tbuckley/cabot-search huggingface dataset:
Abstract 1360: Genistein-AR antagonist conjugate potently induce growth arrest in both androgen dependent and independent prostate cancer cell lines
Authors: Idris O. Raji, Alex George, Omer Kucuk, Adegboyega K. Oyelere
Journal: Cancer Research (2016)

Abstract The ability of prostate cancer to transition from androgen dependent- to androgen independent state (castration resistant), during androgen deprivation therapy, requires that new chemotherapeutic agents be introduced that will retain activity in the two prostate cancer types. Though described as androgen independent, castration resistant prostate cancer (CRPC) still relies heavily on androgen receptor (AR) signaling for survival. Enzalutamide, an AR antagonist, is probably that most effective drug used in androgen deprivation therapy for CRPC and AR dependent prostate cancer. Despite its clinical success, there is the fear of resistant to enzalutamide due to mutation in the ligand binding domain of AR. This poses a challenge that requires developing new agents devoid of resistance, in the event of mutation. One of the approaches being proposed is to develop new agents that can selectively induce AR degradation, an approach that was successfully used to develop the selective estrogen receptor degrader, fulvestrant. In our study, we incorporate genistein, a soy isoflavone known to perturb multiple biochemical pathways relevant for cancer survival, into an AR binding template to give AG-1-33. AG-1-33 was evaluated for growth inhibitory activity in LNCaP (AR dependent) and DU-145 (AR independent) prostate cancer cell lines. This compound retained its AR antagonist activity and also showed low micromolar anti-proliferation activity in the two prostate cancer cell lines. We also evaluated the effect of AG-1-33 on AR expression, as well as its ability to act as a selective AR degrader in LNCaP. Citation Format: Idris O. Raji, Alex George, Omer Kucuk, Adegboyega K. Oyelere. Genistein-AR antagonist conjugate potently induce growth arrest in both androgen dependent and independent prostate cancer 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 1360.
Abstract 2960: Potent <i>in vivo</i> activity of site-specific indolino-benzodiazepine antibody-drug conjugates (ADCs) generated via engineered cysteine conjugation
Authors: Nicholas C. Yoder, Chen Bai, Alan Wilhelm, Erin K. Maloney, Olga Ab, Emily E. Reid, Manami Shizuka, Daniel Tavares, Rassol Laleau, Xiuxia Sun, Megan E. Bogalhas, Lintao Wang, Jan Pinkas, Michael L. Miller, Ravi Chari, Thomas A. Keating
Journal: Cancer Research (2016)

Abstract ADCs are widely studied for cancer therapy, with numerous agents in preclinical and clinical development embodying a wide array of targets, linker chemistries, and cytotoxic effector classes. A fourth element of ADC design that has received much attention recently is the site of conjugation of the cytotoxic molecule to the antibody. Historically, lysine- or interchain cysteine-directed conjugation has been used, but site-specific chemistries have become increasingly popular. Our previous evaluation of site-specific and lysine-linked ADCs utilizing a tubulin-acting maytansinoid effector molecule found the lysine-linked version was more active in vivo (Yoder et al., AACR 2015 #645). Here we present a comparison of engineered cysteine site-specific and lysine-linked ADCs utilizing the previously described indolino-benzodiazepine (henceforth referred to as IGN) effector IGN-P1 (Miller et al., AACR 2015 #652) which is designed to undergo proteolytic cleavage upon cell uptake to release a potently cytotoxic DNA alkylator. We show that HC-S442C mutants of human IgG1 can be conjugated via maleimide chemistry to IGN-P1 to give stable, potent, and homogeneous ADCs with drug to antibody ratio (DAR) of 2. The in vitro potency of engineered-cysteine IGN-P1 ADCs is largely dependent on the DAR of the ADC, although some difference is observed between HC-S442C and other cysteine mutants used for conjugation. Pharmacokinetic study of C442 maleimide conjugates suggests that the chemical linkage between effector and antibody is stable upon administration in mice. Further, and in contrast to our previous observations utilizing maytansinoid ADCs, the site-specific and Lys-linked IGN-P1 ADCs showed comparable efficacy in vivo on a molar drug basis. This effect was observed across two different antibodies targeting two different cell surface antigens. These results suggest that, in certain cases, site-specific conjugation chemistry can offer comparable activity to heterogeneous conjugation at well-tolerated doses. Citation Format: Nicholas C. Yoder, Chen Bai, Alan Wilhelm, Erin K. Maloney, Olga Ab, Emily E. Reid, Manami Shizuka, Daniel Tavares, Rassol Laleau, Xiuxia Sun, Megan E. Bogalhas, Lintao Wang, Jan Pinkas, Michael L. Miller, Ravi Chari, Thomas A. Keating. Potent in vivo activity of site-specific indolino-benzodiazepine antibody-drug conjugates (ADCs) generated via engineered cysteine conjugation. [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 2960.
Submucosal tunneling endoscopic resection for leiomyomas located on opposite esophageal walls: the role of a tortuous submucosal tunnel
Authors: Fuxi Zhou, Yuyong Tan, Yi Chu, Changmei Hu, Jirong Huo, Deliang Liu
Journal: Endoscopy (2016)

A 50-year-old man presented to our hospital with a 1-month history of epigastric discomfort. Esophagogastroduodenoscopy (EGD) revealed two protruding lesions on the anterior and posterior esophageal walls, about 27 cm and 30 cm from the incisors, respectively ([Fig. 1 a]; [Video 1]). Endoscopic ultrasonography (EUS) revealed that the tumors were originating from the muscularis propria layer and had no risk features.
Abstract 248: Utility of Central Telemetry Monitoring in 2011
Authors: Shuja ur Rehman, Richard J Kovacs
Journal: Circulation (2011)

Introduction: ECG monitoring via central telemetry (TECG) is commonly used in modern hospitals. Guidelines for the application of TECG are infrequently updated, and the value of TECG in an era of concern over escalating costs is not known. Our institution is critically examining the role of TECG in overall patient safety and needed baseline data on the outcomes of patients undergoing TECG. Objective: Describe the frequency of clinically important events in patients undergoing TECG. Methods: During a 3 month period in 2011, 11,520 patient-days of telemetry were surveyed in a large urban multihospital network with central telemetry staffed by trained technicians. Those patients that required a call from a telemetry technician to a nurse and subsequent intervention were included in the study. Subsequent interventions included additional diagnostic testing, drug administration, and transfer to a higher acuity of care, rapid response team intervention or code 99. Results: 3 months of TECG monitoring yielded a total of 280 telemetric events and 62 (22.1%) required intervention. The most common arrhythmias requiring intervention were atrial fibrillation (N=27), ventricular tachycardia (N =7) and supra ventricular tachycardia (N=5) (figure 1). One case of Torsade de Pointes was detected. The most common interventions were drug administration (N=26), additional diagnostic testing ordered (N=36) and code 99, transfer to higher acuity of care or rapid response team intervention (N=11). Conclusion: Our results suggest that central telemetry monitoring in a modern hospital results in a substantial number of interventions in response to telemetry findings. We intend to use these data in further studies assessing the utility of central telemetry compared to local monitoring techniques.
Abstract 1803: Breast cancer cell lines with acquired resistance to selective ERα degraders (SERDs) are dependent on PI3K signaling
Authors: Christy Ong, Anneleen Daemen, Jason Oeh, Ellen Ingalla, Alfonzo Arrazate, Michelle Nanini, Deepak Sampath, Lori Friedman, Thomas O’Brien
Journal: Cancer Research (2016)

Abstract Estrogen positive (ER+) breast cancer accounts for the majority of all breast cancers and is primarily treated with endocrine therapy. However, even though current endocrine treatments are effective, a subset of patients inevitably become resistant to these treatments. The novel oral SERD, GDC-0810/ARN-810, is currently in Phase II clinical trials in ER+ breast cancer patients. GDC-0810 induces ERα degradation in ER+ MCF7 and T47D cells and inhibits cell proliferation. Moreover, it is also efficacious in ER+ tumor models in vivo, including in MCF7-ESR1 Y537S xenografts and in WHIM20 ESR1 mutant Y537S PDX tumors. Given that little is known about resistance mechanisms to SERDs, our aim was to understand what mechanisms may underlie resistance after continuous exposure. We generated cell lines resistant to GDC-0810 and show that all of these lines were also cross-resistant to fulvestrant and tamoxifen. We determined that cells with acquired-resistance were more sensitive than parental cells to inhibitors of the PI3K/AKT signaling pathway. Additionally, in some resistant clones, ERα protein expression was lost, but this loss was transient and could be regained after long-term growth in the absence of SERDs. A range of approaches are being undertaken to explore the underlying mechanisms driving acquired-resistance to SERDs. These preclinical studies may inform future clinical combinations. Citation Format: Christy Ong, Anneleen Daemen, Jason Oeh, Ellen Ingalla, Alfonzo Arrazate, Michelle Nanini, Deepak Sampath, Lori Friedman, Thomas O’Brien. Breast cancer cell lines with acquired resistance to selective ERα degraders (SERDs) are dependent on PI3K signaling. [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 1803.
PWE-051 Real life data of steroid free remission with adalimumab for ulcerative colitis: Abstract PWE-051 Table 1
Authors: K Kemp, D Byrne, R Campbell, T Law, W McManus, R Willert
Journal: Gut (2015)

<h3>Introduction</h3> The efficacy of Adalimumab (ADA) in ulcerative colitis (UC) has been demonstrated in controlled trials. However there is little information on the real data of steroid free remission within UK clinical practice. <h3>Method</h3> This was a retrospective multicentre cohort study of 4 hospital Trusts within the NorthWest region of the UK. Demographic data, concomitant therapy, CRP and faecal calprotectin were recorded at baseline. Baseline glucocorticosteroids (GS) was compared at week 8 and 12 and 6 month outcomes following induction of ADA, 160 mg, 80 mg, 40 mg EOW. <h3>Results</h3> 43 patients were identified from the 4 sites who received a minimum of 12 weeks treatment. Of these 26 were on GS at induction. 3 patients remained on GS at week 8 and all patients were steroid free at week 12. There was 6 month data on 15 of the 43 patients that had received ADA. 6 of 15 patients had discontinued ADA by 6 months of treatment with 1 skin infection and 5 loss of response with 1 requiring colectomy. Number of males (%) was 27 (63%), median age (SD) (range) 54 yrs (16.3) (20–74yrs). <h3>Conclusion</h3> Real life data of ADA within this cohort demonstrates that all the patients were steroid free at week 12 with only just over half (60%) continued ADA beyond 6 months. <h3>Disclosure of interest</h3> K. Kemp Speaker Bureau of: Abbvie, MSD, Takaeda, Actavis, Dr Falk, D. Byrne: None Declared, R. Campbell: None Declared, T. Law Speaker Bureau of: MSD, W. McManus: None Declared, R. Willert Speaker Bureau of: Abbvie, MSD, Takaeda.
Abstract 3086: Cyclopamine tartrate, an anti-cancer agent targeting Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration
Authors: Md Maksudul Alam, Sagar Sohoni, Sarada Preeta Kalainayakan, Massoud Garrossian, Li Zhang
Journal: Cancer Research (2016)

Abstract The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in mammalian embryonic development. These processes include stem cell maintenance, determination of cell fate, tissue polarity, cell survival, cell differentiation and proliferation. Although this pathway is usually silenced in adult tissues, constitutive activation of the Hh pathway can lead to tumorigenesis. This aberrant characteristic can be observed in different types of human cancer including basal cell carcinomas, medulloblastoma, lung cancer, ovarian cancer, gastrointestinal cancer, breast and prostate cancer. This pathway has been shown to regulate proliferation of cancer stem cells and increase tumor invasiveness. Targeted inhibition of Hh signaling pathway is shown to be effective in cancer treatment and prevention. Therefore, the discovery of Hh pathway inhibitors can pave the way of finding effective cancer treatments. The steroidal alkaloid cyclopamine was the first compound found to inhibit Hh signaling and has been invaluable for understanding the function of Hh signaling in development and cancer. Cyclopamine tartrate (CycT) is an improved analogue of cyclopamine with increased water solubility and bioavailabilty. We performed numerous experiments to examine the effect of CycT in inhibiting Hh signaling on an array of non-small-cell lung cancer (NSCLC) lines. We discovered that CycT has a novel activity in disrupting mitochondrial function and aerobic respiration. Our data show that CycT causes a substantial decrease in aerobic respiration of NSCLC cells, similar to the effect of glutamine deprivation. Mitotracker staining showed that CycT causes mitochondrial fragmentation by increasing mitochondrial fission, which is indicated by the localization of DRP1 at fission sites. Further experiments showed that CycT increases ROS generation, which is presumably a consequence of mitochondrial hyperpolarization. Concomitantly, CycT causes apoptosis and suppress proliferation of NSCLC cells. Citation Format: Md Maksudul Alam, Sagar Sohoni, Sarada Preeta Kalainayakan, Massoud Garrossian, Li Zhang. Cyclopamine tartrate, an anti-cancer agent targeting Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration. [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 3086.
Abstract 5162: Id1 is an oncogenic target of RNA binding protein HuR in gastric cancer
Authors: Shuang Han, Xiaoqing Wu, Yuxiao Guo, Jing Zhang, Xuan Gu, Rebecca T. Marquez, Jeffrey Aube, Liang Xu
Journal: Cancer Research (2016)

Abstract Hu antigen R (HuR), a ubiquitous RNA-binding protein (RBP), has been shown to be overexpressed in gastric cancer. Cytoplasmic HuR is reported to be associated with high stage, distant metastases and unresectability. HuR efficiently regulates cancer-related gene expression by binding to AU- and U-rich sequences (ARE) in the 3’ and 5’-untranslated region (UTR) of mRNAs. Id1 (Inhibitor of DNA binding) is a putative oncogene that we previously found was upregulated in gastric cancer and associated with poor prognosis. Id1 mRNA contains several putative HuR ARE sites. Our goal is to determine the impact of HuR on Id1 expression. We first confirmed Id1 is a HuR target by Ribonucleoprotein Immunoprecipitation (RNP-IP) in gastric cancer cells. Then, we found KH-3, a potent and specific inhibitor of HuR, inhibited Id1 mRNA and protein expression. The proliferative and invasive capabilities of the gastric cancer cells were also inhibited by KH-3. We conclude that Id1 is a target of RNA-binding protein HuR in gastric cancer. HuR specific inhibitor, KH-3, may be a promising therapeutic agent in treating HuR/Id1 high gastric cancers. Citation Format: Shuang Han, Xiaoqing Wu, Yuxiao Guo, Jing Zhang, Xuan Gu, Rebecca T. Marquez, Jeffrey Aube, Liang Xu. Id1 is an oncogenic target of RNA binding protein HuR in gastric 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 5162.
Brief Report: Changes in Antiphospholipid Antibody Titers During Pregnancy: Effects on Pregnancy Outcomes
Authors: Cecile M. Yelnik, T. Flint Porter, D. Ware Branch, Carl A. Laskin, Joan T. Merrill, Marta M. Guerra, Michael D. Lockshin, Jill P. Buyon, Michelle Petri, Lisa R. Sammaritano, Mary D. Stephenson, Mimi Y. Kim, Jane E. Salmon
Journal: Arthritis & Rheumatology (2016)

Objective To measure variance in antiphospholipid antibody (aPL) levels during pregnancy and to determine if variation affects pregnancy outcomes. Methods We used data from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a multicenter prospective study of pregnant women with aPL and/or systemic lupus erythematosus (SLE). Antiphospholipid antibodies were considered present if any of the following were positive: anticardiolipin (aCL), anti–β 2 ‐glycoprotein I (anti‐β 2 GPI) titers ≥40 IgG phospholipid (GPL) or IgM phospholipid (MPL) units, and/or lupus anticoagulant (LAC). Antiphospholipid antibodies were measured every trimester and postpartum. Adverse pregnancy outcomes were defined as fetal/neonatal death, preterm delivery (&lt;36 weeks) due to preeclampsia or placental insufficiency, or growth restriction. Results One hundred fifty‐two aPL‐positive patients were studied. Fifty‐seven percent had clinical antiphospholipid syndrome (APS) and 36% had SLE. IgG aPL levels were significantly lower during the second and third trimesters compared to initial screening, but IgG aCL and anti‐β 2 GPI remained high‐positive through pregnancy in 93% of patients during the second trimester, and in 85% of patients during the third trimester. IgM aPL titers were negative in the majority of patients and decreased modestly during pregnancy among patients who were positive. LAC frequency also decreased, but 75% of patients remained positive through the second trimester. Only 4% of patients with aPL at baseline did not have aPL in either the second or third trimesters. Changes in aPL levels or aPL status were not associated with adverse pregnancy outcomes. LAC was the only aPL associated with adverse pregnancy outcomes. Conclusion The aPL in the cohort decreased marginally during pregnancy, and changes were not associated with pregnancy outcomes. Our results suggest that, among women with aPL and/or SLE, measuring aPL early in pregnancy is sufficient to assess risk. Repeat aPL testing through pregnancy is unnecessary.
Oncogenic Micrornas In Cerebrospinal Fluid and Sera Reflect Therapy Efficacy and Their Reappearance Precedes Clinical Relapse In Primary and Secondary CNS Lymphoma
Authors: Vit Pospisil, Heidi Mocikova, Magdalena Klanova, Monika Palickova, Tomas Kozak, Marek Trneny, Tomas Stopka
Journal: Blood (2013)
Abstract 1179: Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s
Authors: Michele Carbone, Erin G. Flores, Mitsuru Emi, Giovanni Gaudino, Sandra Pastorino, Haining Yang, Todd Johnson, Tatsuhiko Tsunoda, Mary Hesdorffer, Harvey I. Pass
Journal: Cancer Research (2016)

Abstract Germline BAP1 mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives. Through screening MM patients with histories of multiple cancers, we found four supposedly unrelated patients that shared an identical germline BAP1 mutation. We investigated whether this BAP1 mutation occurred in a ‘hot-spot’ for “de novo” mutations or whether these four MM patients shared a common ancestor. Using molecular genomics analyses we found that they are related. By genealogic studies we traced their ancestor to a couple that emigrated from Germany to North America in the early 1700’s; we traced the subsequent migration of their descendants, who are now living in at least three different US States. Our findings demonstrate that BAP1 mutations are transmitted among subsequent generations over the course of centuries. This knowledge and methodology is being used to identify additional branches of the family carrying BAP1 mutations. Our study shows that the application of modern genomic analyses, coupled with “classical” family histories collected by the treating physician, and with genealogical searches, offer a powerful strategy to identify high-risk germline BAP1 mutation carriers that will benefit from genetic counseling and early detection cancer screening. Citation Format: Michele Carbone, Erin G. Flores, Mitsuru Emi, Giovanni Gaudino, Sandra Pastorino, Haining Yang, Todd Johnson, Tatsuhiko Tsunoda, Mary Hesdorffer, Harvey I. Pass. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s. [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 1179.
Abstract 2112: ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells
Authors: Takaaki Oba, Ken-ichi Ito, Shun’ichiro Taniguchi
Journal: Cancer Research (2016)

Abstract Background: Eribulin is a key drug for the patients with metastatic breast cancer; however, the mechanisms of how breast cancer cells become resistant to eribulin have not been fully elucidated. The purpose of this study is to analyze the mechanisms of eribulin resistance in breast cancer cells. Cell lines: Eribulin resistant cell lines were established for three estrogen receptor (ER) positive cell lines (MCF7/E, BT474/E,ZR75-1/E), three triple negative cell lines (MDA-MB-231/E, Hs578T/E, MDA-MB-157/E), and one HER2 positive cell line (SKBR3/E) by exposing to stepwise increased doses of eribulin. Results: The mRNA and protein expressions of both ABCC11 and ABCB1 were increased in all eribulin resistant cell lines regardless of their subtype. Inhibition of either ABCC11 or ABCB1 by small interfering RNA (siRNA) partially restored the sensitivity to eribulin in MCF7/E, BT474/E, and ZR75-1/E cells. Moreover, dual inhibition of ABCC11 and ABCB1 additively restored the sensitivity to eribulin in MCF7/E cells. On the other hand, overexpression of exogenous ABCC11 caused eribulin resistance in MCF7 and MDA-MB-231 cells (resistance ratio; MCF7; 13.8±0.85, MDA-MB-231; 11.4±0.74). Interestingly, inhibition of ER expression by siRNA or down regulation of ER by fluvestrant decreased ABCC11 expression and increased the sensitivity to eribulin in MCF7/E cells. Discussion: Our data demonstrates that ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells regardless of their subtype; moreover, our data suggests the possibility of involvement of ER pathway in the regulation of ABCC11 expression in the ER positive breast cancer cells. Although further studies should be required, the expression of ABCC11/ABCB1 may be used as biomarkers for prediction of response to eribulin in breast cancer. In addition, the inhibition of ABCC11/ ABCB1 might be of service in a novel strategy to enhance the antitumor effect of eribulin. Citation Format: Takaaki Oba, Ken-ichi Ito, Shun’ichiro Taniguchi. ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells. [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 2112.