tbuckley/cabot-search huggingface dataset:
Abstract 501: A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling
Authors: Lauren Jin Suk Joo, Jocelyn Weiss, Anthony J. Gill, Roderick Clifton-Bligh, Himanshu Brahmbhatt, Jennifer A. MacDiarmid, Matti L. Gild, Bruce G. Robinson, Stan B. Sidhu, Jing Ting Zhao
Journal: Cancer Research (2018)

Abstract Background Medullary thyroid carcinoma (MTC), which comprises 3-5% of all thyroid cancers, originates from a small population of neuroendocrine calcitonin C-cells of thyroid gland. Gain-of-function mutations of the human Rearranged during Transfection (RET) proto-oncogene have been recognized as the key driver of MTC tumorigenesis. RET has been targeted by tyrosine kinase inhibitors (TKIs), however with modest efficacy. Many of the microRNAs (miRNAs) identified in human genome have been associated with cancer and have prompted interest in the establishment of miRNA-based therapeutics. However miRNA studies in MTC has been hampered due to the lack of normal C-cell tissue as a differential expression comparator. Aims We aimed to characterize differentially expressed miRNAs, which play fundamental roles in MTC tumorigenesis and in modulation of TKI responses. Methods RET of human MTC cells were silenced using TKI, Cabozantinib, or siRNA. Small RNA sequencing was performed (AGRF) to identify differentially expressed miRNAs before and after RET inhibition. MiRNA effects on cell proliferation (MTS assay), cell cycle and apoptosis (flow cytometry, Western blot) were investigated with gain-of-function studies. For in vivo study, MTC xenografts were established and miRNAs were intravenously delivered using nanoparticle delivery vehicles invented by biotechnology company - EnGeneIC Ltd. Results miR-153-3p was identified to be under-expressed in MTC following RET inhibition. Restoration of miR-153-3p significantly reduced cell proliferation, induced G2 cell arrest and increased cell apoptosis. Furthermore, combined treatment of miR-153-3p and Cabozantinib caused greater cell proliferation inhibition compared to individual treatment. miR-153-3p targets ribosomal protein S6 kinase B1 (RPS6KB1) and reduced phosphorylation of Bcl-2 associated death promoter (BAD) protein. In vivo delivery of miR-153-3p significantly impeded tumor growth compared to scrambled sequence. Combination of miR-153-3p delivery and oral administration of Cabozantinib resulted in further tumor stabilization effect. Conclusion miR-153-3p reveals a significant tumor suppressive role in MTC via S6K signaling, demonstrating its important therapeutic potential for MTC patients. Citation Format: Lauren Jin Suk Joo, Jocelyn Weiss, Anthony J. Gill, Roderick Clifton-Bligh, Himanshu Brahmbhatt, Jennifer A. MacDiarmid, Matti L. Gild, Bruce G. Robinson, Stan B. Sidhu, Jing Ting Zhao. A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling [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 501.
Abstract 4800: Targeting the polyamine pathway as a novel therapeutic treatment against diffuse intrinsic pontine glioma
Authors: Aaminah Khan, Maria Tsoli, Denise Yu, Swapna Joshi, Laura Gamble, Laura Franshaw, Michelle Haber, David S. Ziegler
Journal: Cancer Research (2018)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brainstem tumour, with a peak incidence in middle childhood and a median survival of less than 1 year in the majority of cases. The dismal prognosis associated with DIPG is exacerbated by the repeated failure of over 250 clinical trials to improve survival over standard radiotherapy. Therefore novel and innovative therapeutic approaches are urgently needed to needed to treat this devastating disease. Polyamines are small intracellular polycations that control key aspects of cell biology, such as cell replication/growth, differentiation and survival and can be found up-regulated in many cancers. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is involved in polyamine synthesis. The aim of this study was to investigate the efficacy of polyamine pathway inhibitors such as DFMO as a therapeutic strategy against DIPG. By RT-qPCR and western blotting, we observed high expression levels of key players of the polyamine pathway in a panel of DIPG samples. Through alamar blue cytotoxicity assays and soft-agar clonogenic assays, DFMO was found to be effective against a panel of neurosphere-forming DIPG cells. The activity of DFMO was synergistically enhanced when combined with a polyamine transport inhibitor, AMXT-1501. Increased apoptotic activity following either DFMO or AMXT-1501 treatment, alone or in combination, was observed by western blotting and flow cytometric analysis of Annexin V/7AAD stained cells. In addition, reduced uptake of the radiolabelled polyamine, spermidine, in the presence of AMXT-1501 confirmed polyamine transport inhibition in DIPG cells. Consistent with the in vitro results, the combination of DFMO and AMXT-1501 significantly prolonged the survival of mice bearing DIPG orthografts, and the combination therapy represents the most effective combination treatment we have tested to date in our DIPG animal model. Our results suggest that the polyamine pathway is a potential therapeutic target for this highly aggressive paediatric brain tumour while a number of clinical trials based on this approach are currently underway in a variety of malignancies. Citation Format: Aaminah Khan, Maria Tsoli, Denise Yu, Swapna Joshi, Laura Gamble, Laura Franshaw, Michelle Haber, David S. Ziegler. Targeting the polyamine pathway as a novel therapeutic treatment against diffuse intrinsic pontine glioma [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 4800.
Assessment of ASC specks as a putative biomarker of pyroptosis in myelodysplastic syndromes: an observational cohort study
Authors: Ashley A Basiorka, Kathy L McGraw, Farnoosh Abbas-Aghababazadeh, Amy F McLemore, Nicole D Vincelette, Grace A Ward, Erika A Eksioglu, David A Sallman, Najla Al Ali, Eric Padron, Javier Pinilla-Ibarz, Rami Komrokji, Erico Masala, Valeria Santini, Olivier Kosmider, Michaela Fontenay, Pierre Fenaux, Lubomir Sokol, Sheng Wei, Brooke Fridley, Alan F List
Journal: The Lancet Haematology (2018)
Abstract 17031: Localization of Premature Ventricular Contractions Using Convolutional Neural Network From 12-lead Electrocardiogram
Authors: Ting Yang, Long Yu, Bin He
Journal: Circulation (2017)

Objective: To localize origins of premature ventricular contractions (PVC) based on the classification of convolution neural network (CNN) from 12-lead electrocardiograms (ECGs). Methods: We constr...
Incidence of chemotherapy (CT)-induced amenorrhea in premenopausal patients (pts) with breast cancer (BC) following adjuvant anthracycline (A), cyclophosphamide (C), and taxane (T).
Authors: Enrico Basso, Luigi Rossi, Federica Tomao, Anselmo Papa, Eleonora Zaccarelli, Gian Paolo Spinelli, Giuseppe Lo Russo, Federica Zoratto, Erika Giordani, Antonio Maria Alberti, Monica Verrico, Martina Strudel, Giulia Pasciuti, Valeria Stati, Giulia Rinaldi, Silverio Tomao
Journal: Journal of Clinical Oncology (2012)

e11039 Background: CT may induce amenorrhea or menopause to a variable extent. These side-effects may impair or impede fertility, cause sexual dysfunction, bone loss and menopausal symptoms in many women. We analyzed incidence of amenorrhea in premenopausal pts affected by BC treated with CT. Methods: In this retrospective study we evaluated the incidence of amenorrhea in 24 premenopausal BC pts (43 median age years) treated with adjuvant A + C +/- T based CT. Overall population (OP) had regular menstrual cycle and no pts began hormone therapy, at the same time. Results: 10 pts (42%) received only A + C, 6 pts (25%) received A + C + T, 8 pts (33%) received A + C and after T. In 22 pts (92%) amenorrhea appeared during CT; in particular, 9/10 pts (90%) treated with A + C , 5/6 pts (83%) with A + C + T and 8/8 pts (100%) with A + C and after T. In OP amenorrhea appeared during first three cycles of CT in 18 pts (82%) and particularly 7 pts (32%) after 1 cycle, 7 pts (32%) after 2 cycles, 4 pts (18%) after 3 cycles and 4 pts (18%) in subsequent doses. Amenorrhea occurred within the first two doses of treatment in 14/22 pts (64%); in 6/9 pts (66.7%) treated with A + C, in 4/5 pts (80%) with A + C + T and in 4/8 (50%) with A + C and after T. In 7 pts (32%), median age 40 years, at the end of CT reappeared menstrual cycle. Conclusions: In our small experience the incidence of amenorrhea during CT was extremely high and there are no differences between subgroups undergoing to CT with A + C alone or combined with T. In the group of pts in which T were given concomitant with A and C, amenorrhea occurred earlier than the other two groups. Menstrual cycle reappeared at the end of CT in younger pts.
Is There Functional Collateral Flow During Vascular Occlusion in Angiographically Normal Coronary Arteries
Authors: KerstinWustmann, StephanZbinden, StephanWindecker, BernhardMeier, ChristianSeiler
Journal: Circulation (2003)

Background— Thus far, it is unknown whether there is functional collateral flow through preexisting anastomoses in patients with angiographically normal coronary arteries. Such preformed coronary collateral vessels could form the basis for subsequently developing protective natural bypasses in the presence of coronary artery disease. Methods and Results— Among 100 patients, the collateral flow index (CFI) was measured in coronary arteries without stenotic lesions. The CFI was determined by simultaneous measurement of mean aortic pressure, central venous pressure, and coronary wedge pressure via a sensor-tipped guidewire at the end of a 1-minute balloon occlusion. Patients were divided in 2 groups according to complete angiographic absence (51 patients) or partial presence (49 patients) of stenotic lesions in coronary arteries other than that undergoing collateral measurement. CFI in all patients (61±10 years; men/women, 69/31) amounted to 0.18±0.08 (range, 0.04 to 0.36). It showed a normal Gaussian freque...
Abstract 17039: Creating Heart Failure-specific Measures From PROMIS®
Authors: Faraz S Ahmad, Karen Kaiser, Karen E Schifferdecker, Anna M Adachi-Mejia, Amy Eisenstein, George J Greene, Susan Yount, David Cella, Michael Kallen, Kathleen L Carluzzo, Elliott S Fisher
Journal: Circulation (2015)

Background: National policies call for aligning specific treatments with patients’ goals of care. The impact of heart failure (HF) on health status varies among patients. Although several generic and HF-specific patient-reported outcomes tools have been developed, none explicitly address how to combine generic and disease-targeted items in a coherent and interpretable way. Our goal was to develop a HF tool that identifies and integrates condition-specific items with measures from PROMIS®--a system of reliable and precise self-reported health assessment. Methods: We conducted focus groups with HF patients and semi-structured interviews with HF clinicians. We analyzed the transcribed recordings in Dedoose. Using an iterative process, we conducted a content analysis of interview codes to identify relevant PROMIS® domains and items. Codes that did not map to existing PROMIS® tools were used to define gap areas. New items were drafted to reflect the gap areas and then underwent cognitive testing. Results: Eight focus groups with a total of 61 patients were conducted. Participants had a mean age of 61, were 39% female, and 90% white. Eleven clinicians (6 MDs, 5 RNs) were interviewed. Sixty-nine items across 12 existing PROMIS® domains were identified. Examples of existing PROMIS® domains were dyspnea, physical function, and depression. Gap analysis and cognitive interviewing produced 22 additional items across 8 domains (3 existing PROMIS® and 5 new domains). The identified new domains were health behavior outcomes, life satisfaction, illness burden, independence, and symptoms. Conclusions: We developed a specific process for creating a tool that integrates existing PROMIS® domains with disease-specific outcomes important to patients and clinicians. While our process was specific to HF, it may be applied to other high impact health conditions. Next steps include the assessment of the stability, validity, and responsiveness of these via testing in 800 HF patients.
Abstract 20090: Three Dimensional Measurement of Aortic Annulus Using En-Face View and Multiplanar Reconstruction
Authors: Yunxiao Zhu, Jeremy J Thaden, Christina Pislaru, Vuyisile T Nkomo, Patricia A Pellikka, Joseph F Maalouf, Thomas A Foley, Kevin L Greason, Sorin V Pislaru, Sushil A Luis
Journal: Circulation (2016)

Background: Accurate measurements of the aortic annulus are critical for valve sizing in transcatheter aortic valve replacement (TAVR). Contrast enhanced multiple detector computed tomography (MDCT...
Defibrillation Efficacy of Commercially Available Biphasic Impulses in Humans
Authors: GeryTomassoni, KeithNewby, SanjayDeshpande, KathiAxtell, JasbirSra, MasoodAkhtar, AndreaNatale
Journal: Circulation (1997)

Background Recent studies have shown that specifically shaped biphasic waveforms can lower energy requirements for ventricular defibrillation. We prospectively compared the defibrillation efficacy of three different biphasic wave shapes incorporated in three commercially available implantable defibrillators. The results led to the development of a second protocol in which the importance of negative-phase peak voltage and duration was investigated. Methods and Results Defibrillation threshold (DFT) testing using different biphasic waveforms was performed randomly on 42 patients undergoing implantation of a cardioverter-defibrillator for ventricular arrhythmias. In 23 patients (group 1), 3 waveforms were tested: a CPI waveform with 60% positive-phase (P1) tilt and 50% negative-phase (P2) tilt, a Medtronic waveform with 65% fixed tilt in both P1 and P2, and a Ventritex waveform with 60% P1 tilt and a P2 leading edge voltage equal to half of the P1 trailing edge voltage. In 19 patients (group 2), 3 biphasic w...
Abstract 3189: Targeting NPM1 for controlling growth of Ewing sarcoma
Authors: Geri Traver, Konjeti R. Sekhar, Narsimha R. Renthala, Peter A. Crooks, Maxwell Ofori, Michael L. Freeman
Journal: Cancer Research (2018)

Abstract Ewing sarcoma is a rare cancer found in children and young adults. Long term survival rates are approximately 70% for patients who present without clinically overt metastases. However, 5 year survival is less than 20% for patients with recurrent tumors or metastasis. Thus, there is a need to improve local tumor control and to treat metastatic disease. Eighty five percent of these cancers are driven by the reciprocal chromosomal translocation t (11;22) (q24;q12), a consequence of a fusion between the 5' portion of Ewing sarcoma breakpoint region 1 on EWSR1 (chromosome 22) and the 3' portion of Friend leukemia virus integration site 1 on FLI1 (chromosome 11). Nucleophosmin1 (NPM1) is a chaperone protein involved in many cellular functions, including DNA repair. NPM1 has been shown to be a novel prognostic biomarker for patients with localized Ewing's sarcoma. Overall survival is significantly lower for patients whose tumors express high levels of NPM1. Besides promoting repair of DNA double strand breaks NPM1 directly interacts with and induces c-Myc-induced hyperproliferation and transformation. Consistent with this knowledge is the observation that relapsed Ewing's patients exhibit high levels of c-Myc expression compared to disease-free patients. Therefore, we wanted to ascertain whether NPM1 represented a molecular target for controlling growth of Ewing's sarcoma. CRISPR/Cas9-mediated targeting of NPM1 exons 3 and 4, as well as lentivirus-mediated shRNA targeting of NPM1 mRNA revealed that targeting of NPM1 expression reduced survival (colony formation) of TC32 and A673 cells (P&amp;lt;0.05). NPM shRNA also reduced TC32 sphere formation under non-adherent conditions. YTR107 and NSC348884 are small molecule inhibitors of NPM1 oligomerization, which is required for NPM1 activity. Both drugs reduced survival of TC32 and A673 Ewing's sarcoma cells in a dose-dependent fashion (P&amp;lt;0.05). We interpret these data to indicate that NPM1 represents a potential molecular target for controlling growth of Ewing's sarcoma. Supported in part by RO1CA140409. Citation Format: Geri Traver, Konjeti R. Sekhar, Narsimha R. Renthala, Peter A. Crooks, Maxwell Ofori, Michael L. Freeman. Targeting NPM1 for controlling growth of Ewing sarcoma [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 3189.
Abstract 2576: Dclk1 can be a predictor for poor survival in patients with resected pancreatic cancer
Authors: Yoshihiro Takemoto, Arata Nishimoto, Yukari Hironaka, Yuki Suehiro, Naruji Kugimiya, Atsushi Suga, Eijiro Harada, Kimikazu Hamano
Journal: Cancer Research (2018)

Abstract Background: Doublecortin-like kinase-1 (Dclk1) shows higher expression levels in human pancreatic cancer compared with human normal pancreatic tissue. Dclk1 positively regulates tumor growth, invasion, metastasis, pluripotency factors, angiogenic factors, and epithelial-mesenchymal transition (EMT)-related genes in pancreatic cancer cells. We previously reported that Dclk1 inhibition in combination with gemcitabine (GEM) treatment offers a novel approach to treat pancreatic cancer. However, few studies focusing on the role of Dclk1 in pancreatic cancer using clinical specimens have been reported. Objective: To investigate the expression of Dclk1 in resected specimens of pancreatic cancer and its prognostic significance. Methods: Tumor specimens were obtained from 26 patients with pancreatic cancer (stage 3 and 4) who underwent resection between April 2005 and March 2015 in our department. Dclk1, Ki67, and phosphorylated MEK expression levels were examined using immunohistochemical staining. The expression levels of these markers were evaluated using Histoscore (Intensity [0-3] x Extent [0-4]). In order to identify proteins phosphorylated by Dclk1, we analyzed a protein microarray using a pancreatic cancer cell line. Results: In total, 42.3% (11/26) of samples expressed high levels of Dclk1 (Histoscore≧3.3) and were classified into the high Dclk1 group. There were no significant differences between patients in the high Dclk1 group and the low Dclk1 group in terms of clinical characteristics and surgical findings. Patients in the high Dclk1 group exhibited significantly shorter survival times than those in the low Dclk1 group (P &amp;lt; 0.05). The expression of phosphorylated MEK, which is observed on a mitogen-activated protein kinase (MAPK) pathway, decreased by &amp;gt;50% in Dclk1-inhibited pancreatic cancer cells by protein microarray. Interestingly, the expression of pMEK and Ki67 in resected specimens tended to increase in samples in the high Dclk1 group. Therefore, Dclk1 might contribute to the progression of pancreatic cancer through the phosphorylation of MEK. Conclusion: Dclk1 may be a marker for poor prognosis in patients with resected pancreatic cancer. Citation Format: Yoshihiro Takemoto, Arata Nishimoto, Yukari Hironaka, Yuki Suehiro, Naruji Kugimiya, Atsushi Suga, Eijiro Harada, Kimikazu Hamano. Dclk1 can be a predictor for poor survival in patients with resected 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 2576.
CT-derived muscle remodelling after bronchoscopic lung volume reduction in advanced emphysema
Authors: Karin J C Sanders, Karin Klooster, Lowie E G W Vanfleteren, Dirk-Jan Slebos, Annemie M W J Schols
Journal: Thorax (2018)

Muscle wasting frequently occurs in severe emphysema. Improving respiratory mechanics by bronchoscopic lung volume reduction using endobronchial valves (EBV) might prevent further loss or even increase in muscle mass. CT-derived skeletal muscle mass gain was observed in 39/49 patients 6 months after EBV. Multiple linear regression showed that gain in muscle (β=2.4; 95% CI 0.2 to 4.6; p=0.036) and intramuscular fat (β=3.1; 95% CI 0.2 to 5.9; p=0.035) is associated with improved 6 min walk distance independent of the change in residual volume. Skeletal muscle remodelling associates with improved exercise capacity after EBV, independent of hyperinflation reduction. Trial registration number Clinical trial registered with the Dutch trial register www.trialregister.nl (NTR2876), Results.
Abstract 742: Nonclinical safety evaluation of STRO-001, a site-specific anti-CD74 antibody-drug conjugate for the potential treatment of B-cell malignancies
Authors: Willy Solis, Venita De Almeida, Abigail Yu, Maureen Bruhns, James Zawada, Adam Galan, Shannon Matheny, Arturo Molina, Trevor Hallam, Mark Lupher
Journal: Cancer Research (2018)

Abstract Antibody-drug conjugates (ADCs) constitute an expanding class of therapeutic molecules in preclinical and clinical development for multiple oncology indications. These antibody-based therapeutics are designed to selectively deliver cytotoxic payloads to tumor targets to improve efficacy and minimize toxicity. Cluster of differentiation 74 (CD74), a membrane-bound glycoprotein, is an antigen amenable ADC targeting because of its low expression in normal tissues and over expression in B-cell malignancies (multiple myeloma and non-Hodgkin's Lymphoma). STRO-001, a well-defined, homogenous, and site-specific ADC, is comprised of maytansinoid cytotoxic drugs conjugated to an anti-CD74 aglycosylated antibody (SP7219) through a noncleavable linker at two engineered non-natural amino acids. In an in vitro immunological activation assay, STRO-001 did not elicit cytokine production when incubated with human PBMCs for 48 hours, suggesting a low risk for immunological response in cancer patients. In a tissue cross-reactivity study with human tissues, STRO-001-specific membranous staining was detected primarily in lymphoid organs and lymphocytic infiltrates in multiple non-lymphoid tissues. In an exploratory nonclinical safety study in cynomolgus monkeys, a pharmacologically relevant model for toxicity testing, STRO-001 was tolerated at 1, 3, and 10 mg/kg, but not at 30 mg/kg, when intravenously administered on days 1 and 15 followed by a 4-week observation period. Dose-dependent and transient decreases in B-cells and monocytes were observed at tolerated doses (on-target pharmacology), with no effects on NK/T-cells. At tolerated doses, the main findings included reversible toxicities to hematopoietic and lymphoid tissues that correlated with cytopenias. Hematopoietic toxicity is considered antigen-independent, clinically manageable, and consistent with that of other ADCs with similar payloads. Toxicokinetic analysis confirmed drug exposures (total antibody, ADC, and a prominent linker-maytansine catabolite) with evidence of non-linearity suggesting target-dependent clearance. In summary, STRO-001 ADC has a favorable nonclinical safety profile and Phase I study of STRO-001 in patients with B-cell malignancies is planned. Citation Format: Willy Solis, Venita De Almeida, Abigail Yu, Maureen Bruhns, James Zawada, Adam Galan, Shannon Matheny, Arturo Molina, Trevor Hallam, Mark Lupher. Nonclinical safety evaluation of STRO-001, a site-specific anti-CD74 antibody-drug conjugate for the potential treatment of B-cell malignancies [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 742.