tbuckley/cabot-search huggingface dataset:
Results from a phase I trial of tivozanib (AV-951) combined with temsirolimus therapy in patients (pts) with renal cell carcinoma (RCC).
Authors: F. F. Kabbinavar, S. Srinivas, R. J. Hauke, R. J. Amato, W. B. Esteves, M. M. Cotreau, A. L. Strahs, P. Bhargava, M. N. Fishman
Journal: Journal of Clinical Oncology (2011)

4549 Background: Tivozanib, a potent and selective oral small molecule tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, and -3, has demonstrated antitumor activity in a phase II study in RCC. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for treatment of advanced RCC. This phase Ib open-label study examined combination tivozanib and temsirolimus therapy in pts with advanced RCC to determine the safety and tolerability, maximum tolerated dose (MTD), and clinical activity. Methods: Pts with advanced RCC (with clear cell component) who had failed up to 1 prior VEGF-targeted therapy received daily oral tivozanib (3 wks on, 1 wk off = 1 cycle) and intravenous temsirolimus (once weekly). A standard 3+3 dose escalation design was used at four levels: 0.5 mg/d and 15 mg/wk; 1.0 mg/d and 15 mg/wk; 1.5 mg/d and 15 mg/wk; and 1.5 mg/day and 25 mg/wk of tivozanib and temsirolimus, respectively. Results: As of 1/24/11, 28 pts had been treated and accrual was closed. Demographic features were: 26 male/2 female; 89% Caucasian; median age 62 years (range, 43-71); Karnofsky Performance Status of 100/90/80 for 16, 7, and 4 pts, respectively (1 pt missing data). Twenty of 28 pts (71%) had received prior VEGF-targeted therapy. Median duration of treatment was 21.1 wks (range, 0.3-94.0). Treatment-related adverse events seen in ≥10% of pts were (number of pts with all grades/grade 3 toxicity): fatigue (20/4), decreased appetite (14/0), stomatitis (13/2), thrombocytopenia (10/4), diarrhea (16/2), nausea (13/1), constipation (10/1), and dypsnea (10/1). There were no grade 4 events. The MTD for the combination of tivozanib and temsirolimus was 1.5 mg/day and 25 mg/week, respectively. No dose limiting toxicities were observed. Clinical activity included: 28% PR, 64% SD and DCR (PR and SD>24weeks) of 48% in pts who had failed VEGF targeted therapies. Conclusions: Tivozanib is the first VEGFR TKI that can be combined with temsirolimus at full dose and schedule of both agents. The combination of tivozanib with temsirolimus was well tolerated and showed encouraging clinical activity in patients with advanced RCC.
T Cells from Chronic Lymphocytic Leukemia (CLL) Patients Display Dysregulated Expression of Immune Checkpoint Molecules and Activation Markers Mainly Restricted to CD4+ Cells and Correlated with Disease Activity
Authors: Marzia Palma, Giusy Gentilcore, Fariba Mozaffari, Kia Heimersson, Barbro Näsman-Glaser, Lotta Hansson, Anders Österborg, Håkan Mellstedt
Journal: Blood (2015)
Clarithromycin (Biaxin)-Lenalidomide-Low-Dose Dexamethasone (BiRd) Versus Lenalidomide-Low-Dose Dexamethasone (Rd) as Initial Therapy for Newly Diagnosed Multiple Myeloma.
Authors: Francesca Gay, S. Vincent Rajkumar, David S Jayabalan, Shaji Kumar, Tomer Mark, Angela Dispenzieri, Roger Pearse, Morie A Gertz, John P Leonard, Martha Q Lacy, Selina Chen-Kiang, Vivek Roy, Morton Coleman, Suzanne R. Hayman, Francis Buadi, John A. Lust, Thomas E. Witzig, Rafael Fonseca, Robert A Kyle, Philip R. Greipp, A. Keith Stewart, Ruben Niesvizky
Journal: Blood (2009)
Predictive biomarkers of endocrine therapy (ET) for stage IV breast cancer (BC).
Authors: C. Shimizu, K. Hashimoto, H. Tsuda, T. Kobayashi, S. Saji, T. Shigekawa, A. Osaki, K. Aogi
Journal: Journal of Clinical Oncology (2011)

e11090 Background: SDF-1, FOXP1, and ER-beta1 expression have been suggested as potential prognostic factors in estrogen receptor (ER) alpha-positive BC in adjuvant setting but their utility in metastatic BC is not known. Methods: This is a multi-institutional, retrospective, exploratory study using archived tissue materials of untreated primary stage IV BC. Pts with ER-alpha positive tumors who were treated by ET as the primary treatment between 2002 and 2009 were included. All laboratory analyses were performed blinded to the clinical data. SDF1, FOXP1 and ER-beta1 protein expression were determined by immunohistochemistry and correlated with tumor response, clinical benefit (CB; CR, PR or stable disease > 6 months), progression-free survival (PFS) of the 1st line ET, and overall survival (OS). SDF-1 was assessed according to the proportion of the stained area (>10% as positive). ER-beta and FOX-P1 expression was scored by Allred’s method; a total score of >2 was defined as
55. Aquaporins and CSF Flux Are Critical Determinants of AAV Mediated CNS Gene Transfer
Authors: Giridhar Murlidharan, Aravind Asokan
Journal: Molecular Therapy (2016)

The central nervous system (CNS) lacks conventional lymphatics for solute clearance. Convective currents of interstitial fluid (ISF) shunt macromolecules across the brain parenchyma into cerebrospinal fluid (CSF) compartments. Here the cargo is either reabsorbed into CNS via subarachnoid ducts or disseminated into the blood or peripheral lymph vessels. Recent studies have identified that flow of water via aquaporin (AQP) channels at the astroglial endfeet enables exchange of biomaterials between ISF and CSF. Conversely, loss of AQP expression due to aging or disease is correlated with ineffective clearance of neurodegenerative accumulations such as Amyloid β and tau. AAV mediated gene therapy of CNS disorders requires a deeper understanding of such factors and their effects on transduction efficiency and biodistribution/clearance. Here, we demonstrate that AQP mediated water transport dictates various aspects of AAV gene transfer in the CNS. We compared the CNS spread, transduction profile and systemic leakage of clinically relevant AAV vectors in wildtype (WT) or AQP knockout (AQP-/-) mice. Within minutes following intracerebroventricular (ICV) administration, AQP-/- mice exhibited highly restricted spread of fluorophore labeled AAVs when compared to wild type mice. Transgene expression was markedly increased from AAV administrations in AQP-/- mice. Further, systemic leakage and off-target transgene expression in peripheral tissues were markedly reduced for some AAV serotypes in AQP-/- mice when compared to WT mice. These results suggest that AQP-mediated water transport plays a critical role in determining the spread, transduction efficiency and systemic leakage of AAV vectors following CNS administration. We hypothesize that altered CSF flux under conditions pertinent to aging and CNS disease, can impact the residence time of AAV vectors and consequently gene transfer efficiency. Further results evaluating the CNS transport properties of AAV in mouse models of aging and disease will be presented.
Abstract 2282: K-RasV12 bone marrow cell reconstitution causes lung cancer in wild type mice
Authors: Elena Belloni, Ines Martin-Padura, Elvira Gerbino, Stefania Orecchioni, Fulvia Fusar-Imperatore, Paola Marighetti, Giovanni Bertalot, Pier Giuseppe Pelicci, Francesco Bertolini
Journal: Cancer Research (2015)

Abstract The potential of recruited bone-marrow-derived cells (BMDCs) to act as a source of malignancy was disputed for a long time. A role for BMDCs in tissue repair has also been proposed, since these cells are capable of homing to the lung and differentiating into multiple epithelial cell lineages so thus contributing in lung tissue repair and regeneration. We tested the ability of bone marrow cells containing an inducible oncogene to initiate lung adenocarcinoma. Since the role of the K-Ras gene in lung cancer is well known, for our experimental strategy, we used a mouse model expressing oncogenic K-RasV12 (K-Ras+/V12RERTert/ert). This model generates a specific neoplastic phenotype induced by the K-RasV12 mutation. Mice usually develop lung tumors with complete penetrance evolving from hyperplasia, through adenoma, to adenocarcinoma, when the oncogene expression is induced by 4-hydroxitamoxifen (4-OHT) administration. Following lethal irradiation, wild-type mice were transplanted with donor bone marrow cells derived from K-RasV12 mice and, once the bone marrow was reconstituted, treated with 4-OHT. Mice were monitored and sacrificed at subsequent post-induction time points (0, 3.5, 5.5, 8.5, 11, 13.5, 15, and 16 months) and lungs and peripheral blood were collected. Analysis of the H&amp;E-stained lung sections from both reconstituted K-RasV12 and control mice revealed diffuse hyperplasia, possibly due to irradiation. Epithelial lesions, adenomas and/or adenocarcinomas, were detected in 4 out of 8 K-RasV12-reconstituted animals at 3.5, 5.5, 13.5 and 15 months post oncogene induction while no lesions were detected in the control group (transplanted but not induced mice). In addition, the K-Ras implication on the origin of the tumor was confirmed by X-Gal staining of lung lesions in reconstituted mice. In our model, -geo is indeed a marker protein coexpressed along with the same K-RasV12 transcript by a bicistronic strategy. Our results suggest a direct implication of BMDCs in lung epithelial tumor development and emphasize the need of further studies to dissect the mechanisms regulating BMDCs’ recruitment to injured tissues and their role in tumor initiation and/or progression. Citation Format: Elena Belloni, Ines Martin-Padura, Elvira Gerbino, Stefania Orecchioni, Fulvia Fusar-Imperatore, Paola Marighetti, Giovanni Bertalot, Pier Giuseppe Pelicci, Francesco Bertolini. K-RasV12 bone marrow cell reconstitution causes lung cancer in wild type mice. [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 2282. doi:10.1158/1538-7445.AM2015-2282
370. F/HN Pseudotyped Lentivirus Generates Therapeutically Relevant and Long-Lasting Alpha-1-Antitrypsin Expression in Mouse Lung
Authors: Michael C. Paul-Smith, Jean-François Gelinas, Kamila Pytel, Mario Chan, Cuixang Meng, Lidia Cammack, Loren Cameron, Caroline Moran, Ian Pringle, Lee Davies, Makoto Inoue, Mamoru Hasegawa, Stephen C. Hyde, Deborah R. Gill, Eric Alton, Uta Griesenbach
Journal: Molecular Therapy (2015)

A protease/anti-protease imbalance is a characteristic feature of inflammatory lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). However, alpha-1-antitrypsin (AAT) enzyme replacement therapy (ERT) trials have not shown conclusive evidence of a therapeutic benefit. This may be due to inefficient protein delivery to the lung and/or the half-life of the protein. The UK Cystic Fibrosis Gene Therapy Consortium (GTC) has pseudotyped a simian immunodeficiency viral vector with the Sendai virus F and HN proteins (rSIV.F/HN) and selected an internal synthetic promoter/enhancer consisting of the elongation factor 1α promoter and the CMV enhancer (hCEF) for efficient transduction of airway epithelial cells. Here, we assessed whether transduction of murine lungs with rSIV.F/HN with a human AAT transgene generates therapeutic levels of AAT. Mice were transduced with rSIV.F/HN-hCEF-AAT (2e8 TU/mouse) by nasal instillation and culled 10 days after transduction. AAT levels in lung homogenate and broncho-alveolar lavage fluid (BALF) were at least 3 logs above controls (p<0.05). A urea assay was used to determine that lavage diluted the epithelial lining fluid (ELF) by ≈40-fold, which allowed us to calculate the AAT concentration in ELF to be 92±28 mg/ml (= 1.4 μμ). In the context of AAT deficiency, an ELF concentration of 70 mg/ml (1.1 μM) AAT is of therapeutic relevance. For comparison transfection of mouse lung with the cationic lipid GL67A complexed to pCMV-AAT only led to 0.4±0.1 mg/ml (n=6) of AAT in ELF. A neutrophil elastase (NE) activity assay showed that the recombinant AAT successfully neutralised NE activity (p<0.05). In a separate experiment, mice were treated with rSIV.F/HN-hCEF-AAT (4e7 TU/mouse) and quantification of AAT 7 and 90 days post-transduction showed that expression was stable over this period. We also transduced mice with rSIV.F/HN-hCEF carrying a secreted Gaussia luciferase reporter gene (1e7 TU/mouse) and showed that stable expression in lung and BALF persisted for at least 12 months. Here, we also demonstrate for the first time that rSIV.F/HN transduction of lung generates significant (p<0.05) levels of GLux and AAT recombinant proteins in serum. AAT enzyme replacement therapy is currently being assessed for the treatment of a range of diseases including diabetes and graft-vs-host disease, but shortage of human plasma-derived protein, as well as high costs, may limit the application. In conclusion, rSIV.F/HN produces therapeutically relevant and long lasting levels of AAT in murine lung. In addition, we showed that AAT escapes from the lung into the circulation, suggesting that gene therapy may help to overcome some of the current bottlenecks of ERT.
Prolonged High-Level Detection of Retrovirally Marked Hematopoietic Cells in Nonhuman Primates after Transduction of CD34+ Progenitors Using Clinically Feasible Methods.
Authors: Tong Wu, Hyeoung Joon Kim, Stephanie E. Sellers, Kristin E. Meade, Brian A. Agricola, Mark E. Metzger, Ikunoshin Kato, Robert E. Donahue, Cynthia E. Dunbar, John F. Tisdale
Journal: Blood (2006)
Heparin coatings for improving blood compatibility of medical devices
Authors: Roy Biran, Daniel Pond
Journal: Advanced Drug Delivery Reviews (2016)

Blood contact with biomaterials triggers activation of multiple reactive mechanisms that can impair the performance of implantable medical devices and potentially cause serious adverse clinical events. This includes thrombosis and thromboembolic complications due to activation of platelets and the coagulation cascade, activation of the complement system, and inflammation. Numerous surface coatings have been developed to improve blood compatibility of biomaterials. For more than thirty years, the anticoagulant drug heparin has been employed as a covalently immobilized surface coating on a variety of medical devices. This review describes the fundamental principles of non-eluting heparin coatings, mechanisms of action, and clinical applications with focus on those technologies which have been commercialized. Because of its extensive publication history, there is emphasis on the CARMEDA® BioActive Surface (CBAS® Heparin Surface), a widely used commercialized technology for the covalent bonding of heparin.
PS01.57: IMpower133: a Phase I/III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with Extensive-Stage SCLC
Authors: Leora Horn, Martin Reck, Tony Mok, Melissa L. Johnson, Xiongwen Tang, Sivuonthanh Lam, Daniel Waterkamp, Ariel Lopez-Chavez, Alan Sandler, Giuseppe Giacconne, Stephen V. Liu
Journal: Journal of Thoracic Oncology (2016)
The initiation of metabolic inflammation in childhood obesity
Authors: Kanakadurga Singer, Carey N. Lumeng
Journal: Journal of Clinical Investigation (2017)

An understanding of the events that initiate metabolic inflammation (metainflammation) can support the identification of targets for preventing metabolic disease and its negative effects on health. There is ample evidence demonstrating that the initiating events in obesity-induced inflammation start early in childhood. This has significant implications on our understanding of how early life events in childhood influence adult disease. In this Review we frame the initiating events of metainflammation in the context of child development and discuss what this reveals about the mechanisms by which this unique form of chronic inflammation is initiated and sustained into adulthood.
294. Characterizing AAV CaptureSelect Affinity Ligand Interactions
Authors: James K.S. Smith, Vibhu Banala, Mario Mietzsch, Paul Chipman, Mavis Agbandje-McKenna
Journal: Molecular Therapy (2016)

Adeno-associated virus (AAV) is one of the most widely studied viral vector systems for therapeutic gene delivery. This application has already experienced success in several human clinical trials, including the treatment of hemophilia B with an rAAV8 vector expressing therapeutic levels of Factor IX protein and for the treatment of Pompe disease, utilizing AAV1 vectors. Recently, an rAAV1 vector packaging a gene for the treatment of lipoprotein lipase deficiency was approved as the first gene therapy drug, validating the utility of this system. However, the effective production and purification of enough viral vector for use in research, preclinical studies, and human treatment is essential for success. Towards this goal, camelid single domain antibody fragments directed against AAV were used to make affinity resin products suitable for fast, one-step purification of AAV vectors of several serotypes. This affinity based purification method can replace current standards of density purification, which are time consuming and require large volumes of reagents, such as sucrose or iodixanol. At present, the collection of affinity resins suitable for AAV purification, i.e. AVB-Sepharose™, POROS™ CaptureSelect™ AAV8 and -AAV9, show varied affinity for different AAV serotypes, resulting in varied efficacies of virus purification. To better understand these differences and improve broad range utility, it is important to understand how these affinity ligands bind to the surface of the AAV capsids. We have thus mapped their binding footprints on several AAV serotypes, including AAV1, AAV5, and AAV9, using cryo-electron microscopy and image reconstruction combined with pseudo-atomic modeling. The sites for different affinity ligands are clustered on regions of the capsid that are common among most serotypes, but display minor variations which likely account for the varied affinities. This information will assist in the synergistic development of affinity ligands with broader serotype coverage and AAV vectors with improved purification outcomes.
Hematopoietic Chimerism LEVELS ARE RELATED to RELAPSE and GRAFT VERSUS Host DISEASE IN REDUCED INTENSITY Allogeneic STEM CELL Transplantion
Authors: Alejandro Contento-Gonzalo, Sandra Diaz-Gallardo, Maria Rosario Prieto-Bonilla, Maria Magdalena Alcala-Peña, Jiri Pavlu, Manuel Barrios, Antonio Jimenez-Velazco, Ana Isabel Heiniger Mazo
Journal: Blood (2010)
Increased risk of neuroendocrine (NE) carcinoma in single-lung transplant survivors.
Authors: P. K. Gopalan, M. A. Baz, M. Zajac-Kaye, C. Cao, A. Gordillo-Villegas, M. Zhang, L. Lu, F. J. Kaye
Journal: Journal of Clinical Oncology (2011)

e21131 Background: Chronic immunosuppression, required to prevent organ rejection in transplant recipients, is associated with an elevated risk for lymphoid and solid tumors. While cutaneous cancers are the most common solid tumors in transplant survivors, an increased risk of lung cancer has been noted in several recent reports. In these studies, the distribution of histologic subtypes of secondary lung cancers was similar between transplant and non-transplant cases. Our goal was to study the incidence and clinicopathologic features of lung tumors arising after lung transplantation. Methods: Medical and histopathologic records of lung transplant recipients at the University of Florida between 1994 and 2010 were reviewed. Results: A total of 505 lung transplant recipients was identified. The incidence of secondary lung cancers in these patients was 1.7% (n=9), although this represents an underestimation due to incomplete follow-up and the lag time required for tumor development. In addition, we identified one case of extrapulmonary small cell carcinoma. None of the patients had a history of lung cancer prior to transplantation. One patient underwent bilateral lung transplant and developed adenocarcinoma in a donor lung. All remaining patients underwent single lung transplants, and tumor developed exclusively in the native lung. Of these cases, we observed 4 small cell lung cancer, 2 large cell NE carcinomas (CD56+), 1 large cell undifferentiated (no NE markers available), 1 CD56+ extrapulmonary small cell carcinoma documented from ascitic fluid, and 1 squamous cell lung cancer. The average time to secondary malignancy was 5.5 years after transplantation. Eight patients were prior smokers with a median of 26 pack-years (range 3-120 pack-years). There was a high response rate to standard chemotherapy and 2 long-term survivors, however, most patients with NE lung tumors relapsed within 1 year and the median overall survival was 4.1 months. Conclusions: We report the novel observation that lung transplant recipients on chronic immunosuppression have an increased risk of aggressive NE carcinoma arising exclusively in the native lung. The molecular basis for this enrichment of neuroendocrine cancers is yet to be defined.
Abstract 2237: Involvement of Retinoic Acid Receptors RARβ and RARγ in growth, self-renewal and differentiation on mammary cancer stem cells
Authors: Damian E. Berardi, Carolina Flumian, Maria I. Diaz Bessone, Stefano M. Cirigliano, Elisa D. Bal de Kier Joffe, Alejandro J. Urtreger, Laura B. Todaro
Journal: Cancer Research (2015)

Abstract Retinoids exert different effects on cell differentiation and malignant phenotype reversion through the modulation of Retinoid Acid Receptors (RAR). In this work we have analyzed the involvement of retinoid system induction on proliferation, self-renewal and differentiation of cancer stem cells (CSC) using the triple negative mammary cell line LM38-LP. In order to obtain a CSC enriched culture, cells where cultured under mammosphere conditions. We performed mammosphere cultures in order to enrich in CSC. The treatment with All-trans retinoid acid (ATRA1μM for 96 h) reduced CSC growth rate evaluated as mammosphere diameter (Control: 176±8 μm vs. ATRA: 129±10 μm; p≤0.05). Surprisingly, ATRA pre-treatment for 96 h increased CSC self-renewal evaluated as the number of secondary mammospheres (Control: 313±19; ATRA: 495±21; p≤0.05) and as the clonogenic capacity of LM38-LP CSC (Control: 6±0.5; ATRA: 11±1.2; p≤0.05). Concomitant with these biological effects, the same treatment showed, by RT-PCR, an increase in RARβ and RARγ levels in LM38-LP- CSC. Through the use of specific RAR antagonists, we found that RARγ inhibition impaired ATRA effects on self-renewal but RARβ inhibition increased the number of secondary mammospheres (Control: 382±27; ATRA: 735±11; ATRA/RARγ antagonist: 352±17; ATRA/RARβ Antagonist: 1260±177; p≤0.05). A similar result was observed when clonogenic capacity in RARγ blocked CSC was analyzed. Finally, we performed a matrigel 3D culture using cells from LM38-LP mammospheres. Under these conditions, colonies presented large irregular structures while ATRA treatment led to the formation of differentiated colonies with evidence of lumen. Our findings suggest that RARγ down modulation and RARβ induction could lead to CSC self-renewal inhibition and differentiation in triple negative mammary cancers. Citation Format: Damian E. Berardi, Carolina Flumian, Maria I. Diaz Bessone, Stefano M. Cirigliano, Elisa D. Bal de Kier Joffe, Alejandro J. Urtreger, Laura B. Todaro. Involvement of Retinoic Acid Receptors RARβ and RARγ in growth, self-renewal and differentiation on mammary cancer stem cells. [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 2237. doi:10.1158/1538-7445.AM2015-2237
Maintenance Therapy with Decitabine in Younger Adults with Acute Myeloid Leukemia (AML) in First Remission: A Phase II Cancer and Leukemia Group B Study (CALGB 10503, Alliance)
Authors: William Blum, Ben Sanford, Rebecca B Klisovic, Daniel J. DeAngelo, Geoffrey Uy, Bayard L. Powell, Wendy Stock, Maria R. Baer, Jonathan E. Kolitz, Meir Wetzler, Eva Hoke, Clara D. Bloomfield, Susan Geyer, Guido Marcucci, Richard M. Stone, Richard A. Larson
Journal: Blood (2012)