bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of neurapheresis therapy in vitro: a novel approach for the treatment of leptomeningeal metastases
Authors: Ejikeme Tiffany , de Castro George C , Ripple Katelyn , Chen Yutong , Giamberardino Charles , Bartuska Andrew , Smilnak Gordon , Marius Choiselle , Boua Jane-Valeriane , Chongsathidkiet Pakawat , Hodges Sarah , Pagadala Promila , Verbick Laura Zitella , McCabe Aaron R , Lad Shivanand P 
Published: April 2020

AbstractBackgroundLeptomeningeal metastases (LM), late-stage cancer when malignant cells migrate to the subarachnoid space (SAS), have an extremely poor prognosis. Current treatment regimens fall short in effectively reducing SAS tumor burden. Neurapheresis therapy is a novel approach employing filtration and enhanced circulation of the cerebrospinal fluid (CSF). Here, we examine the in vitro use of neurapheresis therapy as a novel, adjunctive treatment option for LM by filtering cells and augmenting the distribution of drugs that may have the potential to enhance the current clinical approach.MethodsClinically relevant concentrations of VX2 carcinoma cells were suspended in artificial CSF. The neurapheresis system’s ability to clear VX2 carcinoma cells was tested with and without the chemotherapeutic presence (methotrexate [MTX]). The VX2 cell concentration following each filtration cycle and the number of cycles required to reach the limit of detection were calculated. The ability of neurapheresis therapy to circulate, distribute, and maintain therapeutic levels of MTX was assessed using a cranial–spinal model of the SAS. The distribution of a 6 mg dose was monitored for 48 h. An MTX-specific ELISA measured drug concentration at ventricular, cervical, and lumbar sites in the model over time.ResultsIn vitro filtration of VX2 cancer cells with neurapheresis therapy alone resulted in a 2.3-log reduction in cancer cell concentration in 7.5 h and a 2.4-log reduction in live-cancer cell concentration in 7.5 h when used with MTX. Cranial–spinal model experiments demonstrated the ability of neurapheresis therapy to enhance the circulation of MTX in CSF along the neuraxis.ConclusionNeurapheresis has the potential to act as an adjunct therapy for LM patients and significantly improve the standard of care.
Efficacy and Safety of Peripherally Acting Mu-Opioid Receptor Antagonists for the Treatment of Opioid-Induced Constipation: A Bayesian Network Meta-analysis
Authors: Ouyang Rong , Li Zhongzhuan , Huang Shijiang , Liu Jun , Huang Jiean 
Published: April 2020

Abstract

Objective
To assess the efficacy and safety of peripherally acting mu-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation (OIC).

Methods
Randomized controlled trials (RCTs) were searched for OIC therapy comparing PAMORAs with placebo. Both a pairwise and network meta-analysis were performed. The surface under the cumulative ranking area (SUCRA) was used to determine the efficacy and safety of OIC treatment using different PAMORAs.

Results
The primary target outcome was a response that achieves an average of three or more bowel movements (BMs) per week. In the network meta-analysis, four PAMORAs (naldemedine, naloxone, methylnaltrexone, and alvimopan) showed a better BM response than the placebo. Naldemedine was ranked first (odds ratio [OR] = 2.8, 95% credible interval [CrI] = 2–4.5, SUCRA = 89.42%), followed by naloxone (OR = 2.9, 95% CrI = 1.6–5.3, SUCRA = 87.44%), alvimopan (OR = 2.2, 95% CrI = 1.3–3.5, SUCRA = 68.02%), and methylnaltrexone (OR = 1.7, 95% CrI = 1.0–2.8, SUCRA = 46.09%). There were no significant differences in safety found between the PAMORAs and the placebo.

Conclusions
We found that PAMORAs are effective and can be safely used for the treatment of OIC. In network meta-analysis, naldemedine and naloxone appear to be the most effective PAMORAs for the treatment of OIC.
Can Strong Creditors Inhibit Entrepreneurial Activity?
Authors: Ersahin Nuri , Irani Rustom M , Waldock Katherine 
Published: April 2020

Abstract
We examine entrepreneurial activity following the staggered adoption of modern-day fraudulent transfer laws in the United States. These laws strengthen unsecured creditors’ rights and are particularly important for entrepreneurs whose personal assets commingle with the firm’s. Using administrative data from the U.S. Census Bureau, we document declines in startup entry—particularly among riskier entrants—and closures of existing firms after these laws pass. Firm financial data shows that entrepreneurs lower leverage by reducing demand for unsecured credit. Our results suggest that strong creditor protections can limit entrepreneurs’ appetite for risk, which may reduce churning along the extensive margin among the smallest firms in the economy.
Leukocyte toll-like receptor expression in pathergy positive and negative Behçet’s disease patients
Authors: van der Houwen Tim B , Dik Willem A , Goeijenbier Marco , Hayat Manizhah , Nagtzaam Nicole M A , van Hagen Martin , van Laar Jan A M 
Published: April 2020

Abstract

Objectives
To investigate whether the auto-inflammatory nature and the pathergic reaction in Behçet’s disease (BD) are driven by a disturbed toll-like receptor (TLR) response.

Methods
We compared both TLR expression by flow-cytometry and TLR response by stimulation assay in 18 BD patients (both pathergy positive and pathergy negative) with 15 healthy controls.

Results
Expression of TLR1 and 2 was significantly elevated in B-lymphocytes of BD patients compared with healthy controls. TLR1, 2 and 4 were significantly more highly expressed in both CD4+ and CD8+ T-lymphocytes of BD patients. Granulocytes of BD patients displayed significantly higher expression of TLR1, 2, 4 and 6. TLR2, 4 and 5 expression was significantly increased on classical monocytes of BD patients. Intermediate monocytes of BD patients showed an increase in expression of TLR2. Furthermore, TLR2 and 5 were significantly more highly expressed in non-classical monocytes of BD patients. In pathergy positive patients, TLR5 was even more highly expressed compared with pathergy negative patients on B- and T-lymphocytes and granulocytes. Furthermore, TLR2 and 5 showed an elevated TNF-α response to stimulation with their cognate ligands.

Conclusion
Immune cells of BD patients overexpress TLR1, 2, 4, 5 and 6. Furthermore, after stimulation of TLR2 and 5, BD patients demonstrate a more potent TNF-α response. Although this is a small cohort, in the pathergy positive patients, TLR5 expression is even further augmented, suggesting that a microbial (flagellin) or damage (HMGB1) associated signal may trigger the exaggerated immune response that is characteristic for the pathergy phenomenon in BD. In conclusion, these results point to an exaggerated TLR response in the auto-inflammatory nature of BD.
The Dynamics of Pseudophosphatase MK‐STYX and HDAC6 Ubiquitination
Authors: Gergel Emma , Hinton Shantá 
Published: April 2020

MK‐STYX [mitogen‐activated protein kinase phospho‐serine/threonine/tyrosine binding protein] is a pseudophosphatase and a member of the MAP kinase phosphatase family. Due to the absence of cysteine and histidine residues in the signature active site motif (HCX5R), MK‐STYX is catalytically inactive. Even so, it maintains the ability to bind phosphorylated residues. MK‐STYX is an important molecule in various signaling pathways, including the stress response pathway. Our previous research showed that the expression of MK‐STYX decreases stress granules [SG], which are aggregates of untranslated mRNA and misfolded proteins caused by cellular stress. However, the molecular mechanism by which MK‐STYX decreases SG remains elusive. Histone deacetylase isoform 6 (HDAC6) serves as a major component of SG. Therefore, we investigated whether MK‐STYX affects the dynamics of HDAC6. Our findings showed that MK‐STYX alters the subcellular localization of HDC6, which became nuclear, and decreased and altered the location of HDAC6‐aggregates. Because HDAC6 contains a ubiquitin binding domain, we investigated whether MK‐STYX affects the ubiquitination of HDAC6 and/or the ubiquitin proteasome system. Ubiquitin assays in stressed and unstressed cells showed that ubiquitinated proteins increased in the presence of MK‐STYX. Immunoprecipitation of HDAC6 and ubiquitin assays show that HDAC6‐ubiquitin interactions decreased in the presence of MK‐STYX, when HEK‐293 cells were exposed to MG132, whereas HDAC6‐ubiquitin interaction increased in cells expressing the active mutant of MK‐STYX (MK‐STYX(active)), which dephosphorylates phosphorylated residues. Overall, our research suggests that MK‐STYX affects ubiquitination; however, further studies are important to determine whether the effects of MK‐STYX on HDAC6 are linked to the decrease in stress granules.Support or Funding InformationDepartment of Biology, Integrated Science Center, William and Mary, Williamsburg, VA 23187
Thermal Tolerance and Metabolism of Archocentrus nigrofasciatus Acclimated to a Large Daily Temperature Fluctuation Reflect its Success as an Invasive Species
Authors: Cooper Cassidy Jean , Eme John 
Published: April 2020

Fish exhibit thermal tolerance and metabolism correlated to recent thermal history, and more studies should examine species’ responses to large fluctuations in daily temperatures. We compared thermal tolerance and metabolic responses between fish acclimated to constant temperatures and a large, daily thermal cycle of 10°C. Black Convict cichlid (Archocentrus nigrofasciatus) is a freshwater teleost native to Central America, with non‐native populations established in numerous locations. Black Convict cichlid were acclimated for two weeks to constant 20°C or 30°C, or a daily cycle of 20–30°C (“cycling group”, ~0900–1500 hrs). Following acclimation, routine metabolism (oxygen consumption, Mo2) and Critical thermal maxima/minima (CTmax/CTmin) were measured. Critical thermal limits were compared via ANOVA, with the cycling group sampled from both the daily minimum at 20°C (0900 hrs) and daily maximum at 30°C (1600 hrs). CTmax (0.3°C per degree of acclimation) and CTmin (0.4 °C per degree of acclimation) increased with acclimation. CTmax for the cycling group were 0.7°C higher when sampled from the maximum 30°C (39.3°C) of the daily cycle compared to 20°C (38.6°C). CTmin values for the cycling group were 2.2°C higher when sampled from the maximum 30°C (14.6°C) of the daily cycle compared to 20°C (12.4°C). Mo2 was measured acutely at 20°C and 30°C for each acclimation group, with the cycling group sampled from the daily minimum at 20°C (0900 hrs) and daily maximum at 30°C (1600 hrs). ANOVA showed that mass‐specific Mo2 decreased with increasing acclimation temperature for fish measured acutely at 30°C, where fish acclimated to 20°C (Mo2 = 0.329 mg/h/g) demonstrated an 84% higher Mo2 than fish acclimated to 30°C (Mo2 = 0.178 mg/h/g). Mass‐specific Mo2 also decreased with increasing acclimation temperature for fish measured acutely at 20°C, where fish acclimated to 20°C (Mo2 = 0.170 mg/h/g) demonstrated a 139% higher Mo2 than fish acclimated to 30°C (Mo2 = 0.071 mg/h/g). Mo2 was measured continually across the 24h daily thermal acclimation cycle of 20 – 30°C for all groups. Total oxygen consumption across the 24h cycle was highest for the constant 30°C group naively exposed to the cycle and lowest for the cycling group. Black Convict cichlid retains more upper thermal tolerance than lower thermal tolerance with altered thermal acclimation, and this hardy species shows metabolic compensation following high temperature acclimation (30°C) and large, daily cycling temperature acclimation (20 – 30°C). These aspects of fish thermal physiology phenotypes are reflective of a successful invasive fish species that may respond more robustly to impacts from anthropogenic climate change.Support or Funding InformationFunding was provided through startup funds to JE from CSUSM.
Comparison of Transcriptomic Analysis between IDH1 Mutant and Wild‐type of Lower Grade Glioma
Authors: Lee MinWook , Jin Hoeyoung , Kim Suwan , Ji SeonYeong , Song SeokJung , Koh DooHyun , Choi JoungWan , Park JeongMan , Lee YunGyeon , Jo GaeHoon , Kim JongIl , Sim JeongMin , Ahn JuWon , Park YoungJoon , Kwack KyuBum 
Published: April 2020

Among glioma patients, the existence of isocitrate dehydrogenase (IDH) 1 mutation is critical in their treatment and prognosis. However, effector genes specifically affected by IDH1 mutation are not identified yet, nor their biological mechanisms. Here, we show a few candidate genes selected by informatics methods, and suggest that inflammasome related CASP‐1, and ‐4 as the effector genes of glioma and future possibility of drug relocations. According to Cox regression analysis, 23, 78 genes were confirmed in the groups of protective genes in IDH1 mutant type and wild type, and 68, 170 genes in risk groups in mutant and wild type each. Interestingly, there were only two overlaps between the mutation group and wild type group within the risk factors, and none within the protective factors. These indicate that the pathophysiological mechanisms directed by the IDH1 mutant type and wild type in glioma are different. The results of Cox regression and GO term enrichment showed that many of the pathways in IDH1 wild type risk group are related to inflammation response, which are known to be pathologic in many different types of cancers. Among the genes related to the pathways, we chose CASP‐1 and ‐4, which are involved in inflammasome functions, and were able to find that high expression of the genes are related with the low survival of the patients, according to the Kaplan‐Meier curves. In conclusion, this research suggests new possibilities of treatment targeted to the genes mentioned above, such as drug relocations.Support or Funding InformationThis study was supported by grants of Basic Research Project in Science and Engineering, funded by the Ministry of Science, Technology and Information, Republic of Korea (Grant no. 2019R1F1A1054920) and of the University Innovation Support Project (UISP) through the National Research Foundation (NRF) funded by MOE.
Early Hepatic Gene Expression Profile of Lipid Metabolism of Mice on High Fat Diet after Treatment with Anti‐Obesity Drugs
Authors: Rizk Nasser M. , Saleh Amina , Elsayegh Dina , Algamal Abdelrahman 
Published: April 2020

Obesity is a multifactorial disorder of global scale. The liver plays a vital role in fat metabolism. Disorder of hepatic fat metabolism is associated with obesity and fatty liver disease. This study aimed to detect the effects of anti‐obesity drugs (sulforaphane; SFN and leptin) on hepatic gene expression of fat metabolism in mice that were fed HFD during an early time of DIO.Thirty‐two wild type (WT) ten‐week‐old CD1 male mice were fed high fat diet for four weeks in order to induce diet‐induced obesity (DIO). The mice were treated with a vehicle, or SFN for one week and then each group is treated with leptin or saline for 24 hours. Four groups of treatment were obtained; control group (vehicle + saline), group 2 (vehicle + leptin), group 3 (SFN + saline), and group 4 (SFN + leptin). Body weight and food intake were monitored during the treatment period. Following the treatments, liver tissue was collected, and total RNA was extracted to assess the expression of 84 genes involved in hepatic fat metabolism using RT‐PCR profiler array technique.Leptin treatment upregulated the genes involved in fatty acid beta‐oxidation (Acsbg2, Acsm4) and fatty acyl‐CoA biosynthesis (Acot6, Acsl6), and down‐regulated the fatty acid transport gene (Slc27a2). SFN upregulated acyl‐CoA hydrolase (Acot3) and long chain fatty acid activation for lipids synthesis and beta‐oxidation (Acsl1). Leptin + SFN upregulated fatty acid beta‐oxidation‐related genes (Acad11, Acam) and acyl‐CoA hydrolases (Acot3, Acot7), and downregulated fatty acid elongation gene, Acot2. As a result, treatment with both SFN and leptin has a more profound effect in ameliorating the pathways involved in hepatic lipogenesis and TG accumulation and body weight gain than other types of intervention.We conclude that early intervention of obesity pathogenesis could ameliorate the metabolic changes of fat metabolism in the liver, as observed in mice on HFD in response to SFN anti‐obesity treatment.Support or Funding InformationThis publication was made possible by NPRP Grant No. 9‐351‐3‐075 from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors. Qatar university grant QUST‐1‐CHS‐2019‐3
Heterogeneity in Insulin‐Stimulated Glucose Uptake Among Different Muscle Groups in People
Authors: Koh Han-Chow E. , van Vliet Stephan , Meyer Gretchen A. , Laforest Richard , Gropler Robert J. , Klein Samuel , Mittendorfer Bettina 
Published: April 2020

Insulin‐stimulated glucose uptake in skeletal muscles is the major mechanism for postprandial glucose disposal. Insulin‐stimulated glucose uptake is greater in type I than in type II muscles in rats. The cellular capacity for glucose uptake and disposal (insulin receptor, GLUT4, hexokinase, and glycogen synthase expression) is also greater in isolated human type I compared with type II fibers. The goal of the present study was to test the hypothesis that insulin‐stimulated glucose uptake rate varies among different muscle groups and is greater in trunk (erector spinae, rectus abdominis, obliques) than leg (quadriceps, hamstrings) muscles and greater in the hamstrings than the quadriceps because trunk muscles generally have a greater percentage of type I fibers than leg muscles and the hamstrings have a greater percentage of type I fibers than quadriceps muscles. We determined abdominal and thigh muscle glucose uptake rates in 10 healthy lean women (age: 43±13 years, BMI: 23±2 kg/m2; mean±SD) by using a hyperinsulinemic‐euglycemic clamp procedure in conjunction with dynamic positron emission tomography imaging after bolus injection of 18F‐fluorodeoxyglucose. In addition, [6,6‐2H2]glucose was infused to determine whole‐body glucose disposal rate per kg fat‐free mass, which is commonly used as an index of muscle glucose uptake, and a muscle biopsy from the vastus lateralis was obtained to determine myofiber composition. Glucose uptake rate in the erector spinae (128±30 μmol/kg/min) was nearly twice as great as in the rectus abdominis (66±14 μmol/kg/min; P<0.01) and approximately 50% greater than in the obliques (88±23 μmol/kg/min; P<0.05). Quadriceps and hamstring glucose uptake rates were not different from each other (85±42 and 91±37 μmol/kg/min, respectively; P>0.05) and not different from glucose uptake rates in the rectus abdominis and obliques but less than in the erector spinae (P<0.05). No significant correlation between fiber type composition and muscle glucose uptake rate in the quadriceps was detected. Whole body insulin stimulated glucose disposal rate was 93±28 μmol/kg fat‐free mass/min. We conclude that: i) insulin‐stimulated muscle glucose uptake is heterogeneous among muscle groups, ii) it is unlikely that differences in fiber type composition among muscles are responsible for the heterogeneity in glucose uptake rates, and iii) whole‐body glucose disposal rate per kg fat‐free mass does not accurately reflect glucose uptake rates in individual muscles.Support or Funding InformationNIH DK115400, DK56341 (Nutrition Obesity Research Center), DK020579 (Diabetes Research Center), and UL1TR000448 (Clinical Translational Science Award), and ADA 1‐18‐ICTS‐119.
Dimethyl fumarate regulates the IL‐17‐ACT1‐TBK1 axis‐mediated IκB‐ζ expression by influencing the phosphorylation of Regnase‐1
Authors: Matsuda Tadashi , Ohagakiuchi Yui , Saino Yuka , Komori Yuki , Sato Ami , Hirashima Koki , KItai Yuichi , Kashiwakura Jun-ichi , Oritani Kenji , Muromoto Ryuta 
Published: April 2020

The signaling elicited by the cytokine interleukin‐17A (IL‐17) is important for antimicrobial defense responses, whereas excessive IL‐17 production leads to autoimmune diseases such as psoriasis and multiple sclerosis. IL‐17–induced stabilization of mRNAs has been recognized as a unique and important feature of IL‐17 signaling. We previously demonstrated that an IL‐17 signaling protein, ACT1 is required to counteract constitutive inhibitor of nuclear factor kappa B zeta (IκB‐ζ) mRNA degradation by the ribonuclease Regnase‐1. In the present study, we tried to clarify this mechanism in more detail and identify an agent that can inhibit IL‐17–induced mRNA stabilization. Experiments using siRNA and an inhibitor of TANK‐binding kinase 1 (TBK1) revealed that TBK1 was also required for IκB‐ζ mRNA stabilization through Regnase‐1 phosphorylation. Interestingly, this TBK1‐mediated phosphorylation of Regnase‐1 was suppressed by the addition of an electrophilic small molecule, dimethyl fumarate (DMF) that has been used to treat IL‐17–related autoimmune diseases. Furthermore, confocal microscopic observation of the cellular localization of ACT1 revealed that DMF treatment resulted in the disappearance of ACT1 nuclear dots and perinuclear accumulation of ACT1. These results suggested that DMF is a small molecule that compromises IL‐17–induced activation of the ACT1‐TBK1 pathway, thereby inhibiting IL‐17–induced mRNA stabilization.Support or Funding InformationThis work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI grant (numbers 254600560, 17K08263, and 19H03364).
TgMIF regulates inflammatory response by mediating TLR signaling
Authors: Kim Donggyu 
Published: April 2020

Toxoplasma gondii (Tg) is an obligate intracellular parasite that can invade and replicate in almost all nucleated cells of warm‐blooded animals. It has a world‐wide geographic distribution and is known to infect many species of birds and mammals, including approximately one third of humans. Macrophage migration inhibitory factor (MIF) is a proinflammatory molecule in mammals that, unusually for a cytokine, exhibits tautomerase and oxidoreductase enzymatic activities. MIF has been demonstrated to be involved in innate and adaptive immune responses by stimulating the production of pro‐inflammatory mediators, such as TNF‐α and IL‐8. In this study, we measured that Toxoplasma gondii MIF (rTgMIF)‐induced levels of TNF‐α, IL‐1β, and IL‐6 by ELISA and protein‐protein interaction involved in TLR signal transduction.We investigated the function of rTgMIF in the inflammatory response. We showed that rTgMIF affects the secretion of pro‐ and anti‐inflammatory cytokines. We showed that rTgMIF also regulates MAPK signaling in BMDMs. Taken together, these results demonstrated that TgMIF is related to pathogenesis of Toxoplasma gondii through regulation of MAPK pathway in TLR signaling.Support or Funding InformationACKNOWLEDGEMENTSThis work was supported by the NRF grant funded by the Korea government (MSIP) 2019R1I1A2A01064237.