tbuckley/cabot-search huggingface dataset:
Protein network mapping of retinoblastomas for the identification of therapeutic targets.
Authors: Elisa Baldelli, John Conor Moran, Nestory Masalu, Said Hassan, Peter Fabian Rambau, Jackson Kahima, Vienna Ludovini, Lorenza Pistola, Francesca Romana Tofanetti, Annamaria Siggillino, Emanuel Petricoin, Mariaelena Pierobon, Lucio Crino
Journal: Journal of Clinical Oncology (2014)

10063 Background: Retinoblastoma is the most common ocular tumor of childhood. Diagnosis times differ across the word, with diagnosis occurring significantly earlier in developed countries. Necrosis and invasion of the optic nerve are usually associated with poor prognosis and higher incidence of recurrence and metastases. Treatment options include surgery, radiotherapy, and chemotherapy while targeted therapies are still not available. The aim of this study was to investigate the protein signaling architecture of retinoblastomas to identify new druggable targets for personalized therapy. Methods: Six paraffin embedded retinoblastomas collected at the Bugando Medical Center (Mwanza, Tanzania) were analyzed in this feasibility study. Samples were collected from patients aged 2 to 10. Two tumors presented invasion of the optic nerve, 2 were free of invasion, and 2 tumors were unclassified. Four tumors were necrotic, while 2 displayed no signs of necrosis. Samples were subjected to laser capture microdissection to isolate the cancer cells from the surrounding microenvironment and analyzed by Reverse Phase Protein Microarray to evaluate the activation status of 52 drug targets and downstream effectors. Results: Unsupervised hierarchical clustering analysis identified 2 major clusters, one with high and one with low activation of the drug targets. Stratification based on age, invasion of the optic nerve, and necrosis showed no clustering based on the signaling network. A clear distinction between the 2 groups was detected for the activation of ErbB family members, IGF-1R, Mek and c-Met. The activation of PDGFRα, PDGFRβ and VEGFR2 was more heterogeneous across all samples and revealed high activation only in a small portion of patients. Conclusions: Based on these preliminary results there is an indication that retinoblastoma has several sub-populations that exhibit different activation of drug targets. Patients whose tumors present with high activation levels for these proteins may benefit from a more targeted and specific treatment. Further analysis is needed to explore the underlying architecture and robustness of these two groups to provide evidence for the use of more targeted therapies in retinoblastoma.
INTRARENAL RENIN ANGIOTENSIN SYSTEM ACTIVATION: PATHOPHYSIOLOGIC AND THERAPEUTIC IMPLICATIONS IN ACUTE DECOMPENSATED HEART FAILURE
Authors: Seethalakshmi Iyer, Denise Heublein, Sherry Benike, Laura Meems, Jeson Sangaralingham, John Burnett
Journal: Journal of the American College of Cardiology (2017)
MITRAL ANNULAR DISJUNCTION PREVALENCE AND PHYSIOLOGIC CONSEQUENCES IN DEGENERATIVE MITRAL REGURGITATION: A DYNAMIC 3-DIMENSIONAL ECHOCARDIOGRAPHIC STUDY
Authors: Francesca Mantovani, Giovanni Benfari, Marie-Annick Clavel, Joseph F. Maalouf, Sunil Mankad, Hector Michelena, Rakesh Suri, Simon Maltais, Maurice Sarano
Journal: Journal of the American College of Cardiology (2017)
COMPARING PCI OUTCOMES IN THE VERY ELDERLY: DOES AGE MATTER? A REPORT FROM OUTCOMES OF SEPTUAGENARIANS, OCTOGENARIANS AND NONAGENARIANS AFTER PCI
Authors: Suraj Rasania, Usman Baber, George Dangas, Roxana Mehran, Srinivas Kesanakurthy, Nitin Barman, Joseph Sweeny, Choudhury Hasan, Annapoorna Kini, Samin Sharma
Journal: Journal of the American College of Cardiology (2017)
ESTUDIO MULTICENTRICO, COMPARATIVO Y ALEATORIZADO DEL SISTEMA ENDOSCOPICO DE ANCLAJE DE SUTURAS PARA EL TRATAMIENTO DE LA OBESIDAD PRIMARIA, FRENTE A LA COMBINACION DE SOLO DIETA Y EJERCICIO: ESTUDIO MILEPOST
Authors: A Mata Bilbao, J Espinós, K Miller, JW Greve, M Radauer, R Turró, J Turró
Journal: Endoscopy (2015)

El POSE (Primary Obesity Surgery Endoscopy) es una intervención endoscópica mínimamente invasiva para el tratamiento primario de la obesidad. Los estudios previos han demostrado su eficacia para inducir la pérdida de peso, reducir la capacidad gástrica y acentuar la fisiología.
Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial
Authors: Hope S Rugo, Lasika Seneviratne, J Thaddeus Beck, John A Glaspy, Julio A Peguero, Timothy J Pluard, Navneet Dhillon, Leon Christopher Hwang, Chaitali Nangia, Ingrid A Mayer, Timothy F Meiller, Mark S Chambers, Robert W Sweetman, J Randy Sabo, Jennifer K Litton
Journal: The Lancet Oncology (2017)
MULTICENTER EVALUATION OF PROSTHESIS OVERSIZING FOR THE SAPIEN 3 TRANSCATHETER HEART VALVE – IMPACT ON NEW PACEMAKER IMPLANTATIONS
Authors: Costanza Pellegrini, Won-Keun Kim, Andreas Holzamer, Thomas Walther, Patrick N. Mayr, Jonathan Michel, Tobias Andreas Rheude, Michael Joner, Teresa Trenkwalder, Albert M. Kasel, Adnan Kastrati, Heribert Schunkert, Michael Hilker, Helge Möllmann, Christian Hengstenberg, Oliver Husser
Journal: Journal of the American College of Cardiology (2017)
Design and Development of Fluorescent Vemurafenib Analogs for <i>In Vivo</i> Imaging
Authors: Hannes Mikula, Shawn Stapleton, Rainer H. Kohler, Claudio Vinegoni, Ralph Weissleder
Journal: Theranostics (2017)

Herein we describe fluorescent derivatives of vemurafenib to probe therapeutic BRAF inhibition in live cells and in vivo.The compounds were evaluated and compared by determining target binding, inhibition of mutant BRAF melanoma cell lines and live cell imaging.We show that vemurafenib-BODIPY is a superior imaging drug to visualize the targets of vemurafenib in live cells and in vivo in non-resistant and resistant melanoma tumors.
Significant enhancement of anti-tumor efficacy of VEGF/PDGF receptor tyrosine kinase inhibitor AG-013736 in combination with docetaxel in chemo-refractory and/or orthotopic xenograft tumor models in mice
Authors: Dana D. Hu-Lowe, Maren L. Grazzini
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2032 

AG-013736 is a small molecule VEGF/PDGF RTK inhibitor that potently and specifically inhibits VEGF-mediated endothelial cell survival, receptor phosphorylation, downstream signal transduction, angiogenesis and tumor growth in preclinical xenograft models (Hu-Lowe et al, manuscript submitted). The agent is currently being evaluated in phase II cancer patients. Previously, we reported that AG-013736 markedly inhibited the primary tumor growth and metastasis in many preclinical human xenograft and murine syngeneic tumor models including the LLC (murine Lewis lung carcinoma) and M24met (human melanoma). Here we present preclinical in vivo data regarding combinational therapy with AG-013736 and docetaxel. The LLC model is docetaxel-refractory and docetaxel at its MTD (40 mg/kg, iv, weekly) has minimal effect on tumor growth delay (TGD). When docetaxel was administered in combination with AG-013736 (3 - 30 mg/kg, PO, BID), there were significant enhancements to tumor growth delay (TGD) and to survival compared to either agent alone. Compared to the control group, TGD was enhanced by 100% by the high dose combination group (30 mg/kg AG-013736 and 40 mg/kg docetaxel), whereas TGD of AG-013736 alone or docetaxel alone increased by 65% and 9%, respectively. The high dose combination group also prolonged animal survival by 86% and 23% compared to either docetaxel or AG-013736 alone, respectively. In general the animals tolerated the combination treatment well although there was a slight increase in animal body weight loss in the combination groups compared to those treated with AG-013736 alone. AG-013736 in combination with docetaxel also produced marked anti-tumor effect in several other orthotopic and/or metastatic xenograft models, including the human melanoma M24met. The reduction of primary tumor growth and metastasis to the local and distant organs of mice will be discussed in detail. These results suggest that it may be beneficial to combine AG-013736 with docetaxel. This combination is currently being tested in phase II clinical trial of front line breast cancer.
PREVALENCE OF ABNORMAL ANKLE BRACHIAL INDEX IN OBESE AND NON-OBESE SUBJECTS, AND ASSOCIATION OF ABNORMAL ANKLE BRACHIAL INDEX WITH ALL-CAUSE AND CARDIOVASCULAR MORTALITY IN THESE GROUPS: RESULTS FROM NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY 1999-2000
Authors: Salman Waheed, Zubair Shah, James Vacek, Deepak Parashara, Buddhadeb Dawn, Kamal Gupta
Journal: Journal of the American College of Cardiology (2017)
Phase I trial of laromustine in combination with infusional ara-C in elderly patients over age 60 with newly diagnosed AML or high-grade MDS
Authors: E. K. Ritchie, G. Roboz, K. Hinchcliff, T. Curcio, J. Scandura, E. Feldman
Journal: Journal of Clinical Oncology (2009)

7054 Background: Laromustine is a novel sulfonylhydrazine-alkylating agent with activity in acute myeloid leukemia (AML). In vitro combinations of laromustine and cytarabine (ara-C) show synergistic cytotoxicity. Laromustine in phase I and II trials shows activity in patients with relapsed/refractory leukemia (1) and elderly patients with new AML (2). Major toxicites include infusion reactions, myelosuppression, and febrile neutropenia. Older patients had a CR rate on phase II trial of 31% (2). Based on this data, a phase I study to evaluate the safety and efficacy of combining escalating doses of laromustine with infusional ara-C in AML and MDS patients over 60. Comprehensive geriatric assessments (CGA) are performed as part of the study. Methods: Laromustine 300 mg/m2 (cohort 1, n = 6), 400 mg/m2 (cohort 2, n = 5) and 500 mg/m2 (cohort 3) was administered by IV infusion over 1 hour on day 1 in combination with ara-C 100 mg/m2/day as a continuous infusion for 7 days. Patients achieving CR after induction therapy were offered up to 2 cycles of consolidation therapy for a maximum cumulative laromustine dose of 1,000 mg/m2. All patients had CGA on days 1, 30, 60, and 90 consisting of validated scales for quality of life, nutrition, activities of daily living, mini-mental status, depression, and medical comorbidities. Results: During induction adverse events included grade 3–4 myelosuppression and febrile neutropenia. One patient had grade 2 dyspnea possibly related to drug and improved with a short course of steroids. GI toxicities included grade 1 mucositis, diarrhea, and nausea. After 2 consolidation cycles, there was possible drug-related pulmonary toxicity with 3 episodes of grade 3 hypoxia. All patients were treated with steroids and symptoms resolved. Two patients in cohort 1, and 2 patients in cohort 2 (n = 3) achieved CR. Data from CGA shows a decrease in depression scale score and increased self-assessment of health from baseline to 30 days post induction. There was decreased ability to perform instrumental activities of daily living at 30 days, but scores rebounded 90 days post induction. Conclusions: Preliminary data suggest laromustine and infusional ara-C is a feasible and active; updated data will be presented at the meeting. No significant financial relationships to disclose.
Bisphosphonates and oral cavity avascular bone necrosis: A review of 12 cases
Authors: N. Salesi, R. Pistilli, V. Marcelli, F. A. Govoni, B. Di Cocco, U. Pacetti, C. Di Fonso, A. Ciorra, M. Natali, E. Veltri
Journal: Journal of Clinical Oncology (2006)

18628 Background: Intravenous bisphosphonates are the current standard of care for the treatment of hypercalcemia of malignancy and for the prevention of skeletal complications associated with bone metastases. Generally, the i.v. administration of bisphosphonates is well tolerated. Recently, retrospective case studies have reported an association between long-term bisphosphonate therapy and osteonecrosis of the jaws. Methods: We reviewed data for 12 patients referred to either an oral and maxillofacial surgeon or an oral medicine specialist for the management of clinically apparent chronic oral osteonecrosis of unknown etiology. All had received therapy cancer-related simultaneously with bisphosphonate management. Results: Typical presenting symptoms were pain and exposed bone at the site of a previous tooth extraction. In most patients, lesions initially occurred after dental extraction or other odontostomatological procedures, and 5 had a spontaneous event. Biopsy of the involved area showed the presence of necrotic lacunae, with infiltration of lymphocytes and histiocytes. In 9 cases, histological or cytological diagnosis of suspicious osteomyelitis was done. There was no observed correlation of the intraoral lesions with myelosuppression secondary to antineoplastic therapy. Conclusions: Based on these patients’ respective histories, clinical presentations, and responses to surgical and antibiotic treatments, it appears that the pathogenesis of this osteonecrotic process is most consistent with localized vascular insufficiency. In our opinion, the mechanism by which bisphosphonates could compromise bone vascularity may be related to its effect on the osteoclasts. The potent bisphosphonate mediated inhibition of osteoclast function serves to decrease bone resorption and inhibit normal bone turnover remodeling, resulting in microdamage accumulation and a reduction in some mechanical properties of bone. No significant financial relationships to disclose.
Targeting Acute Myeloid Leukemia with a New CXCR4 Antagonist IgG1 Antibody (PF-06747143)in NOD/SCID Mice
Authors: Yanyan Zhang, Erika Saavedra, Ruoping Tang, Shu-Hui Liu, Tod Smeal, Valeria Fantin, Stephane De Botton, Ollivier Legrand, William Vainchenker, Flavia Pernasetti, Fawzia Louache
Journal: Blood (2015)
Pharmacologically derived schedule of flavopiridol has significant efficacy in refractory, genetically high risk chronic lymphocytic leukemia (CLL)
Authors: J. C. Byrd, T. S. Lin, J. T. Dalton, M. Phelps, B. Fischer, M. Moran, K. Blum, B. Rovin, A. D. Colevas, M. R. Grever
Journal: Journal of Clinical Oncology (2006)

6516 Background: Promising pre-clinical activity with flavopiridol in CLL was followed by disappointing clinical trial results. Differential protein binding of flavopiridol in pre-clinical studies may have misdirected the target concentration and administration schedule in CLL trials. Methods: We initiated a phase I study based on pharmacokinetic (PK) modeling showing that 1.5–2.0 μM flavopiridol for 4–6 hours was necessary for anti-CLL activity in vitro with 10% human serum. A 30 minute loading dose followed by a 4 hour infusion every 4 of 6 weeks was pursued. Eligibility included refractory/relapsed CLL, intact organ function, and performance status of ≤ 2. Results: Fifty-six pts have been enrolled ( Table ) with a median of 4 prior therapies, and most fludarabine-refractory. Dose-limiting toxicity in cohort 2 was tumor lysis syndrome (TLS). Cohort 1 was expanded with aggressive TLS prophylaxis. Of 20 pts in cohort 1, 8 (40%) had a partial response (PR) with a median response duration exceeding 12 months. The 0.5 and 4.5 hr C max were 2.08 μM and 0.96 μM. PK modeling showed that higher dose in the 4-hr infusion would achieve desired 4.5 hr C max . This escalation was done in cohorts 3 and 4 ( Table 1 ) with acceptable toxicity. In cohort 3, 19 pts enrolled with 14 pts being dose escalated. Improved cytoreduction was seen in most pts with dose escalation. Ten (53%) of pts attained a PR. The 0.5 and 4.5 hr C max was 1.95 μM and 1.54 μM in cohort 3;dose escalation continues in cohort 4. WBC of ≥ 200 × 10 9 /L was associated with TLS (5 of 8 pts) versus those with WBC &lt; 200 × 10 9 /L (1 of 34 pts). As such, cohort 4 excludes pts with WBC ≥ 200 × 10 9 /L for safety. Currently there are 14 pts in cohort 4 with only 1 case of TLS. Response assessment for cohort 4 is underway; activity appears similar to cohort 3. Conclusions: Flavopiridol with this PK directed schedule has significant clinical activity independent of the presence of del(17p13.1) and is one of the most active agents in clinical trials for CLL. [Table: see text] No significant financial relationships to disclose.
SD-101, a Novel Class C CpG-Oligodeoxynucleotide (ODN) Toll-like Receptor 9 (TLR9) Agonist, Given with Low Dose Radiation for Untreated Low Grade B-Cell Lymphoma: Interim Results of a Phase 1/2 Trial
Authors: Ronald Levy, Patrick M. Reagan, Jonathan W. Friedberg, Nancy L Bartlett, Leo I. Gordon, Abraham Leung, Joanna Peterkin, Biao Xing, Robert Coffman, Robert Janssen, Albert Candia, Michael Khodadoust, Matthew J. Frank, Steven R Long, Debra K Czerwinski, Michael Chu
Journal: Blood (2016)
Flavopiridol given as a 30-min intravenous (IV) bolus followed by 4-hr continuous IV infusion (CIVI) results in clinical activity and tumor lysis in refractory chronic lymphocytic leukemia (CLL)
Authors: T. S. Lin, J. T. Dalton, D. Wu, B. Fischer, M. Moran, D. Lucas, K. Cunningham, A. D. Colevas, M. R. Grever, J. C. Byrd
Journal: Journal of Clinical Oncology (2004)

6564 Background: CLL patients (pts) with del(17p13) [p53 gene] have a poor outcome and do not respond to most conventional therapies. Flavopiridol induces apoptosis in CLL cells in a p53-independent manner, but phase I/II studies using a 24–72-hr CIVI schedule showed no activity. Increased drug binding to human plasma proteins prompted pharmacokinetic modeling indicating an optimal dosing schedule of 30-min IV bolus (IVB) followed by 4-hr CIVI. Methods: We report preliminary results of an ongoing phase I study using this schedule. Results: Nine pts (median age 60, range 44–73) with fludarabine-refractory CLL have been enrolled (median prior therapies 7, range 2–13). Five pts had del(17p13); 6 pts were stage III/IV. Pts received 50% of the dose by 30-min IVB and 50% by 4-hr CIVI weekly for 4 doses on a 6-week cycle. Six pts in cohort 1 received 60 mg/m2/dose; 3 pts in cohort 2 received 80 mg/m2/dose. Grade 3–4 toxicity was seen (neutropenia 6, thrombocytopenia 1, dyspnea 1, edema 1, diarrhea 1), but most toxicity was grade 1–2 (fatigue 7, nausea 6, anorexia 6). Tumor lysis was seen in 3 pts in cohort 2. Two pts had tumor lysis to the first dose. One pt completed cycle 1 without further tumor lysis. The other pt died of overwhelming tumor lysis, with predominant hyperkalemia not responding to forced alkaline hydration and IV insulin, and cardiac arrhythmia. A third pt had tumor lysis to dose 1 of cycle 2 and responded to medical management. This pt also developed hypotension that resolved with steroids, suggesting a cytokine release syndrome. Pts completed a median of 1 cycle (range 0–2). Treatment was stopped due to disease progression (3), infection (1), tumor lysis (2), and study interruption to institute guidelines to prevent further tumor lysis (3). Two pts in cohort 1 experienced an NCI 96 partial response lasting 5+ months; 1 of these pts has del(17p13). Conclusions: Single agent flavopiridol given weekly by 30-min IVB followed by 4-hr CIVI is active in refractory CLL, resulting in clinical responses and tumor lysis. Further study of this pharmacokinetically modeled schedule is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals
AN UNRESTRAINED PROINFLAMMATORY M1 MACROPHAGE POPULATION INDUCED BY IRON NANOCRYSTALS IMPAIRS MYOCARDIAL HEALING AFTER HEMORRHAGIC INFARCTION
Authors: Ivan Cokic, Avinash Kali, Richard Tang, Hsin-Jung Yang, Andreas Kumar, Frank S. Prato, Joseph Francis, Eduardo Marban, Rohan Dharmakumar
Journal: Journal of the American College of Cardiology (2017)
T cells take directions from supporting cast in graft-versus-host disease
Authors: Derk Amsen
Journal: Journal of Clinical Investigation (2017)

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only treatment option for several severe hematological malignancies. The development of graft-versus-host disease (GVHD) is a common complication of the procedure and results when donor T cells become activated against recipient-specific antigens. The factors that drive the alloreactive T cell response are not completely understood. In this issue of the JCI, Chung and colleagues present evidence that stromal cells within lymphoid tissue express the Notch ligands Delta-like 1/4 (DLL1 and DLL4), which in turn directly activate T cells. Importantly, inhibition of DLL1/DLL4-mediated Notch signaling in murine HSCT models dramatically reduced GVHD and improved graft survival.
ASSOCIATION OF CORONARY ARTERY CALCIUM PROGRESSION WITH CORONARY PLAQUE PROGRESSION DETERMINED BY QUANTITATIVE CORONARY ARTERY PLAQUE ANALYSIS
Authors: Indre Ceponiene, Rine Nakanishi, Kazuhiro Osawa, Mitsuru Kanisawa, Sina Rahmani, Negin Nezarat, Michael Kim, Eranthi Jayawardena, Alexander Broersen, Pieter Kitslaar, Matthew Budoff
Journal: Journal of the American College of Cardiology (2017)
Patterns of regional node irradiation therapy following breast-conserving surgery: Report from the National Cancer Data Base 2003-2007.
Authors: Ningqi Hou, Katharine Yao, Nora T. Jaskowiak, Yasmin Hasan, David J. Winchester, David Porter Winchester, Dezheng Huo
Journal: Journal of Clinical Oncology (2012)

1101 Background: A recent randomized trial (MA.20) showed that regional nodal irradiation (RNI) in addition to breast irradiation in high risk node negative and 1-3 node positive patients undergoing breast-conserving therapy (BCT) reduced the risk of recurrence and improved disease-free survival. We investigated the trends of RNI use in the United States and related factors for the use of RNI using the National Cancer Data Base. Methods: This study includes 292,598 stage I-III breast cancer patients without neoadjuvant therapy who underwent BCT from 2003-2007. We investigated pathological, patient, and facility factors related to RNI use, by multivariable logistic regression, with odds ratio (OR) estimations. Results: The proportion of radiotherapy use after BCT slightly declined from 78.6% in 2003 to 75.6% in 2007. The use of breast irradiation plus RNI decreased from 10.8% in 2003 to 8.3% in 2007 (p&lt;0.0001). The number of tumor positive lymph nodes strongly determined the use of additional RNI: 4.4% patients with negative nodes, 22.8% patients with 1-3 nodes, and 39.7% patients with 4 or more nodes received breast irradiation plus RNI after undergoing BCT (p&lt;0.0001). The proportion of patients undergoing RNI significantly decreased over the study period from 43.3% to 37.2% in the 4+ node positive group, and from 23.6% to 22.0% in the 1-3 node positive group. At comprehensive community cancer centers, 25.5% patients with 1-3 positive nodes were treated with breast irradiation plus RNI (vs. 23.2% in community cancer centers and 21.1% in academic/research cancer centers). Among node negative patients, 11.5% of those with tumor size greater than 5 cm received additional RNI, compared to 4.3% in patients with tumors less than 5cm (p&lt;0.0001). Other significant factors related to RNI use included higher tumor grade, younger age, facility location, and facility volume. Conclusions: The use of RNI varies by number of tumor positive nodes and facility factors. Only 22.8% of patients with 1-3 positive nodes underwent RNI. Future studies are needed to determine if the use of RNI will increase after publication of the MA.20 trial especially for the 1-3 node positive group.