tbuckley/cabot-search huggingface dataset:
Abstract 5228: Estrogen receptor expression is associated with DNA repair capacity in breast cancer
Authors: Jaime L. Matta, Luisa Morales, Carmen Ortiz, Damian Adams, Wanda Vargas, Patricia Casbas, Julie Dutil, Miguel Echenique, Erick Suarez
Journal: Cancer Research (2016)

Abstract Estrogen receptor (ER) status is an established therapeutic and prognostic biomarker for breast cancer (BC). ER signaling has a propensity to increase proliferation, which can lead to mutations when DNA repair is dysregulated. Deficiencies in DNA repair capacity (DRC) is a hallmark of BC. Recent studies have documented interactions between ER and DNA damage response/repair. Moreover, our previous work showed that DRC in BC patients is approximately 50% less than in women without the disease (p&amp;lt;0.001), and a deficiency in the Nucleotide excision repair (NER) pathway figures prominently in the pathobiology of sporadic BC. Estrogen-receptor-positive (ER+) tumors employ complex signaling that engages in crosstalk with multiple pathways through genomic and non-genomic regulation. A greater understanding of these pathways is important for developing improved biomarkers that can better determine treatment choices, risk of recurrence, and cancer progression. In this study, we aimed to determine whether ER signaling influences DRC. DRC, in terms of the NER pathway, was measured in lymphocytes by means of a host cell reactivation assay with a luciferase reporter gene. A multivariate linear regression model (MLRM) was used to estimate the mean of the DRC and analyze the association between ER positivity (% receptor activation) obtained from pathological reports and DRC in 270 BC patients. These were further stratified by HER2 receptor status. An ordinal logistic regression model (OLRM) was used to confirm the relationship between DRC and ER status using the maximum likelihood method for parameters estimation. Our results show an association between ER status and mean DRC values in BC patients who have HER2-negative (HER-) tumors: that is, the mean DRC value in ER-/HER2- tumors was significantly lower as compared with ER-/HER2+ tumors (p&amp;lt;0.05). In contrast, the mean DRC among patients with ER+/HER2+ tumors did not significantly differ from ER-/HER2+ tumors (p&amp;gt;0.05). The data followed similar patterns when DRC was categorized in tertiles. In conclusion, there is an association between DRC levels and ER status, and this association is modified by HER2 receptor status. Supported by grants from the NCI Center to Reduce Health Disparities and NIH-NIGMS MBRS SCORE and RISE Programs grants # S06 GM008239-20, 9SC1CA182846-04 GM082406 and PSM-MCC Partnership grant # 5U54CA163071-04. Citation Format: Jaime L. Matta, Luisa Morales, Carmen Ortiz, Damian Adams, Wanda Vargas, Patricia Casbas, Julie Dutil, Miguel Echenique, Erick Suarez. Estrogen receptor expression is associated with DNA repair capacity in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5228.
Unmet Needs in LDL-C Lowering: When Statins Won’t Do!
Authors: Stephan Krähenbühl, Ivana Pavik-Mezzour, Arnold von Eckardstein
Journal: Drugs (2016)

The use of low-density lipoprotein cholesterol (LDL-C)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statin therapy, one of the cornerstones for the prevention and treatment of cardiovascular disease (CVD), has been demonstrated to be effective in lowering LDL-C levels and in reducing the risk for CVD and is generally well-tolerated. However, compliance with statins remains suboptimal. One of the main reasons is limitations by adverse events, notably myopathies, which can lead to non-compliance with the prescribed statin regimen. Reducing the burden of elevated LDL-C levels is critical in patients with CVD as well as in patients with very high baseline levels of LDL-C (e.g. patients with familial hypercholesterolaemia), as statin therapy is insufficient for optimally reducing LDL-C below target values. In this review, we discuss alternative treatment options after maximally tolerated doses of statin therapy, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors. Difficult-to-treat patients may benefit from combination therapy with ezetimibe or a PCSK9 inhibitor (evolocumab or alirocumab, which are now available). Updates of treatment guidelines are needed to guide the management of patients who will best benefit from these new treatments.
USE OF CYCLOSPORIN A (CIA) ONLY AFTER CADAVERIC RENAL-TRANSPLANTATION - RENAL-FUNCTION STUDIES DURING CONVERSION TO PREDNISOLONE (P) AND AZATHIOPRINE (A) 4 MONTHS AFTER TRANSPLANTATION
Authors: Adam Tegzess, Sytze Meijer, van Willem Son, F van der Woude, M Slooff, Gjalt van der Hem, L van der Slikke, Willem Sluiter, Vaclav Fidler
Journal: Kidney International (1984)
Cellular and molecular immunologic mechanisms in patients with atopic dermatitis
Authors: Thomas Werfel, Jean-Pierre Allam, Tilo Biedermann, Kilian Eyerich, Stefanie Gilles, Emma Guttman-Yassky, Wolfram Hoetzenecker, Edward Knol, Hans-Uwe Simon, Andreas Wollenberg, Thomas Bieber, Roger Lauener, Peter Schmid-Grendelmeier, Claudia Traidl-Hoffmann, Cezmi A. Akdis
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 3978: Lipid tethering to enable real-time imaging of breast tumor cell cytoskeletal dynamics and rapid drug testing in free-floating metastatic microenvironments
Authors: Kristi Riti Chakrabarti, James Andorko, Rebecca Whipple, Peipei Zhang, Elisabeth Sooklal, Christopher Jewell, Stuart Martin
Journal: Cancer Research (2016)

Abstract Free-floating tumor cells located in the peripheral circulation of cancer patients, known as circulating tumor cells (CTCs), play an important role in cancer and have become key targets for studying metastasis. The presence of CTCs in the bloodstream or lymphatics correlates with decreased cancer patient survival and provides a minimally invasive method to study disease progression and treatment response. Understanding the molecular characteristics and functional properties of CTCs have been impeded by the challenges of imaging CTCs under conditions that model the free-floating microenvironments of the circulation. Upon extracellular-matrix (ECM) detachment, breast tumor cells form tubulin-based protrusions known as microtentacles (McTNs) that play a role in the aggregation and re-attachment of tumor cells to increase their metastatic efficiency. In this study, we have designed a strategy to spatially immobilize ECM-detached tumor cells within a microfluidic device while maintaining their free-floating character. We use cytophobic polyelectrolyte multilayers deposited on microfluidic substrates to prevent tumor cell adhesion and the addition of lipid moieties to tether tumor cells to these surfaces through interactions with the cell membrane. This approach enables high-resolution time-lapse microscopy of McTNs on viable free-floating tumor cells and real-time analysis of dynamic cellular features. In addition, tethering makes it now possible to rapidly measure drug responses of tumor cells in free-floating microenvironments to select effective therapies and avoid drugs that could inadvertently increase metastasis. The ability to image tumor cells in the absence of ECM attachment can immensely enhance our understanding of CTCs under conditions that better recapitulate the free-floating microenvironments that tumor cells encounter during metastasis. Citation Format: Kristi Riti Chakrabarti, James Andorko, Rebecca Whipple, Peipei Zhang, Elisabeth Sooklal, Christopher Jewell, Stuart Martin. Lipid tethering to enable real-time imaging of breast tumor cell cytoskeletal dynamics and rapid drug testing in free-floating metastatic microenvironments. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3978.
Abstract 4477: Loss of EZH2 accelerates STAT5 loss mediated fatty liver and cancer development through non-methyltransferase function
Authors: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, Kyung Keun Kim
Journal: Cancer Research (2016)

Abstract Background: The molecular mechanisms underlying the development of fatty liver and hepatocellular carcinoma are not fully understood. Loss of STAT5 from liver tissue results in hepatosteatosis and hepatocellular carcinoma (HCC). Enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up-regulated in human HCC. STAT5 recruits EZH2, which represses a substantial subset of genes regulated by STAT5 during B lymphopoiesis. However, it is not clear if EZH2 can affect STAT5-target genes in liver. Methods: To investigate the role of STAT5 and EZH2 in liver, mice were generated that carried EZH2fl/fl alleles, STAT5fl/fl alleles, EZH2fl/flSTAT5fl/fl alleles and an Alb-Cre transgene. Lipid analysis in serum and liver, and RNA-seq were examined at 3 &amp; 8 months of age. Mice were also examined by chronic 3 months injection by carbon tetrachloride (CCl4). Results: The deletion of STAT5 in hepatocyte caused fatty liver and increased cholesterol in serum and liver. The deletion of EZH2 did not make a difference in H3K27me3 expression, and lipid in serum and liver. However, combined loss of EZH2 and STAT5 caused severe fatty liver, increase triglyceride and the ratio liver/body weight compare to STAT5 KO mice (the ratio; 0.097 vs. 0.058, p &amp;lt; 0.05). In response to 3 months treatment with CCl4, combined loss of EZH2 and STAT5 showed accelerated development of hepatocellular carcinoma at 12 months of age. Transcriptome analysis identified the expression of several genes was significantly increased (cd36, pparγ, cyp4a14, lipoprotein lipase, fasn) and decreased (nox4, bbc3, bcl2l1, cdkn2b) which were well known as STAT5 target genes in combined loss of EZH2 and STAT5. Conclusions: This work demonstrates that loss of EZH2 in liver affects the expression of STAT5 target genes and accelerates STAT5 loss mediated fatty liver and hepatocellular carcinoma development through non-methyltransferase function. Citation Format: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, Kyung Keun Kim. Loss of EZH2 accelerates STAT5 loss mediated fatty liver and cancer development through non-methyltransferase function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4477.
Abstract 3228: High salt induces anti-inflammatory MΦ2-like phenotype in peripheral macrophages
Authors: Suneetha Amara, Toral R. Mehta, Margaret Whalen, Venkataswarup Tiriveedhi
Journal: Cancer Research (2016)

Abstract Macrophages play a critical role in inflammation and antigen-presentation. Abnormal macrophage function has been attributed in autoimmune diseases and cancer progression. Recent evidence suggests that high salt tissue micro-environment causes changes in macrophage activation. In our current report, we studied the role of extracellular sodium chloride (NaCl) on phenotype changes in peripheral circulating monocyte/macrophages collected from healthy donors. High salt (0.2 M NaCl) treatment resulted in a decrease in MΦ1 macrophage phenotype (CD11b+CD14highCD16low) from 77.4±6.2% (0.1 M) to 29.3±5.7% (0.2 M, p&amp;lt;0.05), while there was an increase in MΦ2 macrophage phenotype (CD11b+ CD14lowCD16high) from 17.2±5.9% (0.1 M) to 67.4±9.4% (0.2 M, p&amp;lt;0.05). ELISA-based cytokine analysis demonstrated that high salt treatment induced decreased expression of in the MΦ1 phenotype specific pro-inflammatory cytokine, TNFα (3.3 fold), IL-12 (2.3 fold), CCL-10 (2 fold) and CCL-5 (3.8 fold), but conversely induced an enhanced expression MΦ2 phenotype specific anti-inflammatory cytokine, IL-10, TGFβ, CCL-17 (3.7 fold) and CCR-2 (4.3 fold). Further high salt treatment significantly decreased phagocytic efficiency of macrophages and inducible nitric oxide synthetase expression. Taken together, these data suggest that high salt extracellular environment induces an anti-inflammatory MΦ2 macrophage phenotype with poor phagocytic and potentially reduced antigen presentation capacity commonly found in tumor microenvironment. Citation Format: Suneetha Amara, Toral R. Mehta, Margaret Whalen, Venkataswarup Tiriveedhi. High salt induces anti-inflammatory MΦ2-like phenotype in peripheral macrophages. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3228.
Abstract LB-053: Towards new cryptophycins as promising payloads for ADC
Authors: Marie-Priscille Brun, Hervé Bouchard, François Clerc, Jidong Zhang, Pierre-Yves Abecassis, Céline Amara, Eric Beys, Florence Efremenko, Céline Nicolazzi, Marie-Hélène Pascual, Olivier Pasquier, Alain Krick, Pierre-François Berne, Laurence Gauzy, Nathalie Karst, Sylvain Huille, Christophe Henry, Anne-Marie Lefebvre, Ingrid Sassoon
Journal: Cancer Research (2016)

Abstract Cryptophycins are a class of macrocyclic depsipeptides produced as secondary metabolites by cyanobacteria of the genus Nostoc and were found to bind to microtubules at the vinca site. The natural product C-1 isolated in 1990 and the synthetic derivative C-52 displayed potent in vitro and in vivo antitumor activity in preclinical models. Cryptophycin C-52 (LY355703) produced marginal antitumor activity at MTD in two phase II lung cancer trials and was therefore discontinued. Considering its higher potency versus other tubulin binders such as maytansine and auristatin, this chemical series was selected for an ADC approach. Several conjugates were evaluated in vitro and in vivo based on the conjugation of C52 derivatized at the para-benzylic position of the macrocycle. As described in this study, this optimization led to the discovery of cryptophycin ADC which displayed potent antitumor activity in vivo. However, these conjugates were found unstable in mice plasma while being stable in the plasma of non-rodent species. This species-dependent instability was shown to be the result of a mice plasmatic metabolization of C52 macrocycle once conjugated to the antibody. We therefore designed and synthesized new cryptophycin ADC which exhibited improved plasmatic stability when tested in mice and enhanced therapeutic index in comparison with C52 ADC. In conclusion, these data demonstrated the potent in vitro and in vivo antitumor activity of these new cryptophycin ADC and warrant further development of this cytotoxic payload for an ADC approach. Citation Format: Marie-Priscille Brun, Hervé Bouchard, François Clerc, Jidong Zhang, Pierre-Yves Abecassis, Céline Amara, Eric Beys, Florence Efremenko, Céline Nicolazzi, Marie-Hélène Pascual, Olivier Pasquier, Alain Krick, Pierre-François Berne, Laurence Gauzy, Nathalie Karst, Sylvain Huille, Christophe Henry, Anne-Marie Lefebvre, Ingrid Sassoon. Towards new cryptophycins as promising payloads for ADC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-053.
Abstract 3056: Combined disulfiram and radiation therapy against atypical teratoid/rhabdoid tumor
Authors: Yeoung Eun Lee, Seung Ah Choi, Pil Ae Kwak, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Youn Joo Moon, Anshika Jangra, Kyeung Min Joo, Seung-Ki Kim
Journal: Cancer Research (2016)

Abstract Disulfiram (DSF) has been studied as an anticancer drug and radiosensitizer. In our previous study, the therapeutic potential of DSF against atypical teratoid/rhabdoid tumor (AT/RT), one of the most aggressive forms of childhood cancer, had been confirmed using in vitro and in vivo studies. To develop more effective and safer therapy in AT/RT, we evaluated the sensitizing potential of DSF on radiation therapy (RT). The effect of DSF in low concentration alone and in combination with RT was investigated in vitro and vivo. Clonogenic assay, western blot analysis, autophagy assay and γ-H2AX foci staining were performed using several primary cultured AT/RT cells and cell lines. Also, in vivo study was performed using AT/RT orthotopic xenograft mouse model. Combination therapy with DSF and RT potently reduced clonogenicity and down-regulated protein expression of survivin and BCL2. The combination treatment strongly promoted the autophagic cell death and produced abundant γ-H2AX foci in all AT/RT cells. Moreover, the combination treatment significantly reduced the tumor growth and prolonged the survival rate compared to single treatment in AT/RT mouse model. Taken together, our results demonstrated that the combination therapy with DSF and RT has a synergistic therapeutic effect on AT/RT, suggesting a potential clinical application for AT/RT patients. Citation Format: Yeoung Eun Lee, Seung Ah Choi, Pil Ae Kwak, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Youn Joo Moon, Anshika Jangra, Kyeung Min Joo, Seung-Ki Kim. Combined disulfiram and radiation therapy against atypical teratoid/rhabdoid tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3056.
Text Messaging and Medication Adherence—Do We Have a Missed Call?—Reply
Authors: Jay Thakkar, Julie Redfern, Clara K. Chow
Journal: JAMA Internal Medicine (2016)

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Abstract 4331: Discovery of potent 2-Indole-acylsulfonamide Mcl-1 inhibitors using structure guided fragment-based methods
Authors: Subrata Shaw, James Chris Tarr, Nicholas Pelz, Zhiguo Bian, Johannes Belmar, Bin Zhao, Craig Goodwin, Allison Arnold, John Sensintaffar, Olivia Rossanese, Taekyu Lee, Edward Olejniczak, Stephen Fesik
Journal: Cancer Research (2016)

Abstract Mcl-1 (Myeloid cell leukemia 1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and is one of the major acquired resistance mechanisms for many anticancer therapies. Targeting Mcl-1 with small molecules is very challenging because Mcl-1 exerts its effects through protein-protein interactions. Here we describe our continuing efforts in the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. We previously described the discovery of small-molecule Mcl-1 inhibitors containing a 2-indole-carboxylic core that primarily bind to the P2 pocket. In order to enhance potency, we extend our molecules to occupy the entire BH3 binding interface. A number of P4 site hits were identified using a fragment-based screening while the P2 pocket of Mcl-1 was saturated with our previously reported lead. P4 site ligands were then linked to our initial lead guided by the ternary Mcl-1 structure containing both P2 and P4 units using an acylsulfonamide as a synthetic handle that retained the critical charged-charged interaction with R263. X-ray co-crystal structures of new inhibitors occupying both P2 and P4 sites bound Mcl-1 provided detailed information on how these small-molecules bind to the target and guided subsequent potency optimization. From the efforts, we discovered a novel series of 2-indole-acylsulfonamide containing Mcl-1 inhibitors that exhibit low nanomolar binding affinities to the target and greater than 500-fold selectivity over Bcl-xL. These compounds represent useful starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers. Citation Format: Subrata Shaw, James Chris Tarr, Nicholas Pelz, Zhiguo Bian, Johannes Belmar, Bin Zhao, Craig Goodwin, Allison Arnold, John Sensintaffar, Olivia Rossanese, Taekyu Lee, Edward Olejniczak, Stephen Fesik. Discovery of potent 2-Indole-acylsulfonamide Mcl-1 inhibitors using structure guided fragment-based methods. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4331.
<i> <scp>CARD</scp> 14 </i> mutations may predict response to antitumour necrosis factor‐α therapy in psoriasis: a potential further step towards personalized medicine
Authors: K.C.P. Wu, N.J. Reynolds
Journal: British Journal of Dermatology (2016)

Linked Article: Coto-Segura et al. Br J Dermatol 2016; 175:134–141.
Abstract 1354: Developing 384-well and 1536-well cell growth inhibition assay workflow for screening drug-drug combination in tumor cell lines
Authors: Yvonne Li, Mike Ma, Julie Chan, Yang Tian, Nikos Pagratis, Derek Stonich, Victor Chen, Louis Zhang, Mark Kenney
Journal: Cancer Research (2016)

Abstract Drug combination has been widely used in treating the most debilitating diseases such as cancer. The ideal drug-drug combination will broaden and/or deepen therapeutic efficacy while overcoming resistance and unwanted off-target effects. We have developed a 384-well combination compound plating method in 8×7 format (8 dilutions of Drug A and 7 dilutions of Drug B), and screened a number of compound pairs that showed synergistic effect in inhibiting tumor cell growth in either suspension or solid tumor lines. Compound vehicle DMSO was used as negative control and puromycin treatment as positive control for calculating% inhibition, and both HSA and Bliss independence synergy models were applied for calculating synergy scores. As 384-well 8×7 format contains one compound pair per plate, we aimed to increase the throughput by developing 384-well 5×5 format (5 dilutions of Drug A and 5 dilutions of Drug B) which contains 3 drug pairs per plate, and 1536-well 8×7 and 5×5 format which contains 4 and 12 drug pairs per plate, respectively. We compared EC50s and synergy scores generated from 384-well and 1536-well with both 8×7 and 5×5 formats, single agent EC50s within combination pairs were generally within 3 fold difference and synergy scores are largely consistent. Therefore, we have validated and enabled higher throughput drug-drug combination screen by using 384-well 5×5, 1536-well 8×7, or 5×5 format. The high-throughput method presented here can be readily adopted for combination studies in other disease areas. Citation Format: Yvonne Li, Mike Ma, Julie Chan, Yang Tian, Nikos Pagratis, Derek Stonich, Victor Chen, Louis Zhang, Mark Kenney. Developing 384-well and 1536-well cell growth inhibition assay workflow for screening drug-drug combination in tumor cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1354.