tbuckley/cabot-search huggingface dataset:
Abstract 4552: Tumor-restricted immune modulation by multispecific molecules from the DARPin toolbox
Authors: Ulrike Fiedler, Christian Reichen, Joanna Taylor, Patricia Schildknecht, Sophie Barsin, Clara Metz, Anja Schlegel, Simon Fontaine, Denis Villemagne, Julia Ahlskog, Yvonne Kaufmann, Alexander Link, Nicolo Rigamonti, Julia Hepp, Michael T. Stumpp
Journal: Cancer Research (2018)

Abstract During the last years, immune-modulating drugs became an important cornerstone in the treatment of cancer patients. In particular, the PD1/PDL-1 and CTLA-4 antagonists revolutionized the field. However, only a limited number of patients benefit from these antagonistic molecules and more combination therapies are on the way to increase the number of patients benefiting from these novel therapies. Among the combinations, drugs that are T-cell or myeloid cell agonists belonging to the TNFR-superfamily show first promising clinical results. However, systemic immune activation bears the risk of severe side effects that will not allow using these powerful drugs at an effective dose. We have developed a new class of DARPin molecules that enable tumor-restricted immune cell activation of TNFR-superfamily agonists in the tumor only, thereby preventing systemic immune-activation. We generated DARPin molecules that bind with high affinity to TNFR-superfamily members (CD134, CD137 and CD40) and DARPin molecules that bind to tumor-specific antigens such as HER2 and EGFR or targets restricted to the tumor stroma compartment like FAP and extra-domain B of fibronectin (ED-B). Using these building blocks from our DARPin toolbox, we constructed a variety of multi-specific molecules consisting of a TNFR-superfamily receptor targeting DARPin molecule and a tumor-localizing DARPin molecule. In reporter cell assays the multi-specific DARPin molecules activate the respective TNF-superfamily receptor only in the presence of a cell expressing the tumor-localizer; e.g. the FAP-CD134 molecule activates CD134 only in the presence of a stromal cell expressing FAP and not in its absence. Moreover, activation of CD134 was dependent on the density of FAP expression on cells, showing that CD134 only becomes activated if a certain level of the tumor-localizing target is expressed. These finding were confirmed in experiments with primary immune cells where we see immune-cell activation only upon binding to the tumor-localizing target. This could be shown for multiple combinations (&amp;gt;8) and supports the concept that multi-specific DARPin molecules are powerful drug-candidates allowing tumor-restricted immune cell activation. Citation Format: Ulrike Fiedler, Christian Reichen, Joanna Taylor, Patricia Schildknecht, Sophie Barsin, Clara Metz, Anja Schlegel, Simon Fontaine, Denis Villemagne, Julia Ahlskog, Yvonne Kaufmann, Alexander Link, Nicolo Rigamonti, Julia Hepp, Michael T. Stumpp. Tumor-restricted immune modulation by multispecific molecules from the DARPin toolbox [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 4552.
Abstract 18989: Determination of Optimal Coronary Flow for the Preservation of “Donation After Circulatory Death” Heart
Authors: Stefano Toldo, Juan F Torrado Arrosa, Adolfo G Mauro, Eleonora Mezzaroma, Heather Reichstetter, Antonio Abbate, Vigneshwar Kasirajan, Martin J Mangino, Mohammed Quader
Journal: Circulation (2016)

Introduction: Transplantation of hearts from donation after circulatory death donors (DCD) have the potential to increase the number of transplants. However, DCD hearts undergo an extended period o...
Abstract 3684: HDAC inhibitors restore BRAF inhibitor sensitivity by altering PI3K and survival signaling in melanoma
Authors: Peter Hersey, Stuart J. Gallagher
Journal: Cancer Research (2018)

Abstract Mutations in BRAF activate oncogenic MAPK signaling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signaling.Here we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo- derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat synergistically induced caspase-dependent apoptotic cell death. HDAC inhibition decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases including AXL, YAP, ERBB2 and ERBB3 but not EGFR or ERBB4. Both NOXA and BIM proteins were implicated as causing cell death, but in a cell line specific manner. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance is due to activation of MAPK-independent pathways. This work identifies patients that may respond well to this drug combination and demonstrates the necessity of disrupting multiple cell survival pathways in melanoma. Citation Format: Peter Hersey, Stuart J. Gallagher. HDAC inhibitors restore BRAF inhibitor sensitivity by altering PI3K and survival signaling in melanoma [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 3684.
Abstract 3551: Lipid raft integrity is essential for metastasis and chemoresistance properties of CD133+ cancer stem cells in pancreatic cancer
Authors: Vineet K. Gupta, Nikita S. Sharma, Kousik Kesh, Patrcia Dauer, Alice Nomura, Bhuwan Giri, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee
Journal: Cancer Research (2018)

Abstract Pancreatic cancer remains a significant health burden associated with limited patient survival and poses a major therapeutic challenge. Among cancer cells, Cancer stem cells (CSCs) are instrumental in inducing chemoresistance and metastasis in pancreatic cancer. CD133 has been identified as a CSC surface marker in several malignancies including pancreatic cancer. However, the functional role of CD133 in CSCs still not clear. The present study investigates the role of caveolar lipid raft integrity in functional properties of CD133+ CSCs. Current study showed first time that CD133 localizes to caveolar lipid rafts in pancreatic cancer cells, and associates with Caveolin1 (Cav-1) and cholesterol to form an integral signaling complex which drives the downstream processes of chemoresistance and metastasis. Further analysis showed that the integrity of the lipid-raft is crucial for maintenance of the functional properties of pancreatic CSCs, and its disruption leads to increased chemo-sensitivity to chemotherapeutic compound paclitaxel both in vitro as well as in vivo. Additionally, disruption of lipid raft results in decreased invasiveness and metastatic ability of the cells by deregulation of FAK signaling. The study also reveals that pancreatic cancer cells that lack the CSC population marker, CD133, did not respond to lipid raft disruption. Our results indicated that targeting the lipid-raft integrity in pancreatic cancer can specifically eradicate the CD133+ CSCs in pancreatic tumors, leading to a better prognosis for the disease. Citation Format: Vineet K. Gupta, Nikita S. Sharma, Kousik Kesh, Patrcia Dauer, Alice Nomura, Bhuwan Giri, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Lipid raft integrity is essential for metastasis and chemoresistance properties of CD133+ cancer stem cells in pancreatic 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 3551.
Abstract 3324: Diagnosis and prognosis of hepatocellular carcinoma with ctDNA methylation markers
Authors: Kang Zhang
Journal: Cancer Research (2018)

Abstract Abstract An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumor DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive “liquid biopsy” for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation markers by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumor DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P&amp;lt;0.001) and was highly correlated with tumor burden, treatment response, and stage (P&amp;lt;0.001). Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P&amp;lt;0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC. Citation Format: Kang Zhang. Diagnosis and prognosis of hepatocellular carcinoma with ctDNA methylation markers [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 3324.
Pooled overall survival and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small cell lung cancer (NSCLC).
Authors: Sai-Hong Ignatius Ou, Leena Gandhi, Shirish M. Gadgeel, Fabrice Barlesi, James Chih-Hsin Yang, Luigi De Petris, Dong-Wan Kim, Ramaswamy Govindan, Anne-Marie C. Dingemans, Lucio Crino, Lena Herve, Sanjay Popat, Jin Seok Ahn, Eric Dansin, Ali Hassan Zeaiter, Barbara Müller, Hrefna Johannsdottir, Bogdana Balas, Peter N. Morcos, Alice Shaw
Journal: Journal of Clinical Oncology (2018)

9072 Background: Alectinib, a highly selective inhibitor of ALK tyrosine kinase, has demonstrated systemic and central nervous system activity in ALK+ NSCLC. Two single-arm, open-label phase II studies (NP28673; global [NCT01801111] and NP28761; North American [NCT01871805]) have previously demonstrated robust overall survival (OS) in crizotinib-resistant ALK+ NSCLC (Yang et al, J Thorac Oncol 2017). We report final pooled phase II OS and safety data after a longer duration of follow-up. Methods: Patients with locally advanced or metastatic ALK+ NSCLC (possible prior chemotherapy) who had progressed on or were intolerant to crizotinib, received twice-daily alectinib 600mg orally until progression, death or withdrawal. This pooled analysis assessed OS and safety after a median follow-up of 92.3 weeks (almost 2 years) (NP28673 105.5 weeks, data cut-off 27 October 2017; NP28761 75.7 weeks, data cut-off 12 October 2017). Results: The pooled data set included 225 patients. At the time of final data cut-off 53.3% of patients had died, 39.1% were alive and in follow-up, and 7.6% had withdrawn consent or been lost to follow-up. Alectinib demonstrated a median OS of 29.1 months (95% CI: 21.3–39.0) in the pooled analysis (NP28673 29.2 months [95% CI: 21.5–44.4]; NP28761 27.9 months [95% CI: 17.2–NE]). Mean dose intensity 94.2%. Grade ≥3 adverse events (AEs; any cause) occurred in 44.0% of patients, with no AE term reported in >4% of patients. The most common AEs (any grade) included constipation (39.1%), fatigue (35.1%), edema peripheral (28.4%), myalgia (26.2%) and nausea (24.0%). Despite the longer treatment duration (median 48.6 weeks), alectinib demonstrated a tolerable safety profile consistent with previous studies; 14.7% of patients experienced AEs leading to dose reductions, 37.3% of patients experienced AEs leading to dose interruptions or modifications and 6.2% of patients experienced AEs leading to withdrawal. Conclusions: This pooled phase II analysis demonstrated a median OS of >2 years in patients with pretreated ALK+ NSCLC receiving alectinib. In addition, alectinib was well tolerated over a median treatment duration of almost one year (48.6 weeks). Clinical trial information: NP28673; NCT01801111; NP28761; NCT01871805.
Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos
Authors: Yanting Zeng, Jianan Li, Guanglei Li, Shisheng Huang, Wenxia Yu, Yu Zhang, Dunjin Chen, Jia Chen, Jianqiao Liu, Xingxu Huang
Journal: Molecular Therapy (2018)

There are urgent demands for efficient treatment of heritable genetic diseases. The base editing technology has displayed its efficiency and precision in base substitution in human embryos, providing a potential early-stage treatment for genetic diseases. Taking advantage of this technology, we corrected a Marfan syndrome pathogenic mutation, FBN1T7498C. We first tested the feasibility in mutant cells, then successfully achieved genetic correction in heterozygous human embryos. The results showed that the BE3 mediated perfect correction at the efficiency of about 89%. Importantly, no off-target and indels were detected in any tested sites in samples by high-throughput deep sequencing combined with whole-genome sequencing analysis. Our study therefore suggests the efficiency and genetic safety of correcting a Marfan syndrome (MFS) pathogenic mutation in embryos by base editing. There are urgent demands for efficient treatment of heritable genetic diseases. The base editing technology has displayed its efficiency and precision in base substitution in human embryos, providing a potential early-stage treatment for genetic diseases. Taking advantage of this technology, we corrected a Marfan syndrome pathogenic mutation, FBN1T7498C. We first tested the feasibility in mutant cells, then successfully achieved genetic correction in heterozygous human embryos. The results showed that the BE3 mediated perfect correction at the efficiency of about 89%. Importantly, no off-target and indels were detected in any tested sites in samples by high-throughput deep sequencing combined with whole-genome sequencing analysis. Our study therefore suggests the efficiency and genetic safety of correcting a Marfan syndrome (MFS) pathogenic mutation in embryos by base editing.
Abstract 5649: Multi-omics data indicate that primary and lymph node oral cancer cells-derived extracellular vesicles carry cargo molecules with a specific aggressive pattern
Authors: Ariane F. Busso-Lopes, Carolina M. Carnielli, Flávia Winck, Diego M. Riaño-Pachón, Ana K. Oliveira, Rute A. Costa, César Rivera, Camila Caldana, Jay W. Fox, Adriana F. Paes Leme
Journal: Cancer Research (2018)

Abstract Oral squamous cell carcinoma (OSCC) exhibits high incidence and morbidity, representing 300,000 new cases and 145,000 deaths per year. Moreover, the 5-year survival rate is 50% and this is directly associated with regional lymph node metastases. To explore how the extracellular vesicles (EVs) play a significant role on OSCC lymph node metastasis, we characterized the EVs released by tumor primary site cells and their paired lymph node metastasis cells using nanoparticle tracking analysis, high-resolution microscopy (Cryo-EM), EVs uptake by HUVEC, BJ-5ta and gingival primary fibroblasts recipient cells and the proteins, lipids, metabolites and miRNAs contents. Both cells-derived EVs showed a similar size, morphology, and the presence of annexin-2 and flotillin-1 surface markers. Interesting, only gingival primary recipient cells were more likely to uptake primary OSCC-derived EVs compared with lymph node-derived EVs. This effect is probably associated with the differential abundance of 490 proteins, 316 miRNAs, 63 lipids and 17 metabolites between the oral cancer cells-derived EVs. Markedly, multilevel omic data integration indicates that metabolic processes were over-represented mainly in primary OSCC-derived EVs, suggesting that these EVs carry specific cargo molecules associated with a more aggressive pattern compared with lymph node OSCC-derived EVs. Financial support: FAPESP (Process number 2016/50005-7). Citation Format: Ariane F. Busso-Lopes, Carolina M. Carnielli, Flávia Winck, Diego M. Riaño-Pachón, Ana K. Oliveira, Rute A. Costa, César Rivera, Camila Caldana, Jay W. Fox, Adriana F. Paes Leme. Multi-omics data indicate that primary and lymph node oral cancer cells-derived extracellular vesicles carry cargo molecules with a specific aggressive pattern [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 5649.
Abstract 20896: Role of the Interaction Cyclophilin D-MPV17 in the Inner Membrane of Mitochondria in Cardiac Ischemia/Reperfusion Injury
Authors: Ngonidzashe B Madungwe, Yansheng Feng, Mihaela Lie, Carolina V da Cruz Junho, Jean C Bopassa
Journal: Circulation (2017)

Introduction: The inner membrane of mitochondria (IMM) has proteins that control mitochondrial membrane potential (ΔΨm), ion transport, ATP production, and is the site of formation of the mitochond...
Primary and Secondary Signaling Pathways in Early Preconditioning That Converge on the Mitochondria to Produce Cardioprotection
Authors: ElizabethMurphy
Journal: Circulation Research (2004)

Cardioprotective mechanisms such as acute or early preconditioning activate several primary signaling pathways that seem to converge on mitochondrial targets, leading to altered cell metabolism and inhibition of apoptosis. Acute preconditioning leads to generation of agonists, which bind to G protein–coupled receptors, and initiates a signaling cascade that involves activation of phosphoinositide-3-kinase, endothelial NO synthase, protein kinase C, glycogen synthase kinase 3β, mitogen-activated protein kinases, and other signaling pathways. Activation of these signaling pathways along with generation of reactive oxygen species leads to alterations in the activity of key mitochondrial proteins such as mitochondrial ATP-sensitive K+ channels, the mitochondrial permeability transition pore, and bcl-2 family members. Alterations in these mitochondrial proteins results in altered metabolism and inhibition of cell death, thus resulting in cardioprotection.
Enhanced Expression of Hepatocyte Growth Factor/c-Met by Myocardial Ischemia and Reperfusion in a Rat Model
Authors: KohOno, AkiraMatsumori, TetsuoShioi, YutakaFurukawa, ShigetakeSasayama
Journal: Circulation (1997)

Background Hepatocyte growth factor (HGF) is a multifunctional factor implicated in tissue regeneration, wound healing, and angiogenesis. Circulating HGF is reportedly elevated during the early stage of myocardial infarction. However, its precise effect on the heart is unknown. To evaluate the regulation of HGF in ischemically damaged myocardium, the production of HGF and its high-affinity receptor, c-Met, was studied in a rat model of myocardial ischemia and reperfusion. Methods and Results The plasma concentration of HGF began to increase within 1 hour of reperfusion after 1 hour of ischemia. The peak level was reached at 3 hours after reperfusion. Northern blotting revealed that HGF mRNA expression in the heart was augmented threefold at 24 and 48 hours and remained elevated by twofold at 120 hours after the myocardium was reperfused. The signal for c-met , high-affinity HGF receptor mRNA, was also upregulated parallel to upregulation for HGF. In the kidney, liver, lung, and spleen, HGF mRNA was also m...
Abstract P276: Self-perceived Diet Quality, Obesity Status, and Household Food Purchasing Behaviors Among US Adults
Authors: Chelsea R Singleton
Journal: Circulation (2016)

Introduction: Previous research suggests that consumer food purchasing behaviors (e.g. food venue choice, food purchasing expenses, convenience meal procurement) are associated with socioeconomic status, neighborhood environment and overall healthiness of diet. Little is known about how household food purchasing behaviors are related to individual diet perception and obesity status. This research aims to determine if self-perceived diet quality is associated with household food purchasing behaviors. Additionally, this research aims to examine how obesity status modifies associations between self-perceived diet quality and household food purchasing behaviors. Hypothesis: Self-perceived diet quality will be associated with household food purchasing behaviors. Associations will differ between obese and non-obese individuals. Methods: Data on a nationally representative sample of 12,095 US adults (i.e. ≥ 19 years old) who participated in the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2012 were obtained and analyzed. Self-perceived diet quality was reported by participants as being excellent, very good, good, fair or poor. Household food purchasing behaviors examined included # of convenience meals purchased per week and amount of money ($) spent per month doing the following: shopping at a supermarket, shopping at other food outlets, dining out, and purchasing carryout/delivered food items. Stratified linear regression models adjusted for age, sex, race/ethnicity, educational level, household size and Supplemental Nutrition Assistance Program participation were used for analyses. Results: The population was on average 46.6 (±0.9) years old, 51.1% female, 22.2% Non-Hispanic Black, 24.7% Hispanic and 36.6% obese (i.e. body mass index ≥ 30). Among all participants, analyses indicated that as self-perceived diet quality decreased, the # of convenience meals purchased per week and the amount of $ spent on carryout/delivery per month increased (p&lt;0.001). Additionally, as self-perceived diet quality decreased, the amount of $ spent at the supermarket per month also decreased (p&lt;0.001). Stratified regression models suggested that associations differed by obesity status. Regardless of how they perceived their diet quality, obese individuals spent similar amounts of $ at the supermarket and on carryout/delivered food items. Conclusions: Self-perceived diet quality is associated with household food purchasing behaviors. Additional research is needed to better understand how the dynamics of household food purchasing influences diet and obesity.
Effect of Timing of Chronic Preoperative Aspirin Discontinuation on Morbidity and Mortality in Coronary Artery Bypass Surgery
Authors: MiriamJacob, NicholasSmedira, EugeneBlackstone, SarahWilliams, LeslieCho
Journal: Circulation (2011)

Background—Aspirin (ASA) has been shown to reduce postoperative coronary artery bypass grafting (CABG) mortality and ischemic events; however, the timing of chronic ASA discontinuation before surgery is controversial because of concern about postoperative bleeding. We evaluated the effect of the timing of ASA discontinuation before CABG on major adverse cardiovascular outcomes and postoperative bleeding using the Cleveland Clinic Cardiovascular Information Registry database. Methods and Results—At the Cleveland Clinic between January 1, 2002, and January 31, 2008, 4143 patients undergoing CABG were taking preoperative chronic ASA. Of these, 2298 discontinued ASA 6 or more days before surgery (early discontinuation), and 1845 took ASA within 5 days of the surgery (late use). Because of substantial differences between these 2 groups, propensity score analysis, and matching based on 31 variables were used for fair comparison of outcomes. This resulted in 1519 well-matched pairs of patients (73%). There was n...