare disease, but is common in Asia. Knowledge of its prognostic indicators is limited. Growing evidence indicates that inflammation plays a critical role in the development and progression of acral melanoma. We developed a novel prognostic model on the basis of preoperative inflammatory markers and examined its prognostic value in a cohort of patients. This retrospective study included 232 acral melanoma patients who underwent radical surgical resection between 2000 and 2010 at the Sun Yat-sen University Cancer Center. Significant predictive factors were identified by multivariate Cox regression analyses, and a prognostic model on the basis of these variables was constructed to predict survival. Kaplan-Meier curves were plotted to estimate overall survival. Multivariate analyses showed that C-reactive protein, albumin/globulin ratio, age, lactic dehydrogenase, and lymph node positivity were related independently to survival. After analyzing these variables, we classified patients into three risk groups. The new prognostic model identified three categories of patients with different prognoses (P

Pollen hydration is a critical step that determines pollen germination on the stigma. KINβγ is a plant-specific subunit of the SNF1-related protein kinase 1 complex (SnRK1 complex). In pollen of the Arabidopsis kinβγ mutant, the levels of reactive oxygen species were decreased which lead to compromised hydration of the mutant pollen on the stigma. In this study, we analyzed gene expression in kinβγ mutant pollen by RNA-seq and found the expression of inward shaker K+ channel SPIK was down-regulated in the kinβγ pollen. Furthermore, we showed that the pollen hydration of the Arabidopsis spik mutant was defective on the wild-type stigma, although the mutant pollen demonstrated normal hydration in vitro. Additionally, the defective hydration of spik mutant pollen could not be rescued by the wild-type pollen on the stigma, indicating that the spik mutation deprived the capability of pollen absorption on the stigma. Our results suggest that the Arabidopsis SnRK1 complex regulates SPIK expression, which functions in determining pollen hydration on the stigma.

This study aimed to identify the associated factors for quality measurement (QM) of shear wave speed (SWS) imaging and to validate the additional value of QM in the diagnosis of breast lesions. From September 2014 to February 2015, conventional ultrasound and SWS imaging were performed in 338 women with 361 breast lesions. Binary logistic regression was used to identify associated factors for QM. Sensitivity, specificity and the area under receiver operating characteristic (ROC) curve (AUC) among maximum SWS (SWS max ), QM and SWS max plus QM (SWS max +QM) were compared to validate additional value of QM. Pathology confirmed 263 (72.9%) benign lesions and 98 (27.1%) malignancies. Maximum depth (Odds ratio [OR]: 1.398) and posterior features (OR: 1.206) were identified as independent associated factors for QM. Compared with SWS max and QM, the sensitivity of SWS max +QM increased from 67.3%, 64.3% to 83.7% whereas the specificity decreased from 90.5%, 72.6% to 65.4% (all P max had the highest AUC in comparison with QM and SWS max +QM (0.849 vs. 0.685 vs. 0.745; P max is useful for breast cancer screening and SWS max alone is useful for breast cancer differentiation.

// Yingshi Zhang 1, 2, 3, * , Jun Hou 4, * , Fan Feng 4, * , Dandan Li 2, 3 , Qiyu Jiang 4 , Xiaojuan Li 4 , Qingchun Zhao 2, 3 and Bo-An Li 1 1 Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing 100039, P.R. China 2 Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110840, P.R. China 3 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China 4 Research Center for Clinical and Transitional Medicine, The 302nd Hospital of Chinese PLA, Beijing 100039, P.R. China * These authors contributed equally to this work Correspondence to: Bo-An Li, email: lba@263.net Qingchun Zhao, email: zhaoqingchun1967@163.com Keywords: UDP-glucuronosyltransferases 1A7, polymorphism, gastrointestinal carcinoma, cancer, network meta-analysis Received: May 16, 2017 Accepted: May 29, 2017 Published: June 27, 2017 ABSTRACT Objective: To identify the association between gastrointestinal carcinomas (GIC) risk and UDP-glucuronosyltransferases (UGTs) 1A7 polymorphisms through a systematic review and network meta-analysis. Results: Seventeen studies were eligible, which included 7738 patients and 18 analyses. First, it was found that compared with non-cancer participants, UGT1A7*1 were significantly decreased in cancer patient groups, especially in hepatocellular carcinoma, colorectal carcinoma, and Asian population groups; UGT1A7*2 was significantly increased in hepatocellular carcinoma and Asian population groups; and UGT1A7*3 was significantly increased in hepatocellular carcinoma, colorectal carcinoma, Caucasian, and Asian population groups. Second, the UGT1A7 polymorphism alleles contrast model and the categorized UGT 1A7 genotypes were compared, and the outcomes revealed that the ratio of UGT1A7*3 vs *2 increased, which may indicate an increased risk for cancer, especially for the pancreatic carcinoma and Caucasian groups. The ratio of Intermediate vs Low increased as well, which may also indicate an increased risk for GIC. Materials and Methods: PubMed, Embase, and the Cochrane library were searched for publications up until May 2017. First, the UGT 1A7 gene polymorphisms genotype in GIC patients were compared with a non-cancer control group, and second, the UGT1A7 polymorphism alleles contrast model and UGT 1A7 genotypes categorized according to enzymatic activity were examined. Conclusions: There is a cancer risk associated with increased UGT1A7 *2 for the hepatocellular carcinoma and Asian groups and with increased UGT1A7 *3 for the hepatocellular carcinoma, colorectal carcinoma, Caucasian, and Asian groups. Moreover, in Caucasian patients with GIC, the ratio of UGT1A7 *3 vs *2 was increased.

Objective To objectively assess the effect of transitional care on readmission for patients with chronic obstructive pulmonary disease. Methods The PubMed, Science Direct, Web of Science, Cochrane Library, CNKI, and Wanfang databases were searched for relevant randomized controlled trials (RCTs) published from January 1990 through April 2016. The quality of eligible studies was assessed by two investigators. The primary outcome assessed was readmission for COPD and all-cause readmission. The pooled effect sizes were expressed as the relative risk and standard mean difference with 95% confidence intervals. Heterogeneity among studies was assessed using the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0) and determined with an I2 statistic. Results A total of seven RCTs that included 1879 participants who met the inclusion criteria were analyzed. The results of subgroup analysis showed significant differences in readmission for COPD at the 6 month and 18 month time points and all-cause readmission at the 18 month follow-up. Transitional care could reduce readmission for COPD at the 6 month [RR = 0.51, 95% CI (0.38,0.68), P Conclusions Transitional care is beneficial to reducing readmission for patients with COPD. Duration of≥ 6 and ≤ 18 months are more effective, and the effect weakens over intervention time, especially after the end of intervention. Both durations point to the importance of ongoing intervention and reinforcement after the end of intervention.

The aim of this study was to compare the diagnostic performance of two different 2D shear wave speed imaging techniques of Virtual Touch Tissue ImagingQuantification (VTIQ) and Toshiba shear wave elastography (T-SWE) in predicting malignant thyroid nodules (TNs).75 TNs in 75 patients which were subject to both VTIQ and T-SWE examinations were enrolled and analyzed. Shear wave speed (SWS) values on VTIQ and T-SWE were computed (SWS_max, min, mean and median). Area under the receiver operating characteristic (AUROC) curve was obtained to assess the diagnostic performance.The AUROC for VTIQ was the highest with SWS_min whereas for T-SWE was SWS_max (0.774 versus 0.851; p 0.05). The AUROC, sensitivity and negative predictive value (NPV) corresponding to SWS_max for VTIQ were significantly lower than those for T-SWE (0.717 versus 0.851, 61.5% versus 92.3% and 78.7% versus 94.3%; all p 0.05). However, no significant differences were found between AUROC with SWS_min, SWS_mean, or SWS_median for VTIQ and SWS_max for T-SWE (all p 0.05).In general, VTIQ is equal to T-SWE for diagnosis of TNs. In the clinical practice, the selection of SWS_max should be avoided in VTIQ whereas should be selected in T-SWE.

To evaluate the diagnostic performance of two different shear wave elastography (SWE) techniques in distinguishing malignant breast lesions from benign ones.From March 2016 to May 2016, a total of 153 breast lesions (mean diameter, 16.8 mm±10.5; range 4.1-90.0 mm) in 153 patients (mean age, 46.4 years±15.1; age range 20-86 years) were separately performed by two different SWE techniques (i.e. T-SWE, Aplio500, Toshiba Medical System, Tochigi, Japan; and S-SWE, the Aixplorer US system, SuperSonic Imagine, Provence, France). The maximum (Emax), mean (Emean) and standard deviation (ESD) of elasticity modulus values in T-SWE and S-SWE were analyzed. All the lesions were confirmed by ultrasound (US)-guided core needle biopsy (n = 26), surgery (n = 122), or both (n = 5), with pathological results as the gold standard. The areas under the receiver operating characteristic curves (AUROCs) were calculated. Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV) were calculated to assess the diagnostic performance between T-SWE and S-SWE. Operator consistency was also evaluated.Among the 153 lesions, 41 (26.8%) were malignant and 112 (73.2%) were benign. Emax (T-SWE: 40.10±37.14 kPa vs. 118.78±34.41 kPa; S-SWE: 41.22±22.54 kPa vs. 134.77±60.51 kPa), Emean (T-SWE: 19.75±16.31 kPa vs. 52.93±25.75 kPa; S-SWE: 20.95±10.98 kPa vs. 55.95±22.42 kPa) and ESD (T-SWE: 9.00±8.55 kPa vs. 38.44±12.30 kPa; S-SWE: 8.17±6.14 kPa vs. 29.34±13.88 kPa) showed statistical differences in distinguishing malignant lesions from benign ones both in T-SWE and S-SWE (all p 0.05). In T-SWE, the diagnostic performance of ESD was the highest (AUROC = 0.958), followed by Emax (AUROC = 0.909; p = 0.001 in comparison with ESD) and Emean (AUROC = 0.892; p 0.001 in comparison with ESD), while in S-SWE, the diagnostic performance of Emax was the highest (AUROC = 0.967), followed by ESD (AUROC = 0.962, p 0.05 in comparison with Emax) and Emean (AUROC = 0.930, p = 0.034 in comparison with Emax). AUROC-max (T-SWE: 0.909 vs.0.967), AUROC-mean (T-SWE: 0.892 vs.0.930) and AUROC-SD (T-SWE: 0.958 vs.0.962) showed no significant difference between T-SWE and S-SWE (all p 0.05). The intra-class correlation coefficients (ICC) of the intra-operator consistency and inter-operator consistency respectively were 0.961 and 0.898 in T-SWE, while 0.954 and 0.897 in S-SWE.T-SWE and S-SWE are equivalent for distinguishing the breast lesions. In T-SWE, ESD had the best diagnostic performance, while in S-SWE, Emax had the best diagnostic performance.

Background: Magnesium influences hepatic lipid deposition in vertebrates, but the underlying mechanism is unknown.Objective: We used yellow catfish and their isolated hepatocytes to test the hypothesis that magnesium influences lipid deposition by modulating lipogenesis and lipolysis.Methods: Juvenile yellow catfish (mean ± SEM weight: 3.43 ± 0.02 g, 3 mo old, mixed sex) were fed a 0.14- (low), 0.87- (intermediate) or 2.11- (high) g Mg/kg diet for 56 d. Primary hepatocytes were incubated for 48 h in control or MgSO4-containing medium with or without 2-h pretreatment with an inhibitor (AG490, GW6471, or Compound C). Growth performance, cell viability, triglyceride (TG) concentrations, and expression of enzymes and genes involved in lipid metabolism were measured. Results: Compared with fish fed low magnesium, those fed intermediate or high magnesium had lower hepatic lipids (18%, 22%) and 6-phosphogluconate dehydrogenase (6PGD; 3.7%, 3.8%) and malic enzyme (ME; 35%, 48%) activities and greater mRNA levels of the lipolytic genes adipose triacylglyceride lipase (atgl; 82% and 1.7-fold) and peroxisome proliferator-activated receptor (ppara; 18% and 1.0-fold), respectively (P < 0.05). Relative mRNA levels of AMP-activated protein kinase (ampk) a1, ampka2, ampkb1, ampkb2, ampkg1a, ampkg1b, Janus kinase (jak) 2a, jak2b, and signal transducers and activators of transcription (stat) 3 in fish fed high magnesium were higher (24% to 3.1-fold, P < 0.05) than in those fed low or intermediate magnesium. Compared with cells incubated with MgSO4 alone, those incubated with MgSO4 and pretreated with AG490, GW6471, or Compound C had greater TG concentrations (42%, 31%, or 56%), g6pd (98%, 59%, or 51%), 6pgd (68%, 73%, or 32%) mRNA expression, and activities of G6PD (35%, 45%, or 16%) and ME (1.5-fold, 1.3-fold, or 13%), and reduced upregulation (61%, 25%, or 45%) of the lipolytic gene, atgl (P < 0.05).Conclusions: Magnesium reduced hepatic lipid accumulation in yellow catfish and the variation might be attributed to inhibited lipogenesis and increased lipolysis. PPARA, JAK-STAT, and AMPK pathways mediated the magnesium-induced changes in lipid deposition and metabolism. These results offer new insight into magnesium nutrition in vertebrates.

Objective To assess the usefulness of thyroid imaging reporting and data system (TI-RADS) for cytological Bethesda Category III thyroid nodules (TNs). Methods This retrospective study included 121 patients with 121 TNs classified as Bethesda Category III at fine needle aspiration (FNA) cytology and thereafter underwent surgery. The TNs were classified according to US TI-RADS category and the malignancy risk of each category was calculated. Results Surgical pathology confirmed 43 (35.5%) malignant and 78 (64.5%) benign TNs. The malignancy risks of categories 3, 4a, 4b, 4c, and 5 TNs were 0%, 4.0%, 12.5%, 62.2%, and 100%, respectively. For those >10 mm (n = 55), the malignancy risks were 0%, 6.2%, 12.5%, 73.3%, and 100%, respectively, whereas for those ≤10 mm (n = 66), the risks were 0%, 0%, 12.5%, 56.7%, and 100%, respectively. Conclusion Bethesda Category III TNs without suspicious US features or those ≤10 mm with only one suspicious US feature can be followed up with US.

Trauma complicated by seawater immersion is a complex pathophysiological process with higher mortality than trauma occurring on land. This study investigated the role of vascular endothelial cells (VECs) in trauma development in a seawater environment. An open abdominal injury rat model was used. The rat core temperatures in the seawater (SW, 22°C) group and normal sodium (NS, 22°C) group declined equivalently. No rats died within 12 hours in the control and NS groups. However, the median lethal time of the rats in the SW group was only 260 minutes. Among the 84 genes involved in rat VEC biology, the genes exhibiting the high expression changes (84.62%, 11/13) on a qPCR array were associated with thrombin activity. The plasma activated partial thromboplastin time and fibrinogen and vWF levels decreased, whereas the prothrombin time and TFPI levels increased, indicating intrinsic and extrinsic coagulation pathway activation and inhibition, respectively. The plasma plasminogen, FDP, and D-dimer levels were elevated after 2 hours, and those of uPA, tPA, and PAI-1 exhibited marked changes, indicating disseminated intravascular coagulation (DIC). Additionally, multiorgan haemorrhagia was observed. It indicated that seawater immersion during trauma may increase DIC, elevating mortality. VECs injury might play an essential role in this process.

Background The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients. Methods This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples. Results Of the 15 patients enrolled, no grade 3–4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3–49.0%) and 33.3% (95% CI 2.5–64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5–5.5) and 5.73 (95% CI 1.1–10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage. Conclusions The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.

The twining habit is a climbing strategy that helps slender plants grow upward by using circumnutation around other plants. In geological history, climbing may have already been present in the first Middle Devonian forests, as indicated by possible climbers among aneurophytalean progymnosperms [1] and lycopsids [2]. By the late Carboniferous, climbing was both more common and diverse - preserved in swamp forests with modes of attachment ranging from aerial roots to appendages modified into hooks and tendrils on the leaves [3]. However, all of these diagnoses of a climbing habit are based upon either indirect morphological characteristics of the purported climber or on direct physical contact with a host plant, but without direct preservation of twining [3,4]. Permineralized epiphytes have been preserved in the Carboniferous [5], but the interpretation of scars purported to have been caused by twiners that have been found on trunk compressions of potential host-plants has been questioned [5] (see Supplemental Information). Direct preservation of a climber engaged in true twining around a host has only been documented in the Miocene Shanwang Formation of Eastern China, albeit with the identity of the twiner difficult to establish and likely to be a self-twiner [6]. Here, we report a climbing fern engaged in left-handed twining around a seed plant from the early Permian Wuda Tuff fossil Lagerstatte of Inner Mongolia, China [7]. Moreover, the host plant is likely to also be a climber based on its overall form. Such a climber-climbing-a-climber phenomenon signals the potential ecological complexity of late Paleozoic forests.

Immune checkpoint blockade of programmed cell death protein 1 (PD-1) had an impressive long-lasting effect in a portion of advanced-stage melanoma patients, however, this therapy failed to induce responses in several patients; how to increase the objective response rate is very important. Cellular FLICE-inhibitory protein (c-FLIP) could inhibit apoptosis directly at the death-inducing signaling complex of death receptors and is also considered to be the main cause of immune escape. The overexpression of c-FLIPL occurs frequently in melanoma and its expression is associated with the prognosis. We found that the level of c-FLIPL expression was associated with the PD-1 blockade response rate in melanoma patients. Thus, we performed this research to investigate how c-FLIPL regulates immunotherapy in melanoma. We demonstrate that down regulation of c-FLIPL enhances the PD-1 blockade efficacy in B16 melanoma tumor model. Down regulation of c-FLIPL could increase the tumor apoptosis and enhance the antitumor response of T cells in the lymphocyte tumor cells co-culture system. Moreover, knockdown of c-FLIPL could decrease the expression of PD-L1 and recruit more effector T cells in the tumor microenvironment. Our results may provide a new combined therapeutic target for further improving the efficacy of PD-1 blockade in melanoma.

The hypothesis of the present study is that apoptosis through an intrinsic mitochondrial pathway may mediate high fat diet (HFD)-induced changes in the metabolism of Pelteobagrus fulvidraco. To this end, we cloned the full-length cDNA sequences of Cycs, Apaf1, Casp9, Casp3a, and Casp3b involved in the mitochondria apoptotic pathway, and explored their mRNA tissue expressions and transcriptional responses to HFD. All of these members shared similar domains to their orthologous vertebrate genes. They were constitutively expressed in all analyzed tissues but varied from tissue to tissue. Compared to the control, HFD up-regulated the mRNA expression of partial genes among these five key genes (Cycs, Apaf1, Casp9, Casp3a, and Casp3b) in mesenteric fat, intestine, ovary and the kidney, indicating the induction of apoptosis in these tissues; in contrast, HFD down-regulated mRNA levels of partial genes among the five key genes (Cycs, Apaf1, Casp9, Casp3a, and Casp3b) in the heart, spleen and gill tissues, indicating the inhibition of apoptosis in these tissues. The present study will facilitate further exploration into the functions of these genes at the molecular level and disclose the critical involvement of these genes against nutrient changes, indicating that processes of apoptosis in various tissues may differentially be modified by HFD.

Our previous study has found that zileuton, a selective 5-lipoxygenase (5LO) inhibitor, abrogated lipopolysaccharide-induced depressive-like behaviors and hippocampal neuroinflammation. Herein, we further extended our curiosity to investigate effects of zileuton on stress-induced depressive-like behaviors. Our data indicated that zileuton significantly ameliorated depressive-like behaviors in mice subjected to chronic mild stress (CMS), as shown in the tail suspension test, forced swimming test and novelty-suppressed feeding test. The further studies indicated that zileuton suppressed hippocampal neuroinflammation, evidenced by lower levels of TNF-α, IL-1β and nuclear NF-κB p65 as well as decreased number of Iba1-positive cells. It also significantly ameliorated hippocampal apoptosis, indicated by deceased number of TUNEL-positive cells, deceased ratio of cleaved caspase-3/procaspase-3 and increased ratio of Bcl-2/Bax. More importantly, zileuton increased the level of synaptic proteins PSD-95 and SYN and the number of NeuN+/BrdU+ cells in the hippocampus. Over all, zileuton alleviated CMS-induced depressive-like behaviors, neuroinflammatory and apoptotic responses, abnormalities of synapse and neurogenesis in the hippocampus, suggesting that it might has beneficial effects on depression.

Objective: To observe the protective role of hapatopoietin Cn (HPPcn) on acute liver injury. Methods: Six hours after 10 mmol/L CCl4, 150 mmol/L ethanol, or 0.6 mmol/L H2O2 treatment, SMMC7721 human hepatoma cells were incubated with 10, 100, or 200 ng/ml recombinant human HPPCn protein (rhHPPCn) for an additional 24 h. The cell survival rate was analyzed using the CCK-8 assay. The CCl4-induced apoptosis of SMMC7721 cells was detected by flow cytometry. Then, the levels of glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), malondialdehyde (MDA), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) in SMMC7721 cell lysates and cell culture supernatant were detected. SMMC7721 cells were treated with different concentrations of rhHPPCn (0, 10, and 100 ng/ml). The cell proliferation indexes (BrdU incorporation and PCNA expression) were detected by immunohistochemistry (IHC). An acute liver injury mouse model was established by a one-time intraperitoneal injection of 20% CCl4 at a volume of 5 ml/kg body weight. One hour after CCl4 injection, 1.25 or 2.5 mg rhHPPCn/12 h/kg body weight was injected via the tail vein. The serum levels of GOT and GPT were detected at different time points. Pathological changes in the liver were evaluated. PCNA expression levels were observed by IHC. Results: rhHPPCn increased the survival rate of SMMC7721 cells and inhibited chemical toxicity-induced cell apoptosis. The levels of GOT, GPT, MDA, and LDH in the cell supernatant were significantly reduced, while GSH-PX and SOD were significantly increased after rhHPPCn treatment in the CCl4-treated SMMC7721 cells. BrdU incorporation and PCNA expression increased in a concentration-dependent manner, indicating that rhHPPCn promotes cell proliferation. The results showed that rhHPPCn significantly reduced the serum levels of GOT and GPT in CCl4-induced acute liver injury mice. rhHPPCn alleviated the tissue damage and increased PCNA expression, indicating the promotion of proliferation after acute injury. Conclusion: rhHPPCn protects hepatocytes from chemical toxins by promoting proliferation and inhibiting apoptosis in vivo and in vitro. Our study provides new insights for the clinical treatment of acute liver injury.

To study the impact of donepezil, rivastigmine, galantamine, and memantine on cognitive, functional, behavioral, global changes and adverse effects in patients with mild, moderate and severe Alzheimer’s disease (AD), we screened the literature published before September 2017 in the Pubmed, Embase, Cochrane library and Web of Science Electronic databases according to the inclusion criteria. Thirty-six studies were finally determined from 1560 preliminary screened articles. The AD Assessment Scale-cognitive Subscale (ADAS-cog), AD Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Clinician’s Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+) were used as valid endpoints. Of the 36 trials included, meta-analyses of these placebo-control trials showed that there were significant differences between the donepezil, rivastigmine and placebo groups using ADAS-cog, ADCS-ADL, and CIBIC+. Meta-analyses of these placebo-controlled trials showed that there were significant differences between the galantamine and placebo groups using ADAS-cog, ADCS-ADL, NPI, and CIBIC+. These observations suggest that memantine is beneficial for stabilizing or slowing the decline in ADAS-cog and ADCS-ADL19 changes in AD patients. However, there was no significant effect according to the ADCS-ADL23, NPI, and CIBIC+ tests, which indicated that memantine treatment has no significant effect on these cognitive aspects of AD patients. Different effects of donepezil, rivastigmine, galantamine, or memantine on AD were found in this study. According to the results, we conclude that galantamine is effective in treating all aspects of AD and is the first choice for the treatment of AD. However, due to limited data, we should consider additional data to obtain more stable results.

As a gaseous biological signaling molecule, nitric oxide (NO) regulates many physiological processes in plants. Over the last decades, this low molecular weight compound has been identified as a key signaling molecule to regulate plant stress responses, and also plays an important role in plant development. However, elucidation of the molecular mechanisms for NO in leaf development has so far been limited due to a lack of mutant resources. Here, we employed the NO-deficient mutant nia1nia2 to examine the role of NO in leaf development. We have found that nia1nia2 mutant plants displayed very different leaf phenotypes as compared to wild type Col-0. Further studies have shown that reactive oxygen species (ROS) levels are higher in nia1nia2 mutant plants. Interestingly, ROS-related enzymes ascorbate peroxidase (APX), catalases (CAT), and peroxidases (POD) have shown decreases in their activities. Our transcriptome data have revealed that the ROS synthesis gene RBOHD was enhanced in nia1nia2 mutants and the photosynthesis-related pathway was impaired, which suggests that NO is required for chloroplast development and leaf development. Together, these results imply that NO plays a significant role in plant leaf development by regulating ROS homeostasis.

Aim: To investigate novel potential biomarkers for antidiastole of tuberculous pleural effusion (TPE) from malignant pleural effusion (MPE). Materials & methods: iTRAQTM-coupled LC–MS/MS were applied to analyze the proteome of TPE and MPE samples. The candidate proteins were verified by enzyme-linked immunosorbent assay. Results: A total of 432 differential proteins were identified. Enzyme-linked immunosorbent assay revealed significantly higher levels of fibronectin (FN) and cathepsin G (CTSG) in MPE than in TPE, but lower levels of leukotriene-A4 hydrolase (LTA4H). The receiver operator characteristic values were 0.285 for FN, 0.64 for LTA4H, 0.337 for CTSG and 0.793 for a combination of these candidate markers. Conclusion: FN, LTA4H and CTSG were identified as potential biomarkers to differentiate TPE from MPE and their combination exhibited higher diagnostic capacity.

OBJECTIVE To investigate the stiffness distribution in the ablated zone after radiofrequency ablation (RFA), we used a device called tissue elastometer based on gross liver samples. MATERIALS AND METHODS: Twelve freshly excised porcine livers were subject to RFA under a same setup to form elliptic ablated samples. Each sample was cut open for gross examination, and then the surface of the section plane was sliced into one piece for Young's modulus test using the tissue elastometer. Five test points along the long- and short-axis on each piece were selected to evaluate stiffness distribution respectively. Among them, four points distributed equidistantly from center to boundary in the ablated zone and one was in the unablated zone. RESULTS In the ablated zone, we found the Young's moduli were significantly different among the four test points both in long- (F = 99.04, p

Aim: To study the expression and prognostic significance of CD80 in patients with gastric adenocarcinoma. Materials & methods: Real-time quantitative PCR, western blot and immunohistochemistry were performed to detect the expression of CD80 in gastric cancer tissues and matched adjacent normal tissues. Double immunohistochemical staining was performed to preliminary examine the relationship between CD80+ cells and CD8+ cytotoxic T lymphocytes. Results: The expression of CD80 was downregulated in tumor tissues compared with normal tissues (p = 0.002). Immunohistochemistry analysis showed that 49 (39.8%) of 123 patients with gastric cancer demonstrated reduced CD80 expression, which was correlated with the tumor differentiation grade. Conclusion: Our data suggest that reduced CD80 expression independently predicts a poor prognosis in patients with gastric adenocarcinoma.

Hyperglycemia fluctuation is associated with diabetes mellitus (DM) complications when compared to persistent hyperglycemia. Previous studies have shown that paeoniflorin (PF), through its antiapoptosis, anti-inflammation, and antithrombotic properties, effectively protects against cardiovascular and cerebrovascular disease. However, the mechanism underlying the protection from PF against vascular injuries induced by hyperglycemia fluctuations remains poorly understood. Herein, we investigated the potential protective role of PF on human umbilical vein endothelial cells (HUVECs) subjected to intermittent glucose levels in vitro and in DM rats with fluctuating hyperglycemia in vivo. A remarkable increased apoptosis associated with elevated inflammation, increased oxidative stress, and high protein level of PKCβ1 was induced in HUVECs by intermittently changing glucose for 8 days, and PF recovered those detrimental changes. LY333531, a potent PKCβ1 inhibitor, and metformin manifested similar effects. Additionally, in DM rats with fluctuating hyperglycemia, PF protected against vascular damage as what has been observed in vitro. Taken together, PF attenuates the vascular injury induced by fluctuant hyperglycemia through oxidative stress inhibition, inflammatory reaction reduction, and PKCβ1 protein level repression, suggesting its perspective clinical usage. ©2019, National Natural Science Foundation of China (no. 81573803), National Natural Science Foundation of China (no. 81703862)

DNA methylation abnormalities are regarded as critical event for cancer initiation and development. Tumor-associated genes encompassing aberrant DNA methylation alterations at specific locus are correlated with chromatin remodeling and dysregulation of gene expression in various malignancies. Thus, technologies designed to manipulate DNA methylation at specific loci of genome are necessary for the functional study and therapeutic application in the context of cancer management. Traditionally, the method for DNA methylation modifications demonstrates an unspecific feature, adversely causing global-genome epigenetic alterations and confusing the function of desired gene. Novel approaches for targeted DNA methylation regulation have a great advantage of manipulating gene epigenetic alterations in a more specific and efficient method. In this review, we described different targeting DNA methylation techniques, including both their advantages and limitations. Through a comprehensive understanding of these targeting tools, we hope to open a new perspective for cancer treatment.

Objectives To investigate the diagnostic performance of a 2-dimensional shear wave elastographic technique (Virtual Touch tissue imaging and quantification [VTIQ]; Siemens Medical Solutions, Mountain View, CA) for predicting thyroid malignancy. Methods A total of 302 thyroid nodules underwent conventional sonography and VTIQ before fine-needle aspiration examination or surgery. Compared with histopathologic or cytologic results in combination with follow-up, the diagnostic performance of various shear wave speed (SWS) indices (minimum [SWSmin], maximum [SWSmax], and mean [SWSmean]) on VTIQ as well as conventional sonographic features for predicting thyroid malignancy was evaluated in all of the nodules. Results Sixty-five malignant and 237 benign thyroid nodules were histopathologically or cytologically confirmed. All SWS indices on VTIQ were lower in benign nodules than thyroid malignancy (all P

// Bo-Ji Liu 1, 2, * , Chong-Ke Zhao 1, 2, * , Hui-Xiong Xu 1, 2 , Yi-Feng Zhang 1, 2 , Jun-Mei Xu 1, 2 , Dan-Dan Li 1, 2 , Xiao-Wan Bo 1, 2 , Xiao-Long Li 1, 2 1 Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Ultrasound Research and Education Institute, Tongji University School of Medicine, Shanghai 200072, China 2 Thyroid Institute, Tongji University School of Medicine, Shanghai Center for Thyroid Diseases, Shanghai 200072, China * These authors contributed equally to this work Correspondence to: Hui-Xiong Xu, email: xuhuixiong@126.com Keywords: shear wave elastography, shear wave speed imaging, thyroid nodule, quality measurement Received: September 26, 2016 Accepted: December 01, 2016 Published: December 16, 2016 ABSTRACT To evaluate the associated factors for quality measurement (QM) on shear wave speed (SWS) imaging and the additional value of QM for differentiation of thyroid nodules. A consecutive series of 238 patients with 254 thyroid nodules were enrolled. They were all evaluated by conventional ultrasound and SWS imaging and were finally proven pathologically. QM was used to assess whether SWS propagation was authentic and was classified as high QM and Low QM. Twelve variables were analyzed to evaluate the associated factors for QM using binary logistic regression. Receiver operating characteristic (ROC) curve was plotted on SWS and SWS+QM. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and area under ROC curve (AUC) were calculated. The study included 170 benign thyroid nodules (160 high QM and 10 low QM) and 84 malignant thyroid nodules (56 high QM and 28 low QM) ( P < 0.001). The mean SWS of benign and malignant nodules were 2.51 ± 0.47 m/s and 3.43 ± 1.21 m/s respectively ( P < 0.001). The sensitivities, specificities, PPVs, NPVs, accuracies and AUCs were 77.4%, 80.0%, 65.7%, 87.7%, 79.1%, 0.82 for SWS alone with SWS ≥ 2.78 m/s; 33.3–34.5%, 91.2–94.1%, 65.9–73.7%, 73.8–74.1%, 72.4–74.0%, 0.63–0.64 for QM alone and 84.5–85.7%, 72.4–75.9%, 60.5–63.4%, 90.8–91.0%, 76.8–78.7%, 0.79–0.80 for SWS+QM. Nodule depth was identified to be the strongest associated factor for QM of SWS, followed by malignancy and SWS. In conclusion, QM for thyroid nodule is associated with nodule depth, malignancy, and SWS. QM improves the specificity in comparison with SWS alone, whereas SWS+QM does not improve the overall diagnostic performance.

Calreticulin (CRT) exposure on the cell surface is essential for inducing immunogenic cell death by chemotherapy. Recent studies have shown conflicting effects of chemotherapy-induced autophagy on CRT exposure in cancer cells. Our data revealed that surface-exposed CRT (Ecto-CRT) emission was attenuated by inhibition of autophagy at early stages; however, inhibition of autophagy at late stages resulted in increased Ecto-CRT. Furthermore, neither autophagy activation nor endoplasmic reticulum (ER) stress induction alone was sufficient for CRT surface exposure. Moreover, chemotherapeutic agents that only activated autophagy without inducing ER stress could not increase Ecto-CRT; therefore, combined use of an autophagy activator and ER stress inducer could effectively promote CRT translocation to the plasma membrane. Together, our results highlight the potential of the combined use of ER stress inducers and autophagy late-stage inhibitors to reestablish and strengthen both the CRT exposure and immunogenicity of chemotherapeutic agents induced death cells.

The purpose of the study was to evaluate the value of 2-D shear wave elastography (SWE) of virtual touch tissue imaging quantification (VTIQ) for ultrasound (US) Breast Imaging-Reporting and Data System (BI-RADS) category 4 lesions. One hundred sixteen lesions were subject to conventional US, conventional strain elastography (SE) of elasticity imaging (EI), acoustic radiation force impulse (ARFI)-induced SE of virtual touch tissue imaging (VTI) and VTIQ before biopsies. Of the 116 lesions, 69 (59.5%) were benign and 47 (40.5%) were malignant. Significant differences were found between benign and malignant lesions in EI score, VTI score and shear wave speed (SWS) on VTIQ (both p

// Bao-Ding Chen 1,2,3,4,5 , Hui-Xiong Xu 1,2,3,4 , Yi-Feng Zhang 1,2,3,4 , Bo-Ji Liu 1,2,3,4 , Le-Hang Guo 1,2,3,4 , Dan-Dan Li 1,2,3,4 , Chong-Ke Zhao 1,2,3,4 , Xiao-Long Li 1,2,3,4 , Dan Wang 1,2,3,4 and Shuang-Shuang Zhao 5 1 Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Ultrasound Research and Educational Institute, Tongji University School of Medicine, Shanghai, China 2 Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Clinical College of Nanjing Medical University, Shanghai, China 3 Thyroid Institute, Tongji University School of Medicine, Shanghai, China 4 Shanghai Center of Thyroid Diseases, Shanghai, China 5 Department of Medical Ultrasound, Affiliated Hospital of Jiangsu University, Zhenjiang, China Correspondence to: Hui-Xiong Xu, email: // Keywords : thyroid nodule, calcification, ultrasound, shear-wave elastography, point shear-wave measurement Received : June 30, 2016 Accepted : August 26, 2016 Published : August 31, 2016 Abstract Conventional ultrasound cannot satisfactorily distinguish malignant and benign thyroid nodules. Shear-wave elastography (SWE) can evaluate tissue stiffness and complement conventional ultrasound in diagnosing malignant nodules. However, calcification of nodules may affect the results of SWE. The purposes of this study are to compare the differences of shear-wave speed (SWS) measurement among different calcification groups and compare the diagnostic performance between using a single uniform SWS cutoff value and multiple individual calcification-specific cutoff values using technique of point SWS measurement. We retrospectively identified 517 thyroid nodules (346 benign and 171 malignant nodules) examined by conventional ultrasound and point SWS measurement. There were 177 non-calcified, 159 micro-calcified and 181 macro-calcified nodules. The diagnostic performance was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC) was computed. The mean SWS in malignant nodules more than doubled that of benign nodules (4.81±2.03 m/s vs. 2.29±0.99 m/s, p 2.42 m/s), micro- (SWS >2.88 m/s) and macro-calcification (SWS >3.59 m/s) nodules in the whole group, the AUC was 0.859 (95% confidence interval [CI], 0.826-0.888), which was significantly better than the AUC of 0.816 (95% CI, 0.780-0.848) if a single uniform cutoff value (SWS >2.72 m/s) was applied to all the nodules regardless of calcification status (p=0.011). The cutoff values of SWS for different calcified nodules warrant future prospective validation.