tbuckley/cabot-search huggingface dataset:
Abstract 4139: Q702, selective Axl, Mer and CSF1R triple kinase inhibitor with dual potentials leading to tumor regression: Immuno-oncology therapy and targeted cancer therapy
Authors: Yeong-In Yang, Hwankyu Kang, Dongsik Park, Yeejin Jeon, Jeongjun Kim, Baejung Choi, Jaeseung Kim, Jinkyung Rho, Jaecheol Lee, Kiyean Nam
Journal: Cancer Research (2019)

Abstract Functional composition of tumor micro-environment (TME) has been regarded as one of the most important factors in tumor progression. Cancer cells induce immune suppressive condition in TME in order to evade immune system as well as to promote metastasis. Axl, Mer and CSF1R play important roles in making tumor friendly TME by increasing regulatory T cells (Tregs), M2 macrophages, myeloid-derived suppression cells (MDSCs) and suppressing antigen presentation. On the other hand, in cancer cells, overexpression of Axl is reported to have correlation with poor prognosis of patients through promoting epithelial-to-mesenchymal transition (EMT) and inducing drug resistance to chemo or targeted therapy. Q702 is an orally available selective Axl, Mer and CSF1R triple kinase inhibitor under IND enabling studies. In this poster, we present dual potentials of Q702 leading to tumor regression through: 1) immune stimulating activities of Q702 through decreasing Tregs, M2 macrophages, MDSCs population and promoting antigen presentation, 2) direct cytotoxic activity in tumor models including acute myeloid leukemia (AML) and EGFR TKI resistant non-small cell lung cancer (NSCLC). Citation Format: Yeong-In Yang, Hwankyu Kang, Dongsik Park, Yeejin Jeon, Jeongjun Kim, Baejung Choi, Jaeseung Kim, Jinkyung Rho, Jaecheol Lee, Kiyean Nam. Q702, selective Axl, Mer and CSF1R triple kinase inhibitor with dual potentials leading to tumor regression: Immuno-oncology therapy and targeted cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4139.
Abstract P291: History of Preeclampsia and Subclinical Cardiovascular Disease in Mexican Women
Authors: Jazmin Mata, Andrés Catzin-Kulhmann, Eduardo Ortiz-Panozo, Carlos Cantú-Brito, Luis Espinosa, Beatriz Rodriguez, Martín Lajous, Ruy López-Ridaura
Journal: Circulation (2018)

Introduction: Preeclampsia is a multisystem hypertensive disorder that affects 4 to 16% of all pregnancies worldwide. Because of its impact on maternal mortality and morbidity, it is considered a major public health problem. However its role as a risk factor for future cardiovascular events, especially subclinical cardiovascular disease, remains unknown. Hypothesis: Women with history of preeclampsia have an increased risk of subclinical cardiovascular disease (sCVD) compared with women with normal pregnancies. Methods: We conducted a cross-sectional analysis of a sample of 1999 women without cardiovascular disease from the Mexican Teacher's Cohort to assess the relationship between history of preeclampsia and carotid intima media thickness (IMT). Information about preeclampsia diagnosis was collected using self-report data from a questionnaire answered by the participants in 2008-2010 which included questions about reproductive history. Carotid IMT was measured on both carotid arteries through ultrasound by standardized neurologists and log transformed. We defined sCVD as mean right and left IMT &gt;0.8mm or the presence of a plaque. Multivariable lineal and logistic regressions were performed to estimate the association between women with history of preeclampsia and IMT or sCVD respectively adjusting for age, sociodemographic factors, BMI at age 18, and age at first pregnancy. Results: Women with a history of preeclampsia (187 of 1999) had slightly higher IMT values (0.69 [IQR 0.12]) than women without (0.67 [IQR 0.12]); they also showed higher prevalence of diabetes (34.7% [65 of 187] vs. 16.8% [306 of 1811]), hypertension (33.1% [62 of 187] vs. 21.9% [398 of 1811]), overweight (44.3[83 of 187] % vs. 41.6% [754 of 1811] ), and obesity (43.3% [81 of 187] vs. 35.1% [636 of 1811). The adjusted IMT was 2.36% (95% CI 0.48, 4.27) higher in women with history of preeclampsia compared with those without. There seems to be an association between preeclampsia and sCVD in the adjusted logistic regression model (odds ratio 1.53 95% CI, 0.97, 2.41), however the association lacked statistical significance. Conclusion: We found an association between history of preeclampsia and increased carotid IMT values. This results support the need of considering the history of preeclampsia in the risk assessment of cardiovascular disease among women later in life to initiate preventive strategies.
Generalized Intestinal Polyposis and Melanin Spots of the Oral Mucosa, Lips and Digits
Authors: Harold Jeghers, Victor A. McKusick, Kermit H. Katz
Journal: New England Journal of Medicine (1949)

Printed in color through the courtesy of Ciba Pharmaceutical Products, Inc., Summit, New Jersey.IN 1944, a brief report was made by one of us1 regarding the association, in 2 patients, of a distinctive type of melanin pigmentation of the oral mucosa, lips and digits with intestinal polyposis.Since then 10 cases, including the 2 referred to above, have been collected from five different hospitals and are reported here in detail along with a review of pertinent literature and a discussion of the significance of this syndrome.Case ReportsCase 1. A 14-year-old American schoolgirl entered the Fifth Medical Service . . .
Pre-clinical development of non-steroidal estrogen receptor GPR30 targeted Tc-99m labeled analogues for breast and endometrial cancer imaging
Authors: Tapan Nayak, Chinnasamy Ramesh, Ritwik Burai, Larry Sklar, Helen Hathaway, Jeffrey Norenberg, Jeffrey Arterburn, Eric Prossnitz
Journal: Cancer Research (2008)

3156  Introduction and rationale  Currently, the estrogen-based radioimaging agents used in clinical applications are not specific for either ER alpha or ER beta and do not differentiate between classical estrogen receptors and novel classes of estrogen receptors such as GPR30. Classical ER antagonist such as tamoxifen is agonists for GPR30, inducing cell proliferation, which may lead to secondary cancers of reproductive organs. As GPR30 is overexpressed in breast, endometrial and ovarian cancers, it is critical to evaluate GPR30 expression in cancer. Recently, we had identified the first GPR30-selective agonist G1, a non-steroidal  tetrahydro-3H-cyclopenta[c]quinoline. Towards this end we have developed non-steroidal G1-modified Tc-99m-labeled GPR30-targeted agents for cancer imaging.  Methods  The parent GPR30-targeted ligand G1 was modified by adding a chelating moiety through various linkers and radiolabeled with Tc-99m using the tricarbonyl approach. Radioligand receptor binding studies were performed on ER alpha/beta- and GPR30-expressing human breast cancer MCF-7 cells and GPR30-expressing human endometrial carcinoma Hec50 cells. Blocking studies were performed with the GPR30-specific ligand G1 and 17 beta-estradiol (E2) to determine GPR30 specificity. In vivo biodistribution studies were performed on ovariectomized female athymic mice bearing human endometrial cancer Hec50 tumors and human breast cancer MCF-7/18 tumors. Blocking studies were performed by co-injecting either G1 or E2. NanoSPECT/CT imaging studies were performed on live tumor-bearing animals to evaluate the potential of Tc-99m agents as cancer imaging agents.  Results  All Tc-99m labeled derivatives were highly stable in plasma for up to 24 hours. The LogP values of the Tc-99m labeled agents ranged from 4.6 - 5.5. In cell binding studies, the Tc-99m labeled agents demonstrated GPR30 specificity. Metabolism and animal studies revealed high liver and intestine uptake as well as radiometabolites in the urine. The Tc-99m-G-ethyne-pyridin-2-yl hydrazine displayed liver uptake of 13-16% ID/g as compared to 21-28% ID/g for Tc-99m-G-ethane- pyridin-2-yl hydrazine. In terms of tumor uptake, the Tc-99m-G-ethyne-pyridin-2-yl hydrazine yielded tumor uptake of 1.05% ID/g at 3 hr PI as compared to 0.40 % ID/g for the Tc-99m-G-ethane-pyridin-2-yl hydrazine and 0.69% ID/g for the Tc-99m-G-ethyne-picolylamine. In imaging studies, the Hec50 tumor was visualized in a live animal for up to 6 hours after injecting the Tc-99m labeled agent.  Conclusion  We have synthesized and evaluated a series of first generation GPR30 targeted radioimaging agents. These GPR30-targeted agents exhibit promising biodistribution characteristics and tumor uptake, and are important lead compounds for ongoing efforts to optimize the GPR30 targeting and imaging characteristics for diagnostic applications.
Abstract 15017: Characterization of a Phenotype-Based Genetic Test Prediction Score for Unrelated Patients with Hypertrophic Cardiomyopathy
Authors: Johan M Bos, Melissa L Will, Bernard J Gersh, Steve R Ommen, Michael J Ackerman
Journal: Circulation (2012)

Background. Hypertrophic cardiomyopathy (HCM) is a disease of profound phenotypic and genotypic heterogeneity and the most common cause of sudden cardiac death (SCD) in young adults. Commercial gen...
Abstract 4639: <i>SLC7A11</i> expression confers cancer stem-like properties in small cell lung cancer cells
Authors: Shohei Kamenori, Kentaro Suina, Juntaro Yamasaki, Subaru Shintani, Yuji Otsuki, Yuki Hirata, Shogo Okazaki, Kenji Tsuchihashi, Oltea Sampetrean, Yoichiro Mitsuishi, Fumiyuki Takahashi, Kazuhisa Takahashi, Hideyuki Saya, Osamu Nagano
Journal: Cancer Research (2019)

Abstract Small Cell Lung Cancer (SCLC) which accounts for 15 % of primary lung cancers is known to grow fast and metastasize easily to whole body at early stages. However, the standard care of SCLC has not been changed for over 10 years and effective treatment remains to be developed. System xc(-) comprises xCT (SLC7A11) and CD98hc subunits and is a major plasma membrane antiporter responsible for the cellular uptake of cystine in exchange for intracellular glutamate. Recently, we studied the impact of xCT inhibitor sulfasalazine (SSZ) in various cancers and found that SCLC cells manifest low level of xCT and are highly sensitive to SSZ treatment compared with non-small cell lines. Furthermore, we found that xCT expression in SCLC cells is regulated by the cellular density and the tumorsphere culture which is known to enhance the cancer stem cell properties also enhances the xCT expression in these cells. To examine the functional relevance of xCT expression to cancer stem-like properties in SCLC cells, we established the stably xCT-expressing SBC-5 cells (SBC5-xCT). Similar to other SCLC cell lines, parental SBC5 cells were not able to proliferate from single-cell level, however, SBC5-xCT cells were found to possess an ability to proliferate from single-cell level. Furthermore, SBC5-xCT cells manifested higher resistance to an anticancer agent cisplatin and higher ability of tumor-initiation than parental SBC5 cells. Our findings establish a new functional role for xCT in the promotion of cancer stem-like properties in SCLC cells. Citation Format: Shohei Kamenori, Kentaro Suina, Juntaro Yamasaki, Subaru Shintani, Yuji Otsuki, Yuki Hirata, Shogo Okazaki, Kenji Tsuchihashi, Oltea Sampetrean, Yoichiro Mitsuishi, Fumiyuki Takahashi, Kazuhisa Takahashi, Hideyuki Saya, Osamu Nagano. SLC7A11 expression confers cancer stem-like properties in small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4639.
Abstract 4260: Novel insights into immunotherapy by deep mining of big cancer genomic data
Authors: Han Liang
Journal: Cancer Research (2019)

Abstract Immunotherapy has revolutionized patient care and cancer research. To gain novel insights into immunotherapy, we performed the pan-cancer analyses of &amp;gt;11,000 tumor samples of 33 cancer types from The Cancer Genome Atlas and CPTAC as well as large amounts of in-house immunotherapy related data. Through the mining on these large-scale cancer genomics and proteomics data, I will discuss three novel ideas that would challenge the current paradigm for developing effective immunotherapy. (I) Checkpoint inhibition: antibody is NOT the only approach. I will discuss the role of enhancers in regulating immune checkpoint. (II) Neoantigen: Somatic mutations are NOT the only source. I will discuss the contribution of RNA editing to proteomics diversity and neoantigen in cancer. (III) Predictive markers: gene-based markers is NOT the only option. I will discuss the utility of a global energy index for predicting the response to anti-PD1 treatment. Collectively, these results suggest novel directions for future immunotherapy development. Citation Format: Han Liang. Novel insights into immunotherapy by deep mining of big cancer genomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4260.
Abstract 2480: MutSpliceDB: A database of splice sites mutations effects
Authors: Alida Palmisano, Suleyman Vural, Yingdong Zhao, Dmitriy Sonkin
Journal: Cancer Research (2019)

Abstract Splice site mutations are one of the well-known classes of genetic alterations playing an important role in biology. Splice site mutations in cancer are most frequently observed as inactivating alterations in tumor suppressor genes (for example, TP53 or RB1) and to a lesser degree as activating alterations in oncogenes (for example MET). Splice site mutations may lead to alterations in mRNA transcripts, causing for example exon(s) inclusion/exclusion or, intron retention. Interpreting the consequences of a specific splice site mutation is not straightforward, especially if the mutation is located outside of the canonical splice sites. Accurate interpretation of the impact a splice site mutation has can further our understanding of biology, influence patient treatment, and in case of germline splice site mutations, may also have relevance to familial disease predisposition. To facilitate the interpretation of splice site mutation effects, we developed MutSpliceDB: https://brb.nci.nih.gov/splicing a public resource of splice sites mutations effects, documenting mutation effect(s) on splicing based on manually reviewed RNA-seq BAM files from sample(s) with particular splice site mutations. Citation Format: Alida Palmisano, Suleyman Vural, Yingdong Zhao, Dmitriy Sonkin. MutSpliceDB: A database of splice sites mutations effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2480.
Abstract 14197: Effects of Metabolic Syndrome on Arterial Responses to Drug-Eluting Stents: Obesity Paradox and Sex-Associated Differences
Authors: Kenji Sakamoto, Katsuhisa Waseda, Hideki Kitahara, Ryotaro Yamada, Ching-Chang Huang, Takao Shimohama, Masao Yamasaki, Ichizo Tsujino, Akiyoshi Miyazawa, Daisaku Nakatani, Kenji Sakata, Osami Kawarada, Paul G Yock, Krishnankutty Sudhir, Peter J Fitzgerald, Yasuhiro Honda
Journal: Circulation (2013)

Background: The impact of metabolic syndrome (MetS) on the efficacy of drug-eluting stents (DES) remains controversial. This may be due in part to a positive influence of obesity (the “obesity para...
Abstract 1253: MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma
Authors: Douglas D. Fang, Guoqin Zhai, Chunhua Xu, Qingyang Gu, Jingwen Wang, Saijie Zhu, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2019)

Abstract Liposarcoma is a rare but highly recurrent soft tissue neoplasm. Combination of surgery and radiotherapy is the main treatment for liposarcoma patients while chemotherapy remains experimental and limited depends on disease subtypes. Well-differentiated and dedifferentiated liposarcoma (WDLPS/DDLPS) represents ~50% of all diagnosed liposarcoma and their benefit from chemotherapy has been documented to be minimal. Concomitant amplifications of MDM2 and CDK4 are frequently found in WDLPS/DDLPS patients, suggesting that the combination with two targeted agents may worth further development for the treatment. APG-115 is a potent, selective, orally bioavailable small molecule inhibitor of MDM2-p53 protein-protein interaction and thus activates tumor suppression activity of p53 in p53 wild-type tumors. Currently, APG-115 is in clinical development as a single agent or in combination with PD-1 blockade immunotherapy for solid tumors, including sarcoma. To further explore the sensitive patient population and predictive biomarkers for APG-115, in this study, we evaluated the effect of the combined MDM2/CDK4 inhibition in p53 wild-type, MDM2 and CDK4 amplified liposarcoma using a preclinical xenograft tumor model derived from a dedifferentiated liposarcoma patient (PDX). Tumor-bearing mice were treated with MDM2 inhibitor APG-115, CDK4 inhibitors palbociclib/ribociclib, or their combinations. In the first experiment, APG-115 administered at 40 mg/kg as a single agent demonstrated antitumor activity in the DDLPS PDX model. In comparison with the single agents, the combination treatment with APG-115 and palbociclib or APG-115 and ribociclib exerted synergistic antitumor effects, resulting in T/C values of 16.9% and 27.1%, respectively (T/C value, average tumor volumes in treatment group vs. the vehicle control group). Partial tumor regression (PR) was achieved in 1/5 animals in both combination treatment groups but not in single arms. Another independent experiment with a higher dose of APG-115 (80 mg/kg) combined with palbociclib showed further improved antitumor activity with T/C value of 7.0% (2/5 PR). Collectively, our results suggest that the combination therapy of APG-115 and a CDK4 inhibitor may benefit WDLPS/DDLPS patients with p53 wild-type, and MDM2 and CDK4 amplifications clinically. Citation Format: Douglas D. Fang, Guoqin Zhai, Chunhua Xu, Qingyang Gu, Jingwen Wang, Saijie Zhu, Dajun Yang, Yifan Zhai. MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1253.
Abstract 4095: Adding fuel to the fire: Augmenting the efficacy of adoptive T-cell therapy with pro-oxidants
Authors: Nada Aboelella, Gang Zhou, Kateryna Fesenkova, Zhi-chun Ding
Journal: Cancer Research (2019)

Abstract Cancer cells face increased oxidative stress driven by oncogene activation, tumor suppressor gene mutation and increased metabolism. Even though cancer cells can resist this redox imbalance by activating various antioxidant defense mechanisms, they are more susceptible to further redox disruption by pro-oxidants. Our previous study indicated that adoptive T-cell therapy (ACT) leads to heightened oxidative stress in tumor cells reflected by depletion of cellular antioxidant glutathione (GSH), accumulation of reactive oxygen species (ROS), and presence of oxidative DNA damages. Based on this observation, we propose that intensifying oxidative stress in tumor with pro-oxidants can sensitize cancer cells to ACT and lead to improved therapeutic outcomes. In this study, we used clinically relevant ACT models to screen a panel of pro-oxidant agents for their ability to potentiate the antitumor effects of ACT. We identified several clinically applicable pro-oxidants, including some commonly used non-steroidal anti-inflammatory drugs (NSAIDs), that can benefit the infusion of tumor-specific CD4+ T cells or CD19-targeting CAR T cells. Our data provide a rationale for combining selected pro-oxidants with ACT to achieve synergistic antitumor effect. Citation Format: Nada Aboelella, Gang Zhou, Kateryna Fesenkova, Zhi-chun Ding. Adding fuel to the fire: Augmenting the efficacy of adoptive T-cell therapy with pro-oxidants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4095.
Pathophysiology, diagnosis and management of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy
Authors: Johann Bauersachs, Tobias König, Peter van der Meer, Mark C. Petrie, Denise Hilfiker‐Kleiner, Amam Mbakwem, Righab Hamdan, Alice M. Jackson, Paul Forsyth, Rudolf A. de Boer, Christian Mueller, Alexander R. Lyon, Lars H. Lund, Massimo F. Piepoli, Stephane Heymans, Ovidiu Chioncel, Stefan D. Anker, Piotr Ponikowski, Petar M. Seferovic, Mark R. Johnson, Alexandre Mebazaa, Karen Sliwa
Journal: European Journal of Heart Failure (2019)
Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination
Authors: Mathieu Grapin, Corentin Richard, Emeric Limagne, Romain Boidot, Véronique Morgand, Aurélie Bertaut, Valentin Derangere, Pierre-Antoine Laurent, Marion Thibaudin, Jean David Fumet, Gilles Crehange, François Ghiringhelli, Céline Mirjolet
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Purpose/objective</h3> Radiotherapy (RT) induces an immunogenic antitumor response, but also some immunosuppressive barriers. It remains unclear how different fractionation protocols can modulate the immune microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors (ICI) in association with RT. However, only few trials aim to optimize the RT fractionation to improve efficacy of these associations. Here we sought to characterize the effect of different fractionation protocols on immune response with a view to associating them with ICI. <h3>Materials/methods</h3> Mice bearing subcutaneous CT26 colon tumors were irradiated using a SARRP device according to different radiation schemes with a same biologically effective dose. Mice were monitored for tumor growth. The radiation immune response (lymphoid, myeloid cells, lymphoid cytokines and immune checkpoint targets) was monitored by flow cytometry at different timepoints after treatment and by RNA sequencing analysis (RNAseq)<b>.</b> The same radiation protocols were performed with and without inhibitors of immune checkpoints modulated by RT. <h3>Results</h3> In the absence of ICI, we showed that 18x2Gy and 3x8Gy induced the longest tumor growth delay compared to 1×16.4Gy. While 3x8Gy and 1×16.4Gy induced a lymphoid response (CD8<sup>+</sup> T-cells, Regulators T-cells), 18x2Gy induced a myeloid response (myeloid-derived suppressor cells, tumor-associated macrophages 2). The secretion of granzyme B by CD8<sup>+</sup> T cells was increased to a greater extent with 3x8Gy. The expression of PD-L1 by tumor cells was moderately increased by RT, but most durably with 18x2Gy. T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression by CD8<sup>+</sup> T-cells was increased with 3x8Gy, but decreased with 18x2Gy. These results were also observed with RNAseq. RT was dramatically more effective with 3x8Gy compared to all the other treatments schemes when associated with anti-TIGIT and anti-PD-L1 (9/10 mice in complete response). The association of anti-PD-L1 and RT was also effective in the 18x2Gy group (8/12 mice in complete response). <h3>Conclusion</h3> Each fractionation scheme induced different lymphoid and myeloid responses as well as various modulations of PD-L1 and TIGIT expression. Furthermore, 3x8Gy was the most effective protocol when associated with anti-PD-L1 and anti-TIGIT. This is the first study combining RT and anti-TIGIT with promising results; further studies are warranted.