tbuckley/cabot-search huggingface dataset:
Role of Anti‐Fractalkine Antibody in Suppression of Joint Destruction by Inhibiting Migration of Osteoclast Precursors to the Synovium in Experimental Arthritis
Authors: Kana Hoshino‐Negishi, Masayoshi Ohkuro, Tomoya Nakatani, Yoshikazu Kuboi, Miyuki Nishimura, Yoko Ida, Jungo Kakuta, Akiko Hamaguchi, Minoru Kumai, Tsutomu Kamisako, Fumihiro Sugiyama, Wataru Ikeda, Naoto Ishii, Nobuyuki Yasuda, Toshio Imai
Journal: Arthritis & Rheumatology (2018)

To elucidate the role of the fractalkine (FKN)/CX3 CR1 pathway in joint destruction in rheumatoid arthritis.We examined the effect of treatment with anti-mouse FKN (anti-mFKN) monoclonal antibody (mAb) on joint destruction and the migration of osteoclast precursors (OCPs) into the joint, using the collagen-induced arthritis (CIA) model. DBA/1 mice were immunized with bovine type II collagen to induce arthritis, and then treated with anti-mFKN mAb. Disease severity was monitored by arthritis score, and joint destruction was evaluated by soft x-ray and histologic analyses. Plasma levels of joint destruction markers were assessed by enzyme-linked immunosorbent assay. FKN expression on endothelial cells was detected by immunohistochemistry. Bone marrow-derived OCPs were labeled with fluorescein and transferred to mice with CIA, and the migration of the OCPs to the joints was then analyzed.Both prophylactic and therapeutic treatment with anti-mFKN mAb significantly decreased the arthritis and soft x-ray scores. Plasma levels of cartilage oligomeric matrix protein and matrix metalloproteinase 3 decreased after treatment with anti-mFKN mAb. Histologic analysis revealed that anti-mFKN mAb inhibited synovitis, pannus formation, and cartilage destruction, as well as suppressed bone damage, with a marked reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. Anti-mFKN mAb strongly inhibited the migration of bone marrow-derived OCPs into the affected synovium.Anti-mFKN mAb notably ameliorates arthritis and joint destruction in the CIA model, as well as inhibits migration of OCPs into the synovium. These results suggest that inhibition of the FKN/CX3 CR1 pathway could be a novel strategy for treatment of both synovitis and joint destruction in rheumatoid arthritis.
Abstract 15333: Choosing Where to Live or Die: Regional Variation in Outcomes Following Out-of-hospital Cardiac Arrest (OHCA) in the United States
Authors: Aiham Albaeni, May A. Beydoun, Shaker M. Eid, Bolanle Akinyele, Lekshminarayan RaghavaKurup, Hind A. Beydoun, Nisha Chandra-Strobos
Journal: Circulation (2015)

Background: Regional Differences in health outcomes following OHCA has been poorly studied, and was the focus of this investigation. Methods: We used the 2002 to 2012 Nationwide Inpatient Sample database to identify adults ≥ 18 years old, with an ICD-9 code principal diagnosis of cardio respiratory arrest (427.5) or ventricular fibrillation (427.1). Trauma patients were excluded. In 4 predefined federal geographic regions: North East, Midwest, South and West, means and proportions of total hospital charges (adjusted to the 2012 consumer price index,) and mortality rate were calculated. Multiple linear and logistic regression models, were adjusted for patient demographics, hospital characteristics and Charlson Comorbidity Index. Trends in binary outcome were examined with YearхRegion interaction terms. Results: From 2002 to 2012, of 155,592 OHCA patients who survived to hospital admission , 26,007 (16.7%) were in the Northeast, 39,921 (25.7% ) in the Midwest, 56,263 (36.2%) in the South, and 33,401 (21.5% ) in the West. Total hospital charges (THC) rose significantly over the years across all regions of the United States ( P trend &lt;0.0001), and were higher in the West Vs the North East (THC&gt;$109,000/admission, AOR 1.85; 95% CI 1.53-2.24, p&lt;0.0001), and not different in other regions. Compared to the Northeast, mortality was lower in the Midwest ( AOR 0.86, 95% CI 0.77-0.97 p=0.01), marginally lower in the South ( AOR 0.91, 95% CI 0.82-1.01 p=0.07), with no difference detected between the West and the Northeast ( AOR 1.02, 95% CI 0.90-1.16 P=0.78). Increased expenditure was not rewarded by an increase in survival, as trends in Mortality did not differ significantly between regions (YearхRegion effects P&gt;0.05, P trend =0.29). Conclusions: Nationwide, there is a considerable variability in survival and charges associated with caring for the post arrest patient. Higher charges did not yield better outcomes. Further investigation is needed to optimize health care delivery.
Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity
Authors: LucPardanaud, LaurencePibouin-Fragner, AlexandreDubrac, ThomasMathivet, IsabelEnglish, IsabelleBrunet, MichaelSimons, AnneEichmann
Journal: Circulation Research (2016)

Rationale:Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood. Objective:We set out to identify factors that promote arterial endothelial cell fate in vivo. Methods and Results:We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regula...
Abstract 2172: Dying tumor cells (tumor debris) stimulate the growth of 4T1 breast cancer tumor in female athymic nude mice
Authors: M Waheed Roomi, Aleksandra Niedzwiecki, Matthias Rath
Journal: Cancer Research (2018)

Abstract Current cancer therapies are based on chemotherapy and radiation. These therapeutic approaches can initially reduce the tumor mass or tumor burden by killing tumor cells. It has been postulated that the resulting dying tumor cells, or tumor debris, can act as sources of tumor stimulation on surviving cells leading to reappearance of the cancer, and thereby drastically reducing the survival rate. In our study we investigated whether 4T1 debris induced by chemotherapeutic agent docetaxel would affect breast tumor growth in female nude mice. Female athymic nude mice were divided into three groups: Group 1 was inoculated with 4T1 cells; Group 2 with 4T1 cells together with their debris and Group 3 with debris alone. All mice were fed a regular diet. After four weeks, the mice were sacrificed; tumors were excised, weighed and processed for histology and immunohistochemistry for inflammation parameters. Tumor weight significantly increased in Group 2 mice compared to the control Group 1. Group 3 mice developed no tumors. Although the tumor histology for both Groups 1 and 2 were similar, there were significant differences in inflammatory parameters in the two groups. Tumors developed in Group 2 mice had intense staining patterns for TNF-alpha, IL-6, Ki-67, i-Nos and VEGF compared to tumors in the control Group 1. Our results show that dying cells from docetaxel treatment, or tumor debris, had stimulatory effect on growth of breast cancer 4T1 cells in nude mice which was associated with increased inflammation. This study represents a novel method to evaluate the effects of chemotherapy or radiation on surviving tumor cells and to investigate the effect of various inhibitors on the growth recurrence. Citation Format: M Waheed Roomi, Aleksandra Niedzwiecki, Matthias Rath. Dying tumor cells (tumor debris) stimulate the growth of 4T1 breast cancer tumor in female athymic nude mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2172.
Abstract 2383: EGFR expression increases following decline in activity of N-acetylgalactosamine 4-sulfatase (ARSB) and SHP2 (PTPN11) and increases in chondroitin 4-sulfate and JNK in prostate
Authors: Sumit Bhattacharyya, Leo Feferman, Joanne K. Tobacman
Journal: Cancer Research (2018)

Abstract The enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) removes 4-sulfate groups from the non-reducing end of dermatan sulfate and chondroitin 4-sulfate (C4S) and is required for degradation of these sulfated glycosaminoglycans. Decline in ARSB and the resultant increase in C4S was previously reported to inhibit the activity of the enzyme SHP2 (PTPN11), a ubiquitous, non-receptor tyrosine phosphatase, and to lead to transcriptional events mediated by the sustained phosphorylation of phospho-ERK1,2 and phospho-p38. Previous experiments had shown that decline in ARSB was associated with increased expression of the epidermal growth factor receptor (EGFR; Her1/ErbB1) in human prostate malignant tissue and in human prostate cells, but the mechanism for this increase was unknown. The current experiments were performed to determine how decline in ARSB leads to increased expression of EGFR. Experiments were performed in human prostate stem and epithelial cells and normal and malignant human prostate tissues. Measurements included: EGFR promoter activity, chromatin immunoprecipitation assay, and binding studies of chondroitin sulfates with SHP2. Materials used included: SR11302, an inhibitor of c-fos binding with nuclear DNA; c-Jun peptide that acts as a c-Jun mimetic and inhibits c-Jun phosphorylation by JNK; JNK-selective inhibitor peptide that inhibits JNK phosphorylation; SHP2 dominant negative and constitutively active DNA constructs; PHPS1, an inhibitor of SHP2; ARSB siRNA, and galectin-3 siRNA. Increased EGFR promoter activation and EGFR expression followed decline in ARSB, decline in activity of SHP2 (PTPN11), enhanced activity of c-Jun N-terminal kinase (JNK), increased nuclear DNA binding of c-Jun and c-Fos, and EGFR promoter activation. These effects demonstrate an impact of ARSB and chondroitin 4-sulfation on the activation of a critical dual phosphorylation threonine-tyrosine kinase and on the mRNA expression of an important tyrosine kinase receptor in prostate cells. Restoration of ARSB activity may provide a new therapeutic approach to malignancies in which there is activation of EGFR-mediated tyrosine kinase signaling pathways. Citation Format: Sumit Bhattacharyya, Leo Feferman, Joanne K. Tobacman. EGFR expression increases following decline in activity of N-acetylgalactosamine 4-sulfatase (ARSB) and SHP2 (PTPN11) and increases in chondroitin 4-sulfate and JNK in prostate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2383.
Sympathetic Control of Canine Abdominal Aorta
Authors: MÁriaGEROVÁ, Jángero, Svatoplukdoležel, IDABLAŽKOVÁ-HuzulÁKOVÁ
Journal: Circulation Research (1973)

In anesthetized dogs the peripheral ends of the cut sympathetic chains (LG1-LG2 level) were stimulated while blood pressure was held constant artificially, and the diameter of the abdominal aorta was monitored. Bilateral stimulation induced a reduction in diameter that was directly related to the stimulation frequency. Maximal diameter reduction of the aorta above the iliac bifurcation averaged 8.01±0.74% of resting diameter. The half-time of contraction (36.5±2.1 to 51.5±3.6 seconds) was indirectly related to the stimulation frequency. The effects of right or left sympathetic chain stimulation were quantitatively similar to each other (51.3±4.4% and 46.7±4.5%, respectively), and the response to bilateral stimulation (92.8±6.1%) did not differ from the calculated value for paired unilateral stimulation (100%). A significant proximo-distal gradient of response (below the branching off of the renal arteries 2.97±0.28%, at the midpoint 5.15±0.52%, and above the iliac bifurcation 8.56±0.79% of resting diamete...
Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair
Authors: LeiYe, PengyuanZhang, SueDuval, LipingSu, QiangXiong, JianyiZhang
Journal: Circulation (2013)

Background—Thymosin β4 (Tβ4) has been shown to enhance the survival of cultured cardiomyocytes. Here, we investigated whether the cytoprotective effects of Tβ4 can increase the effectiveness of transplanted swine mesenchymal stem cells (sMSCs) for cardiac repair in a rat model of myocardial infarction (MI). Methods and Results—Under hypoxic conditions, cellular damage (lactate dehydrogenase leakage), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelingc cells), and caspase-8 activity were significantly lower, whereas B-cell lymphoma-extra large protein expression was significantly higher, in sMSCs cultured with Tβ4 (1 μg/mL) than in sMSCs cultured without Tβ4, and Tβ4 also increased sMSC proliferation. For in vivo experiments, animals were treated with basal medium (MI: n=6), a fibrin patch (Patch: n=6), a patch containing sMSCs (sMSC: n=9), or a patch containing sMSCs and Tβ4 (sMSC/Tβ4: n=11); Tβ4 was encapsulated in gelatin microspheres to extend Tβ4 delivery. Four weeks after treatme...
Abstract 15769: Association of Rate-dependent Conduction Block of Coronary Sinus - Left Atrial Connections With Atrial Fibrillation/Flutter Initiation at EP Study
Authors: Dong Huang, Joseph E Marine, Jing-bo Li, Tarek Zghaib, Esra G Ipek, Muhammad Balouch, Hiroshi Ashikaga, Ronald D Berger, Sunil Sinha, David D Spragg, Hugh Calkins, Saman Nazarian
Journal: Circulation (2016)

Introduction: Although clinically recognized, variations in distal coronary sinus musculature and left atrial myocardium (CS-LA) connections have not been systematically evaluated. Hypothesis: We s...
Agreement between histopathologic regression and MRI Tumour Regression (mrTRG) scales used to assess response for rectal cancers
Authors: M. Siddiqui, S. Balyansikova, I. Nagtegaal, N. West, G. Murray, S. Bosch, None A. van-Tilberg, C. Kaur, A. Wotherspoon, N. Bottomley, C. Finlayson, P. Tekkis, S. Rasheed, A. Abulafi, G. Brown
Journal: International Journal of Surgery (2018)
Dose-Dependent Contribution of CD34-Positive Cell Transplantation to Concurrent Vasculogenesis and Cardiomyogenesis for Functional Regenerative Recovery After Myocardial Infarction
Authors: HirotoIwasaki, AtsuhikoKawamoto, MasakazuIshikawa, AkiraOyamada, ShukoNakamori, HiromiNishimura, KazuyoSadamoto, MikiHorii, TomoyukiMatsumoto, SatoshiMurasawa, ToshihikoShibata, ShigefumiSuehiro, TakayukiAsahara
Journal: Circulation (2006)

Background— Multilineage developmental capacity of the CD34+ cells, especially into cardiomyocytes and smooth muscle cells (SMCs), is still controversial. In the present study we performed a series of experiments to prove our hypothesis that vasculogenesis and cardiomyogenesis after myocardial infarction (MI) may be dose-dependently enhanced after CD34+ cell transplantation. Methods and Results— Peripheral blood CD34+ cells were isolated from total mononuclear cells of patients with limb ischemia by apheresis after 5-day administration of granulocyte colony-stimulating factor. PBS and 1×103 (low), 1×105 (mid), or 5×105 (high) CD34+ cells were intramyocardially transplanted after ligation of the left anterior descending coronary artery of nude rats. Functional assessments with the use of echocardiography and a microtip conductance catheter at day 28 revealed dose-dependent preservation of left ventricular function by CD34+ cell transplantation. Necropsy examination disclosed dose-dependent augmentation of ...
Abstract 4798: Targeting hTERT for treatment of glioblastoma (GBM)
Authors: Saumya Reddy Bollam, Hyun-Jin Kang, Sen Peng, Vijay Gokhale, Laurence Hurley, Michael Berens, Harshil Dhruv
Journal: Cancer Research (2018)

Abstract Approximately 86% of GBM tumors exhibit a mutation at -124 or -146 bp upstream from the ATG start site in the transcription activating promoter region of Human telomerase reverse transcriptase (hTERT). Mutations in the hTERT promoter are known to impair repression, leading to overexpression of hTERT and tumor maintenance. Yet, complete understanding of mechanistic implications is still necessary. While overexpressed hTERT is associated with oncogenesis and resistance to apoptosis, we also observe phenotypes unrelated to the reverse transcription function. We characterized long-term glioma cell lines and glioma PDX models by hTERT promoter mutation status, hTERT mRNA expression, and hTERT protein expression in subcellular fractions. The -124 and -146 mutations are located in the major 5-12 G-quadruplex and result in misfolding of the silencer element, thus causing over-expression of hTERT. Using a diverse small molecule library, we identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, TG-4260, which binds to the 26 mer base-pair heteroduplex loop, which is the nucleation site for cooperative folding of the major 5-12 G-quadruplex. The chaperone effect of TG-4260 corrects DNA hTERT G-quadruplex misfolding resulting from the promoter mutations and restores the silencer function of the G-quadruplex. TG-4260 directly decreases the transcription activity of the −124, −124/125, −138/139, and −146 mutants to a similar extent and suppresses the downstream gene BCL2, which activates caspase-3 and produces cell-cycle arrest, leading to cell death. This is the first example of the use of a pharmacoperone molecule to correct the misfolding of a DNA G-quadruplex element resulting from mutations in an early folding intermediate. We screened GBM cell models against this novel small molecule inhibitor that interferes with mutated hTERT promoter and demonstrated that TG-4260 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. Finally, telomere phenotypes from treated cells indicate non-canonical functions of telomerase may also contribute to glioma pathogenesis. Citation Format: Saumya Reddy Bollam, Hyun-Jin Kang, Sen Peng, Vijay Gokhale, Laurence Hurley, Michael Berens, Harshil Dhruv. Targeting hTERT for treatment of glioblastoma (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4798.
Abstract 1128: Exosomal ID3 is pro-metastatic through guiding NRF1-induced breast cancer stem cells across the blood-brain-barrier
Authors: Jayanta K. Das, Mayur Doke, Alok Deoraj, Quentin Felty, Deodutta Roy
Journal: Cancer Research (2018)

Abstract Nuclear respiratory factor 1 (NRF1) and inhibitor of differentiation protein 3 (ID3) are transcription regulating proteins. Recently we have uncovered a novel oncogenic function of NRF1 in breast cancer development and progression. In this study, we tested the postulate that exposure to PCB153 contributes in ID3 over-expressing endothelial stem cells (EndSCs) chaperoning and guiding of mesenchymal NRF1 breast cancer stem cells (BCSCs) across the blood-brain barrier. BCSCs/EndSCs were subjected to functional gain/loss of ID3 and/or NRF1 to test if PCB153 [1ng/ml] exposure produces NRF/ID3 signals regulating lineage specific BCSCs organ entry. First, we tested whether NRF1 promotes transmigration of breast cancer using a 3D blood-brain barrier (BBB) model consisting of breast tumor initiating cells (BTICs) or MDAMB231 cells, brain endothelial cell layer, and astrocytes. NRF1 overexpression increased the propensity for BTICs and mesenchymal enriched MDAMB231 BCSCs to adhere to brain endothelial cells and migrate across a human BBB model. Increased adhesion of NRF1+ BCSCs with ID3+ EndSCs was detected. ID3 EndSCs promoted the transmigration of BCSCs through the BBB. We found differential effects by endocrine disruptors, namely PCB153 and PCB77. The treatment with PCB153 showed increased growth of NRF1+ BCSCs tumor spheroids. PCB153 also induced the tumor cell adhesion to microvascular endothelium and transendothelial migration of BCSCs. The exosomal ID3 released from endothelial cells helped the mesenchymal NRF1+ BCSCs to cross through blood brain barriers. Xenograft experiments showed that ID3+ brain EndSCs not only supported the growth of estrogen treated NRF1+ BCSC tumorospheroids, but guided them to the brain in zebrafish. These findings show for the first time a key role for ID3 and NRF1 by which specific circulatory EndSCs accompany a particular sub-type of BCSCs to distant metastatic sites where they most likely facilitate the seeding, survival, and proliferation of BCSCs. This knowledge is important for pre-clinical testing of NRF1/ID3 modifying agents that prevent the spread of breast cancer to the brain. This work was, in part, supported by a VA MERIT Review (VA BX001463) grant to DR. Citation Format: Jayanta K. Das, Mayur Doke, Alok Deoraj, Quentin Felty, Deodutta Roy. Exosomal ID3 is pro-metastatic through guiding NRF1-induced breast cancer stem cells across the blood-brain-barrier [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1128.
Abstract 2257: AGISTM-OncoGxKB: A simple tool for actionable genomic knowledgebase curation and clinical interpretation
Authors: Pengfei Yu, Cheng Yan
Journal: Cancer Research (2018)

Abstract Nowadays, targeted therapy and immunotherapy have become the mainstream of cancer therapy because of their overall merit over traditional chemotherapy. With the increasing number of drug targets being discovered, cancer patients are more likely to benefit from these advanced therapies. However, the interpretation of actionable variants from patients is still a challenge in cancer clinical sequencing workflows. Here we present OncoGxKB, a crowdsource-based knowledgebase system tailored to provide clinical interpretation of variants in cancer. Based on genetic makeup of patient tumor, OncoGxKB provides actionable therapeutic strategies that maximize treatment efficacy and minimize side effects. The clinical recommendations provided cover targeted therapies, immunotherapies and clinical trials associated with actionable variants. Interpretations are rendered in tiers based on clinical evidence and stratified cancer types, following the newest AMP guideline. The crowdsource-based implementation keeps OncoGxKB comprehensive, updated, transparent and accessible to scientific community. The application programming interface (API) availability can also make the interpretation system be easily adopted to different existing pipelines. OncoGxKB is publicly available at: https://agis.admerahealth.com/OncoGxKB. Citation Format: Pengfei Yu, Cheng Yan. AGISTM-OncoGxKB: A simple tool for actionable genomic knowledgebase curation and clinical interpretation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2257.