bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilateral ureteral obstruction is rapidly accompanied by ER stress and activation of autophagic degradation of IMCD proteins, including AQP2
Authors: Somparn Poorichaya , Boonkrai Chatikorn , Charngkaew Komgrid , Chomanee Nusara , Hodge Kenneth G. , Fenton Robert A. , Pisitkun Trairak , Khositseth Sookkasem
Published: November 2019

After the release of bilateral ureteral obstruction (BUO), postobstructive diuresis from an impaired urine concentration mechanism is associated with reduced aquaporin 2 (AQP2) abundance in the inner medullary collecting duct (IMCD). However, the underlying molecular mechanism of this AQP2 reduction is incompletely understood. To elucidate the mechanisms responsible for this phenomenon, we studied molecular changes in IMCDs isolated from rats with 4-h BUO or sham operation at the early onset of AQP2 downregulation using mass spectrometry-based proteomic analysis. Two-hundred fifteen proteins had significant changes in abundances, with 65% of them downregulated in the IMCD of 4-h BUO rats compared with sham rats. Bioinformatic analysis revealed that significantly changed proteins were associated with functional Gene Ontology terms, including “cell-cell adhesion,” “cell-cell adherens junction,” “mitochondrial inner membrane,” “endoplasmic reticulum chaperone complex,” and the KEGG pathway of glycolysis/gluconeogenesis. Targeted liquid chromatography-tandem mass spectrometry or immunoblot analysis confirmed the changes in 19 proteins representative of each predominant cluster, including AQP2. Electron microscopy demonstrated disrupted tight junctions, disorganized adherens junctions, swollen mitochondria, enlargement of the endoplasmic reticulum lumen, and numerous autophagosomes/lysosomes in the IMCD of rats with 4-h BUO. AQP2 and seven proteins chosen as representative of the significantly altered clusters had a significant increase in immunofluorescence-based colocalization with autophagosomes/lysosomes. Immunogold electron microscopy confirmed colocalization of AQP2 with the autophagosome marker microtubule-associated protein 1A/1B-light chain 3 and the lysosomal marker cathepsin D in IMCD cells of rats with 4-h BUO. We conclude that enhanced autophagic degradation of AQP2 and other critical proteins, as well as endoplasmic reticulum stress in the IMCD, are initiated shortly after BUO.
TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis
Authors: Wen Yi , Rudemiller Nathan P. , Zhang Jiandong , Robinette Taylor , Lu Xiaohan , Ren Jiafa , Privratsky Jamie R. , Nedospasov Sergei A. , Crowley Steven D.
Published: November 2019

Nephrotoxic serum nephritis (NTN) models immune-mediated human glomerulonephritis and culminates in kidney inflammation and fibrosis, a process regulated by T lymphocytes. TNF-α is a key proinflammatory cytokine that contributes to diverse forms of renal injury. Therefore, we posited that TNF-α from T lymphocytes may contribute to NTN pathogenesis. Here, mice with T cell-specific deletion of TNF-α (TNF TKO) and wild-type (WT) control mice were subjected to the NTN model. At 14 days after NTN, kidney injury and fibrosis were increased in kidneys from TNF TKO mice compared with WT mice. PD1+CD4+T cell numbers and mRNA levels of IL-17A were elevated in NTN kidneys of TNF TKO mice, suggesting that augmented local T helper 17 lymphocyte responses in the TNF TKO kidney may exaggerate renal injury and fibrosis. In turn, we found increased accumulation of neutrophils in TNF TKO kidneys during NTN. We conclude that TNF-α production in T lymphocytes mitigates NTN-induced kidney injury and fibrosis by inhibiting renal T helper 17 lymphocyte responses and infiltration of neutrophils.
Intracellular Neuroprotective Mechanisms in Neuron-Glial Networks Mediated by Glial Cell Line-Derived Neurotrophic Factor
Authors: Mitroshina Еlena V. , Mishchenko Tatiana A. , Shirokova Olesya M. , Astrakhanova Tatiana A. , Loginova Maria M. , Epifanova Ekaterina A. , Babaev Alexey A. , Tarabykin Victor S. , Vedunova Maria V.
Published: November 2019

Glial cell line-derived neurotrophic factor (GDNF) has a pronounced neuroprotective effect in various nervous system pathologies, including ischaemic brain damage and neurodegenerative diseases. In this work, we studied the effect of GDNF on the ultrastructure and functional activity of neuron-glial networks during acute hypoxic exposure, a key damaging factor in numerous brain pathologies. We analysed the molecular mechanisms most likely involved in the positive effects of GDNF. Hypoxia modelling was performed on day 14 of culturing primary hippocampal cells obtained from mouse embryos (E18). GDNF (1 ng/ml) was added to the culture medium 20 min before oxygen deprivation. Acute hypoxia-induced irreversible changes in the ultrastructure of neurons and astrocytes led to the loss of functional Сa2+ activity and neural network disruption. Destructive changes in the mitochondrial apparatus and its functional activity characterized by an increase in the basal oxygen consumption rate and respiratory chain complex II activity during decreased stimulated respiration intensity were observed 24 hours after hypoxic injury. At a concentration of 1 ng/ml, GDNF maintained the functional metabolic network activity in primary hippocampal cultures and preserved the structure of the synaptic apparatus and number of mature chemical synapses, confirming its neuroprotective effect. GDNF maintained the normal structure of mitochondria in neuronal outgrowth but not in the soma. Analysis of the possible GDNF mechanism revealed that RET kinase, a component of the receptor complex, and the PI3K/Akt pathway are crucial for the neuroprotective effect of GDNF. The current study also revealed the role of GDNF in the regulation of HIF-1α transcription factor expression under hypoxic conditions.
Numerical Simulation of Particle Breakage of Granular Assemblies in Discrete Element Analyses
Authors: Zhang Tao , Zhang Chi
Published: November 2019

This paper presents numerical simulations of high‐pressure biaxial tests on breakable granular soils with the discrete element method. The 2D setting is more economic in terms of computational cost, which allows simulation with a larger number of particles with a wider size distribution. The results of breakable and unbreakable agglomerates show that particle breakage has a significant influence on the macro‐ and micromechanical behaviors of the assembly. Higher confining pressure and larger axial strain result in the variation of particle grading and agglomerate numbers. The evolution of bond breakage during shearing makes it possible to trace the failure process and breakage mechanism at the microlevel. The breakage energy is found to account for a small fraction of total energy input compared with friction energy. A hyperbolic correlation between relative particle breakage and total energy input per unit volume was established regardless of the influence of confining pressure.
Ozone Exerts Cytoprotective and Anti-Inflammatory Effects in Cardiomyocytes and Skin Fibroblasts after Incubation with Doxorubicin
Authors: Simonetti V. , Quagliariello V. , Franzini M. , Iaffaioli R. V. , Maurea N. , Valdenassi L.
Published: November 2019

Introduction. Skin reactions and cardiotoxicity are one of the most common side effects of doxorubicin in cancer patients. The main mechanisms based on the etiopathogenesis of these reactions are mediated by the overproduction of proinflammatory cytokines, metalloproteases, and the disruption of mitochondrial homeostasis. Ozone therapy demonstrated anti-inflammatory effects in several preclinical and clinical studies. The aim of this research is based on the evaluation of cardioprotective and dermatoprotective effects of ozone during incubation with doxorubicin, giving preliminary evidences for further studies in the field of cardio-oncology. Methods. Human skin fibroblast cells and human fetal cardiomyocytes were exposed to doxorubicin at subclinical concentration (100 nM) alone or combined with ozone concentrated from 10 up to 50 μg/mL. Cell viability and multiple anti-inflammatory studies were performed in both cell lines, with particular attention on the quantification of interleukins, leukotriene B4, NF-κB, and Nrf2 expressions during treatments. Results. Ozone decreased significantly the cytotoxicity of doxorubicin in skin fibroblasts and cardiomyocytes after 24 h of incubation. The best cytoprotective effect of ozone was reached to 30 μg/mL with a plateau phase at higher concentration. Ozone also demonstrated anti-inflammatory effects decreasing significantly the interleukins and proinflammatory mediators in both cells. Conclusion. Ozone exerts cardioprotective and dermatoprotective effects during incubation with doxorubicin, and the involved mechanisms are mediated by its anti-inflammatory effects. The overall picture described herein is a pilot study for preclinical studies in oncology.
Susceptibility of Toxoplasma gondii to Ethanolic Extract of Tinospora crispa in Vero Cells
Authors: Sharif Alhassan Abdullahi , Unyah Ngah Zasmy , Nordin Norshariza , Basir Rusliza , Wana Mohammed Nasiru , Alapid Ahmad Ashraf , Mustapha Tijjani , Majid Roslaini Abd.
Published: November 2019

Background. Toxoplasmosis remains widely distributed globally and is one of the major neglected parasitic zoonotic infections. The infection is still endemic in most parts of the world due to poor control as well as challenges of the currently used medications which can be overcome by using natural products. This study evaluated the effect of ethanolic extract from the stem of Tinospora crispa (EETC) on host cell invasion and intracellular replication of Toxoplasma gondii. Method. The stem powder of T. crispa was soaked in absolute ethanol for 72 hours. The resulting ethanolic extract was screened for the presence of phytochemicals. Vero cells monolayer in 96-well plate was infected with RH strain of T. gondii and treated with concentrations of the EETC, Veratrine alkaloid, and clindamycin ranging from 1.56 to 200 μg/mL. MTT assay was conducted after 24 hours to evaluate the cytotoxicity and antiparasitic activities of the EETC. Four and 24 hours treatment models were adapted to assess the infection index and intracellular proliferation of T. gondii in vitro. Microscopic analysis was conducted after 24 and 48 hours exposure to EETC in both treatment models. Results. The study revealed that the EETC had no cytotoxic effects on Vero cells with IC50 = 179 μg/mL, as compared to clindamycin (IC50 = 116.5 μg/mL) and Veratrine alkaloid (IC50 = 60.4 μg/mL). The EETC had good anti-toxoplasma activities with IC50 = 6.31 μg/mL in comparison with clindamycin (IC50 = 8.33 μg/mL) and Veratrine alkaloid (IC50 = 14.25 μg/mL). The EETC caused more than 70% and 80% reduction in infection index and intracellular proliferation in both treatment models, respectively. Conclusion. This in vitro study showed that the EETC contains promising phytochemicals effective against T. gondii and safe to the host cells.
In SituSynthesis of Structural Hierarchy Flowerlike Zeolite and Its Application for Fluoride Removal in Aqueous Solution
Authors: Tian Zhihan , Gan Yiqun
Published: November 2019

A three-dimensional hierarchically structured flowerlike zeolite was synthesized using naturally occurring nanohalloysite (HNT) by hydrothermal methods. Halloysite a hydrated aluminum silicate with nanohollow morphology, microporosity, and environmentally friendly properties was chosen to be the sole precursor. The morphology and structure of the composite that was prepared was characterized using XRD, FT-IR, BET, TG, SEM, HRTEM, and NMR. SEM and HRTEM images indicated that the synthesized zeolite has a flowerlike hierarchical structure, with well-defined edges and uniform pore channels. FT-IR and NMR spectra indicated that different species of silicon and aluminum were present in the synthesized zeolite. The zeolite was applied in fluoride (F-) removal from aqueous solutions. Single-factor studies, including the initial concentration of F-, initial adsorbent concentration, and the effect of pH value on the adsorption properties, were investigated to evaluate the removal behavior of F-by the zeolite. The zeolite exhibited strong adsorption properties for fluoride ions (F-), with an adsorption capacity up to 161 mg g-1. The pseudo-second-order kinetics and Freundlich models were the best fit to the kinetics and isotherm experimental data, respectively.
The Ubiquitin-Specific Protease 18 Promotes Hepatitis C Virus Production by Increasing Viral Infectivity
Authors: Li Yujia , Ma Max Xuezhong , Qin Bo , Lin Liang-Tzung , Richardson Christopher D. , Feld Jordan , McGilvray Ian D. , Chen Limin
Published: November 2019

Background and Aims. Ubiquitin-specific protease 18 (USP18) is involved in immunoregulation and response to interferon- (IFN-) based treatment in patients chronically infected with hepatitis C virus (HCV). We investigated whether and how its upregulation alters HCV infection. Methods. Overexpression of wild-type (USP18 WT) or catalytically inactive mutant (USP18 C64S) USP18 was examined for effects on HCV replication in the absence and presence of IFNα or IFNλ using both the HCV-infective model and replicon cells. The IFN signaling pathway was assessed via STAT1 phosphorylation (western blot) and downstream ISG expression (real-time PCR). Mechanistic roles were sought by quantifying microRNA-122 levels and J6/JFH1 infectivity of Huh7.5 cells. Results. We found that overexpression of either USP18 WT or USP18 C64S stimulated HCV production and blunted the anti-HCV effect of IFNα and IFNλ in the infective model but not in the replicon system. Overexpressed USP18 showed no effect on Jak/STAT signaling nor on microRNA-122 expression. However, USP18 upregulation markedly increased J6/JFH1 infectivity and promoted the expression of the key HCV entry factor CD81 on Huh7.5 cells. Conclusions. USP18 stimulates HCV production and blunts the effect of both type I and III IFNs by fostering a cellular environment characterized by upregulation of CD81, promoting virus entry and infectivity.
Examining the Accuracy of Network RTK and Long Base RTK Methods with Repetitive Measurements
Authors: Baybura Tamer , Tiryakioğlu İbrahim , Uğur Mehmet Ali , Solak Halil İbrahim , Şafak Şeyma
Published: November 2019

Real-time kinematic (RTK) technique is important for mapping applications requiring short measure time, the distance between rover and base station, and high accuracy. There are several RTK methods used today such as the traditional RTK, long base RTK (LBRTK), network RTK (NRTK), and precise point positioning RTK (PPP-RTK). NRTK and LBRTK are popular with the advantage of the distance, the time, and accuracy. In the present study, the NRTK and LBRTK measurements were compared in terms of accuracy and distance in a test network with 6 sites that was established between 5 and 60 km. Repetitive NRTK and LBRTK measurements were performed on 6 different days in 2015-2017-2018 and additionally 4 campaigns of repetitive static measurements were carried out in this test network. The results of NRTK and LBRTK methods were examined and compared with all relevant aspects by considering the results of the static measurements as real coordinates. The study results showed that the LBRTK and NRTK methods yielded similar results at base lengths up to 40 km with the differences less than 3 cm horizontally and 4 cm vertically.
Reactive Oxygen Species and Nrf2: Functional and Transcriptional Regulators of Hematopoiesis
Authors: Hu Linping , Zhang Yawen , Miao Weimin , Cheng Tao
Published: November 2019

Hematopoietic stem cells (HSCs) are characterized by self-renewal and multilineage differentiation potentials. Although they play a central role in hematopoietic homeostasis and bone marrow (BM) transplantation, they are affected by multiple environmental factors in the BM. Here, we review the effects of reactive oxygen species (ROS) and Nrf2 on HSC function and BM transplantation. HSCs reside in the hypoxic microenvironment of BM, and ROS play an important role in HSPC regulation. Recently, an extraphysiologic oxygen shock/stress phenomenon was identified in human cord blood HSCs collected under ambient air conditions. Moreover, Nrf2 has been recently recognized as a master transcriptional factor that regulates multiple antioxidant enzymes. Since several years, the role of Nrf2 in hematopoiesis has been extensively studied, which has functional similarities of cellular oxygen sensor hypoxia-inducible factor-1 as transcriptional factors. Increasing evidence has revealed that abnormally elevated ROS production due to factors such as genetic defects, aging, and ionizing radiation unexceptionally resulted in lethal impairment of HSC function and hematopoiesis. Both experimental and clinical studies have identified elevated ROS levels as a major culprit of ineffective BM transplantation. Lastly, we discuss the possibility of using small molecule antioxidants, such as N-acetyl cysteine, resveratrol, and curcumin, to augment HSC function and improve the therapeutic efficacy of BM transplantation. Further research on the function of ROS levels and improving the efficacy of BM transplantation may have a great potential for broad clinical applications of HSCs.
Effect of Motorized Elephant-Assisted Therapy Program on Balance Control of Children with Autism Spectrum Disorder
Authors: Nuntanee Satiansukpong , Daranee Sasat
Published: November 2019

Children with autism spectrum disorder (ASD) have poor balance, and this limitation has effects on their daily living activities. The purpose of this study was to create the motorized elephant-assisted therapy program (METP) and examine the effect of the METP on balance control improvement in individuals with ASD. Twenty participants, aged 8 to 19 years, were recruited from occupational therapy clinics around Chiang Mai city and were divided into 2 groups: control and experimental. Participants’ balance control was tested by measuring their postural sways in a bipedal stance by using a Swaymeter under four conditions: “floor-eyes open,” “floor-eyes closed,” “foam-eyes open,” and “foam-eyes closed.” Pretests were administered one week before participation in the METP, and then, posttests were administered one week after completing the METP. Each participant took a 1.5-hour session of the METP, twice a week for a 4-week duration. In one session, 2 participants were assigned to work with two motorized elephants in 4 activities: washing the elephant, climbing up and down the elephant, riding the elephant, and playing a game while riding the elephant. Results showed that the pretest control and experimental groups were not significantly different in their balance control, but at posttest, the postural sway of the experimental group was significantly different from that of the control group in two conditions: floor-eyes open and floor-eyes closed. Their lesser anteroposterior range of postural sway showed that the experimental group gained balance control improvement. In conclusion, the finding of this study showed that the METP could be an alternative treatment method to facilitate better balance control in individuals with ASD.
Methane-Rich Saline Counteracts Cholestasis-Induced Liver Damage via Regulating the TLR4/NF-κB/NLRP3 Inflammasome Pathway
Authors: Li Zeyu , Chen Dongdong , Jia Yifan , Feng Yang , Wang Cong , Tong Yingmu , Cui Ruixia , Qu Kai , Liu Chang , Zhang Jingyao
Published: November 2019

Cholestatic liver injury, due to obstruction of the biliary tract or genetic defects, is often accompanied by progressive inflammation and liver fibrosis. Methane-rich saline (MRS) has anti-inflammatory properties. However, whether MRS can provide protective effect in cholestatic liver injury is still unclear. In this study, Sprague-Dawley rats received bile duct ligation (BDL) to generate a cholestatic model followed by MRS treatment (10 mL/kg, ip treatment) every 12 h after the operation to explore the potential protective mechanism of MRS in cholestatic liver injury. We found that MRS effectively improved liver function, alleviated liver pathological damage, and localized infiltration of inflammatory cells. MRS treatment decreased the expression of hepatic fibrosis-associated proteins to alleviate liver fibrosis. Furthermore, MRS treatment suppressed the TLR4/NF-κB pathway and further reduced the levels of proinflammatory factors. Downregulation of NF-κB subsequently reduced the NLRP3 expression to inhibit pyroptosis. Our data indicated that methane treatment prevented cholestatic liver injury via anti-inflammatory properties that involved the TLR4/NF-κB/NLRP3 signaling pathway.
Interaction of Cleat-Matrix on Coal Permeability from Experimental Observations and Numerical Analysis
Authors: Wang Chunguang , Zang Yuxiao , Wang Linsen , Chen Zhongwei , Cui Guanglei , Fan Kunkun , Liu Weitao
Published: November 2019

Gas transport through porous coal contains gas laminar flow in the cleat network and gas adsorption/diffusion in the matrix block. Since permeable capacity of the cleat is greater than that of the matrix, change of the matrix pressure readily lags behind change in the cleat pressure. Such unsynchronized pressure changes can result in a complex compatible deformation of a cleat-matrix system, significantly affecting the coal permeability. In this paper, we investigated the cleat-matrix interaction on coal permeability by using a modified pressure pulse decay method integrated with numerical analysis. The experimental results indicate that the bulk volume of the coal sample rapidly expanded at the beginning of gas injection, and then the volume expansion rate of the coal sample slowed down as the downstream pressure of the coal sample gradually equilibrated with the upstream pressure. During this process, the coal permeability was observed to gradually decrease with time. Numerical analysis results indicate that gas transport from the cleat to the matrix can attenuate the differential pressure between the cleat and the matrix. A smaller ratio of initial matrix permeability to initial cleat permeability can prolong decay duration of the differential pressure inside the cleat-matrix system. Although the coal sample is subjected to a stress-controlled condition, the coal permeability response to gas diffusion is closer to the case using a constant volume boundary. The dynamic change of coal permeability is significantly affected by the cleat-matrix interaction, in cases where the short-term change is mainly attributable to the cleat network and the long-term change is controlled by matrix swelling/shrinkage.
Intestinal Adenocarcinoma Arising from a Mature Cystic Teratoma
Authors: Wan King Man , Foroughi Forough , Bansal Rajni , Oehler Martin K.
Published: November 2019

Mature cystic teratomas are the most common ovarian germ cell tumour and account for 10–20% of all ovarian neoplasms. Malignant transformation of mature cystic teratomas is rare and has an incidence rate of less than 1%. The most common malignancy are squamous cell carcinomas. Here we present the case of an intestinal adenocarcinoma which is an exceedingly rare malignant entity arising within a mature cystic teratoma. Clinical presentation, imaging and histopathological diagnosis are discussed and previously presented cases in the literature reviewed.
Could Increased Expression of Hsp27, an “Anti-Inflammatory” Chaperone, Contribute to the Monocyte-Derived Dendritic Cell Bias towards Tolerance Induction in Breast Cancer Patients?
Authors: de Azevedo-Santos Ana Paula Silva , Rocha Mirtes Castelo Branco , Guimarães Sulayne Janayna Araujo , Vale André Alvares Marques , Laginha Fabio Martins , Nascimento Flavia Raquel F. , Nagai Maria Aparecida , Bergami-Santos Patrícia C. , Barbuto José Alexandre Marzagão
Published: November 2019

Dendritic cells (DCs) are the most efficient antigen-presenting cells and link the innate immune sensing of the environment to the initiation of adaptive immune responses, which may be directed to either acceptance or elimination of the recognized antigen. In cancer patients, though DCs would be expected to present tumor antigens to T lymphocytes and induce tumor-eliminating responses, this is frequently not the case. The complex tumor microenvironment subverts the immune response, blocks some effector mechanisms, and drives others to support tumor growth. Chronic inflammation in a tumor microenvironment is believed to contribute to the induction of such regulatory/tolerogenic response. Among the various mediators of the modulatory switch in chronic inflammation is the “antidanger signal” chaperone, heat shock protein 27 (Hsp27), that has been described, interestingly, to be associated with cell migration and drug resistance of breast cancer cells. Thus, here, we investigated the expression of Hsp27 during the differentiation of monocyte-derived DCs (Mo-DCs) from healthy donors and breast cancer patients and evaluated their surface phenotype, cytokine secretion pattern, and lymphostimulatory activity. Surface phenotype and lymphocyte proliferation were evaluated by flow cytometry, interferon- (IFN-) γ, and interleukin- (IL-) 10 secretion, by ELISA and Hsp27 expression, by quantitative polymerase chain reaction (qPCR). Mo-DCs from cancer patients presented decreased expression of DC maturation markers, decreased ability to induce allogeneic lymphocyte proliferation, and increased IL-10 secretion. In coculture with breast cancer cell lines, healthy donors’ Mo-DCs showed phenotype changes similar to those found in patients’ cells. Interestingly, patients’ monocytes expressed less GM-CSF and IL-4 receptors than healthy donors’ monocytes and Hsp27 expression was significantly higher in patients’ Mo-DCs (and in tumor samples). Both phenomena could contribute to the phenotypic bias of breast cancer patients’ Mo-DCs and might prove potential targets for the development of new immunotherapeutic approaches for breast cancer.
Circulating MicroRNAs as Prognostic Molecular Biomarkers in Human Head and Neck Cancer: A Systematic Review and Meta-Analysis
Authors: Lamichhane Shree Ram , Thachil Thanuja , Gee Harriet , Milic Natalie
Published: November 2019

Background. Circulating microRNAs (miRNAs) are potential molecular biomarkers for cancer detection; however, little is known about their prognostic role in head and neck cancer. This current study is aimed at evaluating the role of novel miRNAs in the survival of head and neck cancer patients. Materials and Methods. We performed a systematic literature search using online databases for articles published between December 2006 and February 2019. A meta-analysis was conducted to assess the correlation between miRNA expressions and overall survival (OS) among the selected head and neck cancer studies. After multilevel screening by reviewers, meta-analysis was performed using hazard ratios (HR) and associated 95% confidence interval (CI) of survival to calculate a pooled effect size. Result. A total of 1577 patients across 13 studies were included in the literature review, with 18 miRNAs upregulated and 4 miRNAs downregulated predicting a poor overall survival. The forest plot generated using cumulated survival data resulted in a pooled HR value of 2.943 (95% CI: 2.394-3.618) indicating a strong association of dysregulated miRNA expression with a poor outcome. Only 2 miRNAs—low levels of miR-9 and high levels of miR-483-5p—were observed in two studies, both showing a significant association with overall cancer survival. Conclusion. To our knowledge, this is the first comprehensive systematic review and meta-analysis that examines the prognostic role of circulating miRNAs from blood in head and neck cancer patients. The combined effect estimates a HR across multiple studies and also supports the previous individual findings that an alteration in miRNA expression is highly associated with poor prognosis. This has the potential to use serum and/or plasma miRNAs as biomarkers and become novel tools for predicting the prognosis of head and neck cancer patients in the near future.
Improved Analgesic Effect of Paravertebral Blocks before and after Video-Assisted Thoracic Surgery: A Prospective, Double-Blinded, Randomized Controlled Trial
Authors: Chu Lihua , Zhang Xiaolin , Lu Yaping , Xie Guohao , Song Shengwen , Fang Xiangming , Cheng Baoli
Published: November 2019

Despite being less invasive, patients who underwent video-assisted thoracic surgery (VATS) suffered considerable postoperative pain. Paravertebral block (PVB) was proven to provide effective analgesia in patients with VATS; however, there is no difference in pain relief between preoperative PVB and postoperative PVB. This study was aimed to investigate the analgesic efficacy of combination of preoperative and postoperative PVB on the same patient undergoing VATS. In this prospective, double-blinded, randomized controlled trial, 44 patients undergoing VATS were enrolled, and they received patient-controlled intravenous analgesia (PCIA) with sufentanil plus preoperative PVB (Group A, n = 15) or postoperative PVB (Group B, n = 15), or combination of preoperative and postoperative PVB (Group C, n = 14). The primary outcome was sufentanil consumption and PCIA press times in the first 24 hours postoperatively. Also, data of postoperative use of PCIA and visual analogue scale (VAS) were collected. In the first 24 hours postoperatively, median sufentanil consumption in Group C was 0 (0–34.75) μg, which was much less than that in Group A (45.00 (33.00–47.00) μg, p=0.005) and Group B (36 (20.00–50.00) μg, p=0.023). Patients in Group C pressed less times of PCIA (0 (0–0) times) than patients in Group A (2 (1–6) times, p<0.001) and Group B (2 (1–3) times, p=0.009). Kaplan–Meier analysis showed patients with combination of preoperative and postoperative PVB had a higher PCIA-free rate than patients with either technique alone (p=0.003). The VAS among the three groups was comparable postoperatively. The combination of both preoperative and postoperative PVB provides better analgesic efficacy during the early postoperative period and may be an alternative option for pain control after VATS. This trial is registered with ChiCTR1800017102.
Metformin Suppresses Self-Renewal Ability and Tumorigenicity of Osteosarcoma Stem Cells via Reactive Oxygen Species-Mediated Apoptosis and Autophagy
Authors: Zhao Bin , Luo Jie , Wang Ye , Zhou Liangfu , Che Jingmin , Wang Fang , Peng Songlin , Zhang Ge , Shang Peng
Published: November 2019

Osteosarcoma is the most frequently diagnosed primary malignant bone sarcoma in children and adolescents. Recent studies have shown that cancer stem cells (CSCs), a cluster of tumor cells with the ability to self-renew, play an essential role in tumor recurrence and metastasis. Thus, it is necessary to develop therapeutic strategies specifically targeting CSCs. Metformin, the first-line drug for type 2 diabetes, exhibits antineoplastic activities in various kinds of tumors. New evidence has suggested that metformin may target CSCs and prevent their recurrence. However, the underlying specific mechanisms remain unclear. In this study, we found that metformin significantly suppressed the self-renewal ability of osteosarcoma stem cells (OSCs) and induced G0/G1 phase arrest by blocking the activity of cyclin-dependent kinases. Furthermore, metformin induced apoptosis through a mitochondria-dependent pathway, leading to the collapse of the mitochondrial transmembrane potential and the production of reactive oxygen species (ROS). Importantly, metformin acted directly on the mitochondria, which resulted in decreased ATP synthesis. This change allowed access to the downstream AMPK kinase, and the activation of AMPK led to the reversal of the mTOR pathway, triggering autophagy. Particularly, metformin-mediated autophagy disturbed the homeostasis of stemness and pluripotency in the OSCs. Additionally, our mouse xenograft model confirmed the potential therapeutic use of metformin in targeting OSCs. In conclusion, our findings suggest that metformin suppresses the self-renewal ability and tumorigenicity of OSCs via ROS-mediated apoptosis and autophagy.
Hot Structure Flight Data of a Faceted Atmospheric Reentry Thermal Protection System
Authors: Boehrk Hannah , Weihs Hendrik , Elsäßer Henning
Published: November 2019

The second sharp-edged flight experiment is a faceted suborbital reentry body that enables low-cost in-flight reentry research. Its faceted thermal protection system consisting of only flat radiation-cooled thermal protection panels is cost-efficient since it saves dies, manpower, and storage. The ceramic sharp leading edge has a 1 mm nose radius in order to achieve good aerodynamic behaviour of the vehicle. The maximum temperature measured during flight was 867°C just before transmission ended and was predicted with an accuracy of the order of 10%. The acreage thermal protection system is set up by 3 mm fiber-reinforced ceramic panels isolated by a 27 mm alumina felt from the substructure. The panel gaps are sealed by a ceramic seal. Part of the thermal protection system is an additional transpiration-cooling experiment in which nitrogen is exhausted through a permeable ceramic matrix composite to form a coolant film on the panel. The efficiencies at the maximum heat flux are 58% on the porous sample and 42% and 30% downstream of the sample in the wake. The transient load at each panel location is derived from the trajectory by oblique shock equations and subsequent use of a heat balance for both cooled and uncooled structures. The comparison to the heat balance HEATS reveals heat sinks in the attachment system while the concurrence with the measurement is good with only 8% deviation for the acreage thermal protection system. Aerodynamic control surfaces, i.e., canards, have been designed and made from a hybrid titanium and ceramic matrix composite structure.
Auditory Neuropathy Spectrum Disorder due to Two Novel Compound Heterozygous OTOF Mutations in Two Chinese Families
Authors: Qiu Yue , Chen Sen , Xie Le , Xu Kai , Lin Yi , Bai Xue , Zhang Hui-Min , Liu Xiao-Zhou , Jin Yuan , Sun Yu , Kong Wei-Jia
Published: November 2019

Auditory neuropathy spectrum disorder (ANSD), also called auditory neuropathy (AN), is a unique type of prelingual hearing impairment. Up to 10% of deaf infants and children are affected by this disease. Mutation of the OTOF gene which encodes otoferlin is the common cause of congenital nonsyndromic ANSD. To date, over 110 mutations have been identified in the OTOF gene according to the Human Gene Mutation Database (HGMD). Here, next-generation sequencing (NGS) revealed that the compound heterozygous mutations c.4748G>A/c.2523+1G>T and c.5248G>C/c.5098G>C of the OTOF gene were present in two Chinese ANSD patients. Each patient had a known pathogenic mutation (c.4748G>A or c.5098G>C) and a novel mutation (c.2523+1G>T or c.5248G>C). Comparative amino acid sequence analysis across different species revealed that the residues at these novel mutation sites are evolutionarily highly conservative. This indicated that the novel mutations were possible causes of the disorder in the patients. Our findings extend the OTOF mutation spectrum and further confirm the role of the OTOF gene in ANSD.
Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer
Authors: Pietrantonio Filippo , Lobefaro Riccardo , Antista Maria , Lonardi Sara , Raimondi Alessandra , Morano Federica , Mosconi Stefania , Rimassa Lorenza , Murgioni Sabina , Sartore-Bianchi Andrea , Tomasello Gianluca , Longarini Raffaella , Farina Gabriella , Petrelli Fausto , Gori Stefania , Randon Giovanni , Corallo Salvatore , Pagani Filippo , Guarini Vincenzo , Palermo Federica , Martinetti Antonia , Macagno Marco , Barault Ludovic , Perrone Federica , Tamborini Elena , Milione Massimo , Di Nicolantonio Federica , Di Maio Massimo , Fucà Giovanni , Di Bartolomeo Maria , de Braud Filippo
Published: November 2019

Purpose:

To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with RAS-mutated, methyl-guanine methyltransferase (MGMT)-methylated metastatic colorectal cancer (mCRC).

Patients and Methods:

In this randomized, phase II trial, we enrolled patients with RAS-mutated, MGMT-methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed MGMT methylation were stratified by first-line progression-free survival (PFS) and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was PFS analyzed on intention-to-treat basis, with 90% power and one-sided significance level of 0.05 to detect an increase of median time from 2 months in arm B to 4 months in arm A.

Results:

Between November 2014 and May 2019, 86 patients were randomly assigned to arm A (n = 43) or arm B (n = 43). After a median follow-up of 30.5 months (interquartile range, 12.2–36.3), 79 disease progression or death events occurred. Superiority of arm A was not demonstrated (one-sided P = 0.223). Progression-free survival and overall survival were 3.5 (2.0–5.0) and 9.5 (8.2–25.8) in arm A versus 3.5 (2.3–6.1) and 10.6 (8.5–20.8) in arm B [HR = 1.19 (0.82–1.72) and HR = 0.97 (0.58–1.61)], respectively. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. Patients with positive MGMT expression by IHC did not benefit from CAPTEM.

Conclusions:

Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.
Alopecia areata: Viele Faktoren spielen eine Rolle
Authors: Gieler Uwe
Published: November 2019

Alopecia areata (AA) is a nonscarring alopecia with an autoimmune etiology, unpredictable course, multiple presentations, and variable psychological distress. We conducted a cross-sectional study which included 126 patients with AA. A complete medical history was documented using the Severity Alopecia Tool (SALT) to assess the severity of the disease, and the following questionnaires were applied to the participants: the Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Scale (HADS), Plutchik Suicide Risk Scale, and the Perceived Stress Scale (PSS-14) for adults. The Child Dermatology Life Quality Index (cDLQI) and the Birleson Depression Self-Rating Scale questionnaires were applied for children. Quality of life (QoL) disturbance was detected in 77.6% of adult participants, 65.9% of them had signs of depression or anxiety, and 12.8% were at risk of committing suicide. The PSS-14 average score for adults was 24.5. QoL disturbance was detected in 76.7% of children participants, and 6.3% of them showed signs of depression with the Birleson Depression Self-Rating Scale. We conclude that patients with AA could experience changes in their QoL and signs of depression, anxiety, and suicide risk, mainly in the adult population, during the course of the disease.
Peri-Infarct Quantification by Cardiac Magnetic Resonance to Predict Outcomes in Ischemic Cardiomyopathy
Authors: Haghbayan Hourmazd , Lougheed Nick , Deva Djeven P. , Chan Kelvin K.W. , Lima João A.C. , Yan Andrew T.
Published: November 2019

Background:

In ischemic cardiomyopathy, cardiac magnetic resonance assessment of the peri-infarct zone, a potential substrate for arrhythmogenesis, may serve as a novel prognosticator and guide the optimal use of implantable cardioverter-defibrillators. We undertook a systematic review and meta-analysis assessing the prognostic value of the peri-infarct zone on late gadolinium enhancement cardiac magnetic resonance in ischemic cardiomyopathy.

Methods:

We searched MEDLINE (Medical Literature Analysis and Retrieval System Online), EMBASE (Medical Literature Analysis and Retrieval System Online), and CENTRAL (Medical Literature Analysis and Retrieval System Online) from inception to January 2019 for prognostic studies relating peri-infarct size with clinical outcomes in ischemic cardiomyopathy. Two authors independently performed study selection and data extraction. Pooled effect estimates were calculated with random effects models, risk of bias and strength of evidence were assessed by the Quality in Prognostic Studies tool and Grading of Recommendations Assessment, Development, and Education, respectively.

Results:

Twenty studies were eligible, representing 14 cohort studies (n=1518) with mean follow-up of 3.6 years and 6 cross-sectional studies (n=189). The extent of the peri-infarct zone was significantly predictive of all-cause mortality (3 studies; n=539; hazard ratio, 1.34/10 g [95% CI, 1.13–1.59];
I

2

=0%; high-quality evidence), appropriate implantable cardioverter-defibrillator therapy (5 studies; n=361; hazard ratio, 1.31/10 g [95% CI, 1.17–1.47];
I

2

=0%; high-quality evidence), and inducibility of ventricular tachycardia on electrophysiological study (5 studies; n=167; OR, 2.63/g [95% CI, 1.39–4.96];
I

2

=14%; low-quality evidence). After adjusting for age and left ventricular ejection fraction, the peri-infarct zone, as a percentage of total infarct size, remained an independent predictor of all-cause mortality (2 studies; n=445; hazard ratio, 1.29/10% [95% CI, 1.15–1.44];
I

2

=0%; high-quality evidence).

Conclusions:

There is limited but consistent evidence that quantification of the peri-infarct zone predicts long-term mortality and appropriate implantable cardioverter-defibrillator therapy in ischemic cardiomyopathy. Future studies should confirm whether late gadolinium enhancement-cardiac magnetic resonance assessment may improve implantable cardioverter-defibrillator treatment decisions.

Clinical Trial Registration:

URL:
https://www.crd.york.ac.uk/prospero/
. Unique identifier: CRD42017077337.
Microvascular Dysfunction Is Associated With Worse Cognitive Performance
Authors: Rensma Sytze P. , van Sloten Thomas T. , Houben Alfons J.H.M. , Köhler Sebastian , van Boxtel Martin P.J. , Berendschot Tos T.J.M. , Jansen Jacobus F.A. , Verhey Frans R.J. , Kroon Abraham A. , Koster Annemarie , Backes Walter H. , Schaper Nicolaas , Dinant Geert-Jan , Schalkwijk Casper G. , Henry Ronald M.A. , Wolfs Elze M.L. , van Heumen Mike J.A. , Schram Miranda T. , Stehouwer Coen D.A.
Published: November 2019

Microvascular dysfunction may be associated with worse cognitive performance. Most previous studies did not adjust for important confounders, evaluated only individual measures of microvascular dysfunction, and showed inconsistent results. We evaluated the association between a comprehensive set of measures of microvascular dysfunction and cognitive performance in the population-based Maastricht Study. We used cross-sectional data including 3011 participants (age 59.5±8.2; 48.9% women; 26.5% type 2 diabetes mellitus [oversampled by design]). Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the sum of the scores on these 3 cognitive domains. The microvascular dysfunction score was associated with a worse cognitive function score (standardized β, −0.087 [95% CI, −0.127 to −0.047]), independent of age, education level, sex, type 2 diabetes mellitus, smoking, alcohol use, hypertension, total/HDL (high-density lipoprotein) cholesterol ratio, triglycerides, lipid-modifying medication, prior cardiovascular disease, depression and plasma biomarkers of low-grade inflammation. The fully adjusted β-coefficient of the association between the microvascular dysfunction score and the cognitive function score was equivalent to 2 (range, 1–3) years of aging for each SD higher microvascular dysfunction score. The microvascular dysfunction score was associated with worse memory and processing speed but not with worse executive function. The present study shows that microvascular dysfunction is associated with worse cognitive performance.
Activation of Transient Receptor Potential Channel Vanilloid 4 by DPP-4 (Dipeptidyl Peptidase-4) Inhibitor Vildagliptin Protects Against Diabetic Endothelial Dysfunction
Authors: Gao Peng , Li Li , Wei Xiao , Wang Miao , Hong Yangning , Wu Hao , Shen Yanjia , Ma Tianyi , Wei Xing , Zhang Qin , Fang Xia , Wang Lijuan , Yan Zhencheng , Du Guan-Hua , Zheng Hongting , Yang Gangyi , Liu Daoyan , Zhu Zhiming
Published: November 2019

Endothelial dysfunction is an early step to the progression of cardiovascular diseases in diabetes. Apart from their anti-diabetic action, DPP-4 (dipeptidyl peptidase-4) inhibitors also reduce cardiovascular events in diabetic patients. However, the underlying mechanism of the beneficial effect of DPP-4 inhibitor on endothelial function is still obscure. In this study, we intervened type 1 or 2 diabetic model mice with vildagliptin for 4 weeks and measured the vascular reactivity. We found that vildagliptin improved endothelium-dependent vasodilation in diabetic mice independent of GLP-1 (glucagonlike peptide-1), but this effect was blocked by a SIRT1 (Sirtuin 1) inhibitor, Ex527. Mechanistically, vildagliptin-activated Transient Receptor Potential Channel Vanilloid 4 (TRPV4) to promote extracellular calcium uptake in endothelial cells, which activated AMPK (AMP-activated protein kinase)/SIRT1 pathway to counteract hyperglycemia-induced endothelial reactive oxygen species generation and senescence. Vildagliptin directly binds to TRPV4 by forming a hydrogen bond, which is critical to vildagliptin-evoked endothelial calcium intake. Knockout or inhibition of TRPV4 erased the beneficial role of vildagliptin. In addition, activation of SIRT1 by SRT1720 improved endothelial function independent of TRPV4 and reduced TRPV4 transcription to maintain an appropriate calcium level. In summary, our findings prove that vildagliptin protects against hyperglycemia-induced endothelial dysfunction by activating TRPV4-meditaed Ca
2+
uptake, which helps to re-understand the mechanism of DPP-4 inhibitors and expand the therapeutic scope.
High Blood Pressure in Young Adult Survivors Born Extremely Preterm or Extremely Low Birthweight in the Post Surfactant Era
Authors: Haikerwal Anjali , Doyle Lex W. , Cheung Michael M. , Wark John D. , Opie Gillian , Roberts Gehan , Patton George , Cheong Jeanie L.Y.
Published: November 2019

More infants born extremely preterm (<28 weeks’ gestation) or extremely low birthweight (<1000 g) are surviving into adulthood in recent years. Preterm adolescents have higher blood pressure (BP) than normal birthweight controls, but how their BP changes with increasing age is not known. We compared BP at 25 years and trajectories of BP (change per year) from 18 to 25 years between survivors born <28 weeks/<1000 g and normal birthweight (>2499 g) controls born in the early 1990s, when survival rates began to rise. Participants were derived from 297 consecutive survivors born <28 weeks/<1000 g in 1991 to 1992 in Victoria, Australia, and 260 contemporaneous controls. At age 25 years, ambulatory BP was measured in 151 and 119 participants, respectively. Participants born <28 weeks/<1000 g had higher 24-hour systolic (mean difference 4.5 [95% CI, 1.2–7.7 mm Hg]), diastolic (3.4 [1.5–5.2 mm Hg]), and mean BPs (3.6 [1.4–5.8 mm Hg]) compared with the controls. Similar patterns were observed for both awake and asleep periods. Asleep ambulatory BP between 18 and 25 years increased more in participants born <28 weeks/<1000 g than in controls (systolic 0.56, diastolic 0.41, and mean 0.41 mm Hg increase per year; all
P
<0.05). Young adults born <28 weeks/<1000 g in the post surfactant era have higher BP and an increased trajectory of ambulatory BP compared with controls. With more survivors born <28 weeks/<1000 g now reaching adulthood, these findings are important for early detection and timely management of hypertension in this high-risk population.