tbuckley/cabot-search huggingface dataset:
Short Aβ peptides attenuate Aβ42 toxicity in vivo
Authors: Brenda D. Moore, Jason Martin, Lorena de Mena, Jonatan Sanchez, Pedro E. Cruz, Carolina Ceballos-Diaz, Thomas B. Ladd, Yong Ran, Yona Levites, Thomas L. Kukar, Justin J. Kurian, Robert McKenna, Edward H. Koo, David R. Borchelt, Christopher Janus, Diego Rincon-Limas, Pedro Fernandez-Funez, Todd E. Golde
Journal: The Journal of Experimental Medicine (2017)

Processing of amyloid-β (Aβ) precursor protein (APP) by γ-secretase produces multiple species of Aβ: Aβ40, short Aβ peptides (Aβ37–39), and longer Aβ peptides (Aβ42–43). γ-Secretase modulators, a class of Alzheimer’s disease therapeutics, reduce production of the pathogenic Aβ42 but increase the relative abundance of short Aβ peptides. To evaluate the pathological relevance of these peptides, we expressed Aβ36–40 and Aβ42–43 in Drosophila melanogaster to evaluate inherent toxicity and potential modulatory effects on Aβ42 toxicity. In contrast to Aβ42, the short Aβ peptides were not toxic and, when coexpressed with Aβ42, were protective in a dose-dependent fashion. In parallel, we explored the effects of recombinant adeno-associated virus–mediated expression of Aβ38 and Aβ40 in mice. When expressed in nontransgenic mice at levels sufficient to drive Aβ42 deposition, Aβ38 and Aβ40 did not deposit or cause behavioral alterations. These studies indicate that treatments that lower Aβ42 by raising the levels of short Aβ peptides could attenuate the toxic effects of Aβ42.
Topographic Pattern of Valve Calcification
Authors: Antonio de Santis, Flavio Tarasoutchi, Jose de Arimatéia B. Araujo Filho, Marcelo C. Vieira, Cesar H. Nomura, Marcelo Katz, Guilherme S. Spina, Roney O. Sampaio, Tarso A.D. Accorsi, Vitor E.E. Rosa, João R.C. Fernandes, Jonathan Brown, Elazer R. Edelman, Pedro A. Lemos
Journal: JACC. Cardiovascular imaging (2017)
Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance
Authors: Cecilia S. Leung, Tsz-Lun Yeung, Kay-Pong Yip, Kwong-Kwok Wong, Samuel Y. Ho, Lingegowda S. Mangala, Anil K. Sood, Gabriel Lopez-Berestein, Jianting Sheng, Stephen T.C. Wong, Michael J. Birrer, Samuel C. Mok
Journal: Journal of Clinical Investigation (2017)

The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.
Abstract 19814: A Randomized, Crossover Pilot Trial of Neuromonitoring-Guided Goal-Direct Post-Arrest Care After Opioid Overdose
Authors: Jonathan Elmer, Katharyn L Flickinger, Maighdlin W Anderson, Allison Koller, Matthew Sundermann, Cameron Dezfulian, David O Okonkwo, Lori A Shutter, David Salcido, Clifton W Callaway, James J Menegazzi
Journal: Circulation (2016)

Introduction: Outcomes after resuscitation from cardiac arrest (CA) remain poor. Preventable secondary injury from ongoing brain tissue hypoxia (BTH) may worsen injury burden. Unfortunately, marker...
A phase 1b/2 study of omaveloxolone in combination with checkpoint inhibitors in patients with unresectable or metastatic melanoma
Authors: S.P. Patel, F.S. Hodi, D. Gabrilovich, M. Chin, G. Gibney, A. Goldsberry, R. Gonzalez, J. Hurt, J. Markowitz, E. Whitman, C. Meyer, A. Salama
Journal: Annals of Oncology (2017)
Abstract 18849: Arterial Calcification Can Be Inhibited via Maintained Mitochondrial Homeostasis in Chronic Kidney Disease
Authors: Chih-Ping Chung, Kenneth Lim, Tzongshi Lu
Journal: Circulation (2013)

Background: Vascular calcification (VC) is a significant contributor to cardiovascular mortality in patients with chronic kidney disease and chronic inflammatory conditions. Previous work by our group has shown that HSP72 is an inducible protein that can preserve mitochondrial complexes II, IV, NADH cytochrome c reductase (NCCR), succinate cytochrome c reductase (SCCR), and cytochrome c oxidase (CCO) activities and prevent cardiomyocyte apoptosis. We recently reported that heat shock protein 72 (HSP72) could be induced in human arteries and prevent human aortic smooth muscle cell (HA-SMC) calcification. However, the molecular mechanisms involved in vasculo-protective effects of HSP72 have yet to be elucidated. In this study, we postulate that inducible HSP72 may exert vasculo-protective effects by stabilizing HA-SMCs phenotype through inhibition of mitochondrial dysfunction. Methods: In vitro long-term calcification model: HA-SMCs treated with calcification medium (CM) containing 5mM CaCl 2 and 5mM β-glycerophosphate for 21 days. Results: Our results show that inducible HSP72 and mitochondrial HSP (HSPA5) are significantly expressed following heat shock treatment in HA-SMCs. Inducible HSP72 inhibited the development of VC in our long-term calcification model, in vitro . We next showed that JC-1 complex, an indicator of mitochondrial membrane potential stability and mitochondrial respiratory chain complexes II, IV was preserved in HA-SMCs treated with calcification medium following induction of HSP72. These cellular protective effects were however abolished following HSP72 knockdown by HSP72 siRNA. Furthermore, p53, Bax and Bak were up-regulated and Bcl-2 was down-regulated in HA-SMCs treated in calcification medium and these pro-apoptotic changes could be reversed following induction of HSP72. Conclusion: HSP72’s anti-calcific effects involve stabilization of mitochondrial function and inhibition of HA-SMC apoptosis. We suggest treatment strategies involving induction of HSP72 as a new approach to inhibit VC.
Surveillance nanotechnology for multi-organ cancer metastases
Authors: Harini Kantamneni, Margot Zevon, Michael J. Donzanti, Xinyu Zhao, Yang Sheng, Shravani R. Barkund, Lucas H. McCabe, Whitney Banach-Petrosky, Laura M. Higgins, Shridar Ganesan, Richard E. Riman, Charles M. Roth, Mei-Chee Tan, Mark C. Pierce, Vidya Ganapathy, Prabhas V. Moghe
Journal: Nature Biomedical Engineering (2017)
Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank
Authors: Nicholas J Thomas, Samuel E Jones, Michael N Weedon, Beverley M Shields, Richard A Oram, Andrew T Hattersley
Journal: The Lancet Diabetes & Endocrinology (2017)

Type 1 diabetes is typically considered a disease of children and young adults. Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes. It is not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years. We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life.
Abstract 13507: Inappropriate Preoperative Stress Testing is Common Across Medical Specialties: A Single-Center Review
Authors: Brandon Peterson, Mehrdad Ghahramani, Matthew Emerich, Benjamin Pinto, Michael Devine, Andrew Foy
Journal: Circulation (2016)

Introduction: According to appropriate use criteria, preoperative stress testing in asymptomatic patients is considered “rarely appropriate” in patients with: 1) moderate to good functional capacity (≥4 METs), 2) no clinical risk factors, or who are 3) asymptomatic following revascularization, normal stress test, or normal coronary angiography within one year. Stress testing is also not recommended in patients estimated to be low-risk (&lt;1%) for adverse cardiac events according to ACC/AHA guidelines. Hypothesis: We hypothesized that cardiologists, when compared with other specialties, would be less likely to order preoperative testing in low-risk patients or for rarely appropriate indications. Methods: We reviewed preoperative stress tests for non-cardiac surgery performed at Hershey Medical Center from January 2012 through December 2014. Stress tests performed for solid organ transplant evaluation were excluded. Chi square analysis was used to compare frequencies of test appropriateness and patient risk. Risk for adverse cardiac events was estimated using the National Surgical Quality Improvement Program (NSQIP) Myocardial Infarction and Cardiac Arrest (NSQIP MICA) risk calculator. Results: 505 preoperative stress tests meeting study criteria were analyzed. Out of 219 preoperative stress tests ordered by cardiologists, 121 (55%) were classified as “rarely appropriate”, compared with 217 of 286 stress tests (76%) ordered by other specialties (p&lt;0.0001). Median cardiac risk for 361 patients with sufficient data to estimate by NSQIP MICA was 0.6% (interquartile range 0.4-1.2%). 248 of 361 stress tests (69%) were performed on patients estimated to be low-risk. Frequency of low-risk testing did not significantly differ (p=0.32) between cardiologists (96 of 146, 66%) and other specialties (152 of 215, 71%). Conclusions: Cardiologists were significantly less likely to order rarely appropriate stress tests compared with other specialties. The majority of stress tests ordered by cardiologists and by other specialties, however, were rarely appropriate and in patients at low-risk (&lt;1%) for cardiac complications. Interventions to reduce inappropriate preoperative stress testing, therefore, require a multispecialty approach.
Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: A sub-analysis of tolerability and cytokine data from the EVOLVE study of enadenotucirev (EnAd), an oncolytic adenovirus
Authors: H. McElwaine-Johnn, G. Pover, S. Alvis, R. Brown, K. Fisher, C. Morris, B. Champion, J. Beadle
Journal: Annals of Oncology (2017)
SIRT6 Is a Target of Regulation by UBE3A That Contributes to Liver Tumorigenesis in an ANXA2-Dependent Manner
Authors: Saishruti Kohli, Abhishek Bhardwaj, Richa Kumari, Sanjeev Das
Journal: Cancer Research (2017)

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor-suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and to epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential, and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease.Significance: These findings provide mechanistic insights into regulation of the tumor suppressive sirtuin SIRT6 and its implications for the development of hepatocellular carcinoma. Cancer Res; 78(3); 645-58. ©2017 AACR.
Abstract 13987: Comparative Effectiveness and Clinical Safety Between Dabigatran, Rivaroxaban, and Warfarin
Authors: Chao-Lun Lai, Ho-Min Chen, Ting-Tse Lin, Min-Tsun Liao, K. Arnold Chan
Journal: Circulation (2016)

Background: Several new oral anticoagulants have been developed for prevention of stroke/systemic embolism in atrial fibrillation (AF) patients. This retrospective cohort study aimed to provide real world data concerning the comparative effectiveness and clinical safety between dabigatran, rivaroxaban, and warfarin. Methods: Incident adult users of oral anticoagulants with a diagnosis of AF at prescription were extracted from the National Health Insurance claims database in Taiwan from between Jun. 1 2012 and Dec. 31 2013. Two propensity scores were derived using multinomial logistic regression to model the probability of receipt of three study medications as a function of baseline characteristics. The proportional hazards models with adjustment of the quintiles of the propensity scores were used to estimate the relative hazards of specific outcomes between study groups. Results: Totally, 16930 subjects including 4280 with dabigatran, 1499 with rivaroxaban, and 11151 with warfarin were identified. The mean age was 72.7 years and the median follow-up duration 8.7 months. Both dabigatran group (adjusted hazard ratio [aHR] 0.37, 95% confidence interval [CI] 0.30-0.46) and rivaroxaban group (aHR 0.50, 95% CI 0.37-0.66) possessed a lower risk of all-cause death in comparison with warfarin group. Comparing with warfarin group, dabigatran group and rivaroxaban group were also associated with lower risks of ischemic stroke (aHR 0.48, 95% CI 0.39-0.59 for dabigatran and aHR 0.50, 95% CI 0.36-0.69 for rivaroxaban), arterial embolism/thrombosis (aHR 0.42, 95% CI 0.26-0.68 for dabigatran and aHR 0.38, 95% CI 0.18-0.83 for rivaroxaban), and intracranial hemorrhage (aHR 0.29, 95% CI 0.16-0.51 for dabigatran and aHR 0.48, 95% CI 0.25-0.95 for rivaroxaban). In addition, we found no statistically significant difference between dabigatran and rivaroxaban in the risks of all the clinical outcomes studied. Conclusions: Both dabigatran and rivaroxaban were associated with significant reductions in risks of all-cause death, ischemic stroke, arterial embolism/thrombosis, and intracranial hemorrhage, compared with warfarin. Besides, no significant difference could be found in the risks of various clinical outcomes between dabigatran and rivaroxaban.
The National Student Association of Medical Research (NSAMR) Publication Pathway
Authors: M. Byrne, H. Jackson, A. Sinha, G. Tong, C. Grafton-Clarke, S. Rees, A. Mathur, B. Cross, E. Christopher, L. Isaacs, S. Banh, Z. Sheng, R. Lundin
Journal: International Journal of Surgery (2017)
Abstract 19486: N-Glycosylation Changes in the Human Aortic Valve Structure During Development and Disease by Imaging Mass Spectrometry
Authors: Peggi Angel
Journal: Circulation (2016)

Introduction:  Changes in polysaccharide and proteoglycan distribution are a hallmark of heart valve development and disease. However, the complex carbohydrate content of the heart valve remains virtually uncharacterized at the molecular level. N-glycosylation is a post translational modification with a role in protein localization, protein-protein interactions and modulation of cell signaling. Our proteomics data on healthy & diseased human aortic valve (AV) showed significant enrichment of functions of N-glycan processing, synthesis and congenital disorders of glycosylation. At the same time, new approaches are available for detection of N-Glycans directly from tissue.   Hypothesis:  Discrete N-glycans and associated signaling networks participate in normal AV development and are deregulated in congenital aortic valve stenosis   Methods:  The approach uses robotic spraying of PNGase F onto formalin fixed paraffin embedded (FFPE) tissue sections of standard thickness (5-6 μm) to release N-glycans from proteins from tissue without delocalization. Imaging mass spectrometry is then used to detect the N-glycans directly from tissue, thus providing information on regulation, structural changes and histological localization.   Results:  From a small but growing cohort, distinct N-glycans are spatially restricted and regulated within the human AV structure. In healthy AV, N-glycans were segregated according to AV subanatomical features. Statistical filtering by Wilcoxon Rank Sum p-value ≤1.0E-3 and area under the receiver operating curve ≥0.7 suggested expression level changes in 27% of N-glycan (30/110) when comparing between healthy AV comparing ages 0-17 years to adult. Structural motif analysis suggested that in the healthy aging valve, core fucosylation may be decreased, while N-glycan complexity increases. Specimens with aortic valve stenosis showed distinct N-glycans that were altered in regions of pathological extracellular matrix compared to age-matched healthy counterparts, with increases in tri- and tetra-antennary structures due to disease.   Conclusions:  The study suggests a novel role for N-glycosylation in healthy AV aging and in AV disease, presenting new therapeutic opportunities for AV disease treatment.
Locally Aggressive Connective Tissue Tumors
Authors: Mrinal M. Gounder, David M. Thomas, William D. Tap
Journal: Journal of Clinical Oncology (2017)

In this review, we highlight the complexities of the natural history, biology, and clinical management of three intermediate connective tissue tumors: desmoid tumor (DT) or aggressive fibromatosis, tenosynovial giant cell tumor (TGCT) or diffuse-type pigmented villonodular synovitis (dtPVNS), and giant cell tumor of bone (GCTB). Intermediate histologies include tumors of both soft tissue and bone origin and are locally aggressive and rarely metastatic. Some common aspects to these tumors are that they can be locally infiltrative and/or impinge on critical organs, which leads to disfigurement, pain, loss of function and mobility, neurovascular compromise, and occasionally life-threatening consequences, such as mesenteric, bowel, ureteral, and/or bladder obstruction. DT, PVNS, and GCTB have few and recurrent molecular aberrations but, paradoxically, can have variable natural histories. A multidisciplinary approach is recommended for optimal management. In DT and PVNS, a course of observation may be appropriate, and any intervention should be guided by symptoms and/or disease progression. A surgical approach should take into consideration the infiltrative nature, difficulty in obtaining wide margins, high recurrence rates, acute and chronic surgical morbidities, and impact on quality of life. There are similar concerns with radiation, which especially relate to optimal field and transformation to high-grade radiation-associated sarcomas. Systemic therapies must be considered carefully in light of acute and chronic toxicities. Although standard and novel therapies are promising, many unanswered questions, such as duration of therapy and optimal end points to evaluate efficacy of drugs in clinical practice and trials, exist. Predictive biomarkers and novel clinical trial end points, such as volumetric measurement, magnetic resonance imaging T2 weighted mapping, nuclear imaging, and patient-reported outcomes, are in development and will require validation in prospective trials.
Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α
Authors: Caitlin D. Lowery, Wayne Blosser, Michele Dowless, Shelby Knoche, Jennifer Stephens, Huiling Li, David Surguladze, Nick Loizos, Debra Luffer-Atlas, Gerard J. Oakley, Qianxu Guo, Seema Iyer, Brian P. Rubin, Louis Stancato
Journal: Clinical Cancer Research (2017)

Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors.Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor.Results:In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin.Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847-57. ©2017 AACR.
Abstract #3252: Effector memory T cells make a major contribution to redirected target cell lysis by T cell-engaging BiTE antibody MT110
Authors: Roman Kischel, Susanne Hausmann, Patrick Baeuerle, Peter Kufer
Journal: Cancer Research (2009)

BiTE antibodies are single-chain bispecific antibody constructs with specificity for CD3 on T cells and a surface antigen on target cells. By transiently bridging T cells and cancer cells, BiTE antibodies are capable to mount a polyclonal T cell response that is no longer limited by T cell receptor specificity, presence of MHC class I, generation and presentation of peptide antigen, or the need for T cell costimulation. An ongoing clinical trial with blinatumomab, a CD19/CD3-bispecific BiTE antibody, in patients with therapy refractory non-Hodgkin\#8217;s lymphoma has shown lasting partial and complete tumor responses. Another BiTE antibody in clinical testing is EpCAM/CD3-bispecific MT110 for the treatment of patients with EpCAM+ cancer. We investigated the contribution of various subpopulations of T cells to the redirected target cell lysis mediated by BiTE antibodies. Naive and effector memory \#945;/\#946; T cells of CD8+ and CD4+ phenotype as well as NKT and \#947;/\#948; \#932; cells were freshly isolated from peripheral blood of healthy donors. T cell subpopulations were used at an effector to target ratio of 10:1 in cytotoxicity assays analyzing dose response of the EpCAM-specific BiTE antibody MT110 and percentage of target cell lysis after 18 h as indicators for the efficacy of redirected target cell lysis. As target for redirected lysis, the EpCAM expressing human KATO III gastric carcinoma cell line was used. The contribution to redirected lysis of central memory \#945;/\#946; T cells was indirectly studied. CD8+ effector memory T cells of CD45RA+ and CD45RO+ phenotype proved to be most efficacious in mediating redirected lysis by BiTE antibodies. CD4+ effector memory T cells were also highly active but with delayed kinetics, apparently, needed to upregulate expression of granzyme B. Naive CD8+ and CD4+ T cells showed very little to no activity. NKT and \#947;/\#948; T cells were also effective in BiTE-induced redirected lysis, however, showed less potency than CD8+ \#945;/\#946; T cells. Our data suggest that, with exception of naive T cells, all other T cell populations currently analyzed can contribute to redirected lysis by BiTE antibodies.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3252.