bluuebunny/crossref_metadata_2025_split huggingface dataset:
Triple negative human breast cancers accumulate significantly less Arg‐pyrimidine moieties, than other subtype lesions (58.3)
Authors: Castronovo Vincent , Chiavarina Barbara , Nokin Marie‐Julie , Durieux Florence , Bianchi Elettra , Irigaray Philippe , Uchida Koji , Belpomme Dominique , Bellahcène Akeila 
Published: June 2021

Metabolic disorders influence breast cancer development and progression.Methylglyoxal (MGX), is a highly reactive glycolytic byproduct able to inflict carbonyl stress to proteins, lipids and DNA. The possible role of MGX in breast cancer development has not been yet extensively explored. We analyzed the accumulation of Arg‐pyrimidine adducts, in a series of more than 100 human breast adenocarcinoma and we observed a consistent increased of MGX adducts in cancer cells compared to the non‐tumoral counterpart. Most triple negative lesions examined exhibited low accumulation of Arg‐pyrimidine residues compared other subtypes. Intriguingly, the level of expression of glyoxalase 1 (Glo‐1), an enzyme that detoxifies MGX, was similar in both triple negative and other subtype lesions, suggesting a potential difference in the Glo‐1 activity. This hypothesis is supported by our preliminary results on breast cancer cell lines, showing that triple negative cells are more efficient to respond to treatment with MGX by increasing the activity of Glo‐1. Our study represent the first observation that Arg‐pyrimidine adducts accumulation is a consistent event in human breast cancer with a differential detection between triple negative and other breast cancer subtypes. Our preliminary data suggest that methylglyoxal production and detoxification could be a molecular link between metabolic diseases and breast cancer.Grant Funding Source: This study is supported by Founds for National Research (FNRS), Belgium
Myoferlin is a key regulator of HER receptor family function in breast cancer (58.5)
Authors: Turtoi Andrei , Blomme Arnaud , Bellahcène Akeila , Hennequière Vincent , Lifrange Eric , Delvenne Philippe , Castronovo Vincent 
Published: June 2021

Myoferlin is a member of the ferlin family of proteins that participate in plasma membrane fusion, repair and endocytosis events. Although few reports associate myoferlin with cancer, its actual role in tumor biology remains to date unveiled. Owing to a proteomic approach, we discovered myoferlin as an overexpressed cell membrane associated protein in human breast adenocarcinoma. We validated this observation in 150 breast cancer cases. We further investigated the biological role of myoferlin in breast cancer and found that it is a key functional regulator of HER receptor family. Myoferlin depletion blocked EGF‐induced breast cancer cell migration and epithelial‐to‐mesenchymal transition. Mechanistically, lack of myoferlin led to impaired degradation of phosphorylated EGFR via dysfunctional caveolae. Inability to degrade pEGFR caused sustained activation and malfunction of downstream targets like AKT. NRG1 stimulation of myoferlin silenced, HER2 positive, breast cancer cells demonstrated similar dysfunctions in HER2 and HER3 activity. Using two different animal models of breast cancer, we show that myoferlin depletion significantly suppressed tumor and metastasis development. Although the effects observed with different HER family members appear to involve distinct mechanisms, the data strongly evidence a paramount role of myoferlin in HER receptor function in cancer.Grant Funding Source: This work is supported by the National Fund for Scientific Research (FNRS, Belgium) and ULG.
Asporin is a key stromal regulator of TGF‐β‐1 function in breast cancer (58.7)
Authors: Maris Pamela , Blomme Arnaud , Bianchi Elettra , Castronovo Vincent , Turtoi Andrei 
Published: June 2021

Asporin is extracellular matrix protein that has been associated with bone and joint diseases. Using innovative proteomic analysis we have previously found asporin as overexpressed in pancreas and breast cancer. In the current work we explore for the first time the functional significance of asporin expression in cancer. We show in 150 cases of breast carcinoma that asporin is a consistent feature of the tumor, whose high levels positively correlate with the good patient outcome. On the molecular level we demonstrate that only tumor‐associated fibroblasts are able to secrete asporin after being reprogrammed by the cancer cells. We found that TGF‐β‐1 alone is able to induce asporin expression and in turn asporin can bind TGF‐β‐1 to inhibit its action on TGF‐β receptors. The main interaction between the two proteins occurs via asporin 159‐205 amino acid region. Synthetic peptide corresponding to this key asporin segment is able to inhibit TGF‐β‐1 induction of SMAD2 phosphorylation in breast cancer cells. Using a TGF‐β‐1‐based model of epithelial to mesenchymal transition (EMT) in A549 cells, we further show that asporin peptide is able to inhibit TGF‐β‐1‐induced EMT.Our work identifies asporin as a natural inhibitor of TGF‐β‐1 activity in cancer, offering a novel possibility of targeting TGF‐β‐1‐driven tumor progression.Grant Funding Source: University of Liege
New arylamidas and arylimidas as potential cholinesterase inhibitors for treatment of Alzheimer’s disease (582.2)
Authors: Cipres‐Flores Fabiola , Trujillo‐Ferrara Jose , Cuevas‐Hernandez Roberto , Correa‐Basurto Jose , Soriano‐Ursua Marvin 
Published: June 2021

Alzheimer’s disease (AD) is a pathology for which major features are by progressive memory lacking as well as gradual and irreversible disruption of cognitive functions that eventually leads to dementia. Furthermore, Alzheimer’s disease presents a loss of forebrain cholinergic neurons and a progressive decreasing of acetylcholine (ACh). ACh activity in the brain is regulated by the hydrolytic action of cholinesterase (AChE). Therefore, the palliative treatment of Alzheimer's disease is given by the AChE inhibitors.The aim of this work was to evaluate 4 arylamides and 4 arylimides synthesized as potential inhibitors of the AChE according to previous evaluations carried out by means of in silico assays. The selected compounds were synthesized from 4‐chloroaniline or N, N‐dimethyl‐P‐phenyl‐endiamine with maleic anhydride and/or succinic anhydride. The synthesis procedure and chemical characterization is in agreement with proposed structures. The evaluation of these compounds as AChE inhibitors allow us to select two of them which showed notably greater inhibition on the enzyme. Thus, these two compounds could have potential therapeutic in AD.Grant Funding Source: Supported by Consejo Nacional de Ciencia y Tecnología (62488), COFAA and SIP of IPN‐Mexico
Hepatic metabolism of 3‐hydroxypropionate, a toxic byproduct in propionic acidemia (590.2)
Authors: Wilson Kirkland , Han Yong , Koshy John , Brunengraber Henri , Tochtrop Gregory , Zhang Guofang 
Published: June 2021

Propionic acidemia (PA) is a rare autosomal recessive disorder leading to inhibition of propionate entering an anaplerotic pathway, via propionyl‐CoA, of the citric acid cycle (CAC). PA is characterized by a defect in the conversion of propionyl‐CoA to methylmalonyl‐CoA through propionyl‐CoA carboxylase (PCC). Decreased activity of PCC shunts propionyl‐CoA into alternative metabolic pathways forming 3‐hydroxypropionate (3‐HPA), which increases in concentration to toxic levels. We investigated the metabolic fates of 3‐HPA in rat livers using the combination of metabolomics studies and mass isotopomer analysis. Isolated rat livers were perfused with recirculating buffer containing 2 mM (un)labeled 3‐HPA ([13C3] and [1‐13C]3‐HPA). Perfusate and liver tissue were analyzed via GC‐MS and LC‐MS/MS. 3‐HPA was shown to be converted to acetyl‐CoA, with loss of carbon‐1 from 3‐HPA rather than enter into the CAC anaplerotically via propionyl‐CoA. The proposed pathway of 3‐HPA conversion to malonyl‐CoA was disproven using [13C3] 3‐HPA labeling studies. Instead β‐alanine was labeled with further conversion to acetyl‐CoA proposed. The newly identified metabolic pathway of 3‐HPA in the rat liver may play important role in the detoxification of this compound.Grant Funding Source: Supported by CRTP T32 Training Grant
Quantitative shotgun proteomics reveals early markers of colorectal carcinogenesis (591.1)
Authors: Uzozie Anuli , Nanni Paolo , Staiano Teresa , Grossmann Jonas , Barkow‐Oesterreicher Simon , Shay Jerry , Tiwari Amit , Buffoli Federico , Laczko Endre , Marra Giancarlo 
Published: June 2021

Colorectal adenomas are cancer precursor lesions of the large bowel. Using iTRAQ 8‐plex labelling, OFFGEL electrophoresis, and LC‐coupled tandem MS, we investigated the proteome of 30 colorectal adenomas and paired normal mucosal samples (prospectively collected during colonoscopy), and that of normal (HCEC) and cancerous (SW480, SW620, CACO2, HT29, CX1) colon epithelial cell lines. A total of 4325 and 2017 non‐redundant protein families were identified and quantified in tissue and cell lines, respectively. Principal component analysis clearly distinguished adenomas from normal mucosa, and cancer cell lines from HCEC cells. Two hundred twelve proteins displayed significant adenoma‐related expression changes (q‐value<0.02, mean fold change +/‐1.4), which correlated (r=0.74) with similar changes previously identified by our group at the transcriptome level. Fifty one proteins displayed directionally similar expression changes in colorectal cancer cells (vs HCEC cells) and were therefore attributed to the epithelial component of adenomas. Although benign, adenomas already exhibited protein expression changes previously documented only in advanced colorectal cancers. They also disclosed several novel changes with potentially important roles in early‐stage large bowel tumorigenesis, including the marked upregulation of a key enzyme in the polyol pathway.Grant Funding Source: Supported by the Swiss National Science Foundation
Characterization of the binding of antiproliferative factor to cytoskeleton associated protein 4 by surface plasmon resonance (592.1)
Authors: Planey Sonia , Ling Jun 
Published: June 2021

Interstitial cystitis (IC) is a chronic, debilitating bladder disease that affects mostly women and is frequently misdiagnosed due to lack of a non‐invasive test to detect the disease. While the cause remains unknown, biomarkers for IC have been described, including antiproliferative factor (APF), a glycopeptide that is detectable in the urine of 95‐97% of IC patients vs. normal controls. Validation of APF as a biomarker and etiologic agent for IC has been hindered by the absence of robust assays to detect and measure its concentration in patient urine. In this study, we evaluated the utility of surface plasmon resonance (SPR) to detect and quantitate APF in solution through binding to its cellular receptor, cytoskeleton associated protein 4 (CKAP4). We purified histidine‐tagged CKAP4 (HT‐CKAP4) and immobilized it on a NTA Sensor Chip surface via ionic interaction. Robust binding to CKAP4 antibody indicated that the purified HT‐CKAP4 was active and in native conformation; moreover, we demonstrated direct binding to APF analyte at a level detectable above the background control. Specificity of the HT‐CKAP4/APF interaction was confirmed by a competition assay demonstrating titration of CKAP4 antibody binding to HT‐CKAP4 by increasing concentrations of APF analyte. Future studies will determine the ability this SPR‐based assay to detect APF in urine from patients with IC with the goal of developing a non‐invasive, point‐of‐care diagnostic test for IC.Grant Funding Source: USA MED Research ACQ Activity W81XWH‐13‐1‐0454
Dietary glutamate: interactions with the enteric nervous system (596.1)
Authors: Wood Jackie , Wang Guo‐Du , Wang Xi‐Yu 
Published: June 2021

Luminal glutamate concentration rises during protein digestion in the small intestine and passes the ENS during absorption. Glutamate, in the brain (CNS), is an excitatory neurotransmitter. We assessed a premise that glutamatergic signalling in the ENS recapitulates its transmitter role in the CNS. Pharmacological analysis with receptor agonists and antagonists together with immunohistochemical localization of glutamate transporters and receptors was used. Analysis focused on electrical and synaptic behavior of ENS neurons, stimulation of mucosal secretion by secretomotor neurons and muscle activity mediated by musculomotor neurons. Immunoreactivity for glutamate was expressed in ENS neurons. ENS neurons expressed immunoreactivity for the EAAC‐1 glutamate transporter. Neither L‐glutamate nor glutamatergic receptor agonists excited ENS neurons. Metabotropic glutamatergic agonists did not stimulate neurogenic mucosal chloride secretion. Neither L‐glutamate nor the metabotropic glutamatergic agonist, ACPD, changed the mean amplitude of spontaneously occurring contractions in circular or longitudinal strips of intestinal wall from guinea pig or human small intestine. Early discoveries, for glutamatergic neurotransmission in the CNS, inspired expectation that study in the ENS would yield discoveries recapitulating the CNS glutamatergic story. We found this not to be the case.Grant Funding Source: The work was supported in part by National Institutes of Health grant: NIH 2 R01 DK 037238 and a gra
Mast cell activation by glia maturation factor, 1‐methyl‐4‐phenylpyridinium and α‐synuclein: implications for Parkinson’s disease (596.5)
Authors: Zaheer Asgar , Kempuraj Duraisamy , Khan Mohammad , Javed Hayate , Zaheer Smita 
Published: June 2021

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra. We have previously reported elevation of glia maturation factor (GMF) in the brains of Alzheimer’s disease and Multiple Sclerosis. Mast cells are both sensors and effectors in communication between nervous, vascular and immune systems, and also mediate inflammation. We have analyzed the effect of GMF on mouse bone marrow‐derived mast cells (BMMCs), human umbilical cord blood‐derived mast cells (hCBMCs) and mouse embryonic brain‐derived astrocytes. We demonstrate that GMF activate BMMCs to release chemokine CCL2, and that BMMCs‐derived from GMF‐KO mice released less CCL2 when compared to BMMCs obtained from Wild type mice. We also report that GMF, and PD‐relevant toxins α‐synuclein and MPP+, a metabolite of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) activated hCBMCs to release IL‐8. We also found novel GMF expression in both hCBMCs as well as BMMCs by immunocytochemistry. Flow cytometric analyses have demonstrated that GMF and MPP+ increased the expression of IL‐33 in mouse astrocytes. GMF also induced the expression of costimulatory protein CD40 in astrocytes. Our findings that activation of mast cells by GMF, MPP+ and α‐synuclein to release proinflammatory molecules along with GMF expression by mast cells may provide a new drug target for neurodegenerative diseases.Grant Funding Source: Supported by VA Merit Review award and NINDS grant NS073670
The amyloid precursor protein of Alzheimer’s disease localizes to a domain adjacent to synaptic vesicles of the presynaptic terminal (596.9)
Authors: Protsenko Ekaterina , DeGiorgis Joseph 
Published: June 2021

Alzheimer’s disease (AD) afflicts an estimated 26 million individuals worldwide and its incidence is predicted to reach 100 million by 2050. While abnormal aggregation of the A‐beta component of the amyloid precursor protein (APP) has been causally linked to AD, APP’s endogenous function remains elusive. While a number of reports claim that APP associates with synaptic vesicles, our recent experiments by confocal microscopy suggest that APP localizes to a region near the synaptic vesicles but does not directly overlap with the vesicular domain. Synaptic vesicles were identified by antibodies against the synaptic vesicle protein SV2, while APP was identified by an antibody against the C‐terminus of human APP. Similar experiments using antibodies against APP and the post‐synaptic marks PSD‐93 and PSD‐95 show that APP also does not overlap with the post‐synaptic density (PSD). We are currently immune‐localizing APP at the EM level in goldfish spinal cord using nano‐gold conjugated secondary antibodies and silver enhancement. All microscopy work was performed using goldfish and lamprey tissues. Sequencing of the species’ respective APP genes shows that these sequences share high sequence homology with the human APP responsible for the disease.Grant Funding Source: Supported by the Rhode Island INBRE Program NIMGS grant 5 P20 GM103430‐13
Desensitization of DMSO‐treated platelets to common agonists via membrane modulation (598.5)
Authors: Yamaguchi Jonathan , Tran Phat , Sen Nivedita , DeCook Tracy , Slepian Marvin 
Published: June 2021

Thrombosis and thromboembolic complications continue to plague mechanical circulatory support devices (MCS). Biochemical pathways involving prostaglandin and ADP are known targets for aspirin and thienopyridines to modulate platelet activation and aggregation, respectively. However, a recent study in our lab has demonstrated the limited ability of these agents to alter shear‐mediated platelet activation. Therefore, this study examines the impact of altering the platelet membrane fluidity by treatment with dimethyl sulfoxide (DMSO) and its inherent effects on platelet activation by standard agonists. DMSO was chosen due to its previously reported antithrombotic properties. Although it was reported that DMSO inhibits platelet activation through cyclooxygenase‐1 inhibition, we believe that the alteration in membrane fluidity also plays a key role in desensitization.Human venous blood was collected from healthy volunteers in citrated buffer with UA‐IRB consent. Platelet rich plasma (PRP) was isolated and treated with DMSO ranging from 0.95%‐60% (v/v). Light transmission aggregometry (LTA) was performed to detect platelet desensitization using arachidonic acid, ADP, collagen, epinephrine, and ristocetin. Platelets were fixed and visualized at the varying DMSO treatments under scanning electron microscopy (SEM).Collagen and epinephrine had limited effect on PRP aggregation ranging from 0.95% to 10% of DMSO. ADP and arachidonic acid showed a clear inhibition at 10% and 5%, respectively. DMSO had no effect on ristocetin‐induced platelet aggregation. SEM of platelets at 5% and 10% showed significant reduction in filopodia.DMSO altered platelet membrane fluidity and desensitized their aggregability from certain common agonists; thus reflecting the role of DMSO in some biochemical pathways that inhibit platelets. Next, we will measure the platelet membrane fluidity using TMA‐DPH and DPH fluorescence anisotropy in the presence of DMSO to further validate our results.
Intestinal epithelium specific knockout of nonmuscle myosin II A disrupts epithelial barrier and exaggerates experimental colitis (60.5)
Authors: Naydenov Nayden , Feygin Alex , Conti Mary , Adelstein Robert , Ivanov Andrei 
Published: June 2021

The integrity of epithelial monolayers depends on the formation of tight junctions (TJ) and adherens junctions (AJ). TJ and AJ associate with underlying actomyosin bundles that are critical for their stability and function. Our previous in vitro studies have identified nonmuscle myosin II A (NM IIA) as a unique regulator of AJ/TJ structure and barrier properties in the intestinal epithelium. In this study, we investigated the roles of NM IIA in the maintenance of the intestinal epithelial barrier in vivo. Mice carrying a floxed allele of NM IIA were crossed with villin‐cre mice. The progeny demonstrated Mendelian inheritance, suggesting that this NM IIA conditional knockout (cKO) is not embryonically lethal. Immunoblotting indicated that NM IIA expression was specifically ablated solely in the intestinal epithelium, but not in the brain, lung, kidney or liver. NM IIA cKO showed an increased baseline mucosal permeability and exaggerated dextran sodium sulfate (DSS)‐induced breakdown of the intestinal barrier. Furthermore, NM IIA cKO animals demonstrated increased body weight loss, amplified disease activity and epithelial damage during DSS colitis. These findings highlight NM IIA as an important regulator of barrier properties of normal and inflamed intestinal mucosa in vivo. Supported by the Crohn’s and Colitis Foundation of America (NGN) and NIH grants DK083968 and DK084953 to AII.Grant Funding Source: Supported by the Crohn’s and Colitis Foundation of America (NGN) and NIH grants DK083968 and DK08495
Necrotizing enterocolitis leads to renal abnormality mediated through tight junction proteins (60.8)
Authors: Garg Parvesh Mohan , Tatum Rodney , Ravisankar Srikant , Hewan‐Lowe Karlene , Shekhawat Prem , Chen Yan‐Hua 
Published: June 2021

.Necrotizing enterocolitis (NEC) is the most common intestinal disease of premature infants. Clinically, it is associated with hyponatremia & fluid imbalance. NEC is associated with changes in the intestinal tight junction (TJ) proteins, but its effect on kidney TJ proteins is unknown. We investigated the expression of TJ proteins in kidney using a mouse NEC model. Four day old C57BL/6 pups were divided into 2 groups: the control group was dam‐fed; the experimental group was fed 50 µl 33% Esbilac formula every 3 h and subjected to asphyxia ( 100% N2 x 60 s) and cold stress (4°C for 10 min) twice a day to develop NEC. After 4 days of treatment, kidneys and intestines were collected. NEC was confirmed in intestines by histological exam. We found that the kidneys from the NEC group displayed interstitial edema. On western blot analysis, claudin‐1, ‐2, ‐3, and ‐7 were increased in the NEC kidney group compared to dam‐fed controls while the claudin‐5 expression remained unchanged. These findings were also confirmed on immunofluorescence. The levels of NF‐κB and p‐ERK1/2 in kidneys were elevated in the NEC group. No obvious apoptotic bodies and necrosis was seen in NEC group compared to controls. In conclusion, expression of several TJ proteins in kidneys was increased in the NEC group which may explain the reason behind kidney abnormality.Grant Funding Source: Supported by NIH grant number HL085752
Global lipocalin 2 deletion does not reverse high‐fat diet‐induced obesity resistance in mice lacking skin stearoyl‐CoA desaturase‐1 (605.10)
Authors: Friedlander Nicholas , Burhans Maggie , O'Neill Lucas , Ade Lacmbouh , Ntambi James 
Published: June 2021

In the past forty years, obesity has grown into a pressing health issue with global implications. Obesity significantly increases the risk of developing secondary conditions ranging from insulin resistance and atherosclerosis to certain types of cancer. Our lab previously determined that mice lacking stearoyl‐CoA desaturase‐1 (SCD1) in the skin (SKO) were lean and protected from high‐fat diet (HFD) induced adiposity and hepatic steatosis. Moreover, expression of lipocalin 2 (Lcn2), a gene with a controversial role in mediating obesity, was significantly elevated in the skin and plasma of these mice. In the current study, we hypothesized that Lcn2 may mediate some of the effects of the protection against HFD‐induced obesity in SKO mice. To analyze this, we crossed Lcn2‐deficient mice with SKO mice to produce Lcn2‐/‐; SKO, or double‐knockout (DKO) mice. Surprisingly, DKO mice remained protected from HFD‐induced obesity and hepatic steatosis relative to SKO mice. In conclusion, our data strongly suggests that, although Lcn2 is significantly upregulated in SKO mice, it does not mediate the beneficial metabolic effects of reduced adiposity and liver triglyceride accumulation under HFD feeding conditions.Grant Funding Source: Supported by NIH