bluuebunny/crossref_metadata_2025_split huggingface dataset:
Facio‐genital dysplasia 5 (FGD5) regulates G‐protein coupled receptors (GPCRs) signaling to phosphatidylinositol 3 kinase (PI3K) pathway
Authors: Azad Abul Kalam , Farhan Maikel , Eitzen Gary , Murray Allan 
Published: April 2020

IntroductionDrugs targeting the VEGF‐pathway have been approved to treat various cancers. However, tumors become resistant to this therapy due to the recruitment of alternative growth factors, acting via cognate endothelial cells (EC) receptor tyrosine kinases (RTK) or g‐protein coupled receptors (GPCR), to cue neo‐angiogenesis. Facio‐genital dysplasia 5 (FGD5) regulates vascular endothelial growth factor (VEGF)‐mediated angiogenesis, and VEGF receptor‐2 trafficking at the endosome. However, the role of FGD5 to regulate other pro‐angiogenic signaling pathways that co‐operate with VEGF has not been explored. Here, we identify a novel role of FGD5 to control G protein‐coupled receptor (GPCR) signaling.MethodsHuman umbilical vein endothelial cells (HUVEC) were mounted on microcarrier beads, suspended in fibrin gels, then co‐cultured with freshly harvested patient‐derived renal cell carcinoma (PD‐RCC) samples. The effect of FGD5 loss on sprouting angiogenesis was evaluated using RNAi against FGD5 in HUVEC. Stromal cell derived factor (SDF)‐1 was used as a model GPCR ligand to study the role of FGD5 in endothelial angiogenesis and PI3K signaling. Further, FDG5 domain‐deletant mutants were transiently overexpressed to rescue the effect of FGD5 knockdown on endothelial PI3K signaling. Western blot and confocal imaging were performed to readout the role of FGD5 in the GPCR/PI3K signaling pathway.ResultsLoss of FGD5 in HUVEC decreased sprouting angiogenesis stimulated by growth factors released from PD‐RCCs. The defect in angiogenesis was accompanied by downregulation of the expression of endothelial tip cell specific marker genes. Knockdown of endothelial FGD5 abolished the SDF‐1 angiogenic effect and SDF‐1 signaling to PI3K‐β and Akt. Inhibition of Rac1, a Rho GTP‐binding protein required for PI3K‐β activity, recapitulated the signaling defects of FGD5 deficiency, suggesting that FGD5 may control PI3K‐β activity through Rac1‐GTP. Overexpression of Dbl (Rho guanine nucleotide exchange factor) domain‐deleted FGD5 (FGD5ΔDbl) reduced SDF‐1‐stimulated Akt phosphorylation, and failed to rescue defective PI3K signalling in FGD5‐deficient cells, indicating that the Dbl domain of FGD5 regulates the activity of PI3K‐β. PI3K‐β and phosphorylated Akt localized to early endosomes after SDF‐1 stimulation, but loss of FGD5 decreased endosomal phosphorylated‐Akt. Failure of Akt activation at PI3K‐β‐positive endosomes suggests a defect in PI3K‐β activity after FGD5 loss.ConclusionsWe identify a novel role of FGD5 to regulate GPCR signaling to PI3K‐β. FGD5 acts at an endosomal convergence node regulating RTK and GPCR angiogenic pathways that may serve as a target for anti‐angiogenic therapy.Support or Funding InformationUniversity of Alberta Doctoral Recruitment Scholarship, Translational Medicine Research Award, Alberta Graduate Excellence Scholarship, Canadian Cancer Society, Division of Nephrology
RGS5 Deficiency Increases Blood Pressure and Causes Cerebral Vascular Oxidative Stress in Aged Male Mice
Authors: Luu Anh , Waldschmidt Ryan , Guisinger Trevor , Seeley Sarah , D’Souza Manoranjan , Chrissobolis Sophocles 
Published: April 2020

Aging is associated with elevated blood pressure, vascular oxidative stress and emotional behavioral abnormalities, such as anxiety and depression. Angiotensin II (Ang II) is reportedly involved in both vascular and emotional behavioral abnormalities. The actions of Ang II are mediated by the Ang II type 1 receptor whose activity is modulated by regulator of G‐protein signaling 5 (RGS5) protein. We have previously reported that RGS5 deficiency exacerbates Ang II‐induced elevations in blood pressure, and emotional behaviors in the absence and presence of elevated Ang II levels in adult (~26 week old) male mice. In this study we assessed the role of RGS5 on blood pressure, vascular and emotional behavioral outcomes in aged male mice in the absence and presence of elevated Ang II levels (1 mg/kg/d for 21 days). Specifically, we used aged (16–20 month old) male mice lacking RGS5 and their wild type counterparts to assess effects of saline or Ang II on systolic blood pressure (SBP), vascular function and oxidative stress, locomotor activity, and anxiety‐ and depression‐like behavior. RGS5 deficiency increased SBP under normal conditions, and increased cerebral vascular superoxide levels in the absence and presence of elevated Ang II levels, suggesting that RGS5 deficiency leads to elevated blood pressure and cerebral vascular oxidative stress in aged mice. RGS5 deficiency did not impair relaxation responses to acetylcholine, or contraction to the nitric oxide synthase inhibitor l‐NAME in aorta, suggesting that RGS5 deficiency had no effect on endothelial function in aorta. Interestingly, elevated Ang II levels increased spontaneous locomotor activity in wild‐type mice, but not in mice lacking RGS5. These data suggest that RGS5 deficiency attenuated responsiveness to Ang II‐induced increases in spontaneous locomotor activity. RGS5 deficiency and Ang II treatment had no effect on anxiety‐ and depression‐like behavior. In summary, these data suggest that RGS5 protects against elevated blood pressure, and has protective effects in the cerebral circulation in the absence and presence of elevated Ang II levels in aged male mice. Clinically, these data suggest that inhibitors of the renin angiotensin system may reduce the risk of cerebrovascular disease in aged males lacking RGS5.Support or Funding InformationThis work was supported by funds from the College of Pharmacy, Ohio Northern University.
Enhancing Vascular Access Training with Ultrasonography
Authors: Canaan Ryan , Cross Evan , Pazdernik Vanessa , Batten Spencer , Kondrashova Tatyana 
Published: April 2020

BackgroundNeedle‐guided procedure training is important since ultrasound‐guided techniques may reduce risk of needle misplacement and complications. Vascular access training with ultrasound‐training models in preclinical education can enhance student confidence with vascular catheterization procedures and increase comfort with needle guidance in the clinical setting. The goal of our study was to assess medical student perception of ultrasound‐guided vascular access training, using training models and hands‐on venipuncture, and its importance for development of clinical skills for future practice.MethodsSecond‐year medical students participated in vascular access training by practicing an upper extremity vascular ultrasound exam on each other and on ultrasound phantoms (PICC line, central line, two‐vessel vein access) and by performing supervised venipuncture under ultrasound guidance. After training, students completed an anonymous paper survey about their perception of ultrasound‐guided vascular access laboratories using training models and hands‐on venipuncture and their importance for development of clinical skills.ResultsStudents agreed training improved understanding of PICC line, central line, and venipuncture procedures (all P<.001). Training with ultrasound models improved skills (all P<.001) and boosted confidence for PICC line (P=.02), central line (P=.04), and ultrasound‐guided venipuncture (P<.001) in a clinical setting. The central line procedure was more challenging than venipuncture (t test P=.03). There was a strong positive correlation for feeling capable of performing the PICC line procedure on the model and in a clinical setting (r=0.68, P=.001). There was a positive, but less significant, correlation for the central line model and clinical practice (r=0.41, P=.08). Training improved image interpretation for all 3 procedures (all P ≤.04). All students agreed ultrasound‐training models improved clinical skills and models were useful for learning practical skills associated with vessel cannulation and access (both P<.001). Students felt prepared to use ultrasound for vascular access in clinical rotations, residency training, and professional practice (P<.001).ConclusionVascular access training helped medical students build practical skills for PICC line, central line, and venipuncture procedures. It boosted confidence performing difficult procedures and introduced use of ultrasound technology for vascular access. Thus, vascular access training was beneficial to students in acquiring a skillset needed in future medical practice.
The Effects of Targeted Marine Phytoplankton Supplementation on Long Term Recovery During Intensified Training
Authors: Wilson Jacob , Sharp Matthew , Book Nicholous , Stefan Matthew , Reber Dallen , Gheith Raad , Ottinger Charlie , Lowery Ryan , Juturu Vijaya 
Published: April 2020

Extended periods of intensified physical training results in decrements in physical and perceptual recovery. As a result, nutritional recovery methods are highly sought after.PurposeThis study investigated targeted enriched marine phytoplankton supplementation (Microalgae Tetraselmis chuii, Oceanix™, OCX) on Perceived Recovery (PRS) and Explosive Strength recovery during long term intensive training.MethodsTrained male and female subjects were divided into placebo (PLA) or Oceanix (OCX) (25 mg per day) conditions. The subjects were all placed on a 6‐week resistance‐training program interspersed with purposeful overreaching on Wk2 and Wk5, and low volume recovery training on Wk6. Recovery scale (PRS) changes (0–10) relative to initial maintenance training levels were taken on each successive week from baseline. Explosive Strength, measured as rate of force development, during a countermovement jump was assessed at pre‐test, and at weeks 2, 5 and 6.ResultsThe relative increase in PRS during the recovery Wk6 of training was greater (+16%) for OCX compared to PLA (p<0.05), indicating greater recovery. Explosive Strength was reduced after overreaching at Wk2 and Wk5 for both conditions (p<0.05). However, explosive strength only recovered fully for OCX and not the PLA during the recovery Wk6.ConclusionsTargeted marine phytoplankton supplementation (Oceanix™ supplementation) during extended periods of intensified training improves long‐term recovery in trained male and female subjects.Support or Funding InformationLonza
The Green Tea Catechin, EGCg, Preserves Both Muscle and Bone in Aging Sarcopenic Rats
Authors: Dvoretskiy Svyatoslav , Cole Todd , Skelding Mary-Beth , Reaves Lisa A. , Edens Neile K. , Pereira Suzette L. 
Published: April 2020

ObjectivesSarcopenia is the progressive decline in muscle mass, strength and function that is exacerbated with age. It is well known that there is an overlap between sarcopenia and osteopenia/osteoporosis in the aging population. Thus, addressing both muscle and bone loss during aging is important. Epigallocatechin gallate (EGCg) is the most abundant green tea catechin and has well established anti‐inflammatory and antioxidant benefits. Green tea consumption has also been associated with bone health. In this study we examined the impact of chronic EGCg treatment on muscle mass and bone structure in aging rats.MethodsAged male Sprague‐Dawley rats (21 months) were fed the following diets ad libitum: Control group (n=9) fed AIN93M diet, and a treatment group (n=10) fed AIN93M diet +EGCg (200 mg/kg) for 8 weeks. At the end of study, gastrocnemius muscles were weighed, and histological analysis was performed to measure muscle fiber cross sectional area (CSA) using hematoxylin & eosin staining. Bones were analyzed by MicroCT imaging (Burker) of the tibia at ~22 μm resolution and images were processed using Inveon Research Workplace software. All bone samples were analyzed for trabecular bone volume, trabecular number, trabecular spacing, trabecular thickness, trabecular pattern factor and bone density.ResultsGastrocnemius muscle wet weights were significantly higher (p<0.05) and fiber CSA tended to be higher (p<0.06) in the EGCg group compared to controls. Tibia bone volume/total volume density was significantly greater (p=0.03) in animals treated with EGCg compared to control. Significant differences were found in trabecular microstructure, with a significant increase in trabecular number per given volume (p=0.01) and a corresponding significant decrease in trabecular spacing (p=0.02) in EGCg‐treated rats compared to control. No significant group differences were found in overall bone density or trabecular thickness. Differences in mean values between control and EGCg groups were determined by student’s t‐test.ConclusionsThese data present novel findings on the osteoprotective mechanism of EGCg on the aging bone through an increase in trabecular bone volume, trabecular number and trabecular spacing. Furthermore, the preservation of muscle mass and muscle fiber CSA suggests that the use of green tea catechin, EGCg, could be a potential nutritional therapy to prevent the progression of muscle and bone loss during sarcopenia.Support or Funding InformationAbbott Nutrition
Alpha Lipoic Acid Attenuates ER Stress and Improves Glucose Uptake Through DNAJB3 Cochaperone
Authors: Dehbi Mohammed , Mahmoud Naela , Khattab Namat , Bensmail Ilham , Diane Abdoulaye 
Published: April 2020

Persistent ER stress, mitochondrial dysfunction and failure of the heat shock response (HSR) are fundamental hallmarks of insulin resistance (IR); one of the early core metabolic aberrations that leads to type 2 diabetes (T2D). The antioxidant α‐lipoic acid (ALA) has been shown to attenuate metabolic stress and improve insulin sensitivity in part through activation of the heat shock response (HSR). However, these studies have been focused on a subset of heat shock proteins (HSPs). In the current investigation, we assessed whether ALA has an effect on modulating the expression of DNAJB3/HSP40 cochaperone; a potential therapeutic target with a novel role in mitigating metabolic stress and promoting insulin signaling. Treatment of C2C12 cells with 0.3 mM of ALA triggers a significant increase in the expression of DNAJB3 mRNA and protein. A similar increase in DNAJB3 mRNA was also observed in HepG2 cells. We next investigated the significance of such activation on endoplasmic reticulum (ER) stress and glucose uptake. ALA pre‐treatment significantly reduced the expression of ER stress markers namely, GRP78, XBP1, sXBP1 and ATF4 in response to both tunicamycin and glucolipotoxicity. In functional assays, ALA treatment abrogated significantly the tunicamycin‐mediated transcriptional activation of ATF6 while it enhanced the insulin‐stimulated glucose uptake. Silencing the expression of DNAJB3 but not HSP72 abolished the protective effect of ALA on tunicamycin‐induced ER stress, suggesting thus that DNAJB3 is a key mediator of ALA‐alleviated tunicamycin‐induced ER stress. Furthermore, the effect of ALA on insulin‐stimulated glucose uptake is reduced significantly in C2C12 cells transfected with DNAJB3 siRNA.In summary, our results are supportive of an essential role of DNAJB3 as a molecular target through which ALA alleviates ER stress and improve glucose uptake.Support or Funding InformationThis work was supported by Qatar Biomedical Research Institute, Hamad Bin Khalifa University intramural grant (IGP 2014‐001) to MD
Acute Effect of Coffee on Central Arterial Stiffness and Hemodynamics
Authors: Holmer Brady J. , Lapierre Stephanie , Lim Jisok , Sakarya Yasemin , New William , Eagle Michael , Hwang Chueh-Lung , Schwartz Cody , Bhattal Gurjaspreet , Maharrey Phillip , Handberg Eileen M. , Christou Demetra D. , Alviar Carlos 
Published: April 2020

Coffee is widely consumed and several studies have examined the acute effects of coffee consumption on blood pressure. However, little attention has focused on the acute effects of coffee on central arterial stiffness, wave reflection, and aortic blood pressure, independent predictors of cardiovascular disease. The objective of this investigation was to conduct a randomized, placebo‐controlled study of the acute effects of coffee on central arterial stiffness and hemodynamics. Sixteen young males (21±2 yrs; means±SE) who were light caffeine users consumed 16 oz. of cold coffee, containing 160 mg caffeine, or placebo (cold water) on two visits separated by at least a week. Central arterial stiffness (carotid to femoral pulse wave velocity; cfPWV), aortic wave reflection (augmentation index normalized at heart rate 75; AIx75) and aortic blood pressures (systolic, diastolic and mean blood pressure; aoSBP, aoDBP, aoMAP and pulse pressure; aoPP) were assessed using SphygmoCor XCEL (AtCor Medical) before and 1hr and 2hr after beverage consumption. In response to coffee, cfPWV increased at 1hr and remained elevated at 2hr (6.29±0.16 vs. 6.48±0.17 vs. 6.53±0.15 m/sec; P=0.03 for base vs. 1hr and P=0.004 for base vs. 2hr), but did not change in response to placebo (6.48±0.13 vs. 6.41±0.16 vs. 6.37±0.19 m/sec; P>0.5 for base vs. 1hr vs. 2hr and P=0.01 for condition × time). AIx75 decreased at 1hr and remained decreased at 2hr following coffee (5.5±2.9 vs. −2.4±3.1 vs. −1.7±3.3 %; P=0.0002 for base vs. 1hr and P=0.008 for base vs. 2hr) and placebo (3.9±2.8 vs. ‐ 3.7±2.5 vs. −6.7±2.6 %; P<0.0001 for base vs. 1hr and for base vs. 2hr), but to a different degree (P=0.015 for condition × time). AoSBP and aoPP were not affected by coffee or placebo (P>0.05). However, aoDBP and aoMAP increased in response to coffee by 7±2 and 5±1 mmHg, respectively, at 1hr and remained elevated at 2hr (aoDBP: 67±1 vs. 74±1 vs. 72±2 mmHg; P=0.002 for base vs. 1hr and P=0.03 for base vs. 2hr, aoMAP: 80±1 vs. 85±1 vs. 84±2 mmHg; P=0.003 for base vs. 1hr and P=0.04 for base vs. 2hr), but did not change following placebo (P>0.9 and P≥0.001 for condition × time). In conclusion, consumption of coffee containing 160 mg caffeine leads to acute changes in central arterial stiffness and hemodynamics in healthy young men. Future investigations should confirm these findings in women and examine whether responses are exaggerated in individuals who are hypertensive or have other cardiovascular disease risk factors.Support or Funding InformationThis work was supported by the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine.
Angiomatoid Fibrous Histiocytoma With ALK Expression in an Unusual Location and Age Group
Authors: De Noon Solange , Fleming Andrew , Singh Manuraj 
Published: April 2020

Abstract:
Angiomatoid fibrous histiocytoma (AFH) is a relatively rare soft tissue tumor of intermediate malignant potential, occurring most commonly in young adults, with a recognized propensity for local recurrence and occasional metastasis. A case of AFH occurring on the finger of a 60-year-old man is described in which the unusual location and age group for this entity raised the original wrong diagnosis of an aneurysmal and cellular fibrous histiocytoma. Further workup demonstrated an EWSR1-CREB1 translocation, confirming the correct diagnosis of AFH. Strong anaplastic lymphoma kinase (ALK) expression using the antibody clone D5F3 was demonstrated in our case on immunohistochemistry, which is in concordance with recent findings of anaplastic lymphoma kinase positivity with this antibody in the majority of AFHs.
Melanoma Ex Blue Nevus With GNA11 Mutation and BAP1 Loss: Case Report and Review of the Literature
Authors: Chang Li-Wei , Kazlouskaya Viktoryia , Kazi Rashek , Davar Diwakar , Ferris Robert L. , Ho Jonhan , Karunamurthy Arivarasan , Jedrych Jaroslaw J. , Bunimovich Yuri L. 
Published: April 2020

Abstract:
Cutaneous melanomas may demonstrate a variety of histopathological features and genetic abnormalities. Melanomas that arise in the setting of blue nevi, also known as “malignant blue nevus” or melanoma ex blue nevus (MBN), share a similar histopathological and mutational profile with uveal melanoma. Most uveal melanomas show characteristic GNA11 or GNAQ mutations; additional BAP1 mutation or loss is associated with the highest risk of metastasis and worst prognosis. However, the significance of BAP1 loss in melanomas ex blue nevus remains unclear. We present a case of MBN arising from the scalp of a 21-year-old woman. The diagnosis was established on histopathological findings demonstrating a markedly atypical melanocytic proliferation with increased mitotic activity, necrosis, and a focus of angiolymphatic invasion. Immunohistochemical analysis demonstrated the absence of BAP1 nuclear expression within tumor cells. Next generation sequencing detected GNA11 Q209L mutation and BAP1 loss (chromosome 3p region loss), supporting the diagnosis. We reviewed another 21 MBN cases with reported BAP1 status from the literature. MBN with BAP1 loss presented at a younger average age (41 vs. 61 years), demonstrated larger average lesion thickness (9.0 vs. 7.3 mm), and had a higher rate of metastasis (50% vs. 33%) compared with BAP1-retained MBN. BAP1 expression studies may assist in the diagnosis and management of MBN, but further research is needed.
Characterization of Hearing Loss in Adult Patients With Nondialysis Chronic Kidney Disease
Authors: Lara-Sánchez Hugo , Calvo David Herrero , Sañudo Elisa Gil-Carcedo , Mayo-Iscar Agustín , Cordero Maria Eugenia Plagaro , Monfá-Bosch José M. , Valdezate Luis Ángel Vallejo 
Published: April 2020

Objective:
To confirm the association between chronic kidney disease and sensorineural hearing loss in non-dialysis non-diabetic patients and to establish the audiological profile of these patients indicating the possible location of the auditory damage.

Study Design:
Cross-sectional study.

Setting:
Tertiary referral center.

Patients:
Patients between 18 and 60 years old with chronic kidney disease, without diabetes mellitus and without personal history of otology disease, were compared with a healthy control group pared by sex and age to establish differences between their audiological profile.

Interventions:
Pure tone audiometry (PTA), transient evoked otoacoustic emissions (TEOAEs), distortion products otoacoustic emissions (DPOAEs), and auditory brainstem responses (ABR) were performed in both groups.

Main Outcome Measures:
Mean and standard deviation of PTA auditory thresholds, TEOAEs reproducibility, DPOAEs level/noise, and ABR absolute latency and interwave latency were measured, and compared using linear mixed models.

Results:
Fifty one cases were included and compared with 51 healthy volunteers. The audiometric profile found in patients with chronic kidney disease was a sensorineural hearing loss in 4 to 8 kHz frequencies in the PTA, a decrease in the TEOAEs reproducibility and a decrease in the DPOAEs level. An enlargement in the V wave absolute latency and III to V and I to V interwave latency in the ABR were also found but within normal range.

Conclusions:
There is an association between chronic kidney disease in non-dialysis non diabetic adults patients and sensorineural hearing loss, affecting high frequencies and having the cochlea as the main site of auditory damage.