tbuckley/cabot-search huggingface dataset:
Abstract 4994: RET isoforms differentially contribute to focal adhesion formation
Authors: Piriya Yoganathan, Eric Lian, Lois M. Mulligan
Journal: Cancer Research (2015)

Abstract RET is a receptor tyrosine kinase crucial for the development of the kidney, and some neuroendocrine tissues. RET activation by its ligand, glial cell-line derived neurotrophic factor (GDNF), results in autophosphorylation of several key tyrosine kinase residues in the intracellular region, which allow binding of adaptor and signalling proteins, and consequently activation of various cellular processes, including survival, proliferation and migration. RET has two major protein isoforms, called RET9 and RET51 after the number of unique amino acids at the C-terminus, generated by alternative splicing. Although the RET isoforms are highly conserved across species, and both isoforms are normally co-expressed, they have major molecular and functional differences, including different transforming abilities, and trafficking properties. RET is implicated in several human diseases. Gain-of-function RET mutations result in the cancer syndrome multiple endocrine neoplasia type 2, that affects neuroendocrine tissues, somatic RET rearrangements are found in papillary thyroid carcinoma, and lung adenocarcinoma, and aberrant wild-type RET activation occurs in many cancers, including breast and pancreatic cancer. Focal adhesion protein complexes are involved in interactions of cells with the extracellular matrix, and are crucial for controlling cancer-related processes, including cell migration and invasion. The contributions of RET isoforms to the processes of focal adhesion formation and dynamics have not yet been investigated. To explore the roles of RET isoforms in focal adhesion formation, we used total internal resonance fluorescence (TIRF) microscopy to assess localization of various focal adhesion proteins, including paxillin, vinculin and zyxin in response to GDNF in a cell-based model system. Our results suggest that RET51 promotes more early (ie. paxillin) and late (ie. zyxin) stage focal adhesion formation than does RET9. Additionally, we demonstrate that the kinase dead form of RET51 results in a decrease of the number of focal adhesions compared to RET51 wild-type, suggesting that the increase in focal adhesion formation in the presence of RET51 is phosphorylation-dependent. Inhibition of SRC and FAK led to a reduction in focal adhesion formation, indicating that these pathways play roles in this process. Ongoing studies are investigating the focal adhesion dynamics of the RET isoforms and further characterizing the molecular differences underlying the ability of RET51 to induce greater focal adhesion formation than RET9. Citation Format: Piriya Yoganathan, Eric Lian, Lois M. Mulligan. RET isoforms differentially contribute to focal adhesion formation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4994. doi:10.1158/1538-7445.AM2015-4994
A phase I/II study of the PARP inhibitor, ABT-888 plus 5-fluorouracil and oxaliplatin (modified FOLFOX-6) in patients with metastatic pancreatic cancer.
Authors: M. J. Pishvaian, R. Slack, A. Witkiewicz, A. R. He, J. J. Hwang, A. Hankin, L. Ley, S. K. Apte, S. J. Littman, L. M. Weiner, J. Marshall, J. R. Brody
Journal: Journal of Clinical Oncology (2011)

TPS170 Background: Inhibitors of Poly(ADP-ribose) polymerase (PARP) are potent sensitizing agents for DNA-damaging chemotherapeutic agents such as the platinum analogs. The sensitizing effects of PARP inhibitors are magnified when cancer cells harbor defects in DNA repair enzymes including BRCA-2, FANCD2, PTEN, and the mismatch repair proteins, and DNA repair defects occur often in patients with pancreatic cancer. ABT-888 is a novel small molecule PARP inhibitor that demonstrates PARP inhibition, in vivo, and has synergistic anti-cancer activity when combined with oxaliplatin, in pre-clinical models. Methods: We have initiated an open label Phase I/II study. Patients with metastatic, unresectable pancreatic cancer who have an adequate performance status and normal hepatic and renal function will be eligible. Patients will receive mFOLFOX-6 (oxaliplatin (85mg/m2), leucovorin (400mg/m2) and 5-FU (400mg/m2) on day 1, followed by a continuous infusion of 5-FU (2400mg/m2) over 46 hours on days 1-3). Patients will also receive ABT-888 orally twice-a-day on Days 1-7 of each 14-day cycle. Patients will be restaged every 4 cycles (every 8 weeks). The Phase I portion will be a traditional 3+3 dose escalation of ABT-888, from 40mg to 100mg twice daily. The Phase II portion is designed as two parallel studies: Arm A for previously untreated patients; Arm B for patients who have received one or more prior therapies for metastatic disease. The primary endpoint is objective response rate (ORR), and each Arm will follow a Simon’s two-stage optimal design. For each Arm, 9 patients will be accrued in the first Stage, and up to 24 patients in the second Stage. The sample sizes of 9 and 24 patients and the decision rules, in Stages 1 and 2 respectively, are designed to differentiate a 5% ORR from a 25% ORR at a 1-sided 10% significance level and 90% power. Secondary clinical endpoints include disease control rate (CR+PR+SD at 6 months), progression free survival, and overall survival. In addition, each patient will undergo a fresh tumor biopsy to assess the expression of a panel of DNA repair proteins, including those listed above. The trial opened in January, 2011 and has accrued the first cohort.
Abstract SY19-01: Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy
Authors: Michael J. Lee, Yogesh Dayma, Anne-Margriet Heijinks, Stephen W. Morton, Erik C. Dreaden, Paula T. Hammond, Michael B. Yaffe
Journal: Cancer Research (2015)

Abstract Dynamic re-wiring of signaling networks is a prominent mechanism responsible for the development of resistance to many molecular-targeted anti-cancer agents. Here we show how this same dynamic re-wiring process can be used therapeutically to enhance the response of tumors to cytotoxic anti-cancer agents. Using cell lines and murine tumor models of triple-negative breast cancer, non-small cell lung cancer, and head and neck cancer, we show that chronic inhibition of EGFR and/or FGFR driver oncogenes dramatically enhances cell death in response to topoisomerase inhibitors and platinum DNA crosslinking drugs. In marked contrast, no such sensitization is observed when the growth factor receptor inhibitors are co-administered with the cytotoxic agents. The molecular mechanism responsible for this time-dependent growth factor inhibitor-induced tumor cell sensitization was explored using a systems biology-based model of DNA damage signaling in which protein kinase activities, substrate phosphorylation, and phosphoprotein-binding events for multiple signaling pathways were quantitatively measured at densely sampled points in time, and mathematically correlated with tumor cell responses including cell cycle arrest, cytokine production, autophagy, and apoptosis. This analysis revealed that sustained EGFR/FGFR suppression unmasks an apoptotic network involving Caspase-8 that is normally suppressed by oncogene addiction, resulting in an enhanced apoptotic response to equivalent amounts of DNA damage. This discovery demonstrates that the timing interval between administration of different drugs in combination chemotherapy can have profound effects on the tumor response through the dynamic re-wiring of cell signaling pathways in real time. Finally, we take advantage of this dynamic re-wiring process by developing tumor-targeted time-staggered release nanoparticles that deliver EGFR inhibitors at early times followed by the delayed release of doxorubicin. We show that these nanoparticles cause dramatic regression of murine NSCLC and TNBC tumor xenografts in vivo, substantiating the utility of therapeutic network re-wiring for anti-cancer therapy in the clinic. Citation Format: Michael J. Lee, Yogesh Dayma, Anne-Margriet Heijinks, Stephen W. Morton, Erik C. Dreaden, Paula T. Hammond, Michael B. Yaffe. Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2015-SY19-01
Health Care Transition Preparation and Experiences in a U.S. National Sample of Young Adults With Type 1 Diabetes
Authors: Katharine C. Garvey, Nicole C. Foster, Shivani Agarwal, Linda A. DiMeglio, Barbara J. Anderson, Sarah D. Corathers, Marisa E. Desimone, Ingrid M. Libman, Sarah K. Lyons, Anne L. Peters, Jennifer K. Raymond, Lori M. Laffel
Journal: Diabetes Care (2016)

OBJECTIVE Young adults with type 1 diabetes transitioning from pediatric to adult care are at risk for adverse outcomes. We developed a survey to evaluate transition experiences in two groups of young adults with type 1 diabetes, before (PEDS) and after (ADULT) transition to adult care. RESEARCH DESIGN AND METHODS We fielded an electronic survey to young adults (18 to &amp;lt;30 years) at 60 T1D Exchange Clinic Registry centers. RESULTS Surveys were completed by 602 young adults, 303 in the PEDS group (60% female, age 20 ± 2 years) and 299 in the ADULT group (62% female, age 24 ± 3 years). In the PEDS group, mean anticipated transition age was 22 ± 2 years; 64% remained in pediatric care because of emotional attachment to the provider. The ADULT group transitioned at age 19 ± 2 years, mainly after pediatric provider recommendation. More than 80% of respondents reported receiving counseling on type 1 diabetes self-management and screening tests from pediatric providers, but less than half (43% PEDS and 33% ADULT) reported discussing reproductive health. In the PEDS group, half had discussed transfer with pediatric providers. Of the ADULT participants, 63% received an adult provider referral, and 66% felt mostly/completely prepared to transition. ADULT participants with fewer pretransition pediatric visits or who felt unprepared for transition had increased odds of gaps &amp;gt;6 months between pediatric and adult care. Receipt of transition preparation counseling was not associated with self-reported hemoglobin A1c &amp;lt;7.0% in either group. CONCLUSIONS These results support the need for intensive efforts to integrate transition preparation counseling and care coordination into pediatric type 1 diabetes care.
135. Optimization of Dual-gRNA Lentiviral Vectors for Targeted Genomic Deletions
Authors: Giulia Pavani, Annalisa Lattanzi, Fatima Amor, Chiara Antoniani, Fulvio Mavilio, Annarita Miccio, Mario Amendola
Journal: Molecular Therapy (2016)

CRISPR-Cas9 technology is a powerful tool for genome editing based therapeutic approaches. Despite its potential, the delivery of Cas9 components into primary cells, such as hematopoietic stem progenitor cells (HSPC), is still a major challenge. In addition, several applications - e.g. the use of Cas9-nickase and the generation of genomic deletions/inversions - require the delivery and expression of two different gRNA. Lentiviral vectors (LV) can efficiently transduce HSPC, but the presence and the orientation of direct repeated elements in the gRNA expression cassettes can potentially trigger recombination events that affect vector stability. To address this issue, we designed different LV encoding for two gRNA pairs, which generate deletions of different size (3 and 13 kb) in the beta-globin gene cluster. gRNA expression was driven by murine and human U6 promoters, having little sequence similarity, to avoid potential recombination events of the LV genome. To further reduce LV rearrangements and optimize expression levels, gRNA cassettes were positioned in different orientations with respect to each other (LV Inward, Tandem and Outward). We compared LV from different vector batches in HCT116 cells and we observed that Tandem configuration resulted in higher viral titers and infectivity, although this difference was not statistically significant. Analysis of proviral integrity on genomic DNA of transduced cells showed the intact dual-gRNA cassette and no sign of recombination for all the LV configurations. To understand if different orientations could affect gRNA expression (measured by RT-qPCR) and consequently deletion/inversion efficiency, we co-transduced erythroleukemic K562 cells with LV-Cas9-Blast and the three different LV. Surprisingly, LV Inward showed poor gRNA expression, negligible deletion and inversion frequency and low efficiency of InDel formation at each gRNA target site (2.4 % and 6.8%). Conversely, LV Tandem and Outward configurations allowed efficient cell transduction and significant and comparable levels of gRNA expression. As a results, we observed a good deletion frequency (11.0% ±1.8 of total alleles for LV Tandem and 12.3 % ± 2.5 for LV Outward), a lower proportion of inversions events (5.4% ±1.3 for LV Tandem and 3.8 % ± 0.4 for LV Outward) and up to 58% of InDels events at each gRNA target sites. Comparable results were also obtained in adult HSPC-derived erythroid cell line (HUDEP-2). Overall, our study indicates LV Tandem and LV Outward as promising tools for genome editing of primary cells; both vectors are now being evaluated in primary HSPC.
Identification of Four New HLA Class II Restricted Minor Histocompatibility Antigens Contributing to Graft Versus Leukemia Reactivity.
Authors: Anita N. Stumpf, Edith D. van der Meijden, Cornelis A.M. van Bergen, Roelof Willemze, J.H. Frederik Falkenburg, Marieke Griffioen
Journal: Blood (2008)
Abstract 2805: Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis
Authors: Yohei Shirakami, Hiroyasu Sakai, Takahiro Kochi, Takayasu Ideta, Tsuneyuki Miyazaki, Masahito Shimizu, Mitsuru Seishima
Journal: Cancer Research (2015)

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to have effects against colorectal cancer (CRC), since evidence has emerged that people who routinely use NSAIDs show a lower risk of CRC. Among NSAIDs, cyclooxygenase-2 (COX2) inhibitors are thought to exert its anti-cancer effect through blocking prostaglandin (PG) E2 whose actions are mediated by signaling via four receptors EP1, EP2, EP3, and EP4. Previous animal experiments have demonstrated that the development of colon tumor is suppressed by knocking down of either EP1 or EP4. In the present study, we investigate the effect of a novel small molecule EP4 antagonist on rat colon tumorigenesis. Employed animal is Kyoto Apc Delta (KAD) rat which has Apc mutation and is susceptible to chemically-induced CRC. Five-week-old KAD rats received injection of azoxymethane (20 mg/kg i.p.) and 2% dextran sodium sulfate in drinking water for two weeks, and then they were divided into two groups: no treatment (control) group and the group treated with an EP4 antagonist RQ-00015986 (RQ-15986) which was kindly provided by AskAt Inc. RQ-15986-treated 17-week-old KAD rats showed lower colon tumor incidence (37.5% vs 100% in control group, P &amp;lt; 0.05) and smaller multiplicity (1.33 ± 0.58 vs 2.86 ± 0.69 in control group, P &amp;lt; 0.05). The expression levels of inflammatory cytokines, including TNF-alpha and IL-6, in colonic mucosa were decreased in RQ-15986-treated group. By treatment with RQ-15986, the expression levels of monocyte chemo-attractant protein-1 (MCP-1) and indoleamine 2,3-dioxygenase (IDO) were also down-regulated in colon mucosa. Immunohistochemical analyses of colonic membrane revealed that PCNA-labeling index was lower and that F4/80 positive cells were fewer in RQ-15986-treated group. These findings suggest that RQ-15986 may suppress CRC development through mediating immune system and controlling chronic inflammation in the colon. Citation Format: Yohei Shirakami, Hiroyasu Sakai, Takahiro Kochi, Takayasu Ideta, Tsuneyuki Miyazaki, Masahito Shimizu, Mitsuru Seishima. Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2805. doi:10.1158/1538-7445.AM2015-2805
Survivin Isoforms and HSP90 Are Downregulated in Erythropoiesis during Lineage Specific Differentiation of MDS Hematopoietic Progenitor Cells.
Authors: Olaf J. Hopfer, Martina Komor, Ina S. Koehler, Matthias Schulze, Claudia Freitag, Dieter Hoelzer, Eckhard Thiel, Wolf-Karsten Hofmann
Journal: Blood (2006)
Transcoronary chemical ablation of atrioventricular node for the treatment of paroxysmal supraventricular tachycardia. A case report.
Authors: Toshihiro Honda, Kazuya Hayasaki, Osamu Doi, Etsuo Morita
Journal: Circulation (1991)

We applied transcoronary chemical ablation of the atrioventricular (AV) node to a patient with uncontrollable paroxysmal supraventricular tachycardia (PSVT). Through an angioplasty dilatation catheter. 99% ethanol at a dose of 1.0 ml was selectively infused into the AV nodal artery. Complete AV block with junctional escape rhythm occurred. Two weeks later, the treadmill exercise test was performed according to a modified Bruce protocol. The patient tolerated for 12 min, and the heart rate increased to 85 beats/min. His bundle electrocardiogram showed that the AV block resulted from atrio-Hisian block. Neither atrial nor ventricular extrastimulus could induce the tachycardia. It appeared that chemical ablation was a good method for controlling medically resistant PSVT. Elevation of serum creatine kinase was observed when ethanol overflowed during the ablation procedure. Occlusion of branches of the AV artery and mild hypokinesis in the inferobasal wall of the left ventricle were seen.
Abstract LB-038: Caspase-mediated iASPP cleavage inhibits NF-kB
Authors: Ying Hu, Wenjie Ge, Xinwen Wang, Xin Lu
Journal: Cancer Research (2015)

Abstract Constitutive activation of the transcription factor nuclear factor-kB (NF-κB) plays an important role in oncogenesis and drug resistance of several types of human cancers. Inhibiting NF-κB pathways is therefore emerging as a promising approach to treat cancer. iASPP was first reported as an NF-κB binding partner and inhibitor in a yeast-two-hybrid system. However, it remains unknown how this activity is regulated in cells. For the first time, we show that the activity of iASPP is regulated by caspase-dependent cleavage at cellular level. iASPP was cleaved by caspases at a very early stage of treatment. Interestingly, in contrast to full-length iASPP that is predominantly cytosolic, the iASPP fragment accumulates in the nucleus. Cleaved iASPP shows increased interaction with NF-kB, which correlates with reduced activity of κB reporter. Overexpression iASPP fragment results in increased apoptosis. It also sensitizes cancer cells’ response to paclitaxe. Thus, this study reveals a novel mechanism by which caspase cleavage relocates iASPP from cytoplasm to the nuclear compartment and to pro-apoptotic machinery by binding and subsequent inhibiting NF-κB. This study also provides insights into new strategies to conquer drug resistance of NF-kB constitutive activated malignancies. Citation Format: Ying Hu, Wenjie Ge, Xinwen Wang, Xin Lu. Caspase-mediated iASPP cleavage inhibits NF-kB. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-038. doi:10.1158/1538-7445.AM2015-LB-038
18. Novel Approach Using Fetal Dopaminergic Grafts In Situ Transduced with AAV-DREADDs Significantly Increases Behavioral Motor Recovery in a Rat Model of Parkinson's Disease
Authors: Patrick Aldrin-Kirk, Andreas Heuer, Bengt Mattsson, Gang Wang, Martin Lundblad, Malin Parmar, Tomas Björklund
Journal: Molecular Therapy (2015)

Over the past decades, cell replacement therapy has emerged as a possible therapeutic alternative for the treatment of Parkinson's disease. Although early trials showed great promise, later double blinded trials displayed varied clinical benefits. In order to improve therapeutic potential, we combined dopaminergic cell replacement therapy with designer receptors exclusively activated by designer drugs (DREADDs) which enable non-invasive, orthogonal, chemical modulation of neuronal activity. To date, most research has focused on optogenetics to achieve such control and though highly useful in pre-clinical research, broad clinical applications may be limited. In order to evaluate if activation of transplanted dopaminergic cells is sufficient to potentiate functional recovery, we grafted embryonic dopaminergic neurons from the ventral mesencephalon of TH-Cre expressing knock-in rats into the striatum of 6-OHDA lesioned wild-type rats Figure 1 | Schematic showing the location of TH-Cre positive dopaminergic fetal grafts within the striatum as well as the injection site of the AAV-8 viral vector expressing either Dq or Ds between the grafts. Using AAV vectors, we expressed DREADDs capable of either increasing or silencing neuronal activity in Cre expressing neurons. Two different pathways (Gq and Gs coupled) were used to increase neuronal activity, either Gq alone or the combination of Gq/Gs. Systemically administered CNO, which serves as the ligand for the DREADDs significantly increased motor recovery in animals expressing Dq and Ds, while animals expressing receptors inducing neuronal silencing, displayed a significant loss of functional recovery. Interestingly, animals expressing the Gs coupled receptor displayed a larger functional recovery while also displaying motor behavior reminiscent of graft induced dyskinesia and increased rotational behavior. Figure 2 | Animals expressing Dq/Ds receptors displayed a significant increase in rotational behavior following s.c. CNO administration, while Dq only and lesion controls displayed no significant increase. Taken together, our findings suggest that modulating activity of neurons used in cell replacement therapy may be able to increase functional recovery in patients with Parkinson's disease and the use of DREADDs may be a potent tool to dissect intracellular regulatory pathways.