tbuckley/cabot-search huggingface dataset:
Abstract 4715: Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium
Authors: Lydia WT Cheung, Katarzyna W. Walkiewicz, Tabot Besong, David Hawke, Stefan T. Arold, Gordon B. Mills
Journal: Cancer Research (2015)

Abstract The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is mediated by association with the p110 catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. Although the best-characterized role of p85α is p110-dependent, intermolecular interactions of p85α protomers have been suggested to result in p85α homodimerization. However, the function of the p85α homodimer remains to be elucidated. Through structural modeling and biochemical analyses, we demonstrate the p110α-independent role of homodimerized p85α in the positive regulation of PTEN. p110α-free p85α homodimerizes via SH3:proline rich domain and BH:BH intermolecular interactions to selectively bind unphosphorylated activated PTEN. p85α homodimer competes for PTEN binding with the E3 ligase WWP2. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from WWP2-mediated proteasomal degradation. Further, p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Importantly, the homodimerization surface and the PTEN-interaction interface are targeted in cancer patient-derived p85α mutants, providing a plausible mechanism for tumor development. These p85α mutants are oncogenic by destabilizing PTEN and inducing PI3K pathway activation. Together, we provide a mechanistic model of how p85α plays a dual role in regulating the PI3K pathway through forming p85α homodimer or p110-bound heterodimer. Our data suggest that the monomer-dimer equilibrium of p85α regulates the PI3K pathway and thereby associates with cancer development. Citation Format: Lydia WT Cheung, Katarzyna W. Walkiewicz, Tabot Besong, David Hawke, Stefan T. Arold, Gordon B. Mills. Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4715. doi:10.1158/1538-7445.AM2015-4715
Six-transmembrane epithelial antigens of the prostate comprise a novel inflammatory nexus in patients with pustular skin disorders
Authors: Yun Liang, Xianying Xing, Maria A. Beamer, William R. Swindell, Mrinal K. Sarkar, Liza Wolterink Roberts, John J. Voorhees, J. Michelle Kahlenberg, Paul W. Harms, Andrew Johnston, Johann E. Gudjonsson
Journal: Journal of Allergy and Clinical Immunology (2016)
Antagonist Anti-CD40 Monoclonal Antibody, CHIR-12.12, Inhibits Growth of a Rituximab-Resistant NHL Xenograft Model and Achieves Synergistic Activity When Combined with Ineffective Rituximab.
Authors: Li Long, Xia Tong, Montesa Patawaran, Lea Aukerman, Julie Klinger, Bahija Jallal, Mohammad Luqman
Journal: Blood (2004)
Increased healthcare use up to 10 years among relapse‐free Hodgkin lymphoma survivors in the era of intensified chemotherapy and limited radiotherapy
Authors: Ingrid Glimelius, Sandra Eloranta, Sara Ekberg, Ellen T. Chang, Martin Neovius, Karin E. Smedby
Journal: American Journal of Hematology (2016)

Abstract With today's excellent cure rates for Hodgkin lymphoma (HL), the number of long‐term survivors is increasing. This study aims to provide a global assessment of late adverse effects for working‐age HL survivors treated with contemporary protocols (combination chemotherapy and limited radiotherapy). From Swedish nationwide registers we identified 1017 HL survivors diagnosed in 2000–2009, aged 18–60 years (median 32) and surviving at least one year post‐diagnosis, and 4031 age‐, sex‐, and calendar‐year‐matched population comparators. Incidence rate ratios (IRR) and 95% confidence intervals (95%CI) for outpatient visits and inpatient bed‐days after the first year up to 14 years post‐diagnosis (through 2013) were estimated across treatment subgroups, considering relapse‐free time and using negative binomial regression. Scheduled outpatient visits for HL were excluded. The rate of outpatient visits was nearly double (IRR = 1.8, 95%CI: 1.6–2.0) that among comparators and higher rates persisted up to 10 years post‐diagnosis. The rate of inpatient bed‐days among relapse‐free survivors was more than three‐fold (IRR = 3.6, 95%CI: 2.7–4.7) that of comparators and the increase persisted up to four years post‐diagnosis. Patients requiring 6‐8 chemotherapy courses had higher rates of outpatient visits (IRR = 1.4, 95%CI: 1.1–1.7) and bed‐days (IRR = 4.7, 95%CI: 2.9–7.8) than patients treated with 2–4 courses + radiotherapy. Previously seldom reported reasons for the excess healthcare use included chest pain, keratitis, asthma, diabetes mellitus, and depression. Contemporary treatment, chemotherapy in particular, was associated with excess healthcare use among HL survivors during the first decade postdiagnosis. The reasons for healthcare visits reflected a wide range of disorders, indicating the need of broad individualized care in addition to specific screening programs.
Abstract 4597: A novel variant in DNA repair gene GTF2H4 is associated with lung cancer risk: A reanalysis of GWAS datasets from the TRICL consortium
Authors: Qingyi Wei, Hongliang Liu, Zhensheng Liu, Christopher I. Amos, Jennifer A. Doherty, Heike Bickeboller, Rayjean J. Hung, Paul Brennan, Richard Houlston, Maria Teresa Landi, Neil E. Caporaso, David Christiani
Journal: Cancer Research (2015)

Abstract DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair is involved in cancer. We hypothesize that genetic variants in DNA repair genes are associated with risk of lung cancer. To test this hypothesis, we performed a large-scale meta-analysis of 123,371 SNPs in 169 DNA repair genes obtained from six datasets of previously published genome-wide association studies (GWASs), consisting of 12,160 lung cancer cases and 16,838 controls. We evaluated functional relevance of the identified, previously unpublished important and significant SNPs. Across the six GWASs, 14 SNPs were found to be significantly associated with lung cancer risk with a false discovery rate (FDR) of P &amp;lt; 0.05, of which rs114596632 in GTF2H4 at 6q31.33 was the most statistically significant SNP (OR = 1.19, 95% CI = 1.12-1.25, Pcombined = 5.40 × 10−10). The SNP rs114596632 was not strongly correlated with the previously reported GWAS hit MSH5 rs3131379 in that region (r2 = 0.383). Further mapping of the human leukocyte antigen (HLA) region identified that rs114596632 was partially tagged by HLA-B*0801 (r2 = 0.592) and HLA-C*0701 (r2 = 0.675). Importantly, the rs114596632 T allele was significantly associated with decreased DNA repair capacity (DRC) measured in peripheral T lymphocytes and decreased mRNA expression levels of GTF2H4 in lymphoblastoid cell lines. We also validated two previously known SNPs in DNA repair genes MSH5 and XRCC4 associated with lung cancer risk. Subsequent pathway analysis with gene relationships across implicated loci (GRAIL) revealed multiple significant connections for GTF2H4, ERCC2, and MMS19. Our results provide evidence that genetic variants of GTF2H4 confer susceptibility to lung cancer and suggest the involvement of GTF2H4 in the etiology of lung cancer. (Supported by U19CA148127, R01CA CA074386, R01CA092824 and the start-up funds from Duke Cancer Institute, Duke University Medical Center) Citation Format: Qingyi Wei, Hongliang Liu, Zhensheng Liu, Christopher I. Amos, Jennifer A. Doherty, Heike Bickeboller, Rayjean J. Hung, Paul Brennan, Richard Houlston, Maria Teresa Landi, Neil E. Caporaso, David Christiani. A novel variant in DNA repair gene GTF2H4 is associated with lung cancer risk: A reanalysis of GWAS datasets from the TRICL consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4597. doi:10.1158/1538-7445.AM2015-4597
Polymorphic Pvu II Sites in the Stage-Selector Elements of the Baboon (P. anubis) γ-Globin Gene Promoter May Determine HbF Levels by Reducing DNA Methylation Density.
Authors: Donald Lavelle, Mahipal Singh, Kestas Vaitkus, Maria Hankewych, Lauren Wilson, Joseph DeSimone
Journal: Blood (2004)
Fake penicillin,<i>The Third Man,</i>and Operation Claptrap
Authors: Paul N Newton, Brigitte Timmermann
Journal: BMJ (2016)

The Third Man is a wonderfully evocative, innovative, and fascinating film, set in the ruins and chaos of post-war Vienna.Released in 1949, it was directed by Carol Reed with the screenplay by Graham Greene.It describes the tortuous chase and grisly subterranean death of the fake penicillin smuggler Harry Lime, played by Orson Welles. 1-4Lime's falsified penicillin results in the death or hospital admission of many Viennese children.To vanish from the police, Lime fakes his own death by having a co-conspirator run over and buried as himself.However, a school friend of Lime, Holly Martins, arrives in Vienna to see Harry and, suspicious that the accident was murder, starts his own amateur investigation-only to be surprised to find Harry still alive in the shadows of nocturnal Vienna.Reluctantly, Martins is recruited to the entrapment of Lime, after being shown evidence of his heinous crimes by Major Calloway, a Royal Armoured Corps intelligence officer, played by Trevor Howard.How did Graham Greene arrive at this unusual and moving pharmaceutical story, that sadly still has so much public health relevance for today?There are multiple fascinating and rather bizarre threads.
Safety &amp; Efficacy of Human Plasma Derived Plasminogen Ophthalmic Drops for Treatment of Ligneous Conjunctivitis: Report of Phase 2/3 Clinical Trial
Authors: Charles T Nakar, Roberto Caputo, Francis W Price, Maria Teresa Sartori, Andrea Leonardi, Anna Lotti Suffredini, Neelam Thukral, Jacopo Secci, Bennie H Jeng, Amy D Shapiro
Journal: Blood (2015)
Abstract 4383: Vitamin E delta-tocotrienol inhibits metastasis and targets cancer stem cell signaling in human pancreatic cancer
Authors: Kazim Husain, Said M. Sebti, Mokenge P. Malafa
Journal: Cancer Research (2015)

Abstract Background: Pancreatic cancer, a lethal and aggressive malignancy is the fourth leading cause of cancer-related deaths in the United States. One of the main reasons for this outcome includes the lack of effective prevention strategies for recurrent disease. Pancreatic cancer stem cells (CSCs) have been implicated in the development of pancreatic cancer metastasis, resistance to chemotherapy and its recurrence following surgical extirpation. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro as well as in vivo models. The purpose of this study was to evaluate the effect of δ-tocotrienol on tumor metastatic EMT, migration, invasion, angiogenesis and CSCs signaling in metastatic human pancreatic cancer cells. Methods: Human metastatic pancreatic cancer cells L3.6pl expressing luciferase were orthotopically implanted into pancreas of Athymic nude mice (n = 10) and after one week they were randomized in two groups: 1) vehicle control (ethanol extracted olive oil) and 2) δ-tocotrienol (200 mg/kg, orally twice a day) for 4 weeks. The tumor volume, tumor weight, liver and lung metastasis were recorded. The tumor tissues were analyzed for metastasis markers, epithelial to mesenchymal transition (EMT), and angiogenesis. In vitro L3.6pl cells were treated with δ-tocotrienol (50 μM) and used for migration and invasion assay, isolation of CSCs and spheroid formation, transcription factors and CSCs signaling markers were determined by Western blotting. Results: Vitamin E δ-tocotrienol significantly inhibited the pancreatic tumor growth [tumor volume (50%) and weight (60%)] and metastasis in the liver and lung, CSCs spheroid formation, migration and invasion compared to control. δ-tocotrienol induced apoptosis (PARP1 cleavage and Bax expression) compared to control. δ-tocotrienol also inhibited EMT (E-cadherin to vimentin), metastasis (MMP9), angiogenesis (VEGF), CSCs transcription factors (Nanog, Oct4, Sox2 and KLF4) and oncogenic signaling (Notch-1 and pERK) compared to control. Conclusion: Vitamin E δ-tocotrienol inhibited metastasis of human pancreatic tumor through inhibition of EMT, migration, invasion, angiogenesis, cancer stem cell signaling and induction of apoptosis. Citation Format: Kazim Husain, Said M. Sebti, Mokenge P. Malafa. Vitamin E delta-tocotrienol inhibits metastasis and targets cancer stem cell signaling in human pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2015-4383
412. The Efficacy and Bio-Distribution of Oncolytic HSV-1 (G47Δ) in Mouse Orthotopic Esophageal Cancer Models
Authors: Shoh Yajima, Yasushi Ino, Hiroshi Fukuhara, Miwako Iwai, Yasuyuki Seto, Tomoki Todo
Journal: Molecular Therapy (2016)

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal among cancer, because it easily metastasizes to the mediastinal lymph nodes and invades adjacent organs. The majority of patients with ESCC are diagnosed at advanced stages. Conventional treatments often result in unsatisfactory clinical outcome, therefore a novel therapeutic approach is urgently needed. Oncolytic viruses emerge as promising therapeutic agents. G47Δ, a third generation oncolytic herpes simplex virus type 1 (HSV-1), shows high replication capability and robust cytopathic effects in a variety of cancer cells. In this study, we examined the efficacy and bio-distribution of G47Δ using mouse ESCC models. A panel of human ESCC cell lines (KYSE70, KYSE180, KYSE220, T.Tn, and TE8) was susceptible to G47Δ by cytotoxicity assays. G47Δ showed moderate to good replication capability in all cell lines tested. Athymic mice harboring subcutaneous tumors (KYSE180, TE8) or orthotopic abdominal esophageal tumors (TE8-luc) were used for in vivo studies. When the subcutaneous tumors reached approximately 6 mm in diameter, they were inoculated twice (days 0 and 3) with G47Δ (4×104, 2×105, or 1×106 pfu) or mock, and the tumor size was measured (n=10). G47Δ was significantly more effective in inhibiting the growth of subcutaneous tumors than mock in both models. The orthotopic TE8-luc tumors were inoculated once with G47Δ (1×106 pfu) or mock under laparotomy 18 days after tumor implantation (n=10). The tumor size was evaluated by measuring photons emitted from the tumors every 3 days using the IVIS and Living Image Software (Xenogen). Tumors treated with G47Δ were significantly smaller than those with mock (p<0.01, Wilcoxon's test). In order to validate the result, the tumor weight was measured on day 31. G47Δ treated tumors were significantly smaller than mock treated tumors (p<0.01, Student's t test). For bio-distribution evaluation, wild type HSV-1 strain F (1×107 pfu) or G47Δ (1×107 pfu) were administered to HSV-1 sensitive A/J mice via oral route or by direct injection to abdominal esophagus under laparotomy. Mice were sacrificed at each time point (1, 3, 5, and 7 days after administration, n=3) and the amount of viral DNA in major organs was examined by quantitative PCR. DNA copy numbers of Strain F remained high in esophagus or dramatically increased in the brain, spinal cord and adrenal gland through day 7. In contrast, G47Δ DNA copy number decreased rapidly in the esophagus and was mostly undetectable in other organs. These results indicate that G47Δ is highly efficacious and safe in both orthotopic and subcutaneous ESCC models. G47Δ may be useful as a new therapeutic approach for ESCC.
Abstract 5307: Analysis of telomere length in classic and variant hairy cell leukemia
Authors: Daniel C. Edelman, Evgeny Arons, Holly Stevenson, Allison Gomez, David Petersen, Hong Zhou, Yonghong Wang, Joshua J. Waterfall, Paul S. Meltzer, Robert Kreitman
Journal: Cancer Research (2015)

Abstract Telomeres are ribonucleoprotein structures which protect the ends of chromosomes from aberrant recombination events and have been reported to be relatively short in several hematologic malignancies; adverse prognosis has been documented in chronic lymphocytic leukemia and several non-B-cell malignancies. However, their association with prognosis of classic and variant hairy cell leukemia (HCL and HCLv) has not been described. To study telomeres in HCL and HCLv, DNA from leukemic cells of patients was measured by monochrome multiplex quantitative PCR (MMQPCR) to determine relative telomere length (RTL). Of 46 patients in the cohort, 5 of 27 HCL (19%) vs. 12 of 19 HCLv (63%) patients had unmutated (&amp;gt;98% homology to germline sequence) immunoglobulin rearrangements (p = 0.0045). IGHV4-34+ rearrangements were present in 12 of the 17 (70%) unmutated cases, including five HCL and seven HCLv. RTL was shown to be shorter in unmutated HCL (p = 0.03) and in patients who had died of their disease (p = 0.03). RTL negatively correlated with IGHV homology to germline sequence (r = -0.331; p = 0.025), and age (r = -0.315; p = 0.035). Shorter RTL was associated with death from disease in either HCL (p = 0.0063) or HCLv (p = 0.0034), in patients with mutated IGHV rearrangements (p = 0.005), or in all patients combined (p = 0.0008). Median survival from diagnosis was less in time in patients with shorter RTL (p = 0.016) and this significant difference persisted when examining just the 19 patients with HCLv (p = 0.029). Gene expression profiling identified several genes related to telomere maintenance with significantly different expression levels between mutated and unmutated cases. This first of kind study in HCL/HCLv suggests that telomeres play a role in the relative pathology of HCL and HCLv and RTL could be used as a prognostic biomarker in gauging the indolent course of these cancers. Citation Format: Daniel C. Edelman, Evgeny Arons, Holly Stevenson, Allison Gomez, David Petersen, Hong Zhou, Yonghong Wang, Joshua J. Waterfall, Paul S. Meltzer, Robert Kreitman. Analysis of telomere length in classic and variant hairy cell leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5307. doi:10.1158/1538-7445.AM2015-5307
50. Long-Term Follow-Up of Diabetic Dogs Treated with Adeno-Associated Viral Vectors Encoding for Insulin and Glucokinase
Authors: Veronica Jimenez, Maria Luisa Jaen, Laia Vila, Jordi Rodo, Miquel Garcia, Ivet Elias, Luca Maggioni, Xavier Leon, Sergio Munoz, David Callejas, Iris Grifoll, Eduard Ayuso, Tura Ferre, Virginia Haurigot, Fatima Bosch
Journal: Molecular Therapy (2016)

Diabetes is a chronic disease for which there is no cure and is associated with severe secondary complications, caused largely by poor glycaemic control. Treatment with exogenous insulin fails to prevent these complications completely, leading to significant morbidity and mortality. We previously demonstrated that it is possible to generate a "glucose sensor" in skeletal muscle through co-expression of glucokinase (Gck) and insulin (Ins) by adeno-associated viral vectors of serotype 1 (AAV1), increasing glucose uptake and correcting hyperglycaemia in diabetic mice and dogs. Here we show the results of a 8-year follow-up study of diabetic dogs previously treated with a single administration of AAV1 vectors encoding for Ins and Gck. Dogs showed normalization of fasting glycaemia, recovery of body weight, reduced fructosamine levels and increased insulin and C-peptide circulating levels throughout the observation period. Vector genome biodistribution analysis confirmed that most of the detectable vector was present in injected muscles, which showed normal muscle morphology. Accordingly, Ins and Gck transgene expression was only detected in skeletal muscle of treated dogs. This was associated with long-term survival without occurrence of secondary diabetic complications or adverse events for 8 years after AAV-mediated gene transfer. Our data represent the first demonstration of long-term correction of diabetes in a large animal model using gene transfer. This study also confirms the long-term safety of the AAV-mediated overexpression of Ins and Gck for the treatment of diabetes, laying the foundation for the clinical translation of this approach to veterinary medicine and to human patients in the future.
Health resource utilization (HRU) and cost associated with bone metastases (BMets) and skeletal related events (SREs) in patients (Pts) with prostate cancer (PC).
Authors: M. Hagiwara, C. Atchison, K. Chung, T. E. Delea
Journal: Journal of Clinical Oncology (2011)

e16542 Background: This study describes HRU and cost associated with BMets and SREs in PC pts who have received hormonal therapy (HT). Methods: Retrospective study using the Thomson MedStat MarketScan databases (9/02 – 5/08). Study subjects were male and had diagnoses of PC (ICD-9-CM 185) and BMets (ICD-9-CM 198.5) and ≥1 claim for HT in the year prior to BMets. HRU was grouped as follows: hospital inpatient, outpatient medical services (OMS) (with sub-groups of physician office/hospital outpatient [PO/HO], emergency room, home health, hospice, skilled nursing facility, lab, other), and outpatient pharmacy. OMS claims were classified first by procedures/treatments (e.g., radiotherapy [RT], intravenous bisphosphonates [IVBPs], bone surgery) then diagnosis (e.g., PC, BMets, fracture); inpatient claims, by diagnosis. For each HRU category and person- quarter (PQ) post BMets, the change in healthcare cost post-BMets vs. mean cost/PQ 1y pre-BMets was calculated. PQs post-BMets were stratified by +/- SREs. Quarterly costs were annualized. Results: Among 1,357 pts with BMets from PC receiving HT, 652 (48%) had ≥1 SRE post-BMets over mean follow-up of 1.2 y. Mean (SE) annual cost pre-BMets was $20,620 ($1,019) in pts with SREs and $19,653 ($808) in pts without SREs. Compared with PQs pre-BMets, annual cost increased by a mean (SE) of $24,106 ($1,369) during PQs post-BMets without SREs (4,098 PQs) and by a mean (SE) of $35,559 ($2,095) during PQs post-BMets with SREs (2,943 PQs). Increases were primarily attributable to OMS, largely those provided in PO/HO setting (mean increase in annual cost of $15,809 during PQs post-BMets without SREs and $22,541 during PQs post-BMets with SREs). The increased PO/HO cost during PQs post-BMets without SREs was mostly associated with claims with a PC or BMets diagnosis or for IVBPs. The increased PO/HO cost during PQs post-BMets with SREs was mostly associated with claims with a PC diagnosis or for RT or IVBPs. Hospital inpatient care accounted for approximately ¼ of the increase in cost during PQs post-BMets both +/- SREs. Conclusions: BMets +/- SREs are associated with increased HRU and cost in PC pts, most of which is attributed to OMS.
Identification of Toyocamycin, an Agent Cytotoxic for Multiple Myeloma Cells, As a Potent Inhibitor of ER Stress-Induced XBP1 mRNA Splicing
Authors: Masaki Ri, Etsu Tashiro, Daisuke Oikawa, Satoko Shinjo, Mio Tokuda, Yumi Yokouchi, Tomoko Narita, Ayako Masaki, Fumiko Mori, Asahi Ito, Jianming (Diane) Ding, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Yukimasa Shiotsu, Akio Niimi, Ryuzo Ueda, Takao Iwawaki, Masaya Imoto, Shinsuke Iida
Journal: Blood (2012)