tbuckley/cabot-search huggingface dataset:
SAT0186 Treatment response of intravenous tocilizumab in patients with rheumatoid arthritis based on the level of prior exposure to biologic therapy: results from the kobio
Authors: K. Shin, S.-K. Lee, S. Oh, H.-A. Kim, Y. W. Song
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Previous studies have showed that response rate to biologic therapy in patients with rheumatoid arthritis (RA) are lower in those who had prior exposure to multiple biologic agents compared with first-time users. However, most of these studies targeted on patients undergoing anti-TNF therapy. <h3>Objectives:</h3> To investigate the treatment response of RA patients using intravenous tocilizumab (TOC) as the first biologic agent, comparing with those who had prior exposure to other biologic agents <h3>Methods:</h3> Data of RA patients treated with TOC were obtained from the Korean College of Rheumatology Biologics Registry (KOBIO). Patients were grouped as first (1st)-line, second (2nd)-line, and third or more (≥3rd)-line users. Clinical outcomes including SDAI changes at the first year and second year of TOC therapy were evaluated, and subsequent switching to another biologic agent and its associated factors were analyzed using the Cox proportional hazard model. <h3>Results:</h3> A total of 408 patients were included in the study; 1st-line (n = 258), 2nd -line (n = 95), ≥3rd -line (n = 55) users. The mean age was 54.0 years, and mean disease duration of 8.2 years. At baseline, mean SDAI was 30.0, and 7.1% of patients were treated without a concomitant conventional DMARD, which increased to 21.6% at the end of the second year. The clinical response of related parameters in 1st -line TOC users were more robust than the 2nd -line or ≥3rd -line users, and greater proportion of 1st -line users achieved remission or low disease activity at the second year (<i>p=</i>0.00291) (figure). In addition, switching to another agent was more frequent in the 2nd -line or ≥3rd -line users within 2 years (1st, 2nd, ≥3rd -line users, 4.7%, 15.1%, 11.1%, respectively). A multivariate analysis revealed that higher baseline SDAI (HR 1.1018, <i>p=</i>0.00680) and multiple prior exposure to biologics (HR 2.5751, <i>p=</i>0.0139) were predictors of subjects switching to other agents. <h3>Conclusions:</h3> Amongst RA patients with high disease activity who receive TOC, patients naïve to biologics have better treatment response and lower switch rates after two years. <h3>Reference</h3> [1]Karlsson JA, et al. Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology2008;47:507–13. <h3>Disclosure of Interest:</h3> None declared
Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group: MPN Experimental Assessment of Symptoms By Utilizing Repetitive Evaluation (MEASURE) Trial
Authors: Allison Gathany, Robyn M. Scherber, Marlene Girardo, Heidi E. Kosiorek, Amylou C. Dueck, Holly Geyer, Veena D. S. Fauble, Alessandro M. Vannucchi, Ana Kerguelen Fuentes, Christen Lykkegaard Andersen, Elisabeth Ejerblad, Gunnar Birgegard, Peter L. Johansson, Bjorn Andreasson, David M Ross, Federico Sackman, Jean-Loup Demory, Constantine S. Tam, Jan J. Michiels, Deepti Radia, Joanne Ewing, Frances Wadelin, Robert N. Lown, Mary Frances McMullin, Wunna Swe, Jonathan O. Cullis, Nigel Sargant, Paul Moreton, Catherine Cargo, Mallika Sekhar, Satareh Shekouhi, Ruben A. Mesa
Journal: Blood (2018)
Abstract #3743: SGI-1776: A novel PIM kinase inhibitor with potent preclinical activity against Acute Myeloid Leukemia (AML)
Authors: Ronan Swords, Kevin Kelly, Ernest Medina, Devalingam Mahalingam, Steffan Nawrocki, David Bearss, Joi Ninomoto, Gregory Berk, Francis Giles, Jennifer Carew
Journal: Cancer Research (2009)

The PIM kinases (PIM1, PIM2, PIM3) are a small family of proto-oncogenes within the CAMK super-family. Overexpression of PIM kinases significantly augments cell survival and accelerates c-myc and N-myc-driven tumorigenesis in mouse models. Accordingly, overexpression of PIM kinases has been reported in a wide range of malignancies including clinical cases of lymphoma, AML, prostate cancer, bladder cancer, lung cancer, oral cancer, melanoma, pancreatic cancer, gastric cancer, and hepatomas. In vitro, prolonged exposure to FLT3 inhibitors leads to FLT3-TKI -resistance via activation of parallel signaling pathways, and resultant altered gene expression, including high levels of PIM1. PIM1 also regulates drug resistance. PIM1 phosphorylates and activates the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp; MDR1; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which are strongly associated with clinical drug resistance in AML and other malignancies, and PIM1 knockdown results in inhibition of drug resistance mediated by both of these proteins. The roles of the PIM kinases in cell survival signaling and tumorigenesis make them very attractive targets for pharmacological inhibition in cancer therapy. SGI-1776 is a novel orally available small molecule inhibitor of PIM kinase activity that has entered Phase I clinical trials. We hypothesized that SGI-1776 would have significant anticancer activity against AML cells due to their high intrinsic expression of PIM-1. In vitro assays conducted in a panel of human AML cell lines demonstrated that low nanomolar concentrations of SGI-1776 potently diminished cell viability and inhibited clonogenic survival. FLT3 ITD positive AML cells were particularly sensitive to SGI-1776, likely due to the dual inhibitory effects of this agent against PIM and FLT3 kinase activity. SGI-1776 induced apoptosis in AML cells in a dose-dependant manner that correlated with a reduction in the intracellular levels of phosphorylated BAD. Oral administration of SGI-1776 to immunodeficient mice bearing xenografts of the human AML cell lines MOLM-13 and MV-4-11 was very well tolerated. SGI-1776 inhibited tumor growth significantly more effectively in these models than administration of the standard of care agents cytarabine and daunorubicin. These data support clinical study of SGI-1776 in patients with AML and further investigation of the role of PIM kinase in AML pathophysiology.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3743.
A Prospective Study of Environmental Exposures and Early Biomarkers in Autism Spectrum Disorder: Design, Protocols, and Preliminary Data from the MARBLES Study
Authors: Irva Hertz-Picciotto, Rebecca J. Schmidt, Cheryl K. Walker, Deborah H. Bennett, McKenzie Oliver, Kristine M. Shedd-Wise, Janine M. LaSalle, Cecilia Giulivi, Birgit Puschner, Jennifer Thomas, Dorcas L. Roa, Isaac N. Pessah, Judy Van de Water, Daniel J. Tancredi, Sally Ozonoff
Journal: Environmental Health Perspectives (2018)

Background: Until recently, environmental factors in autism spectrum disorder (ASD) were largely ignored. Over the last decade, altered risks from lifestyle, medical, chemical, and other factors have emerged through various study designs: whole population cohorts linked to diagnostic and/or exposure-related databases, large case–control studies, and smaller cohorts of children at elevated risk for ASD. Objectives: This study aimed to introduce the MARBLES (Markers of Autism Risk in Babies—Learning Early Signs) prospective study and its goals, motivate the enhanced-risk cohort design, describe protocols and main exposures of interest, and present initial descriptive results for the study population. Methods: Families having one or more previous child with ASD were contacted before or during a pregnancy, and once the woman became pregnant, were invited to enroll. Data and biological samples were collected throughout pregnancy, at birth, and until the child’s third birthday. Neurodevelopment was assessed longitudinally. The study began enrolling in 2006 and is ongoing. Results: As of 30 June 2018, 463 pregnant mothers have enrolled. Most mothers (&gt;75%) were thirty years of age or over, including 7.9% who are fourty years of age or over. The sample includes 22% Hispanic and another 25% nonHispanic Black, Asian, or multiracial participants; 24% were born outside the United States. Retention is high: 84% of participants whose pregnancies did not end in miscarriage completed the study or are still currently active. Among children evaluated at 36 months of age, 24% met criteria for ASD, and another 25% were assessed as nonASD nontypical development. Conclusion: Few environmental studies of ASD prospectively obtain early-life exposure measurements. The MARBLES study fills this gap with extensive data and specimen collection beginning in pregnancy and has achieved excellent retention in an ethnically diverse study population. The 24% familial recurrence risk is consistent with recent reported risks observed in large samples of siblings of children diagnosed with ASD. https://doi.org/10.1289/EHP535
Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion
Authors: Elena M. Stoffel, Shannon E. McKernin, Randall Brand, Marcia Canto, Michael Goggins, Cassadie Moravek, Arun Nagarajan, Gloria M. Petersen, Diane M. Simeone, Matthew Yurgelun, Alok A. Khorana
Journal: Journal of Clinical Oncology (2018)

Purpose An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO’s membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members’ curated files. Provisional Clinical Opinion All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .
Comparison of Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T-Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL
Authors: Jordan Gauthier, Alexandre V. Hirayama, Kevin A. Hay, Daniel Li, James Lymp, Alyssa Sheih, Janaki Purushe, Barbara S. Pender, Reed M. Hawkins, Aesha Vakil, Tinh-Doan Phi, Rachel N. Steinmetz, Aude G. Chapuis, Brian G. Till, Tejaswini Dhawale, Paul C. Hendrie, Hans-Peter Kiem, Jorge Ramos, Mazyar Shadman, Ryan D. Cassaday, Utkarsh H. Acharya, Stanley R. Riddell, David G. Maloney, Cameron J. Turtle
Journal: Blood (2018)
Abstract 13789: Developing Xeno-Free Human Induced Pluripotent Stem Cell-Derived Cardiac Construct for Regeneration Therapy Using a Rat Myocardial Infarction Model
Authors: Motoko Shiozaki, Shigeru Miyagawa, Satsuki Fukushima, Itsunari Minami, Keitaro Domae, Shin Yajima, Emiko Ito, Kazuhiro Aiba, Takashi Asada, Norio Nakatsuji, Yoshiki Sawa
Journal: Circulation (2015)

Background: Use of induced pluripotent stem cells (hiPSC) is promising to establish cardiac regenerative medicine in clinical arena; however, safety is concerned by regulatory scientific view, including use of xeno-biological materials for production of the graft. We have explored synthetic small molecules, KY, instead of standard xeno-materials to induce cardiomyogenic differentiation, such as BMP4, Activin A or insulin. We herein studied therapeutic efficacy of hiPSC-derived cardiomyocytes (CMs) generated by xeno-free condition on chronic myocardial infarction (MI) in rat. Methods: Lentivirus vector carrying Oct3/4, Sox2 and Klf4 was transfected in human dermal fibroblasts to establish hiPSC cell-line. KY was added to the hiPSCs, which displayed 80±10%-positivity in cardiac-troponin T. Scaffold-free cardiac graft was produced by hiPSC-CMs that were cultured in thermoresponsive dishes, and transplanted over the cardiac surface of athymic nude rats that were subjected to left coronary artery ligation 2 weeks prior to the treatment, or sham operation was performed. Results: Echocardiographically, ejection fraction recovered after the treatment in the hiPSC-CM group (48±4% at baseline, 55±4% at 1 week, 55±4% at 2 weeks, and 56±3% at 4 weeks), whereas the sham group showed gradual reduction in ejection fraction (46±5% at baseline, 42±5% at 1 week, 38±4% at 2 weeks, and 34±6% at 4 weeks). Immunohistochemistry showed that cardiac-troponin T and human nuclear antigen double positive-hiPSC-CMs were present in the lateral cardiac surface in the hiPSC-CM hearts. In the hiPSC-CM group, collagen fibers significantly decreased in the infarct-border and remote areas (p&lt;0.01 and p&lt;0.01, respectively). CD31-positve capillary number in the infarct-border area was significantly greater in the hiPSC-CM group (p&lt;0.01) than the sham group. Conclusion: Transplantation of scaffold-free human iPSC-CMs grafts produced by xeno-free synthetic small molecules was effective on rat chronic MI heart, warranting further studies to optimize production of iPSC-based artificial cardiac graft for cardiac regeneration therapy.
Epicardial Adipose Tissue and Myocardial Fibrosis in Aortic Stenosis Relationship With Symptoms and Outcomes
Authors: Laurent Davin, Alain Nchimi, Federica Ilardi, Raluca Dulgheru, Stella Marchetta, Olivier Gach, Patrick Marechal, Sara Cimino, Pierre-Julien Bruyère, Andreas Georgiopoulos, John Epoh Dibato, Gessica d'Amico, Maurizio Galderisi, Valentina Parisi, Cécile Oury, Patrizio Lancellotti
Journal: JACC. Cardiovascular imaging (2018)
A blueprint for cancer screening and early detection: Advancing screening’s contribution to cancer control
Authors: Richard C. Wender, Otis W. Brawley, Stacey A. Fedewa, Ted Gansler, Robert A. Smith
Journal: CA A Cancer Journal for Clinicians (2018)

Abstract From the mid‐20th century, accumulating evidence has supported the introduction of screening for cancers of the cervix, breast, colon and rectum, prostate (via shared decisions), and lung. The opportunity to detect and treat precursor lesions and invasive disease at a more favorable stage has contributed substantially to reduced incidence, morbidity, and mortality. However, as new discoveries portend advancements in technology and risk‐based screening, we fail to fulfill the greatest potential of the existing technology, in terms of both full access among the target population and the delivery of state‐of‐the art care at each crucial step in the cascade of events that characterize successful cancer screening. There also is insufficient commitment to invest in the development of new technologies, incentivize the development of new ideas, and rapidly evaluate promising new technology. In this report, the authors summarize the status of cancer screening and propose a blueprint for the nation to further advance the contribution of screening to cancer control.
The attenuated salmonella typhimurium strains expressing anti-cancer proteins have overcome host immune barrier to infiltrate tumor tissues and induce massive cancer cell death
Authors: Qiuhong He, Vitaly Chibisov, Gabrielle Ramus, Huiwen Liu, Kaung-Ti Yung, He Zhu
Journal: Cancer Research (2007)

4809   The current cancer therapeutic modalities have encountered tremendous challenges in treating hypoxic cancer cells due to poor drug delivery for effective chemotherapy or low level of tumor oxygenation for effective radiation therapy. Bacteria can penetrate into hypoxic tumor regions and deliver therapeutic proteins, therefore treating cancer cells that usually escape from conventional cancer therapies. Recently, the attenuated Salmonella typhimurium strain was introduced with >10,000 virulence attenuation and ~1,000 tumor tropism in a variety of animal tumor models. The bacteria can be easily manipulated to introduce therapeutic genes and proteins for cancer treatment. However, in a human melanoma trial, the bacterial strain showed poor tumor tissue attraction, indicating that the bacteria injected i.v. in the cancer patients might be eliminated by human immune response. To resolve this issue, we hypothesize that genetic engineering of the attenuated Salmonella strain with therapeutic protein expressions may improve bacterial infiltration in tumor tissues by overcoming the host immune response. This was tested experimentally in Lewis lung carcinoma (LLC), a murine tumor model that eliminated the parent strain in immunocompetent C57BL/6J mice. Initially, an anti-cancer protein recombinant methioninase was successfully expressed in the Salmonella strain. The attenuated Salmonella typhimurium expressing methioninase not only infiltrated the LLC tumors in C57BL/6J mice but also induced massive tumor tissue destruction. On the other hand, the original Salmonella strain, which was not able to survive in the LLC tumors in the C57BL/6J mice, could successfully infiltrate the LLC tumors implanted in the immunodeficient CB-17 SCID mice. Therefore, the original Salmonella strain was likely eliminated by the host immune response in LLC on C57BL/6J mice. Similar results were observed with Salmonella expressing TNFalpha or a combination of Methioninase and TNFalpha. Tumor cell apoptosis and macrophage activation were revealed by TUNEL and immunochemical staining. Using magnetic resonance diffusion-weighted imaging (DWI) technique, the rapid tumor tissue destruction induced by the bacteria was monitored longitudinally in vivo in a period of two weeks. Importantly, the new bacteria were observed to migrate to distant tumor sites and, therefore, may be used to treat cancer metastasis. In conclusion, the Salmonella strains expressing methioninase and/or TNFalpha have overcome the host immune barrier and infiltrated LLC tumor tissues that usually eliminated the parent salmonella strain in C57BL/6J mice. The rapid tumor tissue destruction can be monitored in vivo by DWI. Thus, attenuated bacteria expressing protein drugs may be designed to overcome human immune barriers for effective human cancer treatment.
Black–White Breast Cancer Incidence Trends: Effects of Ethnicity
Authors: Brittny C Davis Lynn, Philip S Rosenberg, William F Anderson, Gretchen L Gierach
Journal: JNCI Journal of the National Cancer Institute (2018)

Recent reports of converging black and white breast cancer incidence rates have gained much attention, potentially foreshadowing a worsening of the black-white breast cancer mortality disparity. However, these incidence rates also reflect the sum of non-Hispanics and Hispanics that may mask important ethnicity-specific trends. We therefore assessed race- and ethnicity-specific breast cancer trends using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 13 Registries Database (1992-2014). Age-period-cohort models projected rates for 2015-2030. Results confirmed merging of age-standardized incidence rates for blacks and whites circa 2012, but not for non-Hispanic black (NHB) and non-Hispanic white (NHW) women. Incidence rates were highest for NHW women (n = 382 290), followed by NHB women (n = 51 074), and then Hispanic white women (n = 48 651). The sample size for Hispanic blacks was too small for analysis (n = 693). Notably, future incidence rates are expected to slowly increase (2015 through 2030) among NHW women (0.24% per year, 95% confidence interval [CI] = 0.17 to 0.32) and slowly decrease for NHB women (-0.14% per year, 95% CI = -0.15 to -0.13). A putative worsening of the black-white mortality disparity, therefore, seems unlikely. Ethnicity matters when assessing race-specific breast cancer incidence rates.
Mechanism of TGF-β receptor RI inactivation in ER+ breast cancer cells
Authors: Sudhakar Ammanamanchi, Michael G. Brattain
Journal: Cancer Research (2004)

4809   Estrogen receptor positive (ER+) breast cancer cells escape growth inhibition by transforming growth factor-beta (TGF-β) due to reduced expression of TGF-β receptors type I (RI) and type II (RII). Treatment of ER+ breast cancer cells, MCF-7L and ZR75 with the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA) led to a dramatic induction of RI, which directly interacts with downstream SMAD family transcription factors to transduce the biological affects of TGF-β. RII was induced to a lesser extent. Accumulation of acetylated histones H3 and H4 was noticed in the SAHA treated cells. Chromatin immunoprecipitation (ChIP) analysis followed by PCR with RI promoter specific primers on the chromatin fragments from control and SAHA treated cells indicated accumulation of acetylated histones in chromatin associated with the RI gene suggesting that histone deacetylation was involved in the transcriptional inactivation of RI. SAHA treatment stimulated RI promoter-luciferase reporter activities, thus suggesting increased transcription was contributing to enhanced RI expression. We are in the process of identifying the SAHA responsive element on the RI promoter. Significantly, SAHA mediated RI expression restored TGF-β response in the ER+ breast cancer cells as indicated by the enhanced activity of a TGF-β responsive element from the plasminogen activator inhibitor.
Efficacy and safety of ramucirumab (RAM) in Asian and non-Asian patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP): Subgroup analysis from two randomized studies
Authors: Y.-K. Kang, M. Kudo, H.-Y. Lim, C.-H. Hsu, A. Vogel, G. Brandi, R. Cheng, I. Carton, P. Abada, Y. Hsu, A. Zhu, C.-J. Yen
Journal: Annals of Oncology (2018)
Knowledge and attitudes of productive age women about visual inspection with acetic acid (VIA) test in early screening of cervical cancer in Tihingan village, Klungkung, Bali
Authors: R.C. Putri, A.B.S. Satyarsa, L. Marina Wirahartato, L.P.D. Virayanti, K. Wiswa Mitra Kenwa, P.A.T. Adiputra, I.W. Sudarsa
Journal: Annals of Oncology (2018)
Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions
Authors: Patricia Heyn, Clare V. Logan, Adeline Fluteau, Rachel C. Challis, Tatsiana Auchynnikava, Carol-Anne Martin, Joseph A. Marsh, Francesca Taglini, Fiona Kilanowski, David A. Parry, Valerie Cormier-Daire, Chin-To Fong, Kate Gibson, Vivian Hwa, Lourdes Ibáñez, Stephen P. Robertson, Giorgia Sebastiani, Juri Rappsilber, Robin C. Allshire, Martin A. M. Reijns, Andrew Dauber, Duncan Sproul, Andrew P. Jackson
Journal: Nature Genetics (2018)
Abstract 16739: Impaired Nedd9-smad3 Binding Upregulates Collagen III Synthesis in Human Pulmonary Artery Endothelial Cells in vitro to Promote Pulmonary Arterial Hypertension in vivo
Authors: Andriy Samokhin, Rui-Sheng Wang, George Alba, Bradley Wertheim, Elena Arons, Frederick Bowman, Lai-Ming Yung, Paul Yu, Vadim Gladyshev, Bradley A Maron
Journal: Circulation (2017)

Genetic mutations that affect Smad-TGF-β signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is characterized by vascular fibrosis and hyperaldosteronism (ALDO...