bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Androgen Receptor and TRAIL: A Novel Treatment Paradigm for Breast Cancer
Authors: Xie Yan , Chen Linjie , Abel Peter W. , Wei Taotao , Luo Xu , Tu Yaping 
Published: June 2021

ObjectiveTRAIL (TNF‐related apoptosis‐inducing ligand is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors. However, most breast cancer cells are resistant to TRAIL‐induced apoptosis. Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.MethodsTo identify modulators of TRAIL‐induced apoptosis, we carried out a genomewide siRNA screen. To validate the screening result, we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL‐induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model. Finally, we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL‐therapy.ResultsWe unexpectedly identified androgen receptor (AR) to be responsible for TRAIL resistance. While AR is classically viewed as the key factor in prostate cancer progression, we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple‐negative breast cancers (TNBC) that are highly aggressive with poor prognosis. Importantly, breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance. AR overexpression in MDA‐MB‐231 and MDA‐MB‐436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF‐7 and MDA‐MB‐453 cells sensitive to TRAIL‐induced apoptosis. AR overexpression also induced TRAIL resistance in breast tumors in vivo. Further, we observed an upregulation of the TRAIL receptor, Death Receptor 5 (DR5) in breast cancer cells, following the removal or inhibition of AR by its antagonists Casodex and MDV3100. Treatment with AR antagonists also enhanced TRAIL‐ induced breast cancer cell apoptosis.ConclusionAR signaling suppresses TRAIL‐induced breast cancer cell apoptosis, in part, by suppressing DR5 expression, and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.Support or Funding InformationThe project supported by the National Institutes of Health (Grants R21CA193271 and R01HL116849); the National Natural Science Foundation of China (Grants 31100595 and 31300683)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential Response of MET inhibition by Glesatinib (MGCD265) and Sitravatinib (MGCD516) in Non‐small Cell Lung Cancer and Malignant Mesothelioma
Authors: Mirzapoiazova Tamara , Tan Carol , Wang Jiale , Mambetsariev Isa , Mambetsariev Bolot , Kulkarni Prakash , Pozhitkov Alex , Wang Yingyu , Christensen James , Engstrom Lars , Salgia Ravi 
Published: June 2021

Aberrant activation of the receptor tyrosine kinase (RTK) MET is frequently involved in malignant transformation and inhibiting its activity in dependent cancers is associated with improved clinical outcomes. Glesatinib (MGCD265) and sitravatinib (MGCD516) are next generation MET RTK inhibitors (RTKIs) and while glesatinib also targets the AXL RTK, sitravatinib inhibits a closely related spectrum of RTKs. The efficacy of these compounds in MET‐dependent non‐small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) cell lines that differed with respect to MET gene expression was evaluated. Both drugs inhibited cell growth and migratory activity with similar potency in NSCLC H1993 cells with clustered MET amplification and A459 cells with ‘wild type’ MET. Also, MPM cell lines H2373 and H2461 with elevated MET expression showed comparable levels of sensitivity to either drug. Kinomics analysis of the affected pathways suggested that both drugs acted similarly, yet distinct signaling was affected when different cell lines were tested. In particular, cellular pathways associated with transformation were inhibited whereas those promoting cell death were activated upon drug treatment. Furthermore, phosphorylation of RON, which interacts with MET, and the downstream signaling molecules AKT and p44/42MAPK were also inhibited in response to hepatocyte growth factor (HGF) stimulation. Importantly, in a pre‐clinical in vivo xenotransplant mouse model, both drugs caused significant tumor growth inhibition. Our data suggest that discerning the expression and activation status of MET and its associated signaling pathways may help guide treatment decisions concerning targeted therapies for NSCLC and MPM.Support or Funding InformationThe National Cancer Institute of the National Institutes of Health under award number P30CA033572 and Mirati Therapeutics.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
New Rock Inhibitors Action Analysis in the Cytoskeleton and Cell Migration of Tumor Cell Line MDA‐MB 231
Authors: Guerra Fabiana Sélos , de Oliveira Ramon Guerra , Fraga Carlos Alberto Manssour , dos Santos Mermelstein Claudia , Fernandes Patricia Dias 
Published: June 2021

Many patients with metastatic tumors have substantially worse survival in comparison with those patients with nonmetastatic tumors. The ability of cancer cells to undergo invasion and migration is a prerequisite for tumor metastasis and these events became targets for the development of new antimetastatic drugs. Rho kinases, ROCK1 and ROCK2, are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. In this regard our group synthesized two sulfonylhydrazones, analogous to Fasudil (a classic Rho kinase inhibitor), named LASSBio 2020 and LASSBio 2065, differing each other by the presence of one methyl in LASSBio 2065. Therefore, the aim of the present work was to investigate the effects of these analogues against human breast carcinoma (MDA‐MB‐231) cell line migration and signalling pathways involved in in this phenomenon as well as cytoskeleton changes.For the study, cells were incubated with LASSBio 2020 or LASSBio 2065 (0.1 to 30 μM) for 24 or 48 hours. The cell viability was evaluated by MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐difenltetrazolium) and plasma membrane integrity assay (lactate desidrogenase, LDH). Migration capacity of cells was evaluated using wound healing assay. Morphological analysis was carried out by phase‐contrast micrography, and analysed using Image J software. Actin structures were visualized by fluorescent phalloidin. Statistical analyses were performed by ANOVA with Newman‐Keuls post‐test (*p<0.05).The results showed that none of analogues altered viability of MDA‐MB 231 cells. The effect of the treatment with 10 and 30 μM of LASSBio 2020 decreased cell migration in 30,38% and 32,7%, respectively, when compared to control. LASSBio 2065 decreased cell migration in 24,51% (10 μM) and 26,14% (30 μM), when compared to control. Control cells presented a sprawling appearance with extended cytoplasm and lamelipodios formation. Cells incubated with 10 μm of LASSBio 2020 and LASSBio 2065 presented area, height and width reduced by 40%, membranes with filopodia, protrusions and a fusiform appearance. The staining for F‐actin showed that the cell body became elongated, less spread and with a narrowing of the cell body shape (figure 1).We can conclude that none of analogues (LASSBio 2020 and LASSBio 2065) reduced cell viability. However, the analogues reduced cell migration, altered cell morphology and interfered with formation of actin filaments. Taken together, our data can suggest that the fasudil analogues are a potential inhibitors of metastasis formation.Support or Funding InformationCapes, FAPERJ and CNPqThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A novel small‐molecule inhibitor of the WNT/β‐catenin pathway show efficacy in treating diet induced alteration of glucose and lipid metabolism
Authors: Obianom Obinna , Yang Wei , Li Yingjun , Ai Yong , Xue Fengtian , Shu Yan 
Published: June 2021

WNT/β‐catenin pathway is well studied for its role in cell differentiation and proliferation. The major effector of this pathway, β‐catenin, interacts with nuclear pool of co‐transcription factors T‐cell factor/lymphoid enhancer factor (TCF/LEF) to initiate transcription of WNT downstream genes that regulate different processes including glucose and lipid metabolism. Here, we screened a library of 90 compounds using a TCF/LEF responsive reporter assay. We identified a potent quinolinium compound, YW1128, which is able to stabilize Axin levels and decrease WNT signaling (IC50 = 8 nM). In vitro validation assays and in vivo efficacy characterization for this compound using a high fat diet C57BL/6J mouse model in contrast to a normal chow mouse model of the same background were carried out. Our western blot and immunocytochemistry results confirm the WNT inhibitory effects of YW1128 in HEK293 cells. Treatment of huh7 cells led to significant decrease in lipid accumulation shown by nile red staining. In mice fed high fat diet, YW1128 alleviated fatty liver disease and slightly improved glucose tolerance as assessed by haemotoxylin and eosin staining and intraperitoneal glucose tolerance tests, respectively. With no effect on toxicity markers, YW1128 significantly decreased serum cholesterol level in high fat diet mice group with no effect in the normal chow group. Treatment mice also had significant decrease in genes involved in glucose metabolism and fatty acid metabolism pathways along with YW1128 inhibitory effect in WNT signaling pathways. To conclude, we identified an novel WNT pathway inhibitor that show promising benefit for treating diseases associated with glucose and lipid metabolism through its effect on WNT signaling pathway.Support or Funding InformationFunded by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under Award R01GM099742This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inositol trisphosphate dynamics underlie physiological calcium signals within the coronary artery endothelium
Authors: Francis Christopher M. , Knighten Jennifer M. , Taylor Mark S. 
Published: June 2021

The arterial endothelium modulates smooth muscle tone in response to its local hemodynamic environment. This process is critical to normal vascular function, and is impaired by endothelial cell injury in coronary artery disease. Last year, we discovered a unique mode of calcium signaling of the porcine coronary artery endothelium, characterized by a pattern of continuous, cell‐wide calcium waves in the absence of agonist stimulation. Stimulation with substance P (10−13 to 10−6 ml/L) amplified this pattern to match dose‐dependent vessel relaxation responses. Here, we investigated the mechanism underlying the formation of this characteristic pattern of endothelial calcium waves with confocal microscopy, utilizing both pharmacological and computational approaches. We found that coronary endothelial cell calcium waves were mediated by inositol trisphosphate receptors (IP3R), which exhibited distinct intracellular isoform distributions. The distribution of the type 1 IP3R isoform corresponded to the area (33.9 ± 2.6 μm2) of propagating calcium waves, including perinuclear IP3R clustering at subcellular sites of constitutively elevated calcium. We utilized a computational model of calcium signaling that included this distinct IP3R distribution, and discovered that cell‐wide waves formed only if intracellular concentration gradients of inositol trisphosphate (IP3) were present along the longitudinal cell axis. Importantly, we found that production and diffusion of IP3 from a focal intracellular source was sufficient to initiate a calcium wave event with the same propagation velocity curve (mean: 6.08 ± 0.61 μm/s) of the experimentally‐observed wave. Furthermore, amplification of IP3 production in our model resulted in an increase of the frequency of elementary wave events which reflected the dose‐dependent expansion of calcium activity induced by substance P. These results indicate a fundamental role for IP3 dynamics as a physiological mediator of vascular responses, underlying both the initiation and expansion of unique endothelial calcium signal modalities.Support or Funding InformationThis work was supported by NIH grants: HL136869, HL085887, and S10RR027535.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Dopamine Receptor D3 Deficiency in Age‐dependent Left Ventricular Remodeling
Authors: Grilo Gabriel Araujo , Shaver Patti Rebecca , Stoffel Hamilton Joseph , Kennedy Kylie Ruthann , Morrow Caleb Anthony , Iyer Rugmani Padmanabhan , Clemens Stefan , de Castro Brás Lisandra Eunice 
Published: June 2021

Aging is an independent risk factor for cardiovascular disease. Additionally, normal aging associates with a decrease on the levels of the neuromodulator dopamine (DA). While the role of DA in the pathophysiology of hypertension and in autonomic function is well‐established in young animals, much less is known on how DA levels and signaling affect cardiac aging. Decreased receptor expression/function of the D2‐like DA receptor family (DRD2 and DRD3) have been implicated in the development of renal and cardiac fibrosis. It is well established that myocardial aging is characterized by left ventricular (LV) fibrosis, which is a component of LV adverse remodeling. Accordingly, the goal of this study was to elucidate the effects of DRD3 deficiency in age‐dependent LV remodeling.MethodsWe used 3, 6, 12, and 18 month old (m.o.) wild type (WT) and DRD3 knockout (D3KO) male and female mice (n=6/sex/age/genotype). Cardiac function was assessed by serial echocardiography, and plasma and left ventricle were harvested to analyze molecular parameters of LV remodeling, particularly extracellular matrix composition.ResultsEchocardiography analysis demonstrated that D3KO mice have a continuous, age‐dependent, increase of the LV anterior wall (LVAW), compared to WT, in both genders, but more markedly in females. This suggests that female D3DKO may have age‐dependent hypertrophy. In addition, the interior diameter in diastole (LVIDd) of D3KO animals was consistently smaller than WT mice of the same age, particularly at 6 and 12 m.o. (Figure 1). Cardiac fibrosis increased in the older male animals (18 m.o.) compared to all other ages in both genotypes. Females, however, showed a distinct genotype‐dependent pattern, suggesting sex‐differences in collagen metabolism with age. Genes associated with cardiac remodeling, as Gsta1, Nrp2, Mmp12 and Vcam1 showed increased expression with aging in WT females, but not in D3KO. Male D3KO however, displayed increased Ccl2 and Ecm1 at 18 m.o. compared to all other ages and Casp1 (an inflammatory response initiator) was increased in D3KO with time.ConclusionOur data suggests that DRD3 function in the heart plays an important gender‐specific role in age‐dependent cardiac remodeling.Support or Funding InformationWe acknowledge support from American Heart Association (14SDG18860050) and the Research and Graduate School at East Carolina University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cardiovascular Mathematics: Prevention, Promotion and Treatment
Authors: Calvachi Paola , Pizano Alejandro , Girón Felipe , Cordovez Juan Manuel 
Published: June 2021

IntroductionCardiovascular disease is the first cause of death in the world, being heart failure responsible for most of the hospital admissions. There is a strong relationship between heart failure and chronic renal disease, where kidney disease is one of the major contributors to cardiac damage and, likewise, heart disease promotes a progression of chronic kidney disease. Our main goal was to understand the dynamics of this vicious cycle in a person with heart failure and investigate mechanisms to prevent and treat this pathology.MethodsTo achieve this, a mathematical model was proposed based on fluid mechanics. We assumed the cardiovascular system as a circuit with two pumps (Right and Left ventricles) and 7 resistances: 4 that represent the cardiac valves (Tricuspid, Pulmonary, Mitral and Aortic), the systemic, renal and pulmonary capillaries. The model included compliances and resistances as parameters, and pressures, volume and flows were determined for each segment in the circulatory system. Parameters were determined according to anatomical and physiological properties found in the literature. The model was implemented in MATLAB (The MathWorks®, Inc.).ResultsThe mathematical model showed how the renal system is integrated with the cardiovascular pump. The model demonstrated that physicians have a short time period of action in order to preserve the renal function in patients with cardiovascular diseases, and also emphasize in a way to prevent the progression from heart disease to renal failure. We were able to compare the pressure‐volume curves for disease and healthy states and establish the main challenges for the circulatory system under these conditions.ConclusionsThe mathematical model was helpful to understand the normal and pathological functioning of the cardiovascular and renal systems. In particular, our ability to keep track of total blood volume gave insight into the relationship between renal and cardiac malfunction. This approach could be the mainstay for health prevention, promotion and opportune treatment in cardiorenal syndrome.Support or Funding InformationResearch Group in Mathematical and Computational Biology (BIOMAC), Department of Biomedical Engineering, Universidad de los Andes, Colombia.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Mouse Heart Attack Research Tool (mHART) 1.0 Database
Authors: DeLeon‐Pennell Kristine Y. , Ma Yonggang , Yabluchanskiy Andriy , Flynn Elizabeth , Halade Ganesh V. , De Castro Bras Lisandra , Lindsey Merry L. 
Published: June 2021

BackgroundThe generation of Big Data has enabled systems‐level dissections into the mechanisms of cardiovascular pathology. Integration of dozens of variables across a variety of platforms and across laboratories fosters discoveries through multidisciplinary investigations, decreased costs, and elimination of unnecessary redundancy in research efforts. Moreover, Big Data brings speed, allowing more rapid and improved decision making. The Mouse Heart Attack Research Tool (mHART) harnesses a large dataset of over 10 years of experiments from a single site, for use by investigators to generate novel hypotheses, uncover hidden relationships, and identify new predictive markers of progressive cardiac remodeling following myocardial infarction (MI) in mice.Methods and ResultsWe designed the mHART database to incorporate our own data, with future plans to integrate community participation. We generated genomic, proteomic, physiological, biochemical, and cellular outputs from plasma and left ventricles obtained from post‐MI and no MI (naïve) control groups. We included both male and female mice ranging in age from 3 to 36 months old. After variable collection, data underwent quality assessment to clean the data (i.e. to eliminate technical errors), check for completeness, remove duplicates, and define terms. Combined, mHART 1.0 contains >888,000 data points and includes results from >2,000 unique mice. Database performance was tested and an example applied to illustrate how this database can be used.ConclusionThe efforts reported here establish the first version of the mHART database.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Vasopressin on Intrinsic Cardiac Activity in Conscious Wistar Rats.
Authors: da Silva Daniel Santana , Cafarchio Eduardo Mazuco , do Vale Bárbara , Antonio Bruno Brito , Venancio Daniel Paulino , de Souza Janaina Sena , Pino Jessica Monteiro Volejnik , Giannocco Gisele , Sato Monica Akemi 
Published: June 2021

BackgroundThe effects of vasopressin on cardiac chronotropism are controversial in different species.ObjectiveTo investigate if vasopressin can influence the cardiac intrinsic activity in conscious Wistar rats.MethodsAll the procedures of this study were approved by the Animal ethics committee (protocol #02/2016). Adult male Wistar rats underwent to a cannulation of the femoral artery and vein for mean arterial pressure (MAP) and heart rate (HR) recordings and drug infusions, respectively, in conscious rats, 24 h after the surgical procedures. After baseline recordings, i.v. atropine 2 mg/kg and i.v. metoprolol 1.7 mg/kg were injected with 5 min interval. After 10 min, i.v. vasopressin 0.0625 mg/mL/5 min (N=6) or saline (1 mL/5 min) (N=6) were infused and the variables were recorded for additional 10 min. Gene and protein expression of V1a, V1b and V2 subtype receptors for AVP were also carried in the right atrium by qPCR and Western Blotting, respectively. The AVP receptor subtypes were also labeled by immunofluorescence technique in the right atrium.ResultsVasopressin evoked bradycardic (−51±5 bpm) and pressor responses (39±6 mmHg) compared to baseline post‐autonomic blockade (130 ±8 mmHg and 406±16 bpm). Saline did not change HR (1±4 bpm) and MAP (−3±1 mmHg) compared to baseline after autonomic blockade (120±5 mmHg and 411±52 bpm). All subtypes of AVP receptors were expressed in the right atrium by qPCR, Western Blotting and immunofluorescence.ConclusionThe bradycardia elicited by vasopressin after cardiac autonomic blockade suggests that vasopressin can affect the cardiac intrinsic activity binding to the receptors in the right atrium.Support or Funding InformationFinancial support: FAPESP, CNPq and NEPAS‐FMABC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.