tbuckley/cabot-search huggingface dataset:
Abstract #2013: Discovery of SGI-1776, a potent and selective Pim-1 kinase inhibitor
Authors: Xiaohui Liu, Eric Gourley, Jeremy Lamb, Cory Grand, Marcy Lloyd, Steven Warner, Bradley Wolfe, David Bearss, Hariprasad Vankayalapati
Journal: Cancer Research (2009)

Pim-1 is a highly conserved serine-threonine kinase that is a key regulator in many cytokine signaling pathways. Activated Pim-1 kinase can induce progression of the cell cycle, inhibition of apoptosis, and modulation of other signal transduction pathways, including its own. Transformation of Pim-1 kinase in conjunction with other oncogenes such as c-myc, N-Myc, and others such as gfi-1, runx-2 leads to malignancies including Burkitt\#8217;s lymphoma, prostate cancer, diffuse large cell lymphoma several other types of human leukemias. These findings suggest that Pim-1 may be a promising drug target for development of anticancer agents. Through the use of Pim-1kinase crystal structure we began our discovery process by performing large-scale virtual screening composed of focused and or diverse virtual libraries. With the application of consensus scoring, binding energies and several drug-like filters we have selected limited set of 72 compounds. Five compounds belongs to imidazo[1,2-b]pyridzaine series were found to inhibit the Pim-1 kinase enzyme with an IC50  from 2 to 10 \#956;M. These active compounds and their binding modes lead to the lead optimization, synthesis and for further design of potent Pim1 kinase inhibitors. The strategies for optimizing the potency and selectivity against the Pim-1 target were undertaken with the focus on the modifications of R1 and R2 groups. A novel synthetic route was developed starting from 1,4-dibromo-trans-2-butene. We prepared 3-bromo-6-chloro-imidazo[1,2-b]pyridazine scaffold in three steps. Suzuki coupling with various substituted aryl boronic acids and followed by introduction of aliphatic amines lead to the synthesis of more than 30 novel chemical entities as Pim-1 kinase inhibitors. Initial SAR studies revealed that the introduction of hydrophobic moiety at R1 and small ring substituent groups with 1 or 2 -CH2 spacer at the 6-amine position are vital for the Pim-1 kinase inhibition. The lead compound SGI-1776 showed very potent activity against Pim-1 kinase with an IC50 of 7 nM and kinases selectivity. We recently filed an IND and anticipate enrollment into the First-in-Human Phase I study in the near future. Design, synthesis and SAR studies will be presented.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2013.
Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells
Authors: Sameer Agnihotri, Sheila Mansouri, Kelly Burrell, Mira Li, Yasin Mamatjan, Jeff Liu, Romina Nejad, Sushil Kumar, Shahrzad Jalali, Sanjay K. Singh, Alenoush Vartanian, Eric Xueyu Chen, Shirin Karimi, Olivia Singh, Severa Bunda, Alireza Mansouri, Kenneth D. Aldape, Gelareh Zadeh
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Hexokinase II (HK2) protein expression is elevated in glioblastoma (GBM), and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient-derived glioma stem cells (GSCs), and mouse models of GBM. Experimental Design: We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2-associated gene signature. We next determined the EC50 of the compounds by treating glioma cell lines and GSCs. Selected compounds showing significant impact in vitro were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on the metabolic activity in glioma cells was also assessed in vitro. Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, ketoconazole and posaconazole displayed the greatest inhibitory effect on GBM both in vitro and in vivo. Treatment of mice bearing GBM with ketoconazole and posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. In addition, treatment with azoles resulted in increased proportion of apoptotic cells. Conclusions: Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM. Combined with existing literature and preclinical results, these data support the value of repurposing azoles in GBM clinical trials.
MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis
Authors: William B. Tu, Yu-Jia Shiah, Corey Lourenco, Peter J. Mullen, Dharmendra Dingar, Cornelia Redel, Aaliya Tamachi, Wail Ba-Alawi, Ahmed Aman, Rima Al-awar, David W. Cescon, Benjamin Haibe-Kains, Cheryl H. Arrowsmith, Brian Raught, Paul C. Boutros, Linda Z. Penn
Journal: Cancer Cell (2018)
Regulating the Dietary Supplement Industry
Authors: Michael Incze, Mitchell H. Katz
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: Focus on recent advances
Authors: Xiaoqian Niu, Jiejian Chen, Jianqing Gao
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington disease and amyotrophic lateral sclerosis throw a heavy burden on families and society. Related scientific researches make tardy progress. One reason is that the known pathogeny is just the tip of the iceberg. Another reason is that various physiological barriers, especially blood-brain barrier (BBB), hamper effective therapeutic substances from reaching site of action. Drugs in clinical treatment of neurodegenerative diseases are basically administered orally. And generally speaking, the brain targeting efficiency is pretty low. Nano-delivery technology brings hope for neurodegenerative diseases. The use of nanocarriers encapsulating molecules such as peptides and genomic medicine may enhance drug transport through the BBB in neurodegenerative disease and target relevant regions in the brain for regenerative processes. In this review, we discuss BBB composition and applications of nanocarriers -liposomes, nanoparticles, nanomicelles and new emerging exosomes in neurodegenerative diseases. Furthermore, the disadvantages and the potential neurotoxicity of nanocarriers according pharmacokinetics theory are also discussed.
Baseline predictive factors for efficacy of anti-PD1 used in first line in melanoma patients: An Italian melanoma intergroup study
Authors: R. Marconcini, E. Tanda, L.A. Di Guardo, O. Nigro, P. Fava, A. Todisco, F. Morgese, A. Cortellini, E. Stroppa, G. Gallizzi, L. Festino, E. Grego, S. Quadrini, C. Orlandini, A. Nuzzo, S. Manacorda, F. Bloise, A. Indini, C. Astrua, A. Falcone
Journal: Annals of Oncology (2018)
Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure
Authors: Milena Armacki, Anna Katharina Trugenberger, Ann K. Ellwanger, Tim Eiseler, Christiane Schwerdt, Lucas Bettac, Dominik Langgartner, Ninel Azoitei, Rebecca Halbgebauer, Rüdiger Groß, Tabea Barth, André Lechel, Benjamin M. Walter, Johann M. Kraus, Christoph Wiegreffe, Johannes Grimm, Annika Scheffold, Marlon R. Schneider, Kenneth Peuker, Sebastian Zeißig, Stefan Britsch, Stefan Rose-John, Sabine Vettorazzi, Eckhart Wolf, Andrea Tannapfel, Konrad Steinestel, Stefan O. Reber, Paul Walther, Hans A. Kestler, Peter Radermacher, Thomas F.E. Barth, Markus Huber-Lang, Alexander Kleger, Thomas Seufferlein
Journal: Journal of Clinical Investigation (2018)

Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.
Flow cytometry analysis of single strand DNA damage in neuroblastoma cell lines using the F7-26 monoclonal antibody
Authors: Rita Grigoryan, Bo Yang, Nino Keshelava, Jerry Barnhart, C. Reynolds
Journal: Cancer Research (2007)

1806   Most chemotherapeutic agents act via DNA damage, and drugs such as alkylating agents and topoisomerase inhibitors act primarily by inducing single-strand DNA (ssDNA) breaks. We developed a flow cytometry method to measure the proportion of cells with ssDNA using the F7-26 monoclonal antibody (Mab) specific for ssDNA. Neuroblastoma cells were treated with melphalan (L-PAM), fenretinide, 4-hydroperoxycyclophosphamide (4-HC) ± pan-caspase inhibitor BOC-d-fmk, topotecan or with 10Gy gamma radiation ± hydrogen peroxide (H 2 O 2 ). Cytotoxicity was measured by DIMSCAN digital imaging fluorescence assay. Apoptosis by TUNEL, reactive oxygen species (ROS) by carboxy-dichlorofluorescein diacetate, and ssDNA by Mab F7-26 were measured with a BD LSRII flow cytometer, with DNA visualized by propidium iodide counterstaining. Irradiated and immediately fixed neuroblastoma cells showed increased ssDNA, but not apoptosis by TUNEL. 4-HC or L-PAM ± BOC-d-fmk increased ssDNA (F7-26-positive), but BOC-d-fmk prevented TUNEL staining in the same cells. Fenretinide increased apoptosis by TUNEL but not ssDNA damage detected with F7-26.  Enhanced ssDNA in neuroblastoma cells treated with radiation + H 2 O 2  was associated with increased ROS. Topotecan increased both ssDNA and cytotoxicity in 4-HC-treated cells.   Table shows mean percentages (%) of ssDNA damage assayed by Mab F7-26 or apoptosis assayed by TUNEL assay in neuroblastoma cell lines (n = 3).   Thus, Mab F7-26 recognized ssDNA due to exogenous DNA damage, rather than apoptosis. This 2-color assay can be used to accurately and sensitively quantify alkylator- and irradiation-induced ssDNA damage, and also to exclude DNA damage as a mechanism of drug action. This assay should be useful not only for studying the mechanism of drug action in cell culture but also as a pharmacodynamic assay with patient specimens.
Abstract 15284: The Impact of Insulin Provision vs. Insulin Sensitization Therapy on the Risk of Myocardial Infarction in Diabetic Smokers With Stable Ischemic Heart Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
Authors: Asrar A Khan, Matthew J Chung, Eric Novak, David L Brown
Journal: Circulation (2016)

Introduction: In the Bypass Angioplasty Revascularization 2 Diabetes (BARI 2D) trial, randomization of diabetic patients with stable ischemic heart disease (SIHD) to insulin provision (IP), as oppo...
Impact of prior bortezomib therapy on the incidence of lenalidomide-induced skin rash in multiple myeloma: A propensity score-matched multi-institutional cohort study
Authors: S. Dote, K. Ito, S. Itakura, T. Yasu, D. Hira, S. Noda, S. Yamada, Y. Kobayashi, T. Terada
Journal: Annals of Oncology (2018)
CDCA7 and HELLS mutations undermine nonhomologous end joining in centromeric instability syndrome
Authors: Motoko Unoki, Hironori Funabiki, Guillaume Velasco, Claire Francastel, Hiroyuki Sasaki
Journal: Journal of Clinical Investigation (2018)

Mutations in CDCA7 and HELLS that respectively encode a CXXC-type zinc finger protein and an SNF2 family chromatin remodeler cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome types 3 and 4. Here, we demonstrate that the classical nonhomologous end joining (C-NHEJ) proteins Ku80 and Ku70, as well as HELLS, coimmunoprecipitated with CDCA7. The coimmunoprecipitation of the repair proteins was sensitive to nuclease treatment and an ICF3 mutation in CDCA7 that impairs its chromatin binding. The functional importance of these interactions was strongly suggested by the compromised C-NHEJ activity and significant delay in Ku80 accumulation at DNA damage sites in CDCA7- and HELLS-deficient HEK293 cells. Consistent with the repair defect, these cells displayed increased apoptosis, abnormal chromosome segregation, aneuploidy, centrosome amplification, and significant accumulation of γH2AX signals. Although less prominent, cells with mutations in the other ICF genes DNMT3B and ZBTB24 (responsible for ICF types 1 and 2, respectively) showed similar defects. Importantly, lymphoblastoid cells from ICF patients shared the same changes detected in the mutant HEK293 cells to varying degrees. Although the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of ICF cells, including centromeric instability, abnormal chromosome segregation, and apoptosis.
Non-vitamin K oral anticoagulants (NOAC) and the risk of myocardial infarction: Differences between factor IIa and factor Xa inhibition?
Authors: Amin Polzin, Lisa Dannenberg, Georg Wolff, Carolin Helten, Alina Achilles, Thomas Hohlfeld, Tobias Zeus, Malte Kelm, Steffen Massberg, Tobias Petzold
Journal: Pharmacology & Therapeutics (2018)
Abstract MP068: Dietary Fatty Acids and Coronary Heart Disease in Mortality in the Alpha Omega Cohort
Authors: Famke J Mölenberg, Janette de Goede, Anne J Wanders, Peter L Zock, Daan Kromhout, Johanna M Geleijnse
Journal: Circulation (2017)

Background: Replacement of saturated fatty acids (SFA) with polyunsaturated fatty acids (PUFA) is associated with a lower risk of coronary heart disease (CHD) in the general population. Whether this is also the case for CHD patients is not yet clear. In this observational study of Dutch CHD patients, we examined the risk of CHD mortality for the exchange of SFA with total unsaturated fatty acids (UFA), PUFA and cis -monounsaturated fatty acids (MUFA). Methods: We included 4146 post-myocardial infarction patients aged 60-80 (78% male; Alpha Omega Cohort) in whom diet was assessed at baseline (2002-2006) by a validated 203-item food-frequency questionnaire. Cause-specific mortality was monitored until January 2013. Iso-caloric replacement of SFA with (subgroups of) UFA in relation to CHD mortality was studied in quintiles and continuously per 5 energy percent (en%), using Cox regression models. Hazard ratios (HR, 95%-CI) were obtained after adjustment for age, sex, BMI, smoking, education, physical activity, cardiovascular drugs (anticoagulants, antihypertensives, statins), diabetes, and dietary factors, i.e. total energy, protein (en%), carbohydrates (en%), trans fatty acids (en%), dietary fiber (g/d) and dietary cholesterol (mg/d). The model for PUFA also included MUFA as a covariate, and vice versa . Results: During a median follow-up of 7.3 years, there were 888 deaths including 249 CHD deaths. SFA replacement was inversely associated with CHD mortality when comparing extreme quintiles of intake, which was statistically significant for total UFA (HR: 0.44; 95% CI: 0.21-0.92; P = 0.03) and non-significant for PUFA (0.58, 0.31-1.09) and MUFA (0.81, 0.45-1.49). When expressed per 5 en% (Figure), replacing SFA with either UFA, PUFA or MUFA was associated with a more than 30% lower risk of CHD mortality. Findings were similar when confined to statin users. Conclusion: In well-treated CHD patients, replacement of SFA by UFA is associated with a lower CHD mortality risk.
Low-level expression of SAMHD1 in acute myeloid leukemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens
Authors: George Z. Rassidakis, Nikolas Herold, Ida Hed Myrberg, Nikolaos Tsesmetzis, Sean G. Rudd, Jan-Inge Henter, Torsten Schaller, Siok-Bian Ng, Wee Joo Chng, Benedict Yan, Chin Hin Ng, Farhad Ravandi, Michael Andreeff, Hagop M. Kantarjian, L. Jeffrey Medeiros, Ioanna Xagoraris, Joseph D. Khoury
Journal: Blood Cancer Journal (2018)

Abstract Sterile alpha motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) limits the efficacy of cytarabine (ara-C) used in AML by hydrolyzing its active metabolite ara-CTP and thus represents a promising therapeutic target. SAMHD1 has also been implicated in DNA damage repair that may impact DNA damage-inducing therapies such as anthracyclines, during induction therapy. To determine whether SAMHD1 limits ara-C efficacy during induction or consolidation therapy, SAMHD1 protein levels were assessed in two patient cohorts of de novo AML from The University of Texas MD Anderson Cancer Center (USA) and the National University Hospital (Singapore), respectively, using immunohistochemistry and tissue microarrays. SAMHD1 was expressed at a variable level by AML blasts but not in a broad range of normal hematopoietic cells in reactive bone marrows. A sizeable patient subset with low SAMHD1 expression (&lt;25% of positive blasts) was identified, which was significantly associated with longer event-free (EFS) and overall (OS) survival in patients receiving high-dose cytarabine (HDAC) during consolidation. Therefore, evaluation of SAMHD1 expression level in AML blasts at diagnosis, may stratify patient groups for future clinical trials combining HDAC with novel SAMHD1 inhibitors as consolidation therapy.
P3.16-44 Robotic-Assisted Thoracic Surgery for Early-Stage Non-Small-Cell Lung Cancer: Initial Experience in Brazil
Authors: R. Terra, B. Bibas, R. Haddad, J.R. De-Campos, P.H. Nabuco-De-Araujo, C.E. Lima, F. Braga, L. Lauricella, P. Pêgo-Fernandes
Journal: Journal of Thoracic Oncology (2018)
GW29-e1709 Branched Chain Amino Acids Disrupt Myocardial Glucose and Fatty Acid Metabolism During Ischemia/Reperfusion Injury.
Authors: Yueyang Li, Fuyang Zhang, Zhenyu Xiong, Wenjun Yan, Yunlong Xia, Ling Tao
Journal: Journal of the American College of Cardiology (2018)
Prediction of response to vemurafenib in BRAF V600E mutant cancers based on a network approach
Authors: R. Falcone, P. Paci, A. Verrienti, G. Fiscon, M. Sponziello, F. Conte, V. Pecce, F. Rosignolo, G. Grani, L. Lamartina, V. Ramundo, C. Durante, L. Farina, S. Filetti
Journal: Annals of Oncology (2018)
Targeting Resistance to Targeted Therapies: Combating a Resilient Foe
Authors: Siddhartha Devarakonda, Ramaswamy Govindan
Journal: Clinical Cancer Research (2018)

While the advent of third-generation therapies has dramatically changed the treatment paradigm for EGFR-mutated lung cancer, resistance to these agents inevitably emerges. Understanding resistance mechanisms and their genomic underpinnings is crucial for developing innovative strategies that are capable of meaningfully prolonging patient survival.See related article by Le et al., p. 6195.
Use of Radiography in Patients Diagnosed as Having Acute Bronchiolitis in US Emergency Departments, 2007-2015
Authors: Brett Burstein, Amy C. Plint, Jesse Papenburg
Journal: JAMA (2018)

This epidemiology study uses National Hospital Ambulatory Medical Care Survey data to characterize trends in use of radiography to diagnose bronchiolitis in children younger than 24 months evaluated in emergency departments between 2007 and 2015.
Impact of prenatal exercise on maternal harms, labour and delivery outcomes: a systematic review and meta-analysis
Authors: Margie H Davenport, Stephanie-May Ruchat, Frances Sobierajski, Veronica J Poitras, Casey E Gray, Courtney Yoo, Rachel J Skow, Alejandra Jaramillo Garcia, Nick Barrowman, Victoria L Meah, Taniya S Nagpal, Laurel Riske, Marina James, Megan Nuspl, Ashley Weeks, Andree-Anne Marchand, Linda G Slater, Kristi B Adamo, Gregory A Davies, Ruben Barakat, Michelle F Mottola
Journal: British Journal of Sports Medicine (2018)

To perform a systematic review of the relationships between prenatal exercise and maternal harms including labour/delivery outcomes.Systematic review with random effects meta-analysis and meta-regression.Online databases were searched up to 6 January 2017.Studies of all designs were included (except case studies) if they were published in English, Spanish or French and contained information on the population (pregnant women without contraindication to exercise), intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise), comparator (no exercise or different frequency, intensity, duration, volume and type of exercise, alone ["exercise-only"] or in combination with other intervention components [e.g., dietary; "exercise + co-intervention"]) and outcome (preterm/prelabour rupture of membranes, caesarean section, instrumental delivery, induction of labour, length of labour, vaginal tears, fatigue, injury, musculoskeletal trauma, maternal harms (author defined) and diastasis recti).113 studies (n=52 858 women) were included. 'Moderate' quality evidence from exercise-only randomised controlled trials (RCTs) indicated a 24% reduction in the odds of instrumental delivery in women who exercised compared with women who did not (20 RCTs, n=3819; OR 0.76, 95% CI 0.63 to 0.92, I 2= 0 %). The remaining outcomes were not associated with exercise. Results from meta-regression did not identify a dose-response relationship between frequency, intensity, duration or volume of exercise and labour and delivery outcomes.Prenatal exercise reduced the odds of instrumental delivery in the general obstetrical population. There was no relationship between prenatal exercise and preterm/prelabour rupture of membranes, caesarean section, induction of labour, length of labour, vaginal tears, fatigue, injury, musculoskeletal trauma, maternal harms and diastasis recti.
GW29-e0171 The potential impact of intestinal microbiota community on cardiac valve calcification and coronary artery disease
Authors: Qingchun Zeng, Zuheng Liu, Jiaying Li, Haiyue Liu, Ying Tang, Wenyan Lai, Yan Tu, Zhonghua Teng, Qiong Zhan, Yujia Bai, Hao Ren, Dingli Xu
Journal: Journal of the American College of Cardiology (2018)