tbuckley/cabot-search huggingface dataset:
Abstract 1894: Identification of novel OTX015-containing combinations for lymphoma treatment
Authors: Eugenio Gaudio, Chiara Tarantelli, Filippo Spriano, Alberto J. Arribas, Luciano Cascione, Emanuele Zucca, Anastasios Stathis, Francesco Bertoni
Journal: Cancer Research (2018)

Abstract Introduction. Epigenetics represents and intriguing target of therapy for lymphomas. The epigenetic mechanisms are regulated by several players (e.g. HDAC, HAT, BET) and among them the BET proteins became of interest a few years ago with demonstrated preclinical anti-cancer activity with the first compounds and early clinical responses first in class clinical-grade BET inhibitor OTX015 (MK-8628/birabresib). Despite a widespread anti-proliferative activity, the cytotoxicity effect of BET inhibitors is limited, and, here, we aimed to identify drugs that improve OTX015 activity performing a screening with the BET inhibitor with a library 348 compounds in two lymphoma cell lines. Methods. Two cell lines derived from germinal center B cell (GCB) diffuse large B cell lymphoma (DLBCL) (OCI-LY-19 and WSU-DLCL2) were exposed to OTX015 (single dose, 100 nM) in combination with two different doses (20 and 1,000 nM) of 348 compounds. Compounds giving a 1.5-fold decreased proliferation with the combination than with the individual compounds were further evaluated in two additional lymphoma cell lines, exposed (72h) to increasing doses of OTX015 alone and in combination with increasing doses of other selected compounds. Synergy was assessed with Chou-Talalay combination index (CI): synergism (&amp;lt;0.9), additive (0.9-1.1), antagonism/no benefit (&amp;gt; 1.1). Results. OCI-LY-19 and WSU-DLCL2 were treated with OTX015 (100 nM) and 348 compounds as single agents and in combination. The combinations of OTX015 with a series of compounds achieved improved anti-tumor activity than single agents. Besides HDAC and mTOR inhibitors, in accordance with what previously reported (Boi, Gaudio, Bonetti et al, Clinical Cancer Res 2015), the ABL/SRC inhibitor dasatinib, the AKT1/2/3 inhibitor MK-2206, the JAK2 inhibitor TG101209 and the LRRK2 inhibitor LRRK2-IN appeared interesting combination partners. These screening results were validated in the DLBCL cell lines with targeted experiments, as well as in chronic lymphocytic leukemia (CLL) (OTX015 plus MK-2206) and mantle cell lymphoma (MCL) (REC1) (Dasatinib, LRRK2-IN). Experiments in additional cell lines and assessing the effects on the apoptosis are on-going and will be presented. Conclusion. A chemical screening has identified novel OTX015-containing combinations active in lymphoma cell lines that are worth of further investigations. Work supported by a San Salvatore Foundation grant. Citation Format: Eugenio Gaudio, Chiara Tarantelli, Filippo Spriano, Alberto J. Arribas, Luciano Cascione, Emanuele Zucca, Anastasios Stathis, Francesco Bertoni. Identification of novel OTX015-containing combinations for lymphoma treatment [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 1894.
Clenbuterol Isomers Display Differing Cardiac Hypertrophic, Heart Rate and Calcium Handling Effects in a Rodent Model of Heart Failure When Used Alone or in Combination with Mechanical Unloading
Authors: Manoraj Navaratnarajah, Carin Van Doorn, Urszula Siedlecka, Michael Ibrahim, Ajay Gandhi, Adarsh Shah, Priyanthi Dias, Magde Yacoub, Cesare Terracciano
Journal: Circulation (2011)
Demonstration of Treatment Response to Trans-arterial Radio-embolization (TARE) on 68Ga-DOTANOC PET/CT in a Patient With Metastatic Neuroendocrine Tumor
Authors: Shelvin Kumar Vadi, Bhagwant Rai Mittal, Rajender Kumar, Ashwin Singh Parihar, Jaya Shukla, Navin Kalra
Journal: Clinical Nuclear Medicine (2018)

Here we report a 31-year-old man with a peri-ampullary neuroendocrine tumor (NET), who underwent Ga DOTANOC-PET/CT for recurrence evaluation, which revealed isolated metastatic lesion in liver segment V. He underwent trans-arterial radio-embolization (TARE) of the isolated hepatic metastasis with Rhenium-microspheres in a lipiodol matrix. The second Ga DOTANOC-PET/CT was performed one month after the TARE therapy revealed resolution of the tracer uptake with good retention of the lipiodol complex replacing the metastasis suggesting a complete response.
Consensus on Molecular Subtypes of High-Grade Serous Ovarian Carcinoma
Authors: Gregory M. Chen, Lavanya Kannan, Ludwig Geistlinger, Victor Kofia, Zhaleh Safikhani, Deena M.A. Gendoo, Giovanni Parmigiani, Michael Birrer, Benjamin Haibe-Kains, Levi Waldron
Journal: Clinical Cancer Research (2018)

Purpose: The majority of ovarian carcinomas are of high-grade serous histology, which is associated with poor prognosis. Surgery and chemotherapy are the mainstay of treatment, and molecular characterization is necessary to lead the way to targeted therapeutic options. To this end, various computational methods for gene expression-based subtyping of high-grade serous ovarian carcinoma (HGSOC) have been proposed, but their overlap and robustness remain unknown.Experimental Design: We assess three major subtype classifiers by meta-analysis of publicly available expression data, and assess statistical criteria of subtype robustness and classifier concordance. We develop a consensus classifier that represents the subtype classifications of tumors based on the consensus of multiple methods, and outputs a confidence score. Using our compendium of expression data, we examine the possibility that a subset of tumors is unclassifiable based on currently proposed subtypes.Results: HGSOC subtyping classifiers exhibit moderate pairwise concordance across our data compendium (58.9%-70.9%; P < 10-5) and are associated with overall survival in a meta-analysis across datasets (P < 10-5). Current subtypes do not meet statistical criteria for robustness to reclustering across multiple datasets (prediction strength < 0.6). A new subtype classifier is trained on concordantly classified samples to yield a consensus classification of patient tumors that correlates with patient age, survival, tumor purity, and lymphocyte infiltration.Conclusions: A new consensus ovarian subtype classifier represents the consensus of methods and demonstrates the importance of classification approaches for cancer that do not require all tumors to be assigned to a distinct subtype. Clin Cancer Res; 24(20); 5037-47. ©2018 AACR.
NHS pay should be linked more closely to performance, think tank argues
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Pay structures in the NHS should be linked more closely with performance and achievement of targets, a new report from a right wing think tank concludes.

Introducing more flexibility into the system, and linking pay more closely with performance and objectives, could boost productivity and improve patients’ outcomes, argues the report by the Centre for Policy Studies.1 It says that existing systems of rewarding and motivating staff are not fit for their purpose and calls for the government and NHS bosses to reform the pay system as an “urgent priority” as part of the new funding settlement announced recently by the prime minister.2

The report also claims that it is “highly misleading” to talk of pay freezes and 1% pay caps for the NHS. It argues that average annual pay rises between …
Progress in Nonmetastatic Prostate Cancer
Authors: Matthew R. Smith
Journal: New England Journal of Medicine (2018)

Since 2010, the Food and Drug Administration (FDA) has approved five new drugs for the treatment of metastatic, castration-resistant prostate cancer on the basis of a primary end point of overall survival.1 Progress in the treatment of nonmetastatic prostate cancer has been slower. A series of phase 3 trials that were designed to investigate treatments for the prevention of bone metastases either were stopped early or did not reach their primary end point.2-4 In a later, placebo-controlled, phase 3 trial, denosumab significantly prolonged bone metastasis–free survival among patients with nonmetastatic, castration-resistant prostate cancer.5 However, in February 2012, an Oncology Drugs . . .
Scrap NHS competition rules, BMA says
Authors: Tom Moberly
Journal: BMJ (2018)

Ministers should repeal competition rules introduced into the NHS through the Health and Social Care Act 2012, the BMA has said.

Delegates at the BMA’s annual representative meeting in Brighton on 25 June passed unopposed a motion saying that these regulations were “wasting significant sums of monies in procurement processes, fragmenting care and destabilising NHS providers through accelerating private sector provision.”

Philip Howard, a member of the BMA’s consultants committee, proposed the motion and …
Polycomb repressive complex 2 haploinsufficiency identifies a high-risk subgroup of pediatric acute myeloid leukemia
Authors: Jonathan Bond, Elise Labis, Alice Marceau-Renaut, Nicolas Duployez, Myriam Labopin, Guillaume Hypolite, Gérard Michel, Stéphane Ducassou, Hélène Boutroux, Brigitte Nelken, Yves Bertrand, André Baruchel, Arnaud Petit, Vahid Asnafi, Guy Leverger, Claude Preudhomme, Elizabeth Macintyre, Hélène Lapillonne
Journal: Leukemia (2018)
Abstract 1966: A novel small-molecule compound targeting PBX1-DNA interaction impedes cancer cell survival and carboplatin resistance
Authors: Yao-An Shen, Jin Jung, Yohan Suryo Rahmanto, Licia Selleri, Ie-Ming Shih, Chi-Mu Chuang, Tian-Li Wang
Journal: Cancer Research (2018)

Abstract Pre-B-cell leukemia homeobox-1 (PBX1), a transcriptional factor and downstream effector of Notch signaling pathway, plays pivotal roles in a wide spectrum of tumors, as well as developmental, inflammatory, autoimmune, and neurodegenerative disorders. Exploiting the crystal structure of the Pbx1-DNA complex, we developed a novel small-molecular inhibitor T417 that can directly block Pbx1-binding to DNA, unlike other existing compounds that interfere with protein-protein interactions. When T417 docks into the hydrophobic pocket of Pbx1 protein, the small molecule can dampen PBX1 transcription activity by hindering its binding to the promoter regions of PBX1 downstream target genes. Intriguingly, the amount of PBX1 expression in cells can dictate its response to T417. Increment of PBX1 expression is found in the high-grade serous carcinoma (HGSC) and carboplatin-resistant (CR) cells, and its expression is generally low in normal tissues as compared to the transformed tissues, making it such an arguably unique therapeutic target in ovarian cancer cells. This expression pattern illustrates the very minimal toxicity of T417 on normal tissues and organs in animal models, while it imposed in vitro and in vivo detrimental effects toward HGSC and CR cells. Besides, T417 holds synergistic cytotoxic effects with DNA damage-related drugs including PARP inhibitor and platinum-based drug. As PBX1 was shown to participate in maintaining cancer stem cell (CSC)-like phenotypes and promoting resistance to antitumor drugs, T417 is able to hammer out the stemness traits of CR cells to revert to a differentiated status through tacking PBX1 signaling cascade. The novel PBX1-targeting compound selectively interferes with PBX1-binding to DNA, which potentially points to powerful therapeutics and broad applications for the treatment of different human malignancies and stem cell therapy. Citation Format: Yao-An Shen, Jin Jung, Yohan Suryo Rahmanto, Licia Selleri, Ie-Ming Shih, Chi-Mu Chuang, Tian-Li Wang. A novel small-molecule compound targeting PBX1-DNA interaction impedes cancer cell survival and carboplatin resistance [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 1966.
Ca2+–mitochondria axis drives cell division in hematopoietic stem cells
Authors: Terumasa Umemoto, Michihiro Hashimoto, Takayoshi Matsumura, Ayako Nakamura-Ishizu, Toshio Suda
Journal: The Journal of Experimental Medicine (2018)

Most of the hematopoietic stem cells (HSCs) within the bone marrow (BM) show quiescent state with a low mitochondrial membrane potential (ΔΨm). In contrast, upon stress hematopoiesis, HSCs actively start to divide. However, the underlying mechanism for the initiation of HSC division still remains unclear. To elucidate the mechanism underlying the transition of cell cycle state in HSCs, we analyzed the change of mitochondria in HSCs after BM suppression induced by 5-fluoruracil (5-FU). We found that HSCs initiate cell division after exhibiting enhanced ΔΨm as a result of increased intracellular Ca2+ level. Although further activation of Ca2+–mitochondria pathway led to loss of HSCs after cell division, the appropriate suppression of intracellular Ca2+ level by exogenous adenosine or Nifedipine, a Ca2+ channel blocker, prolonged cell division interval in HSCs, and simultaneously achieved both cell division and HSC maintenance. Collectively, our results indicate that the Ca2+–mitochondria pathway induces HSC division critically to determine HSC cell fate.
Abstract 837: Antitumor effects of anti-EGF antibodies generated by vaccination in NSCLC tumor cells
Authors: Silvia Garcia-Roman, Jordi Codony-Servat, Miguel Angel Molina-Vila, Jordi Bertran-Alamillo, Ana Gimenez-Capitán, Niki Karachaliou, Erik d'Hondt, Rafael Rosell
Journal: Cancer Research (2018)

Abstract Background: Immunization against Epidermal Growth Factor (EGF) has demonstrated clinical efficacy in a phase III trial including unselected NSCLC patients. We are currently analyzing if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) showed antitumor activity in EGFR-mutant, Kras-mutant (mut) and Anaplastic Lymphoma Kinase (ALK) translocated non-small cell lung cancer cells (NSCLC), alone or in combination with tyrosine kinase inhibitors (TKI). In an EGFR-mut and in an ALK translocated cell lines we are also studying if the anti-EGF VacABs can delay the emergence of resistance to TKIs. Methods: Anti-EGF VacAbs were obtained by immunizing rabbits with recombinant EGF. Cell lines were treated with anti-EGF VacABs alone and in combination with TKIs in EGFR (PC9, H1975) and ALK translocated (H3122, H2228) cell lines. In KRAS-mut cells (A549, H23) the combination was with chemotherapy agents. Cell viability was analyzed by MTT and apoptosis and cell cycle by fluorescence-activates cell sorting analysis (FACS). Changes of total and phosphorylated proteins were determined by Western blot. Sera from advanced NSCLC patients immunized with anti-EGF vaccine were also tested Results: Anti-EGF VacAbs suppressed EGF-induced cell proliferation and inhibited downstream EGFR signaling in all cell lines tested. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of gefitinib, erlotinib, osimertinib and afatinib in EGFR-mut cells, potentiated Erk ½ phosphorylation, arrested cell cycle progression and increased apoptosis. In addition, anti-EGF VacAbs blocked the activation of STAT3, downregulated the expression of proteins related to EGFR resistance, such as AXL, and significantly delayed the emergence in vitro of clones resistant to EGFR TKI. Sera from patients vaccinated against EGF also suppressed Erk ½ phosphorylation. Results for the combination of ALK TKIs and chemotherapy agents in ALK translocated and KRAS-mut cell lines will be presented at the meeting. Conclusions: Anti-EGF VacAbs decreased cell proliferation and inhibited the activation of EGFR-pathway downstream proteins in EGFR-mut, KRAS-mut and ALK translocated cell lines. Also, they potentiate the effects of TKIs and prevent the emergence of resistance in EGFR-mut NSCLC cells. Two clinical trials are currently testing anti-EGF vaccination in EGFR-wt and EGFR-mut advanced NSCLC patients. Citation Format: Silvia Garcia-Roman, Jordi Codony-Servat, Miguel Angel Molina-Vila, Jordi Bertran-Alamillo, Ana Gimenez-Capitán, Niki Karachaliou, Erik d'Hondt, Rafael Rosell. Antitumor effects of anti-EGF antibodies generated by vaccination in NSCLC tumor 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 837.
Identification of a unique <i>Staphylococcus aureus</i> ribosomal signature in severe atopic dermatitis
Authors: M. Brandwein, G. Fuks, A. Israel, D. Nejman, R. Straussman, E. Hodak, M. Harari, D. Steinberg, Z. Bentwich, N. Shental, S. Meshner
Journal: British Journal of Dermatology (2018)
Settable polymer/ceramic composite bone grafts stabilize weight-bearing tibial plateau slot defects and integrate with host bone in an ovine model
Authors: Sichang Lu, Madison A.P. McGough, Stefanie M. Shiels, Katarzyna J. Zienkiewicz, Alyssa R. Merkel, Joseph P. Vanderburgh, Jeffry S. Nyman, Julie A. Sterling, David J. Tennent, Joseph C. Wenke, Scott A. Guelcher
Journal: Biomaterials (2018)
Patent Foramen Ovale and Risk of Perioperative Stroke
Authors: Gianluca Rigatelli, Marco Zuin
Journal: JAMA (2018)

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Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection
Authors: Daniel E. Freedberg, Margaret J. Zhou, Margot E. Cohen, Medini K. Annavajhala, Sabrina Khan, Dagmara I. Moscoso, Christian Brooks, Susan Whittier, David H. Chong, Anne-Catrin Uhlemann, Julian A. Abrams
Journal: Intensive Care Medicine (2018)
Abstract P059: Arterial Thickness and Stiffness are Independent Predictors of Myocardial Strain
Authors: Connie E McCoy, Philip R Khoury, Stephanie N Stewart, Lauren E Longhshore, Nicolas L Madsen, Lawrence M Dolan, Thomas R Kimball, Elaine M Urbina
Journal: Circulation (2015)

Vascular dysfunction is associated with cardiac dysfunction, a precursor of CV events (MI,CHF) in adults. We hypothesized that abnormalities in vascular structure and function are associated with cardiac systolic dysfunction as measured by cardiac strain and strain rate in young adults. Carotid ultrasound and echocardiography were performed on 338 subjects (22.2 + 3.7 years; 38% male (M); 63% non-white (NW); 33% lean, 36% obese and 31% T2DM). CIMT was traced along the far wall of the distal CCA, bulb, and proximal ICA. Stiffness measures included carotid-femoral pulse wave velocity (PWVf), brachial distensibility (BrachD) and Peterson’s Elastic Modulus in the CCA (PEM). LV systolic function was assessed by global longitudinal (4-chamber) strain (GS) and strain rate in systole (GSRs). Anthropometry, BP, HR, fasting lipids, CRP, and glucose were collected. Correlations were calculated between vascular measures and cardiac strain. General linear models were constructed to determine if vascular measures were independent predictors of GS and GSRs. Covariates included age, sex, race, BMI z-score, MAP, group, TG, HDL, LDL, insulin, glucose, and CRP. GS and GSRs correlated with peripheral arterial stiffness (lower BrachD, higher PEM, higher PWVf) and structure (thicker CIMT), all p&lt;.01 (Figure). After adjusting for other risk factors, BrachD was an independent predictor of poorer GSRs: GSRs=-1.1611 -.13*BrachD + .05 (if M) + .06 (if NW) + .004*MAP - .0003*glucose + .07*Insulin. CCA IMT independently predicted both GS and GSRs: GS=-.26 + 4.6* CCA + .92 (if M) + .58*BMIZ + .56*MAP- .03*HDL + 1.06*insulin; GSRs= -1.4 + .26*CCA+ .05 (if M) + .03*BMIZ + .003*MAP - .0003*glucose + .06*Insulin. All factors were significant at p&lt;.05 in these models. We conclude that adverse pre-clinical vascular and cardiac findings are present in youth simultaneously and may increase risk for future CV events. Assessment of vascular structure and function may add incremental benefit in stratifying risk in young adults for future CV events.
Abstract 253: Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer
Authors: Urvi Kolhatkar, Kshiti Dholakia, Gabriela Sikorska, Avinash Kumar, Luis A. Martinez, Anait S. Levenson
Journal: Cancer Research (2018)

Abstract Overexpression of chromatin modifier protein, metastasis-associated protein 1 (MTA1) in prostate cancer contributes to tumor aggressiveness and metastasis. MTA1 ChiP-Seq analysis identified downstream targets that are transcriptionally regulated by MTA1 and suggested a link between MTA1 and ETS2. The effects of ETS2 in cancer are context-dependent and both oncogenic and tumor suppressive functions have been described. We have shown that there is a positive correlation between MTA1 and ETS2 using loss of function studies and various preclinical models of prostate cancer. Our conclusion that MTA1 functions as a co-activator for regulating ETS2 expression in prostate cancer leading to promotion of prostate cancer progression, prompted us to look for pharmacological inhibitors of MTA1/ETS2 axis. In our previous studies, we reported inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of PIN and adenocarcinoma in xenografts and transgenic mouse models by inhibiting MTA1 expression and signaling. Here, we found that Gnetin C, double-resveratrol, has more potent inhibition of MTA1/ETS2 axis than other stilbenes. Gnetin C, a resveratrol dimer, is found abundantly in melinjo plant widely cultivated in Southeast Asia; its seeds and fruits are common ingredients in Indonesian culinary. As resveratrol and pterostilbene, Gnetin C has been reported to possess anti-inflammatory and anticancer activity, however it has not been considered as chemopreventive agent in prostate cancer. Using two prostate cancer cell lines, namely DU145 and PC3M cells, we found that Gnetin C shows significant inhibitory effect on cell proliferation, more potent effects in colony formation and wound healing assays than resveratrol or pterostilbene. Importantly, Gnetin C specifically and strongly downregulates MTA1 and ETS2 expression in prostate cancer cells. Taken together, our findings implicate the potential of Gnetin C in MTA1/ETS2-mediated chemoprevention and therapy in prostate cancer. Citation Format: Urvi Kolhatkar, Kshiti Dholakia, Gabriela Sikorska, Avinash Kumar, Luis A. Martinez, Anait S. Levenson. Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer [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 253.