bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic variations driving malignant follicular lymphoma regulatory circuitry (LB489)
Authors: Sandoval Luis , Koues Olivia , Oltz Eugene 
Published: June 2021

Regulatory elements play a major role in establishing cell‐specific gene expression patterns. Perturbations in these non‐coding DNA regions (e.g., promoters and enhancers) facilitate gene expression changes associated with lymphomagenesis. To investigate the regulatory circuitry driving follicular lymphoma (FL), a germinal center‐derived B cell lymphoma, we generated global chromatin maps of histone modifications associated with active REs in primary FL tumors and normal human B cells. Comparative epigenomic analyses produced a collection of enhancers that are dysregulated during lymphomagenesis. We then identified sequence motifs that are enriched significantly in the augmented regulatory elements (REs) from ten FL samples. The most recurrent and significant motifs bind families of factors known to be important for transcriptional regulation in lymphocytes, including SPI, BCL6, KLF, POU, and TCF. Subsequent informatics analyses revealed transcription factor (TF) binding motifs within a subset of enhancers that were altered by single nucleotide variants (SNVs), suggesting a functional role for intergenic SNVs in tumor pathogenesis. Because changes to the epigenome are reversible, improved understanding of these pathogenic regulatory circuits will provide attractive therapeutic targets to reverse malignant gene expression. Data from our approach are expected to facilitate early NHL diagnosis, enhance prognostic schemes, and identify novel therapeutic targets.Grant Funding Source: Supported by NIH grant CA156690
Diabetic hyperglycemia improves lipid profile and oxidative stress after myocardial infarction in rats (LB49)
Authors: Paixão dos Santos Camila , Ferreira Freitas Sarah Cristina , Rocha Zepter Rita de Cássia , Henriques Dutra Marina Rascio , da Palma Renata Kelly , Andrade Barboza Catarina , Irigoyen Maria‐Cláudia , De Angelis Katia , Malfitano Christiane 
Published: June 2021

This study was designed to evaluate the lipid and oxidative stress profiles in diabetic rats that had undergone 15 days of myocardial infarction. Male Wistar rats were divided into control (C), diabetic (D), myocardial infarction (MI) and diabetic myocardial infarction (DMI). Left coronary artery occlusion was performed after 15 days of diabetes (STZ) and accompanied for more 15 days. The free fatty acids and triacylglycerol content and oxidative stress profile were determined by biochemical analysis in left ventricle. The free fatty acids were increased in DMI: 1.16±0.2 vs D: 0.45±0.09; MI: 0.72±0.1 and C: 0.4±0.05 mg/g of tissue, however the triacylglycerol was increased in D: 2.12±0.3 and decreased in DMI: 0.72±0.1 and MI: 1±0.2 vs C: 1.45±0.1 mg/g of tissue. The catalase activity was increased in DMI: 0.62±0.1; D: 0.56±0.09 vs C: 0.29±0.05 and MI: 0.35± 0.02 nmol/mg and glutathione peroxidase increased in DIM: 0.04±0.008 vs D: 0.02±0.003; MI: 0.02 ±0.0002 and C: 0.01±0.005 umol/min/mg. The superoxide anion and protein carbonylation were increased in MI group: 7±0.9 vs D:4±0.5; DIM:4±0.5 and C:4±0.4 O2‐mmoles/mg and MI:2.65 ± 0.36 vs D: 1.5 ± 0.24; DIM: 1.22 ± 0.2 and C: 1.45 ± 0.26 nmol/mg. These findings suggest that diabetic rats exposed to an ischemic injury showed an increase in the lipids utilization and an oxidative stress reduction, supporting previously published data of improvement of the cardiac function in these model.Grant Funding Source: Fapesp
Triiodothyronine regulates indirectly Amphiregulin gene expression in estrogen‐positive breast cancer cell line. (LB494)
Authors: Conde Sandro , De Síbio Maria , De Oliveira Miriane , Moretto Fernanda , Olímpio Regiane , Luvizon Aline , Padovani Carlos , Nogueira Celia 
Published: June 2021

Amphiregulin (AREG) is considered an oncogene whose expression is related to several types of cancer. Our group identified a triiodothyronine (T3) action on different genes of breast cancer cell lines through the microarray approach, including AREG; however, there are no works about how T3 regulates AREG gene expression. The relation between AREG and T3 remains unclear and, for this reason, in this study we are looking for nuclear and extra‐nuclear action of T3 on AREG gene expression in MCF‐7, an estrogen‐receptor‐positive breast cancer cell line. Cells were treated with 10‐8 M T3 for 10, 30, 60 and 240 minutes, separately. Treatments were organized with or without Cycloheximide (CHX ‐ 50uM), a protein synthesis inhibitor, and with or without Fulvestrant (ICI ‐ 1uM), an estrogen receptor antagonist. The mRNA was analyzed by real‐time PCR approach. T3 increases gene expression of AREG in MCF‐7 cell lines, independently of incubation time, but this action was converted to the control level when T3 was associated with CHX, indicating that prior protein synthesis is required in this process. Addition of ICI to T3 for 10 minutes augmented gene expression in relation to those cells treated only with T3, but after 30 minutes, ICI plus T3 decreased AREG gene expression when compared with T3 itself. Therefore, T3 regulation of AREG gene expression is dependent on prior protein synthesis and estrogen receptor. Estrogen receptor is necessary for AREG gene expression in contrary ways when comparing 10 minutes with 30, 60, 240 minutes. The alteration in AREG gene expression is dependent on the time elapsed after the treatment, indicating that metabolism changes could be altered after 10 minutes in T3‐dependent AREG gene expression.Grant Funding Source: Supported by FAPESP grant 2009/15607‐2 and 2013/11111‐8
Non‐invasive ultrasound in the study of recombinant CTGF‐CT therapy in mice gastric cancer model (LB497)
Authors: Lee Hsinyu , Chang Cheng‐Chi , Chen Chia‐I , Chen Chiung‐Nien 
Published: June 2021

Aim: Connective tissue growth factor (CTGF) has been known to play important roles in normal physiological conditions as well as pathological conditions. In gastric cancer, previous study has shown that CTGF expression elevation blocks the adhesion of gastric cancer cells to peritoneum in vitro and in vivo. In this study we aimed to purify CTGF from E. coli using a His‐tag purification system and setup a non‐invasive small animal model to study the effect of recombinant CTGF in gastric cancer progression.Material and methods: Recombinant CTGF‐CT was purified using a His‐tag purification system. Gastric cancer cell was injected with or without recombinant CTGF‐CT into SCID mice intraperitoneally. Growth of gastric cancer tumor was observed using small animal ultrasound and survival was calculated using the Kaplan‐Meier survival probability assay.Results: Recombinant CTGF‐CT was shown to have about 50% inhibition in in vitro adhesion assay (p‐value < 0.001). Ultrasound scans have shown higher average tumor sizes and numbers in non‐treated, and vehicle treated group compared to recombinant CTGF‐CT treated group. 100% mortality of mice in recombinant CTGF‐CT treated group compared to vehicle treated group and non‐treated group were at 2 months and 7 days, 1.5 months, and 1 month respectively.Conclusion: Purified recombinant CTGF‐CT significantly reduced the number and size of gastric cancer tumors in mice determined using non‐invasive ultrasound and is a potential therapeutic drug in gastric cancer therapy.Grant Funding Source: Supported by National Science Councel, Taiwan
Dexmedetomidine reduced astrocyte connexin 43 and attenuated neuropathic pain induced by partial sciatic nerve ligation in rats (LB503)
Authors: Wang lingzhi , Huang huansen , Xia weiyi , He yanbing , Cheung Chi‐Wai , Xia zhengyuan 
Published: June 2021

Dexmedetomidine(DEX) has been shown to attenuate neuropathic pain (NP), but the mechanism is unclear. Astrocytes connexin 43(Cx43) is increased in subjects with NP and plays an important role in the development and maintenance of NP (Glia. 2012;60(11):1660‐70). We thus investigated the role of astroglia Cx43 in DEX‐induced anti‐nociceptive effects in rats with NP. Peripheral NP was induced by partial sciatic nerve ligation (PSNL) in SD rats. After 10 days of inducing NP, DEX was intrathecally administrated for 5 days and ipsilateral mechanical allodynia and thermal hyperalgesia were examined by Von Frey Test and Hargreaves Test. Compared with control rats, PSNL induced significant ipsilateral mechanical allodynia and thermal hyperalgesia (P<0.05) that were coincident with enhanced Cx43 and increased astroglia activation in ipsilateral lumbosacral dorsal spinal cord. DEX inhibited astroglia Cx43 expression and attenuated NP (P<0.05 vs. control). Cx43 gene knock‐down did not significantly further enhance DEX mediated attenuation of NP. We concluded that astroglia Cx43 plays a critical role in DEX mediated anti‐nociceptive effects in rats with NP.Grant Funding Source: Supported by Departmental development fund Supported by Science and Technology Planning Project of Guangdong Province(2010B060900089). The authors are grateful to Pro.Huang for critical design and revise. huanghs5480@163.com
Extraintestinal helminth infection reduces the development of colitis‐associated colorectal cancer (LB518)
Authors: Terrazas Luis , Callejas Blanca , León‐Cabrera Sonia , Perez‐Plasencia Carlos , Gutiérrez‐Cirlos Emma Bertha , Chirino Yolanda , Ledesma‐Soto Yadira , Avila‐Moreno Federico , Rodriguez‐Sosa Miriam 
Published: June 2021

Whereas a causal association between viral and bacterial infections with tumor development has been well established in animal and epidemiological studies, the impact of parasitic infections in cancer development is almost unknown. Evidences indicate that cancer can be triggered by chronic or deregulated inflammatory processes, such as colitis‐associated colorectal cancer (CAC). Using a helminth infection model, we have analyzed the role of helminth‐induced anti‐inflammatory response in determining the outcome of CAC. Following Taenia crassiceps infection and development of CAC, mice displayed inhibited colonic inflammatory responses and reduced circulating and colonic CD11b+Ly6C+CCR2+ monocytes. Instead they increased the expression of IL‐4 and alternatively activated macrophages (AAMs) markers at the colonic tissue. Strikingly, T. crassiceps‐infected mice developed few tumors and reduced pathology. In contrast, uninfected mice mounted strong inflammatory responses, did not express AAMs markers, developed severe pathology and displayed multiple tumors. Thus, immunomodulatory activities induced by helminth infections may have a role in the resistance and progression of CAC.Grant Funding Source: Supported by 167799 CONACYT (Mexico), PAPIIT‐UNAM IN213512, PAPCA‐2013 FES‐Iztacala 16, 19, 28
An IL‐33 immunotherapy that blocks tumor growth by establishing innate lymphoid cells. (LB52)
Authors: KIM JUYANG 
Published: June 2021

An IL‐33 immunotherapy that blocks tumor growth by establishing innate lymphoid cells.Wonyoung Kim1, Juyang Kim1, Hyun Ju Kim2, U‐jeong Moon2, So Yeon Jung2, Hye‐Jeong Choi3, H. R. Cho1,4, B. Kwon1,21Biomedical Research Center, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan, Korea2School of Biological Sciences, University of Ulsan, Ulsan, Korea3Department of Pathology, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan, Korea4Department of Surgery, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan, KoreaAbstract A long‐standing question in the field of tumor immunotherapy is how type 2 T helper cell (Th2) cytokines can block tumor growth. The anti‐tumor effects of Th2 cytokines are particularly prominent when they are manipulated to be continuously secreted in tumor mass. This observation suggests that Th2 cytokines may create a tumor microenvironment unfavorable for tumor growth independently of adaptive immunity. We show here that sustained intratumoral expression of IL‐33 establishes a high numbers of innate lymphoid cells secreting high levels of CXCL1/2 which are induced scenescence of tumor cells. IL‐33 increased intratumoral hypoxia which is induced high levels of CXCR2 and down‐regulation of HIF‐1α in tumor. CXCR2 signaling strongly induces apoptosis of tumor cells, thereby preventing normal angiogenesis in tumor mass. Our results identify a previously unrecognized function of ILC2s which mediate type‐2 innate immunity leading to antitumor activity.$graphic_B005C94A‐61C7‐4E8A‐A3BD‐C0DF9DCCE278$
Histamine blockade reduces femoral blood flow with no apparent change in vascular permeability after muscle damaging exercise (LB523)
Authors: Ely Matthew , Romero Steven , Gilbert‐Gard Kacy , Sieck Dylan , Buck Tahisha , Halliwill John 
Published: June 2021

Blood flow to previously exercised muscle remains elevated for up to two hrs after exercise and is mediated by activation of histamine receptors. Activation of histamine receptors could lead to increased vascular permeability, an initial stage of inflammation, associated with muscle damage. Therefore, the purpose of this experiment was to determine if histamine receptors contribute to the increased permeability in a model of exercise‐induced muscle damage. Muscle damage was induced in seven volunteers (2F, 5M) by 45‐min of downhill running (‐10% grade) at a heart rate of ~150 BPM. Volunteers were randomly assigned to histamine blockade (540 mg fexofenadine; an H1 blocker and 300 mg ranitidine; an H2 blocker) or control (no drug). Prior to and for 120 min following exercise, femoral blood flow was measured using Doppler ultrasound, while vascular permeability was measured as a change in thigh and calf circumference during four min of supravenous pressure occlusion. The rise in femoral blood flow after exercise was 52 ± 12% (Mean ± SE) lower with histamine blockade vs control (p<0.05). Additionally, thigh and calf vascular permeability tended to be higher with histamine blockade (109 ± 92%; 42 ± 21%) vs control (73 ± 58%; 34 ± 20 %)(p>0.05). Thus, it appears that post‐exercise histamine receptor activation may not contribute to the initial stages of an inflammatory response for muscle damaging exercise.Grant Funding Source: NIH grant HL115027
Biochemical and pharmacological rationale for the use of newer oral anticoagulants in the long term management of heparin induced thrombocytopenia (LB526)
Authors: Fareed Jawed , Hoppensteadt Debra , Walenga Jeanine , Jeske Walter , Lewis Bruce 
Published: June 2021

Introduction: Heparin induced thromboycytopenia (HIT) is a catastrophic complication of heparin therapy. While parenteral antithrombin agents can be used for acute/intravenous management of this syndrome there is a need for long term outpatient antithrombotic management of HIT patients. The purpose of this study is to investigate the use of newer oral anticoagulant agents (NOACs) as substitute anticoagulants for HIT patients.Material and Methods: Individual (25) and pooled (5 )HIT sera were used to investigate their effects on platelet aggregation, PF4 release and thrombin generation. The effect of rivaroxaban, apixaban and dabigatran was compared with unfractionated heparin (UFH) in platelet rich plasmas normal donors. The relative immunogenic potential of each of these agents was also compared in a rabbit model.Results: In contrast to UFH none of the NOACs produced any aggregation of platelets (7+3) vs (64+9%) While heparin resulted in a release of PF4 from platelets (179 + 11) the NOACs produced marginal release (<30ng/ml). In the thrombin generation assays variable results were obtained with NOACs. The relative immunogenicity of NOACs was marginal in comparison to heparin in rabbits.Conclusion: These results suggest that the NOACs do not interact or release PF4 from patients. Moreover, none of these agents produce activation or aggregation of platelets. These observations warrant bridged clinical trials with parenteral anticoagulant agents to ensure the efficacy and safety of NOACs in HIT.
Genomic Annotation of Drosophila biarmipes Dot Chromosome Contig 19 (LB531)
Authors: McCullough Austin , Greuel Brian 
Published: June 2021

Comparative analysis of the genome of Drosophila melanogaster with other Drosophila species at various evolutionary distances can reveal information about differences in euchromatic and heterochromatic gene structure, and how evolutionary processes have changed the expression of genes located in these regions. The goal of this project, performed in conjunction with the Genomics Education Partnership at Washington University, was to annotate all the major features of Drosophila biarmipes dot chromosome Contig 19 ‐ including genes, pseudogenes, and repetitive sequences ‐ to generate a high quality section of the genome of this species. Basic Local Alignment Search Tool (BLAST) was used along with Gene Record Finder to compare the protein sequence of D. melanogaster exons to the D. biarmipes contig in order to locate the placement of the homologous exons in the latter species. Gene predicting programs were used to examine regions of the genome not immediately shown to contain genes. This information was entered into Gene Model Checker to compile a comprehensive map of the contig. Contig 19 is on the fourth (dot) chromosome of Drosophila biarmipes and it contains three genes, Syt7, Rad23 and Zip102B. Both the Syt7 and Rad23 genes showed high sequence conservation with their orthologs in D. melanogaster and are present in the same orientation. The Zip102B gene showed evidence of greater sequence divergence. Consistent RNAseq data and agreement between gene prediction programs led to the conclusion that this sequence divergence was due to the accumulation of point mutations relative to a common ancestral species. The contig displayed a repetitive element percentage of 40.32 percent, which is consistent with a heterochromatic DNA classification. No pseudogenes were identified in this contig.Grant Funding Source: Supported by HHMI grant # 52005780 to SCR Elgin at Washington University (St. Louis).
Reducing leukocyte‐endothelial interactions through FPR2/ALX in microglial instigated stroke (LB543)
Authors: Smith Helen , Gavins Felicity 
Published: June 2021

Members of the formyl peptide receptor family (in particular FPR2/ALX; Fpr2/3 in mouse) act as endogenous anti‐inflammatory/pro‐resolving agents. We investigated the mechanism through which an inflammatory response was generated in a model of global stroke, as well as the pharmacological potential of FPR ligands in modulating this inflammation.Mice underwent bilateral common carotid artery occlusion (BCCAO, 5min) and reperfusion (40min or 2h). FPR agonists (Annexin A1 peptide Ac2‐26 (AnxA1Ac2‐26) and 15‐epi‐lipoxin A4 (15‐epi‐LXA4)) were administered at the start of reperfusion, and resulting cerebral leukocyte‐endothelial (L‐E) interactions viewed using intravital microscopy. Leukocyte rolling and adhesion were then quantified in each mouse.At 40 min reperfusion, 15‐epi‐LXA4 (0.5μg and 4μg/mouse) reduced inflammation vs. vehicle treatment, although this reduction was not sustained at 2h with 0.5μg/mouse. AnxA1Ac2‐26 treatment decreased leukocyte adhesion at 40min and 2h vs. vehicle. Combined treatment of AnxA1Ac2‐26 and FPR antagonists Boc2 or WRW4 (FPR2/ALX‐selective) abrogated the effects of AnxA1Ac2‐26 at 40min, suggesting an Fpr2/3 mechanism. Abrogation was not sustained at to the same extent at 2h. Immunogold‐labeling showed co‐localization of endogenous AnxA1 with Fpr2/3 in the brain in treatment groups, further indicating a protective Fpr2/3 mechanism in the model.Further work identified microglial activity as a potential mechanism for increased L‐E interactions in vehicle‐treated groups. Increased numbers of microglia were observed following BCCAO and 2h reperfusion in immunostained brain slices. In addition, pre‐treatment with minocycline (an inhibitor of microglial activity) abrogated the increased L‐E interactions observed through intravital microscopy.To conclude, 15‐epi‐LXA4 and AnxA1Ac2‐26 reduced L‐E interactions (which were at least in part instigated through microglial activity) in this model of stroke, in a dose and time‐dependent manner, and likely via FPR2/ALX. These novel data indicate that that modulation of FPR2/ALX could produce significant protective effects in clinical stroke.Grant Funding Source: Supported by BBSRC
Reenergizing aged mitochondria to combat retinal degeneration (LB555)
Authors: Mills William , Alam Nazia , Prusky Glen , Szeto Hazel 
Published: June 2021

Bioenergetic failure is the major risk factor for Age‐Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). Within the eye, the delicate microvasculature of the choroid and the metabolically active retinal pigment epithelium (RPE) are especially sensitive to the stresses of age and diabetes. Using mouse models of diabetes and advanced age, we demonstrated diabetes/aging‐induced abnormalities of the mitochondria in the choroid and RPE, alterations to the choroidal microvasculature, disruption to the RPE, and an increase in inflammation markers. Treatment with the novel cardiolipin‐targeted antioxidant tetrapeptide SS‐31, after onset of diabetes or in aged mice, restored proper RPE integrity and mitochondrial morphology, as well as reduced the intrusion of neovascular tufts from the choroid through the RPE and the level of inflammation markers. Moreover, SS‐31 administration restored visual function as demonstrated by optokinetic tracking. Thus we are the first to pioneer a mitochondrial‐targeted approach for resolving feed‐forward mitochondrial damage and restoring bioenergetic capacity in the choroid and RPE, thereby preventing disease progression and restoring visual function in early AMD and DR.Grant Funding Source: Supported by the Tri‐Institutional Training Program in Vision Research (5T32EY007138‐20)
Phenotyping age‐sependent changes in the 5xFAD Alzheimer’s Disease Model mice (LB556)
Authors: Yang Charles , Feng Ruiben , Yang Ling , Jiang Shujuan , Liu Na , Yan Li , Liu yi , Yang Cecilia , Wang KeWei 
Published: June 2021

5XFAD transgenic (Tg) mice express 5 human familial Alzheimer’s Disease (AD) gene mutations ‐ Amyloid Precursor Protein mutations from the Swedish, Florida and London families, along with 2 mutations in presenilin‐1. Their early onset brain pathology, accelerated Aβ42 amyloid deposition, age‐dependent neurodegeneration and cognitive decline, make these mice an attractive translatable AD model.We used behavioral, biochemical and electrophysiological analyses to track age‐dependent changes in 5XFAD mice, compared with their age‐matched wild‐type mice. With sensitive NanoPro Western, 3 month old 5XFAD mice showed a significant increase of p‐T181‐Tau in the cerebral spinal fluid. Their hippocampal ELISA Aβ40 and 42 levels increased progressively from 2,3,6 months. Under confocal microscopy, the secondary and tertiary dendritic spine counts in Golgi‐stained 9 month prefrontal and hippocampal pyramidal neurons showed a significant loss. Hippocampal slice electrophysiology using the multielectrode MED64 system is used to assess synaptic plasticity, i.e. long‐term potentiation.Using the Laboras vibration‐sensitive platforms, we discovered that there was a significant dark phase hyperactivity and bi‐directional circling that resembled striatal degeneration, and hyperlocomotion at 9, 12, but not 2 month, matching the chronic EEG recordings of a significant reduction in NREM and REM sleep at 9 month. The onset of cognitive decline started at 4 months (working memory, Y‐maze spontaneous alteration), 5 month (episodic memory, Novel Object Recognition), and 6 month (spatial memory, Morris Water Maze). Sub‐chronic treatment in 4 months old 5XFAD mice by: a) Donepezil + Memantine (2 weeks), or b) Traditional Chinese herbal formula (1 month), led to a significantly improvement in Y‐maze spontaneous alternation performance.Findings from these studies guide us to select the right ages of 5XFAD mice to test for pharmacological changes in AD biomarkers and behaviors in AD research.