tbuckley/cabot-search huggingface dataset:
A randomized, double-blind, placebo-controlled, multicenter phase II study to compare the efficacy and safety of sorafenib added to standard treatment with topotecan to standard treatment alone in patients with platinum-resistant recurrent ovarian cancer (TRIAS): Results of a NOGGO-AGO intergroup pilot-study.
Authors: K. El Khalfaoui, S. Mahner, R. Richter, F. Hilpert, R. Lorenz, P. Harter, P. Klare, U. A. G. Wagner, R. Chekerov, J. Sehouli
Journal: Journal of Clinical Oncology (2011)

e15548 Background: Response rates in patients with platinum resistant ovarian cancer are generally low and prognosis is very poor. Therefore new treatment strategies including the combination of chemotherapy and targeted therapies may improve the therapeutic index. TRIAS is a phase II trial of Sorafenib, a novel multitargeted kinase inhibitore plus Topotecan, an approved topoisomerase inhibitor, vs Topotecan alone in patients with platinum-resistant recurrent ovarian cancer. Here we present results from a preplanned blinded safety analysis. Methods: This is the first randomized, double-blind, placebo-controlled phase II trial in patients with in patients with platinum-resistant recurrent ovarian cancer. Primary endpoint is progression free survival. In total 184 patients will be randomized to receive either Topotecan 1,25mg/m2/d1-5 q 21d and Sorafenib (400mg twice daily, d 6-15/q21d) or Topotecan 1,25mg/m2/d1-5 q 21d and placebo. All hematological and non-hematological toxicities were compared with the data of the published TOWER study (J Clin Oncol). Results: Overall 12 consecutive patients were analyzed. A total of 38 cycles with a median (range) were evaluatedd. 7 SAE in 5 patients were reported: pleura effusion, port infection, anemia (two events), cholecystis, vomiting, rash. 4 patients discontinued therapy. A total of 31 Grade 3/4 events were observed. (. table 1) 9 non-hematological events grade 3/4 were observed including ALT/AST elevation γ-GT elevation, rash and pain). Conclusions: The combination of Sorafenib and standard regimen Topotecan is feasible and safe with an expected hematological and non-hematological toxicity profile allowing the continuation of this phase II trial.
Feasibility and Efficacy of BEAM as a Frontline High Dose Chemotherapy Supported by Autologous PBSCT in Elderly Patients (≥60 Years) with DLBCL
Authors: Vadim Ivanov, Diane Coso, Jerome Rey, Therese Aurran, Anne-Marie Stoppa, Jean-Marc Schiano di Collela, Didier Blaise, Reda Bouabdallah
Journal: Blood (2008)
Abstract 5202: Magnolin suppresses cell migration by abrogation of ERK-mediated RSK2/NF-κB signaling pathway
Authors: Cheol-Jung Lee, Mee-Hyun Lee, Ji-Hong Song, Sun-Mi Yoo, Yong-Yeon Cho
Journal: Cancer Research (2015)

Abstract Our previous study demonstrated that RSK2 directly phosphorylated IκBα at ser 32, resulted in its degradation which leads to promote NF-κB activation and might be an important role in metastasis. Therefore, it is reasonable the discovery of chemotherapeutic and/or chemopreventive agent. Magnolin, an ingredient of magnolia species, suppressed EGF-induced neoplastic cell transformation by targeting of ERK 1 and 2. In this study, we found that magnolin inhibited cell migration and invasion of normal cell and human lung cancer cells. Further, we demonstrated that magnolin suppressed epidermal growth factor-induced ERK/RSK2 signaling pathway, resulting in suppression of NF-κB activity in JB6Cl41 cells. The EGF-induced NF-κB activity was abrogated up-regulation of COX-2 mRNA expression and COX-2 protein levels by co-treatment of EGF and magnolin. Interestingly, magnolin suppressed ERK-mediated MMP-2 and NF-κB-mediated MMP-9 expression. In addition, we found that the protein expression of N-cadherin involved in metastasis was markedly attenuated upon treatment with magnolin. Notably, magnolin suppressed the migration and invasion of lung cancer cells in a dose-dependent manner. Taken together, these results demonstrated that magnolin is beneficial for the anti-invasion and -migration in cancer metastasis. Citation Format: Cheol-Jung Lee, Mee-Hyun Lee, Ji-Hong Song, Sun-Mi Yoo, Yong-Yeon Cho. Magnolin suppresses cell migration by abrogation of ERK-mediated RSK2/NF-κB signaling pathway. [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 5202. doi:10.1158/1538-7445.AM2015-5202
More Than One Mutation Is Required for Leukemia Development Following Retroviral Vector-Mediated Gene Transfer.
Authors: Olga Kustikova, Manfred Schmidt, Ute Modlich, Zhixiong Li, Sonja Schmidt, Anette Deichmann, Cornelia Rudolph, Nils von Neuhoff, Brigitte Schlegelberger, Boris Fehse, Christof Kalle, Christopher Baum
Journal: Blood (2004)
In Vitro Colony Growth, RAS Genes Sequencing, and Expression of Bcl-2 and Bax Proteins in Chronic Myelomonocytic Leukemia.
Authors: Francesco Onida, Clara Ricci, Federica Servida, Elisa Fermo, Mauro Molteni, Clara Cesana, Agostino Cortelezzi, Davide Soligo, Giorgio Lambertenghi-Deliliers
Journal: Blood (2004)
373. Optimization of AAV-Gene Therapy for GM1-Gangliosidosis
Authors: Lorelei Stoica, Sophia Todeasa, Jaclyn Lata, Douglas Martin, Miguel Sena-Esteves
Journal: Molecular Therapy (2016)

GM1-gangliosidosis is an autosomal recessive disease caused by mutations in the GLB1 gene encoding for the lysosomal acid beta-galactosidase (βgal) enzyme. The resulting enzymatic deficiency leads to accumulation of GM1-ganglioside in neurons and eventually massive neurodegeneration. The incidence of GM1-gangliosidosis is estimated at 1:100,000-200,000 live births, and there is currently no available treatment. Intracranial delivery of recombinant adeno-associated virus (AAV) vectors has been shown to be highly effective in animal models of this disease. The choice of injection sites and promoters driving transgene expression are important parameters to translate into clinical trials a safe and effective AAV-based therapy for GM1 gangliosidosis. We performed a study using AAVrh10 vectors to determine the safest and most effective promoter and delivery route combination for AAVrh10-βgal gene therapy in a GM1-mouse model. We used a combination of two direct intracranial injection site - bilateral thalamic and deep cerebral nuclei infusions (Th+DCN), or bilateral thalamic and CSF infusion into one cerebral lateral ventricle (Th+ICV). We tested three different promoters of varying strengths. The CBA promoter, composed of the chicken beta actin promoter with an enhancer element and an artificial intron; the CBi, identical to the previous promoter but lacking the enhancer element; the CB, the basic chicken beta-actin promoter without an enhancer or intron. All vectors were delivered at a total dose of 4E9 (Th+DCN) or 1E10 (Th+ICV) vector genomes. At four weeks post injection, we analyzed the brain histologically, for beta-galactosidase expression and decrease in lysosomal storage. Additionally, we analyzed the enzyme activity of beta-galactosidase, as well as the total GM1-gangliosidosis storage by enzymatic assays and LC-MS/MS mass spectrometry, respectively. The AAVrh10-CBA-βgal vector restored GM1 ganglioside levels to normal, and generated the highest βgal activity of all three vectors. Additionally, the distribution was more extensive for the AAVrh10-CBA vector, showing distribution to the frontal cortex, while for the other vectors the enzyme was mostly restricted to the injection site and the immediate area. However, at this vector dose we did not detect any apparent toxicity or cell death. Thus, we determined that the AAVrh10-CBA-βgal vector is safe and effective, and thus appropriate to carry out long-term therapeutic studies in GM1 mice toward a clinical trial.
A Multicenter Phase II Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) for Patients with Relapsed or Refractory Multiple Myeloma.
Authors: James Berenson, Ralph Boccia, David Siegel, Marek Bozdech, Alberto Bessudo, Edward Stadtmauer, J. Talisman Pomeroy, Ronald Steis, Marshall Flam, Jose Lutzky, Syed Jilani, Joseph Volk, Tiberio Lindgren, Robert Moss, Ravi Patel, Delina Ferreti, Howard Yeh, Sal Bevivino
Journal: Blood (2005)
308. Inclusion of Heterologous ITRs in Dual AAV Vectors for Retinal Gene Therapy
Authors: Elisabetta Toriello, Pasqualina Colella, Andrea Sommella, Ivana Trapani, Andrea Maddalena, Alberto Auricchio
Journal: Molecular Therapy (2015)

AAV cargo capacity limited to about 5 kb prevents their applications from treatment of inherited blinding conditions which require the transfer of genes with larger coding sequences. However, dual AAV vectors, each containing one of the two halves of a large gene expression cassette, are emerging as promising tools to overcome this limitation. However, dual AAV show lower levels of transgene expression than a single AAV vector and are associated with production of proteins shorter than expected from either the 5'- or 3'-half AAV These limitations can be in part overcome by improving the productive tail-to-head AAV genome concatemerization by including heterologous inverted terminal repeats (ITRs) at both ends of each dual AAV vector genome. We have generated dual AAV hybrid vectors with heterologous ITRs from AAV2 (ITR2) and AAV5 (ITR5) which are the most divergent among the various AAV serotypes. However, we found a significant reduction in the yields of AAV vectors with heterologous ITR2 and 5 when compared to those of vectors with homologous ITR2. In addition, the genome titer performed on ITR2 sequences results lower than that on a different part of the genome suggesting that ITRs might not be intact in AAV vectors with heterologous ITRs. Finally, the amount of full length protein relative to shorter was similar between vector with homologous and heterologous ITRs. We are currently testing dual AAV hybrid vectors with ITRs derived from other serotypes divergent from AAV2 which could overcome some of the limitations we have found using ITR5.
Abstract 2683: Simultaneous inactivation of TP53 and loss of PTEN diminish response to targeted therapy in V600EBRAF mutant melanoma
Authors: Elena Galvani, Kelly Brooks, Franziska Baenke, Maria Romina Girotti, Gabriela Gremel, Amit Kumar Mandal, Amaya Viros, Clare McManus, Matthew Smith, Kok Haw Jonathan Lim, Rebecca Lee, Alberto Fusi, Paul Lorigan, Richard Marais
Journal: Cancer Research (2015)

Abstract Numerous cancers are driven by mutationally activated kinases, many of which can be employed to define subsets of cancers and therefore patients most likely to benefit from treatment with rationally designed targeted therapies. Defining the landscape of genetic alterations that participate in cancer transformation provides insight into the diversity of clinical responses observed to targeted treatments. Here, we identified concurrent mutational inactivation of the tumor suppressors TP53 and PTEN as a mechanism of resistance to BRAF inhibitors in melanomas harboring mutant V600EBRAF. Defects in TP53 function and PTEN loss occur in 17% and 12% of malignant melanomas respectively, rendering cells dependent on CHK1 to maintain normal cell cycle progression. We demonstrate that CHK1 inhibition increases sensitivity to a variety of alkylating agents and targeted therapies in V600EBRAF mutant, TP53/PTEN deficient cell lines and patient derived xenografts. Inhibition of CHK1 concurrently with the induction of either DNA damage or replication stress leads to ‘‘mitotic catastrophe’’ and cell death in our in vitro and in vivo models of TP53/PTEN deficient tumors. In the case of externally applied cellular stress from chemotherapeutics, our results suggest CHK1 inhibition may sensitise this genetically defined subset of melanomas to such treatments. Our results provide some insight into the heterogeneity of clinical outcomes observed when treating BRAF mutant melanomas with BRAF inhibitor and suggest a need for comprehensive screening of TP53 and PTEN inactivation in these patients. Citation Format: Elena Galvani, Kelly Brooks, Franziska Baenke, Maria Romina Girotti, Gabriela Gremel, Amit Kumar Mandal, Amaya Viros, Clare McManus, Matthew Smith, Kok Haw Jonathan Lim, Rebecca Lee, Alberto Fusi, Paul Lorigan, Richard Marais. Simultaneous inactivation of TP53 and loss of PTEN diminish response to targeted therapy in V600EBRAF mutant melanoma. [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 2683. doi:10.1158/1538-7445.AM2015-2683
Effects of AMN107, a Novel Aminopyrimidine Tyrosine Kinase Inhibitor, on Human Mast Cells Bearing Wild-Type or Mutated Codon 816 c-kit.
Authors: Srdan Verstovsek, Cem Akin, Giles J. Francis, Manshouri Taghi, Ly Huynh, Paul W. Manley, Leila Alland, Margaret Dugan, Jorge E. Cortes, Kantarjian M. Hagop
Journal: Blood (2005)
IMPS-35UNUSUAL TUMOR INFILTRATING LYMPHOCYTES IN DE NOVO GLIOBLASTOMA FOLLOWING PRE-TREATMENT WITH ANTI-PD-L1 THERAPY FOR PRECEDING METASTATIC NSCLC: CASE PRESENTATION WITH DISCUSSION
Authors: Robert Reznik, Behrooz Hakimian, Ray Chu, Keith Black, Serguei Bannykh, Stephen Shiao, Jeremy Rudnick
Journal: Neuro-Oncology (2015)

The use of immunotherapy, specifically immune checkpoint inhibitors, is a rapidly emerging and evolving treatment modality for many solid tumor types. In this abstract, we describe a case of a 70 year old male with history of PD-L1 expressing metastatic poorly differentiated NSCLC treated with anti-PD-L1 therapy who was subsequently diagnosed with a glioblastoma with evidence of unexpected tumor infiltrating lymphocytes (TILs). The lung cancer was initially treated with combination chemotherapy with excellent response. This regimen was stopped prematurely due to significant treatment-related side effects. He then received the investigational anti-PD-L1 monoclonal antibody, MPDL3280A (Roche), under the Phase II Trial of MPDL3280A for PD-L1 positive locally advanced or metastatic NSCLC (NCT02031458). He experienced partial response without significant treatment-related side effects. Two weeks after completion of his 9th cycle of the study drug, he experienced altered mental status, personality changes, and confusion. A contrast brain MRI demonstrated a multifocal, rim-enhancing, left frontal lobe lesion with corpus callosal involvement. Of note, CT brain imaging prior to anti-PD-L1 study enrollment showed no evidence of abnormal enhancement. Stereotactic biopsy was performed with pathology showing glioblastoma with significant reactive lymphoid component noted (majority of lymphoid cells CD20 positive, scattered lymphocytes CD3 positive). He then underwent near image complete resection with pathology again demonstrating glioblastoma with 20-70% tumor necrosis, with 3 genomic alterations (CDKN2A/B loss; APCI1307K; TERT promoter – 124C > T) identified on Foundation One (Cambridge, MA) Next Generation Sequencing. This is the first reported case of a patient treated with anti-PD-L1 therapy for a high grade malignancy, who then developed a de novo glioblastoma with unusual biopsy findings of CD20 and CD3 positive TILs. Although more correlative studies are currently being performed, the immune implications for the use of immunotherapy for pre-treatment of glioblastomas may correspond to improved treatment response and patient outcomes.
Characterization of T and B cell repertoire diversity in patients with RAG deficiency
Authors: Yu Nee Lee, Francesco Frugoni, Kerry Dobbs, Irit Tirosh, Likun Du, Francesca A. Ververs, Heng Ru, Lisa Ott de Bruin, Mehdi Adeli, Jacob H. Bleesing, David Buchbinder, Manish J. Butte, Caterina Cancrini, Karin Chen, Sharon Choo, Reem A. Elfeky, Andrea Finocchi, Ramsay L. Fuleihan, Andrew R. Gennery, Dalia H. El-Ghoneimy, Lauren A. Henderson, Waleed Al-Herz, Elham Hossny, Robert P. Nelson, Sung-Yun Pai, Niraj C. Patel, Shereen M. Reda, Pere Soler-Palacin, Raz Somech, Paolo Palma, Hao Wu, Silvia Giliani, Jolan E. Walter, Luigi D. Notarangelo
Journal: Science Immunology (2016)

Differences in B and T cell repertoires in patients with RAG deficiency associate with clinical severity.
Prolonged survival after two-stage resection of advanced colorectal liver metastases: Impact of an intensified chemotherapy.
Authors: Marie-Hélène Pissas, Sebastien Carrere, Lise Roca, Pierre-Emmanuel Colombo, Martin Bertrand, Olivia Sgarbura, Fabienne Portales, Emmanuelle Samalin, Marc Ychou, Bernard Saint-Aubert, Philippe Rouanet, François Quenet
Journal: Journal of Clinical Oncology (2015)

748 Background: Patients with advanced colorectal liver metastases (CRLM) experience poor prognosis. The impact of two-stage resection (TSR) after downstaging by chemotherapy is still controversial. Methods: Data on 899 patients with CRLM in a single institution during a 9-year period (2004–2013) were prospectively collected. We used intent-to-treat analysis to evaluate the survival of patients who underwent TSR associated with intensified chemotherapy before and between the two surgical stages. Results: 73 patients were eligible for the first stage of TSR. In this population, 54 patients underwent an intensified chemotherapy based on FOLFIRINOX (26 patients) or a standard chemotherapy associated with cetuximab or bevacizumab (28 patients). The first surgical stage was a clearance of the left liver in 56% of cases. An average of two radio-frequency ablations and two wedge resections were necessary. The post-operative morbidity of the first stage was 18%. 78% of patients received chemotherapy between the two stages. The average interval between two stages was 228 days (36-1561). 68% of TSR patients completed the second stage. The second resection was mainly a standard right lobectomy (32%). Morbidity after the second resection was 12%. One patient died post-operatively because of post operative liver failure. Median overall survival of patients who completed TSR was 48 months. In contrast, there was no survival advantage for patients who underwent only the first stage because of progression (median overall survival: 19 months) (p = 0.0003). The median overall survival of the whole population was 43 months and the median recurrence-free survival was 15 months. Conclusions: Intensified chemotherapy in association with TSR allows excellent outcome in patients with advanced CRLM. Chemotherapy delivered between the two surgical stages is responsible for an important waiting time but could contribute to a better control of the evolution of the disease.
Abstract 4708: Mammalian glutamine metabolism controls circadian rhythm through regulation of reactive oxygen species
Authors: Brian J. Altman, Zachary E. Stine, Annie L. Hsieh, Ralph J. Deberardinis, Chi V. Dang
Journal: Cancer Research (2015)

Abstract Circadian rhythms are twenty-four hour physiologic cycles present in all eukaryotes that control a variety of organismal processes, including metabolism, but the role of metabolism in control of circadian rhythms is still not well understood. Peripheral clocks such as those present in the liver control metabolic pathways such as glucose metabolism and respiration as well as amino acid metabolism. It has been recently demonstrated that the availability of the metabolite NAD (nicotinamide adenine dinucleotide) can feed back to control circadian rhythm. There is much interest in targeting glutamine metabolism in cancer, but it is still not fully understood how inhibition of glutamine metabolism affects normal cell physiology, including circadian rhythm. Here we show using the commonly-used circadian model U2OS osteosarcoma cells and other cell lines that glutamine withdrawal blocked proper circadian oscillation of gene expression. Glutamine withdrawal led to distinct and dramatic changes in circadian gene expression in several cell lines with highly different tissue origins, which could be rescued by addition of the cell permeable TCA-intermediate α-ketoglutarate. However, cells withdrawn from glutamine did not show signs of metabolic stress or impairment of the mTOR pathway. While alterations to histone modifications possibly stemming from impairment of αKG-dependent enzymes were observed, these did not explain the observed alterations in circadian rhythm. Rather, RNA-seq analysis of genetic changes after glutamine withdrawal and α-ketoglutarate rescue revealed strong induction of several genetic pathways associated with reactive-oxygen species (ROS) induction, particularly those resulting from chemotherapy or photodynamic therapy of cancer. Further supporting the importance of ROS in regulation of circadian rhythm, addition of cell permeable antioxidants rescued the disruption of circadian oscillation in the absence of glutamine. Finally, inhibiting expression of the key ROS-defense catalase phenocopied circadian rhythm disruption observed after glutamine withdrawal. Together, these data suggest that glutamine availability and metabolism are critical to support circadian rhythm and gene expression through modulation of intracellular ROS, and furthermore that cancer treatments that lead to induction of ROS could affect normal cellular circadian rhythm. We thank the following funding: NIH F32CA180370, NIH F32CA174148, NIH R01CA051497, LLS 610614 Citation Format: Brian J. Altman, Zachary E, Stine, Annie L. Hsieh, Ralph J. Deberardinis, Chi V. Dang. Mammalian glutamine metabolism controls circadian rhythm through regulation of reactive oxygen species. [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 4708. doi:10.1158/1538-7445.AM2015-4708