tbuckley/cabot-search huggingface dataset:
Follow-up study of chemotherapy plus hormone therapy for biochemical relapse after definitive local therapy for prostate cancer.
Authors: M. Nakabayashi, W. Xie, G. Buckle, G. Bubley, M. S. Ernstoff, W. V. Walsh, D. Morganstern, P. W. Kantoff, M. M. Regan, M. Taplin
Journal: Journal of Clinical Oncology (2011)

4657 Background: Treatment options for prostate cancer (PCa) patients with biochemical relapse (BR) after local therapy include surveillance, salvage local therapy, androgen deprivation therapy (ADT) and clinical trials. We previously reported the feasibility of chemotherapy and ADT for a cohort of 62 men with BR with a median follow-up (f/u) of 3.1 years (JCO 2006, 24:5408-13). We now report longer term f/u of this cohort. Methods: Treatment was 4 cycles of docetaxel (D) (70mg/m2) every 3 weeks and estramustine 280 mg TID (days 1-5) followed by 15 months of goserelin acetate/bicalutamide. The primary endpoint was proportion of men whose PSA < 0.1 with recovered testosterone (T) 5 years after completion of protocol therapy. Secondary endpoints included time to progression (TTP), time to re-initiate ADT, the proportion of patients with castration-resistant prostate cancer (CRPC), and overall survival (OS). Progression was defined as 2 serial rises PSA (> 2.0 ng/ml in radiation only patients and > 0.2 ng/ml in prostatectomy patients) or reinitiation of ADT for rising PSA. Results: Sixty two patients were in the original cohort. Median f/u since the start of D was 7.9 years (range: 1.3-11.1) and 43 had f/u data 5+ years after completion of protocol therapy. At 5 years after protocol therapy, 6 (10%) patients had PSA <0.1 (4 undetectable); 8 (13%) had PSA> 0.1 (0.1-0.4 in 5 and 1.6-3.7 in 3) but without reinitiation of ADT. Of the 14 men (23%), 13 have recovered T to assay normal range, and one had T level of 59 ng/dL. Median TTP after the start of D was 35.0 months (95% CI: 31.7, 39.2). At the time of analysis, 39 men (63%) restarted ADT, 20 men had CRPC, and 9 had received chemotherapy. Median time to reinitiation of ADT from completion of trial was 33.9 months (range: 0-107.6). Median OS was not yet reached and there were 15 deaths (7 PCa specific). Conclusions: Chemotherapy plus ADT resulted in durable (> 5 years) complete responses (<0.1) in 6/62 men (10%). 23% of men have not reinitiated ADT 5 years from completion of protocol ADT.
High-Dose Therapy and Autologous Stem Cell Transplant (HD-ASCT) for Transformed Non-Hodgkin Lymphoma (NHL) In the Rituximab Era
Authors: Makiko Ban-Hoefen, Jonathan W. Friedberg, Jennifer L. Kelly, Steven H. Bernstein, Jane L. Liesveld, Faith Young, Richard I Fisher, Louis Constine, Michael Becker, Gordon L. Phillips
Journal: Blood (2010)
Circulating Angiogenic Cytokines in Chronic Lymphocytic Leukemia: Relationship to Modern Prognostic Factors and Effect of Fludarabine-Based Treatment
Authors: Lukas Smolej, Ctirad Andrys, Sona Pekova, Lenka Kucerova, Monika Hrudkova, David Belada, Jaroslav Maly
Journal: Blood (2008)
Metronomic chemotherapy with daily low-dose temozolomide and celecoxib in elderly patients with newly diagnosed glioblastoma multiforme.
Authors: Frank Anton Giordano, Grit Welzel, Julian Emanuel Gehweiler, Stefanie Brehmer, Jens-Uwe Appelt, Andreas von Deimling, Marcel Seiz-Rosenhagen, Peter Schmiedek, Frederik K. Wenz
Journal: Journal of Clinical Oncology (2015)

e13046 Background: Chemotherapy is often omitted in elderly patients with glioblastoma multiforme due to a fear of side effects. We applied metronomic chemotherapy with low-dose temozolomide and celecoxib (LD-TEM/CEL) during and after external beam radiotherapy (EBRT) and here report on how this regimen compares to standard temozolomide radiochemotherapy (SD-TEM) in elderly patients. Methods: We retrospectively analyzed records of 146 patients aged 65 years and older that underwent EBRT. Factors of interest were age, performance status, comorbidities, MGMT status, therapy (resection/biopsy, radiotherapy/dose, chemotherapy/regimen/dose), progression-free (PFS) and overall survival (OS) status. Results: Irrespective of the regimen, addition of chemotherapy more than doubled median survival rates (EBRT only: 4.2 mo.; EBRT + LD-TEM/CEL: 8.5 mo.; EBRT + SD-TEM: 10.8 mo.; p ≤ .008). Although patients receiving metronomic LD-TEM/CEL were significantly older (62% were ≥ 75 years vs. 22% ; p < .001), had significantly lower performance scores (50% had a KPS < 70 vs. 28%; p = .049) and were significantly more comorbid (73% had ≥ 4 comorbidities vs. 37%; p = .002) than patients of the SD-TEM group, there were no significant differences in PFS and OS, and LD-TEM/CEL had to be discontinued less often after radiochemotherapy than SD-TEM (8 vs. 28%; p = .032). Conclusions: Independent of other factors, omission of chemotherapy significantly impairs progression-free and overall survival. Metronomic chemotherapy with LD-TEM/CEL was seen equieffective and eventually better tolerated than SD-TEM. It may be offered to elderly patients that are not eligible for standard chemotherapy.
627. Concerted Evolution of Pseudogenes Facilitated Contiguous Deletion of the Canine Dystrophin and TMEM47 Genes by Homologous Recombination
Authors: Daniel H. VanBelzen, Alock Malik, Joe Kornegay, Hansell H. Stedman
Journal: Molecular Therapy (2016)

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder caused by sporadic mutations in the 2.4 Mb dystrophin gene. The large size of the gene is responsible for one of the highest loss-of-function mutation rates in the entire human genome. The majority of dystrophin mutations that cause DMD are deletions that span multiple exons. As the resulting absence of central immunological tolerance has the documented potential to complicate gene therapies in which recombinant dystrophin is expressed, there is an urgent need for well characterized, deletional null animal models for DMD. Preliminary characterization of a naturally occurring mutation in a German shorthaired Pointer (GSHPMD) suggested that the canine dystrophin gene was disrupted by a single, large deletion. Here, we further characterize the GSHPMD deletion and determine the breakpoints to be within short, highly homologous DNA elements spaced over 5.6 Mb apart, suggesting homologous recombination as the most plausible mechanism. The deletion generously flanks the entire dystrophin gene, and additionally encompasses the TMEM47 gene. This is reminiscent of the famous B.B. deletion in the DMD patient whose DNA was used for subtractive hybridization in the cloning of the DMD and nearby CGD loci. Further investigation revealed that the homologous canine DNA elements are ferritin-like pseudogenes, and surprisingly that there are several additional copies present on the X-chromosome. Phylogenomic comparison of the physical map positions of the orthologous pseudogenes in proximity to the dystrophin gene shows a pattern of positional synteny, consistent with the expansion of this pseudogene family prior to the mammalian radiation. Unexpectedly, only in the canine lineage have the pseudogene sequences remained virtually identical to one another, suggesting the existence of a heretofore uncharacterized process of concerted molecular evolution spanning large physical distances. The fully characterized deletional null animal model represents an invaluable resource for the evaluation of the immunological consequences of recombinant dystrophin expression via gene therapy, as it provides the only mammalian system in which the complete absence of dystrophin prevents the development of central tolerance, as would be expected in most cases of DMD. Thus the GSHPMD model can be uniquely leveraged to address a major safety concern as the field pursues strategies for systemic gene delivery in DMD. Of note, published studies have revealed evidence for deleterious immunological responses following administration of vectors expressing recombinant HUMAN dystrophin in both DMD and the Golden Retriever canine model (NEJM 363: 1429-1437 and Mol. Ther. 18:1501-1508).
680. TransfeX-Mediated HSV-tk/Ganciclovir Suicide Gene Therapy in HeLa Cervical Carcinoma and HSC-3, FaDu, and H357 Oral Cancer Cells
Authors: Jennifer G. Cheung, Krystyna Konopka, Nejat Düzgünes
Journal: Molecular Therapy (2016)

INTRODUCTION: Herpes Simplex Virus thymidine kinase/ganciclovir (HSV-tk/GCV)-induced suicide gene therapy has been used to successfully treat various cancers. TransfeX-mediated transfection of pCMV.Luc into HeLa cervical carcinoma and HSC-3, FaDu, and H357 oral squamous cell carcinoma (OSCC) cell lines in the presence of 10% serum has proved to be highly efficient, with low non-specific cytotoxicity. The plasmid pNGVL1-tk encoding HSV-tk under the control of the CMV promoter was delivered to the cells in vitro via the novel cationic liposomal reagent, TransfeX, followed by treatment with ganciclovir. METHODS: HeLa, HSC-3, FaDu, and H357 cells were seeded in 48-well culture plates one day prior to transfection, at a density of 1.5 × 105 cells per well in 1 ml of complete DMEM medium containing 10% serum (DME/10). Lipoplexes for transfection were prepared by mixing 1 µg pCMV.Luc or pNGVL1-tk per 100 µl of serum-free DMEM followed by the addition of 2 µl of TransfeX. Lipoplexes were added directly to cells grown in the presence of 10% serum. Twenty-four hours after transfection, 20 µg of ganciclovir was added per well and cells were incubated an additional 24 h. The Alamar blue assay was used to determine cell viability after 24, 48, and 120 h. Fresh medium and ganciclovir were added after each of these readings. RESULTS: After 24 h, 65% and 50% cytotoxicity were seen in HeLa cells and HSC-3 cells, respectively. FaDu and H357 cells were more resistant to treatment, showing 15% and 5% cytotoxicity, respectively, after 24 h. After 120 h, cytotoxicity remained the same in HeLa, and increased to 90% in HSC-3. In FaDu and H357, 65% and 30% cytotoxicity, respectively, were observed after 120 h. CONCLUSIONS: Suicide gene therapy is most effective against HSC-3 OSCC among the cells examined. Longer periods of incubation with ganciclovir or prolonged gene expression via enhanced episome vectors may be necessary to increase cytotoxicity in FaDu and H357 cells.
Abstract 1671: Fibroblast growth factor receptor 3 enhances progression of hepatocellular carcinoma
Authors: Jakob Paur, Lisa Nika, Christiane Maier, Julia Kostka, Petra Heffeter, Sonja Kappel, Daniela Kandioler, Klaus Holzmann, Brigitte Marian, Walter Berger, Michael Grusch, Bettina Grasl-Kraupp
Journal: Cancer Research (2015)

Abstract Purpose of the study. To provide mechanistic evidence that fibroblast growth factor receptor 3 (FGFR3) and its two splice variants, FGFR3-IIIb and -IIIc, impact considerably on the malignant phenotype of hepatocellular carcinoma (HCC). Experimental procedures. The occurrence of FGFR3 and its two isoforms was analyzed in human HCC samples by qRT-PCR and immunostaining. In hepatoma/hepatocarcinoma cell lines FGFR3-isoforms were overexpressed by lentiviral constructs or were down-modulated by siRNA or an adenoviral kinase-dead FGFR3 (kdFGFR3) construct. Cell lines were tested for anchorage-independent growth, proliferation at low-densities and their cell-cycle distribution, as well as their ability to form tumors after subcutaneous injection into the flanks of SCID-mice. Results. Upregulated FGFR3 was found in almost 50% of HCC patients, which was often due to the enhanced expression of FGFR3-IIIb. Furthermore, patients with FGFR3-IIIb overexpression showed early tumor recurrence indicating that this isoform may be a major player in tumor progression. In hepatoma/hepatocarcinoma cells, upregulated FGFR3-IIIb or FGFR3-IIIc conferred an enhanced capability for proliferation and tumor growth. Both isoforms enhanced downstream signaling and increased the cells’ ability to grow at low densities. The tumorigenicity of cells in SCID-mice was augmented more by variant IIIb than by IIIc. This stronger impact of FGFR-IIIb on cell proliferation could also be seen in analysis of the cell cycle distribution, which was shifted to the S-phase. Conversely, siFGFR3 and kdFGFR3 affected both receptor-variants and strongly reduced clonogenic growth at low density and anchorage-independent growth. Furthermore, kdFGFR3 arrested the cells in G2/M and strongly attenuated tumor formation in vivo. Conclusions: Upregulated FGFR3 is associated with development and progression of hepatocellular carcinoma. Accordingly, blockade of FGFR3-mediated signaling may be a promising therapeutic approach to antagonize growth and malignant behavior of HCC cells. Citation Format: Jakob Paur, Lisa Nika, Christiane Maier, Julia Kostka, Petra Heffeter, Sonja Kappel, Daniela Kandioler, Klaus Holzmann, Brigitte Marian, Walter Berger, Michael Grusch, Bettina Grasl-Kraupp. Fibroblast growth factor receptor 3 enhances progression of hepatocellular carcinoma. [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 1671. doi:10.1158/1538-7445.AM2015-1671
Pancreatic Uptake by 18F-FDOPA PET/CT in Patients With Hypoglycemia After Gastric Bypass Surgery Compared With Controls With or Without Carbidopa Pretreatment
Authors: André P. van Beek, Loek J.M. de Heide, Bram van Ginkel, Riemer H.J.A. Slart, Anouk N.A. van der Horst-Schrivers, Ronald Boellaard, Elisabeth G.E. de Vries, Walter Noordzij, Andor W.J.M. Glaudemans
Journal: Clinical Nuclear Medicine (2016)

The use of Fluorine-labeled dihydroxy-phenyl-alanine (F-FDOPA) PET/CT in patients with hypoglycemia suspected to be caused by pancreatic disease can be helpful to localize the source of excess insulin production. In this setting, carbidopa pretreatment is not recommended. However, quantitative comparisons of pancreatic tracer uptake in patients with or without carbidopa pretreatment and in diffuse pancreatic disease are lacking. Therefore, we aimed to describe and quantify pancreatic F-FDOPA uptake in patients without pancreatic disease with or without carbidopa pretreatment and in patients with hypoglycemia after gastric bypass surgery.This is a retrospective data analysis of F-FDOPA PET/CT scans performed at a university medical center in the period from 2009 to 2015. All scans were reconstructed and calculated based on the European Association of Nuclear Medicine/EANM Research Ltd guidelines. Of 358 patients without evidence of pancreatic disease or hypoglycemic disorders, 344 received carbidopa and 14 did not. Another 9 patients had post-gastric bypass hypoglycemia. The main outcome measurement was F-FDOPA SUVmax for pancreatic head, body, and tail regions.Carbidopa pretreated patients had a lower median SUVmax (-1.15, -1.20, and -0.84 in pancreatic head, body, and tail [all P < 0.01]) than patients without carbidopa pretreatment. Patients with post-gastric bypass hypoglycemia scanned without carbidopa pretreatment had higher median SUVmax (+1.18, +1.39, and +1.63, all P < 0.03) compared with controls without pretreatment.Patients with post-gastric bypass hypoglycemia have increased uptake in all pancreatic regions. Carbidopa pretreatment lowers pancreatic F-FDOPA uptake in the nonaffected pancreas and may therefore mask disease activity in post-gastric bypass hypoglycemia.
Efficient Duplex Real-Time Quantitative RT-PCR of BCR-ABL and ABL Gene Transcripts for Monitoring of Minimal Residual Disease
Authors: Qianli Jiang, Shan Jiang, Fanyi Meng, Ru Feng, Bing Xu, Lanlin Song, Liu Yang, Bing Li, Rong Lin, Xiaolan Xu, Shuyun Zhou
Journal: Blood (2008)
INCB018424, a Selective Inhibitor of JAK1 and JAK2, Downregulates the Expression of Leukocyte Alkaline Phosphatase (LAP) On Circulating Granulocytes in Patients with Polycythemia Vera and Essential Thrombocythemia.
Authors: Francesco Passamonti, Elisa Rumi, Matteo G Della Porta, Monica Portolan, Chiara Elena, Luca Arcaini, Cristiana Pascutto, Laura Vanelli, Kris Vaddi, Mario Lazzarino, Mario Cazzola
Journal: Blood (2009)
In Vitro Characterization of Wnt/β-Catenin Pathway Inhibition in Multiple Myeloma Cell Lines Using a Novel Class of Small Molecules.
Authors: Jeffrey W. Strovel, Tammy Lawrence, Pachai Natarajan, Stephen Glanowski, Irina Lonskaya, Zoe Weaver, Janka Padia, Jeffrey W. Watthey, Wieslaw M. Cholody, J. Michael Hamilton, David K. Bol, Stephen K. Horrigan
Journal: Blood (2007)
Abstract 1266: Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence
Authors: Christelle Lenain, Olga Gusyatiner, Sirith Douma, Daniel S. Peeper
Journal: Cancer Research (2015)

Abstract Cellular senescence is a stable form of cell cycle arrest triggered by a variety of damages and stresses including oncogene expression (oncogene-induced senescence or OIS). We and others previously demonstrated that OIS occurs in human benign lesions, acting as a potent tumor suppressor mechanism preventing cancer progression. Numerous phenotypic changes occur during OIS both in the cytoplasm and in the nucleus. These include the activation of autophagy, a catabolic process operating in the cytoplasm, and downregulation of lamin B1, a component of the nuclear lamina. However, it is unknown whether these changes relate to each other. We discovered that cells entering BRAFV600E- or H-RASV12-induced senescence downregulate not only lamin B1 but also lamin A, as well as several other nuclear envelope (NE) proteins. This depletion was associated with an altered NE morphology. We further found that the global loss of NE proteins is a consequence of their degradation by the autophagy machinery. This occurs concomitantly with autophagy induction and increased lysosomal content and activity. Our study reveals for the first time to our knowledge, a connection between autophagy and the disruption of nuclear envelope integrity during OIS. Note: This abstract was not presented at the meeting. Citation Format: Christelle Lenain, Olga Gusyatiner, Sirith Douma, Daniel S. Peeper. Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence. [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 1266. doi:10.1158/1538-7445.AM2015-1266
Human Natural Killer (NK) Cells: Differential Expression of Phosphatase and Tensin Homologue Deleted On Chromosome Ten (PTEN) During NK Cell Development Regulates Its Cytolytic Activity Against Leukemic Target Cells
Authors: Edward L. Briercheck, Rossana Trotta, Jordan P. Cole, Tyler D. Cole, Alex S. Hartlage, Chelsea K. Martin, Gustavo Leone, Michael A. Caligiuri
Journal: Blood (2012)
Beneficence In Utero: A Framework for Restricted Prenatal Whole-Genome Sequencing to Respect and Enhance the Well-Being of Children
Authors: W. Kevin Conley II, Douglas C. McAdams, G. Kevin Donovan, Kevin T. FitzGerald
Journal: The American Journal of Bioethics (2016)

"Beneficence In Utero: A Framework for Restricted Prenatal Whole-Genome Sequencing to Respect and Enhance the Well-Being of Children." The American Journal of Bioethics, 17(1), pp. 28–29
A Phase Ib/IIa Trial of the Combination of Romidepsin, Lenalidomide and Carfilzomib in Patients with Relapsed/Refractory Lymphoma Shows Complete Responses in Relapsed and Refractory T-Cell Lymphomas
Authors: Neha Mehta-Shah, Alison J Moskowitz, Matthew Lunning, Peggy Lynch, Mark Scheuerman, Anita Kumar, John F Gerecitano, Andrew D. Zelenetz, Paul A Hamlin, Ariela Noy, Matthew J. Matasar, M. Lia Palomba, Anas Younes, Wendy Schaffer, Ravinder Grewal, Jurgen Rademaker, Craig S Sauter, Parastoo B. Dahi, Patricia Myskowski, Meenal Kheterpal, Ahmet Dogan, Melissa Pulitzer, Laura Tang, Ai Ni, Steven M Horwitz
Journal: Blood (2016)
229. Engineered Macrophage-Based Cell Therapy for Cancer Treatment
Authors: Saul Kivimae, Simon Lee, Francis C. Szoka
Journal: Molecular Therapy (2015)

Physiological barriers such as poorly developed vasculature, interstitial pressure, dense extracellular matrix in solid tumors limit distribution of liposomal and polymer drug carriers deep into the disease tissue leading to poor efficacy of treatment. Unlike synthetic drug carriers however, a number of immune cell types, most prominently macrophages, are actively recruited to tumor sites. Macrophages permeate tumor tissue to perform various anti-and pro-tumor functions. Thus, macrophages represent an attractive candidate as a cellular vehicle for intra-tumoral drug delivery and immune modulation. We have devised a strategy to produce therapeutic macrophages ex vivo. The strategy is based on recent advances in controlling macrophage differentiation by over expressing the Hoxb family of transcription factors1. The resulting macrophages can be loaded with liposomal drugs and genetically engineered to express proteins to influence the immune response against tumors when the macrophages are re-introduced in vivo. We have generated isogenic mouse macrophage progenitor cell lines from BALB/c and c57Bl6 genetic backgrounds utilizing CreERT recombinase controlled conditional expression of floxed Hoxb8 and a fluorescent reporter protein. Conditionally immortalized non-adherent macrophage progenitor cell lines expand very rapidly in vitro doubling every 12h in standard cell culture conditions. Upon CreERT activation with 10nM 4-hydroxytmoxifen (three doses every two days the first week), 100% of the progenitors in culture can be differentiated into macrophage-like cells over a 2-week period. Upon differentiation these macrophage-like cells become adherent, develop cytoplasmic granules and become highly phagocytic. We utilize the high phagocytic capacity of ex vivo differentiated macrophages to load them in culture with cytotoxic drugs encapsulated in stable fluorescently–labelled liposomes. Liposome uptake depends upon liposome composition, concentration and is saturable. Results on the in vivo distribution of the macrophages and cargo upon their re-introduction in BALB/c mice containing the 4T1 orthotopic syngeneic mouse breast tumor will be presented. Supported by NIH R21 CA182703. Simon Lee is supported by Fellowship from the Natural Sciences and Engineering Research Council of Canada.
Dementia Research—A Roadmap for the Next Decade
Authors: Bryan J. Traynor, Rosa Rademakers
Journal: JAMA Neurology (2016)

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