tbuckley/cabot-search huggingface dataset:
Abstract 2052: A novel PHD2/VHL- mediated regulation of YAP1 and its role in vascular mimicry and tumor angiogenesis
Authors: Namrata Bora Singhal, Biswarup Saha, Srikumar Chellappan
Journal: Cancer Research (2018)

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death worldwide. In this study, we show that transcriptional co-activator YAP1, the oncogenic component of the Hippo pathway, may contribute to the progression of NSCLC by supporting tumor angiogenesis and vascular mimicry of cancer stem-like cells (CSCs). NSCLC CSCs were found to have higher mRNA expression of VEGF receptor II (KDR) and Angiopoietin-2 (AngPT-2); depletion of YAP1 inhibited the promoter activity as well as the mRNA expression of VEGF, KDR and AngPT-2, with a corresponding reduction in vascular mimicry as well as tumor growth in a mouse xenograft studies. These results suggest a possible mechanism by which YAP1 regulates tumor angiogenesis. A role for YAP1 in tumor angiogenesis was further supported by the finding that NSCLC cells grown in hypoxic conditions showed higher levels of YAP1. There was little to no changes in the canonical Hippo pathway proteins like LATS1/2, MST1/2, SAV and MOB as well as in the expression of TAZ, an orthologue of YAP1. Elevated YAP1 was found to associate with HIF1α under hypoxic conditions and enhance its transcriptional activity; YAP1 could increase HIF1α-mediated induction of the VEGF promoter confirmed by chromatin immunoprecipitations and transient transfection assays. Elevated levels of YAP1 and HIF1α interaction was detected in lung tumor tissues compared to normal lung tissue, as detected by proximity ligation assay (PLA), suggesting that the higher association of YAP1 with HIF1α and resulting transcriptional activity might have contributed to tumor growth. An examination of the underlying mechanism by which YAP1 levels are elevated under hypoxic conditions revealed a novel regulation of YAP1 protein by prolyl hydroxylase PHD2 and E3 ubiquitin ligase VHL, which are mainly known to regulate HIF1α under normoxia. PHD2 was found to hydroxylate proline residue(s) of YAP1 between aa 284 to aa 289 as seen by mutational studies. YAP1 was found to directly associate with PHD2 as well as with VHL. Depletion of PHD2 or treatment with DMOG, an inhibitor of prolyl hydroxylases, reduced YAP1 association with VHL ligase. This further elevated YAP1 levels in the nucleus. Interestingly, disruption of the YAP1-PHD2 interaction using a domain specific peptide enhanced the angiogenic tubule formation by endothelial cells. Our data therefore identifies a novel non-canonical pathway of regulation of YAP1 that supports angiogenesis and tumor growth. Citation Format: Namrata Bora Singhal, Biswarup Saha, Srikumar Chellappan. A novel PHD2/VHL- mediated regulation of YAP1 and its role in vascular mimicry and tumor angiogenesis [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 2052.
An unsuspicious duodenal foreign body
Authors: Ricardo Marcos-Pinto, Mónica Garrido, Marta Rocha, Marta Salgado, Anabela Rocha, Isabel Pedroto
Journal: Endoscopy (2018)

A 56-year-old woman with Peutz–Jeghers syndrome, who underwent a laparoscopic right hemicolectomy for colon adenocarcinoma 19 months earlier, presented for elective single-balloon antegrade enteroscopy to remove a 25 mm jejunal polyp previously identified on video capsule endoscopy.
Promoting Inclusion in Academic Medicine
Authors: Elena Fuentes-Afflick
Journal: JAMA Network Open (2018)

Jaya Aysola, MD, DTM&H, MPH; Frances K. Barg, PhD, MEd; Ana Bonilla Martinez, BS, CHES; Matthew Kearney, MPH; Kareha Agesa, BA; Carlos Carmona, BA; Eve Higginbotham, SM, MD
Abstract 16476: Safety Profile of Bivalirudin in the Treatment of ST-Segment Elevation Myocardial Infarction Patients in Clinical Practice - Results From the Bremen STEMI Registry
Authors: RobertZabrocki, EduardFiehn, HarmWienbergen, SusanneSeide, JohannesSchmucker, DanielaGarstka, RainerHambrecht
Journal: Circulation (2014)

Introduction: Previous studies demonstrated that treatment of patients (pts) being affected by ST-segment elevation myocardial infarction (STEMI) with bivalirudin (biv) instead of heparin (hep) reduced rates of major bleedings. Results regarding a reduction in all-cause mortality are inconclusive, stent thromboses however were slightly increased. Real world data in pts with STEMI treated with biv in the era of new anti-thrombotic treatment are still spare. The aim of this study was to evaluate safety of biv for all-comers. Methods: All pts with STEMI from the metropolitan area of Bremen (Germany) are admitted to the Bremen heart center and documented in the Bremen STEMI-registry (BSR) since 2006. In May 2013 we adapted our anticoagulation strategy to the current guidelines from hep with glycoprotein IIb/IIIa inhibitors (GPI) to biv with provisional use of GPI. Pts receiving biv were compared to all pts until April 2013 in the BSR without chronic renal failure. Results: Baseline and interventional characte...
Insulin Modulation of β-Adrenergic Vasodilator Pathway in Human Forearm
Authors: GiuseppeLembo, GuidoIaccarino, CarmineVecchione, VirgilioRendina, LuciaParrella, BrunoTrimarco
Journal: Circulation (1996)

Background Insulin modulates sympathetic vasoconstriction, but the mechanisms underlying this effect are not completely elucidated. We have recently investigated the insulin effect on the α1- and α2-adrenergic vasoconstriction pathway, where it is still conflicting with the possible insulin influence on the β-adrenergic vasodilator pathway. The aim of the present study was to investigate this issue. Methods and Results The study was performed on the forearm of healthy humans, and all test substances were infused into the brachial artery at systemically ineffective rates. In five subjects, we evaluated isoproterenol-induced vasodilation (1, 3, 6, and 9 ng·kg−1·min−1) both under control conditions and during insulin infusion (0.05 mU·kg−1·min−1). In another group of five subjects, we tested whether the vasorelaxant effect of sodium nitroprusside (1, 2, 4, and 8 ng·kg−1·min−1) was modified by insulin. Moreover, to explore whether the interaction between insulin and forearm β-adrenergic pathway participates i...
Effect of Increased Exercise in School Children on Physical Fitness and Endothelial Progenitor Cells
Authors: ClaudiaWalther, LuiseGaede, VolkerAdams, GötzGelbrich, AlexanderLeichtle, SandraErbs, MelanieSonnabend, KatiFikenzer, AntjeKörner, WielandKiess, MathiasBruegel, JoachimThiery, GerhardSchuler
Journal: Circulation (2009)

Background— The aim of this prospective, randomized study was to examine whether additional school exercise lessons would result in improved peak oxygen uptake (primary end point) and body mass index–standard deviation score, motor and coordinative abilities, circulating progenitor cells, and high-density lipoprotein cholesterol (major secondary end points). Methods and Results— Seven sixth-grade classes (182 children, aged 11.1±0.7 years) were randomized to an intervention group (4 classes with 109 students) with daily school exercise lessons for 1 year and a control group (3 classes with 73 students) with regular school sports twice weekly. The significant effects of intervention estimated from ANCOVA adjusted for intraclass correlation were the following: increase of peak Vo2 (3.7 mL/kg per minute; 95% confidence interval, 0.3 to 7.2) and increase of circulating progenitor cells evaluated by flow cytometry (97 cells per 1×106 leukocytes; 95% confidence interval, 13 to 181). No significant difference w...
Abstract 4283: A structure network approach to predict the dynamics and structural stability effects of germline <i>PTEN</i> mutations associated with cancer versus autism phenotypes
Authors: Iris N. Smith, Stetson Thacker, Charis Eng
Journal: Cancer Research (2018)

Abstract Individuals with germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN), irrespective of clinical presentation, are referred to as PTEN hamartoma tumor syndrome (PHTS). PHTS confers a high risk of breast, thyroid and other cancers. Yet, PTEN mutations are found in up to 20% of individuals with autism spectrum disorder (ASD) and macrocephaly. What remains unclear is why mutations in one gene can lead to seemingly disparate phenotypes. Thus, we sought to identify differences in cancer- vs. ASD-associated PTEN mutations by investigating putative structural effects. We utilized a computational theoretical approach combining protein structure network (PSN), normal mode analysis (NMA), and elastic network models (ENMs) to interrogate 6 PTEN mutations from patients with PHTS-associated cancer, 6 mutations from those with ASD only, 4 mutations shared across both phenotypes, and 1 mutation with both ASD and cancer. Combined with in silico prediction methods we calculated structural stability changes induced by each mutation. All 6 cancer-associated mutations showed decreases in structure stability and increased dynamics across domain interface. In contrast, 5 of 6 ASD-associated mutations showed only localized destabilization. We coupled ENM-NMA with PSN and found PTEN R130G (cancer only) and R173C (shared in patients with both ASD and cancer), play a role in inter-residue signal propagation, indicating both residue positions are crucial to structural stability. Our data suggest that ASD-associated mutations affect local structural dynamics, whereas cancer-associated mutations mediate long-range perturbations significantly altering structural stability and salient communication pathways. These approaches lend insight into altered structural effects of germline PTEN mutations associated with PTEN-ASD and PTEN-cancer, potentially aiding in identification of specific mutations that contribute to each phenotype. Moreover, this work may illuminate the shared and separate molecular features that contribute to autism or cancer – providing a deeper understanding of genotype-phenotype relationships for germline PTEN mutations. The ability to accurately predict PTEN-ASD may spare patients the need to undergo high-risk cancer surveillance that is now performed in all with PHTS. Citation Format: Iris N. Smith, Stetson Thacker, Charis Eng. A structure network approach to predict the dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes [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 4283.
Organoids for Drug Discovery and Personalized Medicine
Authors: Toshio Takahashi
Journal: The Annual Review of Pharmacology and Toxicology (2018)

A wide variety of organs are in a dynamic state, continuously undergoing renewal as a result of constant growth and differentiation. Stem cells are required during these dynamic events for continuous tissue maintenance within the organs. In a steady state of production and loss of cells within these tissues, new cells are constantly formed by differentiation from stem cells. Today, organoids derived from either adult stem cells or pluripotent stem cells can be grown to resemble various organs. As they are similar to their original organs, organoids hold great promise for use in medical research and the development of new treatments. Furthermore, they have already been utilized in the clinic, enabling personalized medicine for inflammatory bowel disease. In this review, I provide an update on current organoid technology and summarize the application of organoids in basic research, disease modeling, drug development, personalized treatment, and regenerative medicine.
Abstract 554: APC loss alters DNA damage repair in breast cancer cells
Authors: Stephanie M. McClintock Batista
Journal: Cancer Research (2018)

Abstract Breast cancer is the second leading cause of cancer deaths in U.S. women. Many of these deaths have been attributed to the development of chemotherapeutic resistance. Thus, understanding the process of chemotherapeutic resistance will help develop new approaches to combat breast cancer and ultimately cause a decrease in breast cancer related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is silenced or mutated in up to 70% of sporadic breast cancer; however, the possible effects of APC loss on chemoresistance has not been elucidated. Using the ApcMin/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we previously showed that APC loss decreased cisplatin and doxorubicin-induced apoptosis. We also have shown that APC loss increased mRNA expression of the multidrug resistance protein 1 (MDR1), which was augmented by doxorubicin treatment. Treatment with doxorubicin and A69, a STAT3 inhibitor, normalized MDR1 gene expression in MMTV-PyMT;ApcMin/+ cells. Here, we hypothesize that loss of APC causes an increase in doxorubicin efflux and a decrease in DNA damage. First, we show that APC loss increased MDR1 activity as measured by calcein flux. To determine whether MDR1 inhibition would restore doxorubicin induced DNA damage, a combination treatment of doxorubicin and the MDR1 inhibitor, Valspodar, was able to restore doxorubicin sensitivity in MMTV-PyMT;ApcMin/+ cells compared to the control MMTV-PyMT;Apc+/+ cells. In addition, we have shown a decrease of γH2AX, a marker of damaged DNA, in MMTV-PyMT;ApcMin/+ cells treated with doxorubicin suggesting that the MMTV-PyMT;ApcMin/+ cells either have less damage due to increased drug efflux via MDR1 or due to increased DNA damage repair. Due to APC binding to Topoisomerase IIa, we also examined the degree of Topoisomerase IIa inhibition (via doxorubicin and etoposide) in MMTV-PyMT;ApcMin/+ compared to MMTV-PyMT;Apc+/+ cells. Topoisomerase IIa activity will also be measured to determine the effect of APC loss on Topoisomerase IIa. To test the hypothesis that loss of APC affected DNA damage repair, the expression of phosphorylated H2AX was measured in MMTV-PyMT;ApcMin/+ and MMTV-PyMT;Apc+/+ cells treated with the following: doxorubicin, etoposide, Valspodar, or a combination treatment. The longevity of doxorubicin-induced double stranded breaks was observed. Future studies will measure DNA damage repair pathway efficiency via reporter plasmids. We also will measure downstream signaling of yH2AX. Overall with an understanding of the role of APC in DNA damage repair, the use of a combination therapy could be advantageous to overcome chemotherapeutic resistance. Citation Format: Stephanie M. McClintock Batista. APC loss alters DNA damage repair in breast cancer cells [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 554.
Abstract 4014: APOBEC3B promotes hepatocarcinogenesis and metastasis through novel deaminase-independent activity
Authors: Irene O L Ng, Wei Ma, Daniel WH Ho, Karen MF Sze, Yue M. Tsui, Lo K. Chan, Joyce MF Lee
Journal: Cancer Research (2018)

Abstract APOBEC3B (A3B), a cytidine deaminase, is known to play important roles in creating de novo genomic C-to-T mutations in cancers and contribute to induction of genomic instability. In this study, we evaluated the roles of A3B in the progression and metastasis of human hepatocellular carcinoma (HCC). Using whole-transcriptome and whole-exome sequencing and quantitative real-time PCR, we found that A3B was overexpressed in human HCCs and A3B expression was significantly correlated with the proportion of genomic C-to-A and G-to-T mutations. Upon clinicopathological correlation, higher A3B expression was associated with more aggressive tumor behavior. Wild-type A3B (wt-A3B) overexpression in HCC cells promoted cell proliferation, and cell migratory and invasive abilities in vitro, and tumorigenicity and metastasis in vivo. On the other hand, knockdown of A3B suppressed cell proliferation, migratory and invasive abilities of HCC cells with high endogenous A3B level. However, to our surprise, overexpression of A3B deaminase-dead double mutant (E68A/E255Q) led to similar results as wt-A3B in HCC both in vitro and in vivo. Furthermore, overexpression of wt-A3B and mutant A3B both enhanced cell cycle progression in HCC cells. Altogether, our data demonstrated a novel deaminase-independent role of A3B in contributing to HCC tumorigenesis and metastasis. Citation Format: Irene O L Ng, Wei Ma, Daniel WH Ho, Karen MF Sze, Yue M. Tsui, Lo K. Chan, Joyce MF Lee. APOBEC3B promotes hepatocarcinogenesis and metastasis through novel deaminase-independent activity [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 4014.
Abstract 5548: The therapeutic potential of AMV564, a novel bispecific bivalent (2x2) T-cell engager, for the treatment of CD33-expressing hematologic malignancies
Authors: Tae H. Han, Jeanmarie Guenot, William S. Denney, Eric J. Feldman
Journal: Cancer Research (2018)

Abstract AMV564 is a novel bispecific bivalent (2x2) immunotherapy that initiates an immunological synapse between T cells and CD33-expressing cells by binding both CD33 and CD3 with strong avidity. CD33 (Siglec-3) is a clinically-validated antigen target that is broadly expressed on the surface of malignant cells in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and other hematologic malignancies, as well as on cells that potently suppress immune function, such as myeloid-derived suppressor cells (MDSC). AMV564 has been shown to eliminate MDSCs and restore hematopoiesis, induce potent cytolysis of leukemic cells in patient blood and bone marrow samples, and produce robust antitumor activity in a disseminated model of AML. In vitro studies, including cytotoxicity assays with AML patient samples, human T-cell activation assays, and cytokine-release assays, as well as animal safety studies were performed to characterize the pharmacokinetics, pharmacodynamics, and potential toxicities of AMV564. AMV564 demonstrated potent in vitro antitumor activity with EC50 values of approximately 0.7 - 3 pM. In vitro studies also demonstrated that leukemic cells are more sensitive to T-cell engagement using AMV564 than peripheral blood mononuclear cells by approximately 10-fold. In animal safety studies, AMV564 was tolerated at exposures that exceed those expected to have clinical antitumor activity by &amp;gt; 10-fold. Toxicological findings noted in these studies were anticipated based on the pharmacological activity of AMV564; observed findings included events related to CD3-mediated T-cell activation, cytokine release, and decreases in neutrophil and monocyte counts with rapid recovery. Results from a pharmacokinetic/pharmacodynamic model integrating the preclinical data suggest the potential for a wide therapeutic index for patients with AML. Based on the in vitro and in vivo preclinical data, AMV564 is expected to have a wide therapeutic index, with robust antitumor activity in AML and MDS at doses well below those predicted to be associated with dose-limiting toxicities, and a predictable and monitorable adverse event profile. Citation Format: Tae H. Han, Jeanmarie Guenot, William S. Denney, Eric J. Feldman. The therapeutic potential of AMV564, a novel bispecific bivalent (2x2) T-cell engager, for the treatment of CD33-expressing hematologic malignancies [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 5548.
White Matter Abnormalities in Never-Treated Patients With Long-Term Schizophrenia
Authors: Yuan Xiao, Huaiqiang Sun, Shulin Shi, Dan Jiang, Bo Tao, Youjin Zhao, Wenjing Zhang, Qiyong Gong, John A. Sweeney, Su Lui
Journal: American Journal of Psychiatry (2018)

This study tested for differences of white matter integrity between treated and never-treated long-term schizophrenia patients, matched on illness duration, and for differential changes in relation to age in these two groups relative to healthy comparison subjects.This cross-sectional diffusion tensor imaging study included 31 never-treated and 46 matched antipsychotic-treated patients with long-term schizophrenia and 58 healthy comparison subjects. Fractional anisotropy measures of white matter tracts were extracted and compared. Linear regression analysis was used to explore the association between age and fractional anisotropy among the three groups.Fractional anisotropy significantly differed among the three groups in 14 of 20 white matter tracts defined in the Johns Hopkins University white matter template. Never-treated patients displayed greater reduction of fractional anisotropy than antipsychotic-treated patients in the left anterior thalamic radiation, the left cingulum-hippocampus pathway, the splenium and genu of the corpus callosum, and the left superior longitudinal fasciculus, and greater fractional anisotropy in the right uncinate fasciculus. Both patient groups showed multiple reductions relative to healthy comparison subjects. Never-treated patients showed an accelerated and clinically relevant age-related reduction of fractional anisotropy in the genu of the corpus callosum.These psychoradiological findings provide insight into the regional distribution of white matter deficits in the years after illness onset in long-term schizophrenia. Findings of greater impairments in never-treated patients, and a greater age-related reduction in the genu of the corpus callosum in these patients, suggest that long-term antipsychotic treatment does not adversely affect white matter tracts over the longer-term course of illness and may confer benefits.