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Li Zhang,1,2,* Mengxi Liu,1,* Chaocheng Lu,1 Dandan Ren,1 Guoqing Fan,1 Chang Liu,1 Mengjiao Liu,1 Gang Shu,1 Guangneng Peng,1 Zhixiang Yuan,1 Zhijun Zhong,1 Wei Zhang,1 Hualin Fu1 1Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, China; 2Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, Sichuan, China *These authors contributed equally to this work Introduction: Toltrazuril (Tol) is used to prevent and combat coccidiosis. However, its low aqueous solubility and poor oral bioavailability limit clinical application. Methods: To overcome the shortcomings, toltrazuril–hydroxypropyl–β-cyclodextrin inclusion complex (Tol-HP-β-CD) was prepared and characterized. The comparative plasma disposition kinetics of Tol was analyzed after a single orally administered dose of 10 mg/kg Tol or Tol-HP-β-CD in rabbits. Solution-stirring method was selected to prepare the inclusion complex. Complex formation was characterized by thin-layer chromatography, Fourier transform infrared spectrophotometry, and 1H nuclear magnetic resonance spectroscopy. In plasma profile, plasma samples were collected between 1 and 10 days following administration. Plasma Tol concentrations were determined by high-performance liquid chromatography. Results: In rabbit plasma, the time to peak concentration (Tmax) of Tol-HP-β-CD was shorter than that of Tol (12 h vs 24 h). Cmax (19.92±1.02 µg/mL) and area under the concentration–time curve (AUC0-∞, 1,176.86±70.26 mg/L h) of the Tol-HP-β-CD group significantly increased (p

Dendrobium officinale is a rare and precious medicinal plant. Southern blight is a destructive disease in the artificial cultivation of D. officinale, and one of its pathogens is Sclerotium delphinii. S. delphinii is a phytopathogenic fungus with a wide host range with extremely strong pathogenicity. In this study, S. delphinii was isolated from D. officinale with southern blight. Subsequently, this specific strain underwent thorough whole-genome sequencing using the PacBio Sequel II platform, which employed single-molecule real-time (SMRT) technology. Comprehensive annotations were obtained through functional annotation of protein sequences using various publicly available databases. The genome of S. delphinii measures 73.66 Mb, with an N90 contig size of 2,707,110 bp, and it contains 18,506 putative predictive genes. This study represents the first report on the genome size assembly and annotation of S. delphinii, making it the initial species within the Sclerotium genus to undergo whole-genome sequencing, which can provide solid data and a theoretical basis for further research on the pathogenesis, omics of S. delphinii., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Constructing a ocean Internet of Things requires an essential ocean environment monitoring system. However, the widely distributed existing ocean monitoring sensors make it impractical to provide power and transmit monitored information through cables. Therefore, ocean environment monitoring systems particularly need a continuous power supply and wireless transmission capability for monitoring information. Consequently, a high-strength, environmentally multi-compatible, floatable metamaterial energy harvesting device has been designed through integrated dynamic matching optimization of materials, structures, and signal transmission. The self-powered monitoring system breaks through the limitations of cables and batteries in the ultra-low-frequency wave environment (1 to 2 Hz), enabling real-time monitoring of various ocean parameters and wirelessly transmitting the data to the cloud for post-processing. Compared with solar and wind energy in the ocean environment, the energy harvesting device based on the defective state characteristics of metamaterials achieves a high-energy density (99 W/m 3 ). For the first time, a stable power supply for the monitoring system has been realized in various weather conditions (24 h)., (© 2024. The Author(s).)

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl 4 -induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor β (GRβ) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRβ ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRβ signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRβ signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment., Competing Interests: Declaration of Competing Interest The authors declare no competing interests. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This study aimed to evaluate the effect of sacubitril valsartan (SV) on heart failure (HF) hospitalization and cardiovascular mortality in patients on hemodialysis with HF with preserved ejection fraction (EF; HFpEF)., Methods: This single-center, prospective study enrolled 155 stable hemodialysis patients with EF > 40% who were followed up for 12 months. Fifty-nine patients were treated with SV; the others were matched for EF (57.89 ± 9.35 vs. 58.00 ± 11.82, P = 0.9) at a ratio of 1:1 and included as controls. The target dosage of SV was 200 mg/day., Results: Twenty-three (23/155; 14.84%) had HF with mid-range EF (HFmrEF), while 132 (85.16%) had HFpEF. After SV treatment, the peak early diastolic transmitral flow velocity/peak early diastolic mitral annular tissue velocity(E/e') improved from 17.19 ± 8.74 to 12.80 ± 5.52 (P = 0.006), the left ventricular (LV) end-diastolic diameter decreased from 53.14 ± 7.67 mm to 51.56 ± 7.44 mm (P = 0.03), and the LV mass index decreased from 165.7 ± 44.6 g/m 2 to 154.8 ± 24.0 g/m 2 (P = 0.02). LVEF (P = 0.08) and LV global longitudinal strain (P = 0.7) did not change significantly. The composite outcome of first and recurrent HF hospitalization or cardiovascular death showed no difference between group. However, the Acute Dialysis Quality Initiative Workgroup (ADQI) HF class improved in 39 and 15 patients and worsened in 1 and 11 patients in the SV and control groups, respectively (P < 0.001). Age, diabetes mellitus, and pulmonary arterial pressure were independent risk factors for HF hospitalization and cardiovascular mortality in patients with HFpEF., Conclusions: SV improved LV hypertrophy, diastolic function, and the ADQI class for HF; however, it failed to reduce the composite endpoints of HF hospitalization and cardiovascular disease-related mortality over 12 months of follow-up in patients on maintenance hemodialysis with EF of > 40%., (© 2024. The Author(s).)

Objective: Arteriovenous fistula is the preferred vascular access for hemodialysis patients. High-flow arteriovenous fistula may cause high-output heart failure. Various procedures are used to reduce high-flow arteriovenous fistula. This study aimed to assess the efficacy of proximal artery restriction combined with distal artery ligation on flow reduction for high-flow arteriovenous fistula and on cardiac function and echocardiographic changes in patients undergoing hemodialysis., Methods: A retrospective analysis was performed on data collected from the medical records of patients undergoing hemodialysis with heart failure and high-flow arteriovenous fistula between May 2018 and May 2021. Thirty-one patients were treated with proximal artery restriction (banding juxta-anastomosis of the proximal artery) combined with distal artery ligation (anastomosis distal artery ligation). Changes in the Acute Dialysis Quality Initiative Workgroup cardiac function class, blood pressure, and echocardiography before and 6 months after flow restriction were compared, and post-intervention primary patency was followed-up., Results: The technical success rate of the surgery was 100%, and no surgery-related adverse events occurred. Blood flow and blood flow/cardiac output decreased significantly after flow restriction. Blood flow decreased from 2047.21 ± 398.08 mL/min to 1001.36 ± 240.42 mL/min, and blood flow/cardiac output decreased from 40.18% ± 6.76% to 22.34% ± 7.21% (P < .001). Post-intervention primary patency of arteriovenous fistula at 6, 12, and 24 months was 96.8%, 93.5%, and 75.2%, respectively. The Acute Dialysis Quality Initiative Workgroup cardiac function class improved significantly after 6 months of flow restriction (P < .001). The systolic and diastolic left heart function improved, as evidenced by a significant decrease in left atrial volume index, left ventricular end-diastolic/end-systolic diameters, left ventricular end-diastolic volume, left ventricular mass index, cardiac output, and cardiac index and an increase in lateral peak velocity of longitudinal contraction, average septal-lateral s', and lateral early diastolic peak velocity after flow restriction (P < .05). Systolic pulmonary artery pressure decreased from 32.36 ± 8.56 mmHg to 27.57 ± 8.98 mmHg (P < .05), indicating an improvement in right heart function., Conclusions: Proximal artery restriction combined with distal artery ligation effectively reduced the blood flow of high-flow arteriovenous fistula and improved cardiac function., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Ventilator-induced lung injury (VILI) is caused by overdistension of the alveoli by the repetitive recruitment and derecruitment of alveolar units. This study aims to investigate the potential role and mechanism of fibroblast growth factor 21 (FGF21), a metabolic regulator secreted by the liver, in VILI development., Methods: Serum FGF21 concentrations were determined in patients undergoing mechanical ventilation during general anesthesia and in a mouse VILI model. Lung injury was compared between FGF21-knockout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect., Results: Serum FGF21 levels in patients and mice with VILI were significantly higher than in those without VILI. Additionally, the increment of serum FGF21 in anesthesia patients was positively correlated with the duration of ventilation. VILI was aggravated in FGF21-KO mice compared with WT mice. Conversely, the administration of FGF21 alleviated VILI in both mouse and cell models. FGF21 reduced Caspase-1 activity, suppressed the mRNA levels of Nlrp3, Asc, Il-1β, Il-18, Hmgb1 and Nf-κb, and decreased the protein levels of NLRP3, ASC, IL-1β, IL-18, HMGB1 and the cleaved form of GSDMD., Conclusions: Our findings reveal that endogenous FGF21 signaling is triggered in response to VILI, which protects against VILI by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These results suggest that boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for the treatment of VILI during anesthesia or critical care., (© 2023. The Author(s).)

Excessive cadmium (Cd) accumulation in vegetables due to farmland pollution constitutes a serious threat to human health. Eggplant has a tendency to accumulate Cd. To investigate the mechanism of the differences in Cd accumulation levels between high-Cd (BXGZ) and low-Cd (MYQZ) eggplant cultivar, physiological and biochemical indicators and mRNA expression of eggplant were examined using photosynthetic apparatus, biochemical test kits, Fourier transform infrared (FTIR) spectroscopy and transcriptome sequencing, etc. The results of biochemical test kits and FTIR revealed that MYQZ enhanced pectin methylesterase (PME) activity, and lignin and pectin content in the root cell wall, which was associated with the upregulation of PME, cinnamyl-alcohol dehydrogenase and peroxidase (PODs). Higher levels of cysteine and glutathione (GSH) contents and upregulation of genes associated with sulfur metabolism, as well as higher expression of ATP-binding cassette transporters (ABCs), cation exchangers (CAX) and metal tolerance proteins (MTPs) were observed in MYQZ. In BXGZ, the higher stomatal density and stomatal aperture as well as higher levels of Ca 2+ binding protein-1 (PCaP1) and aquaporins and lower levels of A2-type cyclins (CYCA2-1) are consistent with an enhanced transpiration rate in BXGZ. Furthermore, a more developed root system was shown to be associated with higher levels of auxin response factor (ARF19), GATA transcription factors (GATA4, 5 and 11) and auxin efflux carrier component (PIN5) in BXGZ. In conclusion, highly active PME, and higher levels of lignin and pectin in MYQZ are expected to reduce Cd toxicity, while Cd translocation can be inhibited with the help of ABC and other Cd transporters. As for BXGZ, the uptake and translocation of Cd were enhanced by the developed root system and stronger transpiration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shen, Huang, Liao, Huang, Xin, Wang and Fu.)

Introduction: Heart valvular calcification (HVC) is an important predictor of cardiovascular events (CEs) and all-cause mortality in dialysis patients. Patients in the early stage of dialysis or those with central venous catheters (CVC) are also at high risk of cardiovascular and all-cause mortality. It could be a confounding factor for the prognosis of HVC on CE., Methods: From March 2017 to April 2022, the prognosis of HVC on CE and all-cause mortality was studied retrospectively in 158 hemodialysis (HD) patients who used arteriovenous fistulas or arteriovenous grafts as vascular access and entered HD for more than 12 months., Results: Out of 158 patients, 70 (44.3%) were diagnosed with HVC via echocardiography. A total of 180 CEs occurred during follow-up. Among them, acute heart failure accounted for 62.66%, and its prevalence was significantly higher in the HVC group than that in the non-HVC group (p &lt; 0.0001). The cumulative incidence of CE-free survival in the HVC group was significantly lower than that in the non-HVC group (p = 0.030). Only 11 patients died, and there was no significant difference in all-cause mortality between the two groups (p = 0.560). Multivariate COX regression analyses showed that HD vintage, mitral valve calcification, and aortic valve regurgitation (AR)/aortic valve stenosis (AS) but not aortic valve calcification were risk factors for CE (p &lt; 0.05)., Conclusion: After excluding the factors of the early stage of HD and CVC, HVC remained a predictor of adverse CE in HD patients., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Pyroptosis is a novel proinflammatory programmed cell death process. This study was designed to investigate the functional mechanisms of long noncoding RNA growth arrest-specific transcript 5 (lncRNA GAS5) on lipopolysaccharide (LPS)-induced human bronchial epithelial cell (HBEC) pyroptosis. LPS was used to induce pyroptosis in HBECs, followed by the detection of the expression of GAS5, forkhead box O3 (FOXO3), and nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway-related factors. Cell viability was evaluated using CCK-8 assay, lactate dehydrogenase (LDH) release was assessed by LDH assay kit and caspase-1 activity by flow cytometry. Furthermore, expression of NOD-like receptor family pyrin domain containing 3 and pyroptosis-related proteins was evaluated using Western blot analysis, while enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factors. The interaction between GAS5 and FOXO3 was confirmed using bioinformatic prediction, RNA immunoprecipitation assay, RNA pull-down, and dual-luciferase reporter gene assay. Treatment of HBECs with LPS upregulated the expression of GAS5 and FOXO3, resulting in the inactivation of the Nrf2/HO-1 signaling pathway. On the other hand, inhibition of both GAS5 and FOXO3 promoted cell viability, reduced LDH release, pyroptosis, and inflammatory response in LPS-induced HBECs. Furthermore, FOXO3 could interact with GAS5, while FOXO3 overexpression reversed the inhibitory effect of GAS5 knockdown on cell pyroptosis. Thus, mechanistically, inhibition of FOXO3 activates the Nrf2/HO-1 pathway to suppress LPS-induced pyroptosis in HBECs. This study revealed that GAS5 knockdown attenuates FOXO3 expression thereby activating the Nrf2/HO-1 pathway to inhibit LPS-induced pyroptosis in HBECs. These findings may contribute to identifying novel targets that inhibit pyroptosis in HBECs., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

The genus Enterobacter is a member of the ESKAPE group, which contains the major resistant bacterial pathogens. Enterobacter cloacae complex (ECC) has emerged as a clinically significant cause of a wide variety of nosocomial infections. Carbapenem-nonsusceptible Enterobacter cloacae complex (CnsECC) has become an emerging threat to public health but there is still a lack of comprehensive molecular and clinical epidemiological analysis. A total of 157 CnsECC isolates were recovered during October 2011 to August 2017. hsp60 gene sequencing and pulsed-field gel electrophoresis (PFGE) were applied to discriminate the species, genetic clusters and clonal relatedness. All the isolates were subjected to polymerase chain reaction (PCR) analysis for carbapenemase, AmpC-type β-lactamase, and extended spectrum β-lactamase (ESBL) genes. Clinical data were collected on all patients for comparing clinical risks and outcomes between patients with carbapenemase-producing (CP)-CnsECC compared with non-CP-CnsECC infection. The most commonly identified species was E. hormaechei subsp. hoffmannii (47.1%), followed by E. hormaechei subsp. steigerwaltii (24.8%). Different species of CnsECC isolates showed heterogeneity in resistance patterns to piperacillin/tazobactam, cefepime and levofloxacin. In the present study, we observed that E. hormaechei subsp. hoffmannii was characterized with higher cefepime and levofloxacin resistance rate but lower piperacillin/tazobactam resistance rate relative to other species of CnsECC. CP-CnsECC comprised 41.1% (65 isolates) and all of these isolates carried IMP-8. In this study, 98% of patients had antimicrobial therapy prior to culture, with a total of 57/150 (38%) patients being exposed to carbapenems. Chronic pulmonary disease (OR: 2.51, 95% CI: 1.25-5.06), received ventilator support (OR: 5.54, 95% CI: 2.25-12.03), steroid exposure (OR: 3.88, 95% CI: 1.91-7.88) and carbapenems exposure (OR: 2.17, 95% CI: 1.10-4.25) were considered risk factors associated with CP-CnsECC infection. The results suggest that CP-CnsECC are associated with poorer outcomes including in-hospital mortality, 30-day mortality and 100-day mortality. Our study provides insights into the epidemic potential of IMP-8-producing E. cloacae for healthcare-associated infections and underscores the importance of understanding underlying resistance mechanisms of CnsECC to direct antibiotic treatment decisions.

Both cadmium (Cd) contamination and boron (B) deficiency in farmland soils pose a threat to the yield and quality of crops in Southern China. The present study investigated the mechanisms by which B reduces Cd accumulation in rice (Oryza sativa) seedlings. Boron supplementation partially restored the decline in shoot and root biomass caused by Cd treatment (26% and 33%, respectively), with no significant difference between the B+Cd and control groups. We also found that B significantly reduced shoot and root Cd concentrations (by 64% and 25%, respectively) but increased Cd concentration (by 43%) and proportion (from 38% to 55%) in root cell walls. Transcriptome analysis and biochemical tests suggested that B supplementation enhanced lignin and pectin biosynthesis, pectin demethylation, and sulfur and glutathione metabolism. Moreover, B decreased the expression of some Cd-induced transporter-related genes (i.e., HMA2, Nramp1, and several ABC genes). These results indicate that B relieved Cd toxicity and reduced Cd accumulation in rice seedlings by restraining Cd uptake and translocation from root to shoot by improving Cd tolerance and chelation ability. These novel findings would benefit further investigations into how B influences Cd uptake, translocation, detoxification, and accumulation in crops., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cadmium (Cd) contamination of croplands has become a threat to crop food safety and human health. In this study, we investigated the effect of sulfur on the growth of water spinach under Cd stress and the amount of Cd accumulation by increasing the soil sulfate content. We found that the biomass of water spinach significantly increased after the application of sulfur while the shoot Cd concentration was considerably reduced (by 31%). The results revealed that sulfur could promote the expression of PME and LAC genes, accompanied by an increase in PME activity and lignin content. Also, the cell wall Cd content of water spinach roots was significantly increased under sulfur treatment. This finding suggests that sulfur could enhance the adsorption capacity of Cd by promoting the generation of cell wall components, thereby inhibiting the transportation of Cd via the apoplastic pathway. In addition, the higher expression of Nramp5 under the Cd1S0 (concentration of Cd and sulfur are 2.58 and 101.31 mg/kg respectively) treatment led to increased Cd uptake. The CAX3 and ABC transporters and GST were expressed at higher levels along with a higher cysteine content and GSH/GSSR value under Cd1S1 (concentration of Cd and sulfur are 2.60 and 198.36 mg/kg respectively) treatment, which contribute to the Cd detoxification and promotion of Cd compartmentalization in root vacuoles, thereby reducing the translocation of Cd to the shoot via the symplastic pathway., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the best time for conducting cesarean section for the establishment of an animal model of lung development with specific pathogen free (SPF) preterm Bama minipigs under the condition of not making medical interventions such as hyperoxia, mechanical ventilation, or medication., Methods: SPF Bama sows at gestational day (GD) 113, GD107, GD104, GD101, and GD98 were selected and cesarean sections were performed. Then, the viability of the preterm piglets were observed. Based on their general data, viability, and paraffin sections stained with hematoxylin and eosin, the best time for performing cesarean section in order to build a SPF preterm pig model of lung development was determined., Results: Cesarean sections were performed on a total of 7 sows and 55 piglets were delivered, among which 25 were still alive 3 hours after delivery. Seven piglets of GD104 and all piglets of GD107 and GD113 survived, while piglets of GD98 and GD101 all died. The survival rate of piglets of GD104 was 33.33% (7/21). Piglets of GD98 already possessed fully developed physical appearance and lung shape. Piglets from GD104 had better lung expansion and higher density of thin-walled alveoli. The lungs of GD107 piglets were basically fully expanded, and the density of thin-walled alveoli was almost the same as that of normal full-term piglets., Conclusions: Findings of this study suggest that SPF preterm piglets of GD104 with no specific pathogen exposure and no medical intervention can be used to establish a SPF preterm pig model of lung development., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Background: There is no doubt that thyroid dysfunction is associated with psychiatric disorders. A large amount of thyroid carcinoma patients displayed mood disorders after the withdrawal of levothyroxine (LT4). However, it is unclear whether the disorders are related to the transient withdrawal of LT4, and if yes, what the possible underlying mechanism is. This study aims to investigate the abnormal regional cerebral glucose metabolism (rCMRglu) in a group of papillary thyroid cancer (PTC) patients without LT4 for 4 weeks and prove the relationship between the abnormal rCMRglu with depression and anxiety., Methods: Brain 18 F-FDG PET/CT data of 38 consecutive PTC patients with high/intermediate-risk from June 2016 to December 2017 have been analyzed. Of the 38 patients, 23 are in the LT4 withdrawal group (WG) and 15 in the LT4 replacement group (RG). These patients were also evaluated for depressive and anxiety symptoms within 24 h after the scans based on the Hamilton Depression Rating Scale (17 items, HRDS-17) and the Hamilton Anxiety Rating Scale (HAMA) respectively., Results: Thirty-eight patients (12 men, 26 women; age range, 25-69 years; mean age, 45.8 years) were selected in the study. Compared with the RG, patients in WG showed depression and anxiety with higher total scores of HRDS-17 and HAMA (14.7 ± 5.8 vs 3.8 ± 5.5, t = -5.74, p = 0.00; 9.3 ± 4.3 vs 2.7 ± 4.1, t = -4.74, p = 0.00, respectively). In the brain glucose metabolism analysis, the WG patients showed lower rCMRglu in Occipital&#95;Mid&#95;R and Postcentral&#95;L. On the other hand, data illustrated significant rCMRglu increases in the Frontal&#95;Sup&#95;Orb&#95;L. Compared with the healthy group (HG), the rCMRglu of the Postcentral&#95;L and Precuneus&#95;L showed hypoactivity, but the Hippocampus&#95;R and the Temporal&#95;Inf&#95;L showed hyperactivity. This analysis yielded a significant correlation between abnormal rCMRglu with the free thyroxine level, the serum thyroid-stimulating hormone level, HRDS-17, and HAMA scores., Conclusions: The findings showed that more PTC patients exhibited depression and anxiety after LT4 withdrawal for 4 weeks. More attention should be paid to these hypothyroid patients while they were in the hospital. Such a short-term LT4 withdrawal also likely induced abnormal rCMRglu. Our study attempts to explain the possible mechanism of mood disorders related to transient hypothyroidism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Feng, Zou, Fu, Sun, Jia, Yin and Wang.)

N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two 11 C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [ 11 C]31 and [ 11 C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [ 11 C]CH 3 I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [ 11 C]CO 2 , respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [ 11 C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [ 11 C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.

Surfactants can improve the hydrophobicity of poorly water-soluble drugs and increase the stability of microparticles by reducing surface tension. This study describes that surfactant-engineered florfenicol instant microparticles (FIMs) increase bioavailability through a micellar solubilization mechanism. The FIMs were prepared by a modified emulsification method, and the optimal prescription was obtained by a combination of single factor investigation and response surface methodology. The microparticles prepared in this study reduce the polymer materials while increasing the drug content. FIM has a smaller particle size and modification of poloxamer, resulting in better solubility and higher bioavailability. The in vitro solubility of FIM is 1.43 times higher than that of the bulk drug, and the dissolution equilibrium can be achieved in 10 minutes. Compared with florfenicol, FIM showed a decrease in T max in the plasma concentration curve, with a peak concentration of 1.43 times and an area of 1.41 times. Considering the advantages of in vitro/in vivo performance and ease of preparation, FIMs may have great application prospects in pharmacy research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The objectives of this study were to develop and optimize ultrasound-assisted extraction (UAE) for shikonin from Arnebia euchroma using response surface methodology (RSM) and to evaluate the antimicrobial activity of shikonin. The maximum yield of shikonin was 1.26% under the optimal extraction conditions (ultrasound power, 93 W; time, 87 min; temperature, 39°C; and liquid-solid ratio, 11 : 1). Shikonin showed inhibitory activity against standard strains and clinical isolates to varying extents (MICs ranging from 128 to 1024  μ g/mL, MBCs ranging from 256 to 2048  μ g/mL), and it was more effective for Gram-positive bacteria as indicated by lower MIC and MBC values. Time-kill curves revealed that antibacterial activity of shikonin exhibited a dose-response relationship. In summary, via this study, we identified ultrasound-assisted RSM as the optimal extraction method for shikonin, which is a potential material for the treatment of bacterial infections., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Xiang-Yue Huang et al.)

Prostaglandin E receptor subtype 4 (EP4) is widely distributed in the heart, but its role in hepatic ischemia/reperfusion (I/R), particularly in mitochondrial permeability transition pore (MPTP) modulation, is yet to be elucidated. In the present study, an EP4 agonist (CAY10598) was used in a rat model to evaluate the effects of EP4 activation on liver I/R and the mechanisms underlying this. I/R insult upregulated hepatic EP4 expression during early reperfusion. In addition, subcutaneous CAY10598 injection prior to the onset of reperfusion significantly increased hepatocyte cAMP concentrations and decreased serum ALT and AST levels and necrotic and apoptotic cell percentages, after 6 h of reperfusion. Moreover, CAY10598 protected mitochondrial morphology, markedly inhibited mitochondrial permeability transition pore (MPTP) opening and decreased liver reactive oxygen species levels. This occurred via activation of the ERK1/2‑GSK3β pathway rather than the janus kinase (JAK)2‑signal transducers and activators of transcription (STAT)3 pathway, and resulted in prevention of mitochondria‑associated cell injury. The MPTP opener carboxyatractyloside (CATR) and the ERK1/2 inhibitor PD98059 also partially reversed the protective effects of CAY10598 on the liver and mitochondria. The current findings indicate that EP4 activation induces ERK1/2‑GSK3β signaling and subsequent MPTP inhibition to provide hepatoprotection, and these observations are informative for developing new molecular targets and preventative therapies for I/R in a clinical setting.

Chlamydia trachomatis (CT) infection has been a major public health threat globally. Monitoring and prediction of CT epidemic status and trends are important for programme planning, allocating resources and assessing impact; however, such activities are limited in China. In this study, we aimed to apply a seasonal autoregressive integrated moving average (SARIMA) model to predict the incidence of CT infection in Shenzhen city, China. The monthly incidence of CT between January 2008 and June 2019 in Shenzhen was used to fit and validate the SARIMA model. A seasonal fluctuation and a slightly increasing pattern of a long-term trend were revealed in the time series of CT incidence. The monthly CT incidence ranged from 4.80/100 000 to 21.56/100 000. The mean absolute percentage error value of the optimal model was 8.08%. The SARIMA model could be applied to effectively predict the short-term CT incidence in Shenzhen and provide support for the development of interventions for disease control and prevention.

Introduction: Enrofloxacin is used in the treatment of a wide variety of bacterial infections in mammals. However, its poor solubility limits the clinical use., Methods: In order to improve the solubility of enrofloxacin, the enrofloxacin mesylate (EM) were obtained by a chemical synthesis method. The characterization of EM was carried out using ultraviolet scan (UV), synchronous thermal analysis (SDT), fourier transform infrared spectrometer (FTIR) and mass spectrometry (MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction analysis (XRPD). Acute toxicity of EM in Kunming mice was studied. Besides, pharmacokinetic studies were performed in New Zealand rabbits at a single oral dose of 10 mg/kg, and the antibacterial activity of EM was also evaluated., Results: EM was successfully synthesized and purified. The stoichiometric ratio of mesylate to enrofloxacin was 1:1 and the aqueous solubility of EM was 483.01±4.06 mg/mL, the solubility of EM was about 2000 times higher than enrofloxacin. The oral lethal dose (LD 50 ) of EM was 1168.364 mg/kg, and the pharmacokinetics indicated that the oral relative bioavailability of EM was about 1.79 times and 1.48 times higher than that of enrofloxacin and enrofloxacin hydrochloride, respectively. In addition, the in vitro antibacterial activity of EM was not significantly changed compared with enrofloxacin and enrofloxacin hydrochloride., Conclusion: EM has higher solubility, low toxicity for oral use, and increases the oral bioavailability in rabbit. This study may be of benefit for the development of new enrofloxacin drugs., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Pei et al.)

Cultivar-dependent cadmium (Cd) accumulation was principal in developing Cd-pollution safe cultivars (PSCs). Proteins related to different Cd accumulations of the low-Cd-accumulating (SJ19) and high-Cd-accumulating (CX4) cultivars were investigated by iTRAQ analysis. Higher Cd bioaccumulation factors and translocation factor in CX4 than in SJ19 were consistent with the cultivar-dependent Cd accumulations. The Cd uptake was promoted in CX4 due to its higher expression of Cd-binding proteins and the lower expression of Cd-efflux proteins in roots. What's more, significantly elevated thiol groups (PC 2 and PC 3 ) in CX4 under Cd stress might contribute to the high Cd accumulation in roots and the root-to-shoot translocation of Cd-PC complex. Up-regulated proteins involved in cellulose biosynthesis and pectin de-esterification in SJ19 enhanced the Cd sequestration of root cell walls, which was considered as the predominant strategy for reducing Cd accumulation in shoots. The present study provided novel insights in the cultivar-dependent Cd accumulation in shoots of B. parachinensis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Enterocytozoon bieneusi , a unicellular enteric microsporidian parasite, can infect humans and a wide range of animals throughout the world. Although E. bieneusi has been identified in many animals, there is no information regarding the genotypes of E. bieneusi in pet birds in China. Birds are important sources of emerging infectious diseases that affect humans, and immunosuppressed individuals can be exposed to potential zoonotic agents shed by birds. The aim of the present study was to determine the prevalence and genotypic diversity of E. bieneusi in pet birds, as well as assessed its zoonotic potential. A total of 387 fecal samples were collected from Psittaciformes (n = 295), Passeriformes (n = 67), and Galliformes (n = 16) from four pet markets in Sichuan province, Southwestern China. The overall prevalence of E. bieneusi in pet birds was 25.1% based on nested polymerase chain reaction analysis of the internal transcribed spacer (ITS) region of the ribosomal RNA (rRNA) gene (Psittaciformes, 21.7%; Passeriformes, 37.3%; Galliformes, 50.0%). Eight genotypes of E. bieneusi were identified, including five known genotypes (D, SC02, BEB6, CHB1, and MJ5) and three novel genotypes (SCB-I, SCB-II, and SCB-III). In phylogenetic analysis, genotypes D and SC02 and one novel genotype SCB-II were clustered within group 1, genotype BEB6 was classified within group 2, and the remaining genotypes (CHB1, MJ5, SCB-I, and SCB-III) clustered with group 10. To the best of our knowledge, this is the first report of E. bieneusi infection in pet birds in China. Genotypes D, SC02, and BEB6 that have been previously identified in humans, were found in pet birds in this study, suggesting that these pet birds can be a potential source of human microsporidiosis in China., (© 2019 The Authors.)

The antioxidant effect of salidroside has been proven, but its role in liver injury is poorly understood. In this study, we aimed to evaluate the protective effects and mechanism of salidroside on liver injury induced by carbon tetrachloride (CCl 4 ) in vivo. Mice were pretreated with salidroside (60 mg/kg, intraperitoneally injected, i.p.) once per day for 14 consecutive days and then administered with CCl 4 (15.95 g/kg, i.p.) for 24 h to produce a liver injury model. Salidroside attenuated hepatic transaminase elevation in serum and ameliorated liver steatosis and necrosis, thereby suggesting its protective effect on the liver. Salidroside antagonized CCl 4 -induced toxicity by equilibrating antioxidation system, thereby inhibiting reactive oxygen species accumulation, and restoring mitochondrial structure and function. Salidroside exerts antioxidant and liver-protective effects by selectively inhibiting the activation of genes, including growth arrest and DNA -damage-inducible 45 α (Gadd45a), mitogen-activated protein kinase 7 (Mapk7), and related RAS viral oncogene homolog 2 (Rras2), which induce oxidative stress in the mitogen-activated protein kinase pathway. These results revealed that salidroside can protect the liver from CCl 4 -induced injury by resisting oxidative stress and protecting mitochondrial function.

Blastocystis is a common enteric protist that colonizes humans and a wide range of animals. Although some studies have reported incidences of Blastocystis in humans and animals in China, there is no information available on the prevalence of Blastocystis in giant pandas, red pandas, or bird species. The aims of the present study were to determine the prevalence, subtype distribution, and genetic characterizations of Blastocystis in these animals in a captive situation in southwestern China, as well as assess the zoonotic potential of Blastocystis isolates. A total of 168 fecal specimens, including 81 from giant pandas, 23 from red pandas, 38 from black swans, 11 from ruddy shelducks, and 15 from green peafowl were collected at the Chengdu Research Base of Giant Panda Breeding in Sichuan province. The overall minimum prevalence of Blastocystis was 11.3% (19/168) based on PCR amplification of the barcode region of the SSU rRNA gene. The highest prevalence of Blastocystis was observed in ruddy shelduck (18.2%) and the lowest was found in green peafowl (6.7%). The prevalence of Blastocystis in giant pandas >5.5 years of age was higher than that in younger giant pandas. Two potentially zoonotic subtypes (ST1 and ST8) were identified, and ST1 (n = 12) was found to be more prevalent than ST8 (n = 7). To the best of our knowledge, this is the first report of the prevalence and subtypes of Blastocystis in giant pandas, red pandas, and bird species in China. The findings of this study will improve our understanding of the genetic diversity and public health potential of Blastocystis.

To explore the possible roles of metallothioneins (MTs) played in cadmium (Cd) accumulation of water spinach, three IaMT genes, IaMT1, IaMT2 and IaMT3 in a high-shoot-Cd (T308) and a low-shoot-Cd accumulation cultivar (QLQ) were cloned, characterized, and quantitated. Gene expression analysis suggested that the expression of the IaMTs was differentially regulated by Cd stress in different cultivars, and T308 showed higher MTs expression overall. Furthermore, only shoot IaMT3 expression was cultivar dependent among the three IaMTs. Antioxidant analysis showed that the high production of IaMTs in T308 should be associated with its high oxidation resistance. The role of IaMTs in protecting against Cd toxicity was demonstrated in vitro via recombinant E. coli strains. The results showed that IaMT1 correlated with neither Cd tolerance nor Cd accumulation of E. coli, while IaMT2 conferred Cd tolerance in E. coli, IaMT2 and IaMT3 increased Cd accumulation in E. coli. These findings help to clarify the roles of IaMTs in Cd accumulation, and increase our understanding of the cultivar-dependent Cd accumulation in water spinach., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Nowadays, the potential scope of nanotechnology in uro-oncology (cancers of the prostate, bladder, and kidney) is broad, ranging from drug delivery, prevention, and diagnosis to treatment. Novel drug delivery methods using magnetic nanoparticles, gold nanoparticles, and polymeric nanoparticles have been investigated in prostate cancer. Additionally, renal cancer treatment may be profoundly influenced by applications of nanotechnology principles. Various nanoparticle-based strategies for kidney cancer therapy have been proposed. Partly due to the dilution of drug concentrations by urine production, causing inadequate drug delivery to tumor cells in the treatment of bladder cancer, various multifunctional bladder-targeted nanoparticles have been developed to enhance therapeutic efficiency. In each of these cancer research fields, nanotechnology has shown several advantages over widely used traditional methods. Different types of nanoparticles improve the solubility of poorly soluble drugs, and multifunctional nanoparticles have good specificity toward prostate, renal, and bladder cancer. Moreover, nanotechnology can also combine with other novel technologies to further enhance effectivity. As our understanding of nanotechnologies grows, additional opportunities to improve the diagnosis and treatment of urological cancer are excepted to arise. In this review, we focus on nanotechnologies with potential applications in urological cancer therapy and highlight clinical areas that would benefit from nanoparticle therapy.

Ubiquitin-specific protease 22 (USP22) is a member of the "death-from-cancer" signature, which plays a key role in cancer progression. Previous evidence has shown that USP22 is overexpressed and correlates with poor prognosis in glioma. The effect and mechanism of USP22 in glioma malignancy, especially cancer stemness, remain elusive. Herein, we find USP22 is more enriched in stem-like tumorspheres than differentiated glioma cells. USP22 knockdown inhibits cancer stemness in glioma cell lines. With a cell-penetrating TAT-tag protein, B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), a robust glioma stem-cell marker, is found to mediate the effect of USP22 on glioma stemness. By immunofluorescence, USP22 and BMI1 are found to share similar intranuclear expression in glioma cells. By analysis with immunohistochemistry and bioinformatics, USP22 is found to positively correlate with BMI1 at the post-translational level only rather than at the transcriptional level. By immunoprecipitation and in vivo deubiquitination assay, USP22 is found to interact with and deubiquitinate BMI1 for protein stabilization. Microarray analysis shows that USP22 and BMI1 mutually regulate a series of genes involved in glioma stemness such as POSTN, HEY2, PDGFRA and ATF3. In vivo study with nude mice confirms the role of USP22 in promoting glioma tumorigenesis by regulating BMI1. All these findings indicate USP22 as a novel deubiquitinase of BMI1 in glioma. We propose a working model of the USP22-BMI1 axis, which promotes glioma stemness and tumorigenesis through oncogenic activation. Thus, targeting USP22 might be an effective strategy to treat glioma especially in those with elevated BMI1 expression., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) and B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) are markers of fast-cycling and quiescent intestinal stem cells, respectively. To determine the functions of these proteins in large animals, we investigated their effects on the proliferation of intestinal epithelial cells from pigs. Our results indicated that LGR5 and BMI1 are highly conserved proteins and that the pig proteins have greater homology with the human proteins than do mouse proteins. Overexpression of either LGR5 or BMI1 promoted cell proliferation and WNT/β-catenin signaling in pig intestinal epithelial cells (IPEC-J2). Moreover, the activation of WNT/β-catenin signaling by recombinant human WNT3A protein increased cell proliferation and LGR5 and BMI1 protein levels. Conversely, inhibition of WNT/β-catenin signaling using XAV939 reduced cell proliferation and LGR5 and BMI1 protein levels. This is the first report that LGR5 and BMI1 can increase proliferation of pig intestinal epithelial cells by activating WNT/β-catenin signaling., Competing Interests: The authors declare no conflict of interest.

0BJECTIVE: We compared the diagnostic accuracy of contrast-enhanced computed tomography (CT), fluorine 18-labeled-fludeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/CT and conventional magnetic resonance imaging (MRI) without and with diffusion-weighted imaging (DWI) for characterization of tubo-ovarian abscesses (TOAs) that mimic adnexal tumors., Materials and Methods: We evaluated (retrospectively) 43 patients who underwent contrast-enhanced CT, PET/CT, conventional MRI without and with DWI, and who were found to have TOAs and complex adnexal tumors. All images were evaluated independently by four radiologists using a two-point grading system. Results of contrast-enhanced CT, PET/CT, MRI without DWI, and MRI with DWI were compared for each patient using receiver operating characteristic curves. Sensitivity, specificity, and positive predictive value (PPV) were calculated and compared using the chi-square test., Results: Sensitivity of MRI with DWI (95%) was significantly higher than that of contrast-enhanced CT (78.6%), PET/CT (86.7%) and MRI without DWI (87.5%). Specificities of these modalities were not significantly different. The PPV of MRI with DWI (100%) was significantly higher than that of the other three modalities (CT, 72.4%; PET/CT 78.5%; MRI without DWI, 81.5%). Overall accuracy of MRI with DWI was significantly higher than that of the other three modalities (CT, 74.4%; PET/CT, 81.4%; MRI without DWI, 83.7%)., Conclusion: MRI with DWI shows high accuracy for characterization of complex ovarian lesions, and is the most useful method for differentiation of TOAs from ovarian tumors., (Copyright © 2018. Published by Elsevier B.V.)

Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios - 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) - of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC 50 values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG 5000 (PEG-TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP-mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-α from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX-modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Increased ubiquitin-specific protease 22 (USP22) has been associated with poor prognosis in several cancers including gastric cancer. However, the role of USP22 in gastric tumorigenesis is still unclear. Gastric cancer stem cells have been identified and shown to correlate with gastric cancer initiation and metastasis. In this study, we found that silencing of USP22 inhibited proliferation of gastric cancer cells and suppressed the cancer stem cell spheroid formation in serum-free culture. Furthermore, cancer stem cell markers, such as CD133, SOX2, OCT4 and NANOG were down-regulated. Additionally, knockdown of USP22 inhibited gastric cancer xenografts growth. Our analysis of TCGA database indicated that BMI1 overexpression may predict gastric cancer patient survival, and TAT-BMI1 proteins reversed the USP22 knockdown-mediated decreased in cancer stem cell properties, and elevated the expression of stemness-associated genes. Furthermore, we found that overexpression of USP22 stabilized the BMI1 protein in gastric cancer cells. Taken together, our study demonstrates that USP22 is indispensable for gastric cancer stem cell self-renewal through stabilization of BMI1. These results may provide novel approaches to the theranostics of gastric cancer in the near future.

Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

Renal cell carcinoma (RCC) is a common form of urologic tumor that originates from the highly heterogeneous epithelium of renal tubules. Over the last decade, targeting therapies to renal cancer cells have transformed clinical care for RCC. Recently, it was proposed that renal cancer stem cells (CSCs) isolated from renal carcinomas were responsible for driving tumor growth and resistance to conventional chemotherapy and radiotherapy, according to the theory of CSCs; this has provided the rationale for therapies targeting this aggressive cell population. Precise identification of renal CSC populations and the complete cell hierarchy will accurately inform characterization of disease subtypes. This will ultimately contribute to more personalized and targeted therapies. Here, we summarize potential targeting strategies for renal cancer cells and renal CSCs, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTOR), interleukins, CSC marker inhibitors, bone morphogenetic protein-2, antibody drug conjugates, and nanomedicine. In conclusion, targeting therapies for RCC represent new directions for exploration and clinical investigation and they plant a seed of hope for advanced clinical care.

Fluorescence microscopy can be used to acquire real-time images of tissue morphology and with appropriate algorithms can rapidly quantify features associated with disease. The objective of this study was to assess the ability of various segmentation algorithms to isolate fluorescent positive features (FPFs) in heterogeneous images and identify an approach that can be used across multiple fluorescence microscopes with minimal tuning between systems. Specifically, we show a variety of image segmentation algorithms applied to images of stained tumor and muscle tissue acquired with 3 different fluorescence microscopes. Results indicate that a technique called maximally stable extremal regions followed by thresholding (MSER + Binary) yielded the greatest contrast in FPF density between tumor and muscle images across multiple microscopy systems.

The methylcytosine dioxygenases TET proteins (TET1, TET2, and TET3) play important regulatory roles in neural function. In this study, we investigated the role of TET proteins in neuronal differentiation using Neuro2a cells as a model. We observed that knockdown of TET1, TET2 or TET3 promoted neuronal differentiation of Neuro2a cells, and their overexpression inhibited VPA (valproic acid)-induced neuronal differentiation, suggesting all three TET proteins negatively regulate neuronal differentiation of Neuro2a cells. Interestingly, the inducing activity of TET protein is independent of its enzymatic activity. Our previous studies have demonstrated that srGAP3 can negatively regulate neuronal differentiation of Neuro2a cells. Furthermore, we revealed that TET1 could positively regulate srGAP3 expression independent of its catalytic activity, and srGAP3 is required for TET-mediated neuronal differentiation of Neuro2a cells. The results presented here may facilitate better understanding of the role of TET proteins in neuronal differentiation, and provide a possible therapy target for neuroblastoma.

FGF10 is a member of fibroblast growth factors (FGFs). We previously showed that FGF10 protects neuron against oxygen-glucose deprivation injury in vitro; however, the effect of FGF10 in ischemic stroke in vivo is unknown. In the present study, we showed that FGF10 was mainly expressed in neurons but not astrocytes, and detected FGF10 in mouse cerebrospinal fluid. The FGF10 levels in neurons culture medium and cell lysate were much higher than those in astrocytes. FGF10 expression in brain tissue and FGF10 level in CSF were increased in mouse middle cerebral artery occlusion (MCAO) model. Administration of FGF10 into lateral cerebroventricle not only decreased MCAO-induced brain infarct volume and neurological deficit, but also reduced the number of TUNEL-positive cells and activities of Caspases. Moreover, FGF10 treatment depressed the triggered inflammatory factors (TNF-α and IL-6) and NF-κB signaling pathway, and increased phosphorylation of PI3K/Akt signaling pathway. Blockade of PI3K/Akt signaling pathway by wortmannin and Akt1/2-kinase inhibitor, partly compromised the neuroprotection of FGF10. However, blockade of PI3K/Akt signaling pathway did not impair the anti-inflammation action of FGF10. Collectively, our results demonstrate that neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice.

Intraoperative assessment of surgical margins is critical to ensuring residual tumor does not remain in a patient. Previously, we developed a fluorescence structured illumination microscope (SIM) system with a single-shot field of view (FOV) of 2.1 × 1.6 mm (3.4 mm2) and sub-cellular resolution (4.4 μm). The goal of this study was to test the utility of this technology for the detection of residual disease in a genetically engineered mouse model of sarcoma. Primary soft tissue sarcomas were generated in the hindlimb and after the tumor was surgically removed, the relevant margin was stained with acridine orange (AO), a vital stain that brightly stains cell nuclei and fibrous tissues. The tissues were imaged with the SIM system with the primary goal of visualizing fluorescent features from tumor nuclei. Given the heterogeneity of the background tissue (presence of adipose tissue and muscle), an algorithm known as maximally stable extremal regions (MSER) was optimized and applied to the images to specifically segment nuclear features. A logistic regression model was used to classify a tissue site as positive or negative by calculating area fraction and shape of the segmented features that were present and the resulting receiver operator curve (ROC) was generated by varying the probability threshold. Based on the ROC curves, the model was able to classify tumor and normal tissue with 77% sensitivity and 81% specificity (Youden's index). For an unbiased measure of the model performance, it was applied to a separate validation dataset that resulted in 73% sensitivity and 80% specificity. When this approach was applied to representative whole margins, for a tumor probability threshold of 50%, only 1.2% of all regions from the negative margin exceeded this threshold, while over 14.8% of all regions from the positive margin exceeded this threshold.

The treatment of soft tissue sarcoma (STS) generally involves tumor excision with a wide margin. Although advances in fluorescence imaging make real-time detection of cancer possible, removal is limited by the precision of the human eye and hand. Here, we describe a novel pulsed Nd:YAG laser ablation system that, when used in conjunction with a previously described molecular imaging system, can identify and ablate cancer in vivo. Mice with primary STS were injected with the protease-activatable probe LUM015 to label tumors. Resected tissues from the mice were then imaged and treated with the laser using the paired fluorescence-imaging/ laser ablation device, generating ablation clefts with sub-millimeter precision and minimal underlying tissue damage. Laser ablation was guided by fluorescence to target tumor tissues, avoiding normal structures. The selective ablation of tumor implants in vivo improved recurrence-free survival after tumor resection in a cohort of 14 mice compared to 12 mice that received no ablative therapy. This prototype system has the potential to be modified so that it can be used during surgery to improve recurrence-free survival in patients with cancer.

Allogeneic hematopoietic stem cell transplantation is a widely used and effective therapy for hematopoietic malignant diseases and numerous other disorders. High-resolution human leukocyte antigen (HLA) haplotype frequency distributions not only facilitate individual donor searches but also determine the probability with which a particular patient can find HLA-matched donors in a registry. The frequencies of the HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes were estimated among 169,995 Chinese volunteers using the sequencing-based typing (SBT) method. Totals of 191 HLA-A, 244 HLA-B, 146 HLA-C, 143 HLA-DRB1 and 47 HLA-DQB1 alleles were observed, which accounted for 6.98%, 7.06%, 6.46%, 9.11% and 7.91%, respectively, of the alleles in each locus in the world (IMGT 3.16 Release, Apr. 2014). Among the 100 most common haplotypes from the 169,995 individuals, nine distinct haplotypes displayed significant regionally specific distributions. Among these, three were predominant in the South China region (i.e., the 20th, 31st, and 81sthaplotypes), another three were predominant in the Southwest China region (i.e., the 68th, 79th, and 95th haplotypes), one was predominant in the South and Southwest China regions (the 18th haplotype), one was relatively common in the Northeast and North China regions (the 94th haplotype), and one was common in the Northeast, North and Northwest China (the 40th haplotype). In conclusion, this is the first to analyze high-resolution HLA diversities across the entire country of China, based on a detailed and complete data set that covered 31 provinces, autonomous regions, and municipalities. Specifically, we also evaluated the HLA matching probabilities within and between geographic regions and analyzed the regional differences in the HLA diversities in China. We believe that the data presented in this study might be useful for unrelated HLA-matched donor searches, donor registry planning, population genetic studies, and anthropogenesis studies.

Malignant meningiomas are a rare meningioma subtype and tend to have post-surgical recurrence. Significant endeavors have been taken to identify functional therapeutic targets to halt the growth of this aggressive cancer. We have recently discovered that RIZ1 is downregulated in high-grade meningiomas, and RIZ1 overexpression inhibits proliferation while promoting cell apoptosis of the IOMM-Lee malignant meningioma cell line. In this report, we show that the N-terminal PR domain of RIZ1 alone possessed growth-inhibitory activity and anticancer activity in primary human meningioma cells. Interestingly, the effects seem to be dependent on differential RIZ1 protein levels. Transducible TAT-RIZ1-PR protein could also inhibit meningioma tumor growth in nude mice models. We further demonstrate that PR protein exerts histone methyltransferase activity. A microarray analysis of TAT-RIZ1-PR-treated human malignant meningioma cells reveals 969 differentially expressed genes and 848 alternative splicing exons. Moreover, c-Myc and TXNIP, two putative downstream targets of H3K9 methylation, may be involved in regulating RIZ1 tumor-suppressive effects. The reciprocal relationship between RIZ1 and c-Myc was then validated in primary meningioma cells and human tumor samples. These findings provide insights into RIZ1 tumor suppression mechanisms and suggest that TAT-RIZ1-PR protein is a potential new epigenetic therapeutic agent for advanced meningiomas., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: RhoGTPase-activating proteins (RhoGAPs) regulate RhoGTPases in cells, but whether individual reactive oxygen species (ROS) regulate RhoGAPs is unknown. Our previous published papers have shown that deleted in liver cancer 1 (DLC1) inhibits cancer cell migration by its RhoGAP activity. The present study was designed to explore the role of H2O2 in regulation of DLC1., Materials and Methods: We treated cells with H2O2 for 24h and phenotypic changes were analyzed by MTT, RT-PCR, Western blotting, immunofluorescence staining and wound healing assays., Results: H2O2 downregulated cyclin D1 and cyclin E to inhibit proliferation, and upregulated BAX to induce apoptosis in MCF-7 cells. Compared with non-tumorigenic cells, H2O2 increased expression of DLC1 and reduced activity of RhoA in cancer cells. Stress fiber production and migration were also suppressed by H2O2 in MDA-MB-231 cells., Conclusions: Our study suggests that H2O2 inhibits proliferation through modulation of cell cycle and apoptosis-related genes, and inhibits migration by decreasing stress fibers via DLC1/RhoA signaling.

Osteoporosis poses a major public health threat in aging societies. Adipose-derived stem cells (ADSCs) are multipotent adult stem cells that have the ability to yield mesenchymal stem cells, and have the potential to undergo osteogenesis and bone regeneration. Bone morphogenetic proteins (BMPs) have been demonstrated to upregulate bone gene expression after mechanical injury and to improve bone injury repair. This study aimed to produce BMP-2 expression in ADSCs by using lentiviral vectors. Subcutaneous adipose tissue from 4-week-old male Sprague-Dawley rats was used. Oil red O staining was used to detect adipocyte formation from ADSCs. Induction of ADSC osteogenesis was confirmed with Alizarin red S staining. The recombinant lenti-hBMP-2/neo was constructed to infect ADSCs, BMP-2 expression was measured by immunoblotting analysis, and cellular alkaline phosphatase levels were examined. We found that >70% of ADSC cells could be induced to differentiate into osteocytes or adipocytes. Under osteogenic induction, ADSCs showed increased intracellular calcium deposition, the formation of calcium tubercles, and the disappearance of cellular structures in calcium tubercles. After infection of ADSCs by lenti-hBMP-2/neo, BMP-2 was expressed after doxycycline induction. We, thus, conclude that ADSCs maintain vigorous growth ex vivo and possess stem cell-like properties. When infected with lenti-hBMP-2/neo, ADSCs can be induced to promote BMP-2 expression.

Objective: To introduce a new modified technique for radial artery catheterization., Materials and Methods: A prolongated needle was made by using routine Vasocan Braunule needle and 1 ml syringe. A table of random digits was used for randomization of 32 interns. 14 interns were involved in group T and 18 interns were in group M. Each intern accomplished 20 cases. Then 640 patients were divided into 2 groups: group T included 280 patients with traditional direct technique, group M included 360 patients with 1 ml hollow tube-assisted technique., Results: Satisfactory results were obtained for 107 patients in group T and 292 patients in group M (P < 0.05). The success rates for catheter insertion after one attempt were 38.2% in group T and 81.1% in group M (P < 0.001). The blood flow times for observation were 1.7 ± 0.2 s in group T and 19.6 ± 1.8 s in group M (P < 0.001)., Conclusion: The authors suggested the use of 1 ml hollow tube-assisted radial artery cannulation technique rather than a direct technique. This modified technique provided easy, safe, quick and less cost cannulation.