tbuckley/cabot-search huggingface dataset:
276. Long-Term Relapse-Free Survival of Patients with Acute Myeloid Leukemia (AML) Receiving a Telomerase-Engineered Dendritic Cell Immunotherapy
Authors: Jane S. Lebkowski, Hanna J. Khoury, Robert H. Collins, William Blum, Patrick Stiff, Edward Wirth, Kevin Nishimoto, John DiPersio
Journal: Molecular Therapy (2016)

There are few treatment options for patients with intermediate and high risk AML, and remission and relapse rates are dismal especially in patients ≥60 years old. A Phase 2 clinical trial was conducted in subjects with AML to assess a dendritic cell immunotherapy (AST-VAC1) engineered to express a modified form of telomerase that is processed through both the MHC Class I and II antigen presentation pathways. AST-VAC1 was prepared from leukapheresis collections from 33 subjects and were transfected with an mRNA encoding near full length telomerase (hTERT) modified with a lysosomal sorting signal, LAMP-1, which enhances presentation to both CD4+ helper and CD8+ cytotoxic T cells. hTERT is essential for maintaining the extended proliferative lifespan of tumor cells. AML patients were enrolled if they were in complete remission (CR1 or CR2) with intermediate or high risk cytogenetics. AST-VAC1 was prepared after induction therapy and before or after completion of consolidation cycles. AST-VAC1 containing 1 × 107 cells was administered as 6 weekly followed by 6 biweekly intradermal injections. If AST-VAC1 doses were available, patients were eligible to receive additional monthly boosts. Twenty one patients (median age: 55) in complete remission (16 CR1 and 3 CR2) or early relapse (2) received at least 3 injections of AST-VAC1. Only one Grade 3 or 4 adverse event, (idiopathic thrombocytopenia), possibly related to the immunotherapy was observed. The majority of adverse events were transient including headache, fatigue, erythema and rash. The two patients who were vaccinated during early relapse progressed rapidly and did not receive the full dosing regimen of AST-VAC1. Of the 19 patients that were in CR, 13 received all 12 doses of AST-VAC1. Fifty-eight percent (11/19) developed T cell immune responses to hTERT as assessed by ELISpot analysis. Eleven of 19 patients (median follow-up 52 mos.) were in remission as of last follow-up; seven developed detectable cellular immune responses to hTERT. Of the 19 CR patients, 7 were ≥ 60 years old at the time of AST-VAC1 immunotherapy. Four of 7 patients ≥ 60 years old remained relapse free 52-59 months post AST-VAC1 immunotherapy with all four developing immune responses to hTERT. The three patients that received AST-VAC1 while in CR2 were in remission as of their last follow-up of 24, 50 and 59 months with two having hTERT immune responses. The median duration of complete remission was greater than that observed in historical controls especially for patients ≥ 60 years old where relapse-free survival at 4 years is typically 5-20%. The results suggest that immunotherapy with AST-VAC1 is safe, can stimulate immune responses to telomerase, and may extend relapse-free survival even in patients with high risk AML.
373. Expression of Human Iduronidase from Sleeping Beauty Engineered Human B Lymphocytes as a Cellular Therapy for Mucopolysaccharidosis Type I
Authors: Eric J. Herbig, Kendra Hyland, Mei Xu, Rian de Laat, Erik Olson, Elena Aronovich, Matthew Scholz, Perry Hackett, R. Scott McIvor
Journal: Molecular Therapy (2015)

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder cause by absence of the glycosidase alpha-L-idurondase (IDUA), resulting in the systemic accumulation of glycosaminoglycan storage materials heparan sulfate and dermatan sulfate. Affected individuals exhibit a range of manifestations including hepatosplenomegaly, skeletal dysplasias, and cardiopulmonary obstruction. The severe form of the disease (Hurler syndrome) is associated with progressive neurologic dysfunction and death by age 10. Current treatments for MPS I include enzyme replacement (ERT), and hematopoietic stem cell transplantation (HSCT). However, these treatments are expensive, insufficiently effective, and allogeneic HSCT is associated with considerable morbidity and mortality. As an alternate approach to MPS I, Immusoft Corporation is developing as a cellular therapeutic primary B cells that have been genetically engineered for long-term expression and secretion of IDUA. At the core of the technology is the generation of genetically engineered autologous human B cells, which are isolated and expanded from patient blood. Mature B cells (specifically long-lived plasma cells) are the ideal cell type to produce protein since they live for long periods of time, occupy diverse tissues throughout the body and are capable of secreting very high levels of protein. In collaboration with Discovery Genomics, Inc., the University of Minnesota and the Fred Hutchinson Cancer Research Center, Immusoft has developed a treatment for Mucopolysaccharidosis type I (MPS I). In initial tests, Sleeping Beauty (SB) transposons expressing the human iduronidase gene were introduced into cultured B lymphoblastoid cells with and without a source of SB transposase, demonstrating long-term, high level expression of IDUA activity in vitro. SB transposons expressing both IDUA and a methotrexate-resistant human dihydrofolate reductase allowed for a >10-fold expansion of IDUA-expressing cells in the presence of methotrexate, as determined by intracellular staining for human IDUA and flow cytometry. Overall IDUA expression was also increased >10-fold in the methotrexate-selected cell population. IDUA encoding SB transposons were also nucleofected along with a source of SB transposase into primary human memory B cells, demonstrating expression of IDUA at levels more than 100 times greater than that observed in cultures of untreated primary B cells. These data support the development of a clinical trial to test SB-engineered B cells in the treatment of MPS I, with implications for improved treatment of other lysosomal storage disorders as well.
Abstract 2422: Pan-pim kinases inhibitor, AZD1208 suppresses tumor growth and synergistically interacts with an AKT inhibitor in gastric cancer cells
Authors: Miso Lee, Kyung-Hun Lee, Ahrum Min, Jungeun Kim, Seock-Ah Im, Seon-Gyeong Kim, Hyemin Jang, Yae-Won Yang, Tae-Yong Kim, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Yung-Jue Bang
Journal: Cancer Research (2015)

Abstract Introduction: Pim kinases are highly conserved serine/threonine kinases that control proliferation and survival pathways in cancer cells. Different expression patterns of each isoforms (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancer including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effect of AZD1208 as a single agent or in combination with an Akt inhibitor on the growth and cell death in gastric cancer cells. Materials and Methods: The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assay. The underlying mechanism was also examined by western blotting, immunofluorescence assay (IFA), and cell cycle analysis. Results: Direct substrates of Pim kinases were downregulated by the treatment with AZD1208, but we could not find any reduction of cell viability in short-term cell cultures. In contrast, cell viability decreased significantly in long-term cultures. Light chain 3B (LC3B), a marker for autophagy, increased in sensitive cells in dose dependent manner with AZD1208 treatment, which suggest that the growth inhibition effect of AZD1208 was achieved through autophagy, but not through apoptosis. Moreover, we found that ATM and Chk2, two critical components of the DNA repair pathway, were activated in an AZD1208-resistant cell line. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. Conclusion: AZD1208 induced cell death through autophagy in gastric cancer cells. Additionally, the combination of AZD1208 with an Akt inhibitor shows synergistic antitumor effects. Citation Format: Miso Lee, Kyung-Hun Lee, Ahrum Min, Jungeun Kim, Seock-Ah Im, Seon-Gyeong Kim, Hyemin Jang, Yae-Won Yang, Tae-Yong Kim, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Yung-Jue Bang. Pan-pim kinases inhibitor, AZD1208 suppresses tumor growth and synergistically interacts with an AKT inhibitor in gastric cancer 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 2422. doi:10.1158/1538-7445.AM2015-2422
181. Real-Time Monitoring of Transcription Factor Activity Using In Vitro and In Vivo Models of Cholestasis
Authors: Juliette M.K.M. Delhove, Dany Perocheau, Suzanne M.K. Buckley, Rajvinder Karda, Simon N. Waddington, Tristan R. McKay
Journal: Molecular Therapy (2015)

Biliary obstruction results in cholestasis characterised by fibrosis, progressive cirrhosis and cholangiocyte hyperplasia leading to liver failure. The underlying molecular mechanisms remain unclear but likely involve deregulation of bi-potent progenitor cells. Transfection of cell lines with vectors containing serial transcription factor (TF) binding sequences upstream of a minimal promoter driving luciferase expression have been widely used to study TF activity in vitro. We have expanded on this technology, both in vitro and in vivo, to enable quantification of bioluminescence output in living cell cultures and animals. We have developed a library of lentiviral vectors expressing either firefly luciferase or a secreted NanoLuc luciferase conditionally activated by a range of TFs. Human HepaRG cells can be cultured as bi-potent progenitors capable of differentiating into cholangiocytes or hepatocytes and act as a valuable tool to understand cholangiocyte hyperplasia. We have evaluated TF activity in living HepaRG cultures subjected to pro-cholestatic agonists by measuring NanoLuc activity in conditioned medium. For in vivo experiments, high-titer VSV-G pseudotyped lentiviral preps containing TF activated reporter cassettes were administered by intravascular injection to P0 neonatal mice. This resulted in liver-restricted transduction and lifelong tolerance of the transgene. After establishing a bioimaging baseline, adult mice injected with either the NF-κB or the Smad2/3 reporter constructs, were subjected to partial bile duct ligation (pBDL) and serial bioimaging thereafter. Responses were observed in NF-kb (p = 0.048) and Smad2/3 (p = 0.009) reporter mice post-BDL. These tools have allowed us to evaluate and compare the temporal activity of candidate TFs during cholestatic insult in living cells and living mice. We envisage that this study could result in the elucidation of novel therapeutic targets.
BCL-2 Expression at the Time of Diagnosis Affects the Clinical Outcome of Patients with Germinal Center and Non-Germinal Center Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Chemo-Immunotherpy
Authors: Sulada Pukiat, Nuttapong Ngamphaiboon, Pooja Advani, Julio Chavez, George Deeb, Anjana Elefante, Francisco J. Hernandez-Ilizaliturri
Journal: Blood (2010)
Comparative analysis of lung cancer in a public hospital versus private hospitals in New York.
Authors: V. Gotlieb, V. Verma, J. Fogel, A. Multz, R. J. Gralla
Journal: Journal of Clinical Oncology (2011)

6037 Background: Modern health care systems tend to unite a few hospitals. Besides financial reasons, this reveals general treatment and diagnostic trends, more efficient approaches for conducting clinical trials and research. It also helps to identify the areas which need improvement and to dedicate resources where certain diseases are prevalent. Hospitals often care for groups with different demographic characteristics. Combining hospital data for overall analyses may overlook the health care profiles particular to the demographic group at a particular hospital. Methods: We analyzed lung cancer data for stages 0 through 4 for 1,412 patients from the tumor registry of three hospitals in the New York City metropolitan area; one was a public hospital, Nassau University Medical Center (NUMC) with patients typically of lower income (n=351), while the other two were private hospitals, North Shore University Hospital (NSUH) (n=680) and Long Island Jewish Hospital (LIJ) (n=381), with patients typically of moderate to higher income. As appropriate, the Pearson Chi square or the Fisher’s exact test was used to analyze the data. Results: Smaller percentages of patients were diagnosed with stages 0 and 1 lung cancer at NUMC (8.55%) versus either NSUH (36.18%, p<0.001) or LIJ (35.70%, (p<0.001). The opposite was observed for advance stage disease of stage 4 lung cancer where NUMC had significantly greater percentages (59.54%) than either NSUH (38.53%, p<0.001) or LIJ (34.38%, (p<0.001). Similar patterns were also observed for adeno- and squamous cell carcinoma. Conclusions: There appears to be a disparity between public and private hospitals with regard to stage. NUMC, the public hospital, had lower percentages than the private hospitals of lung cancer in early stages where there could potentially be effective treatments, including cure in 70%, while greater percentages than the private hospitals at stage 4 where there are very few useful treatments. This disparity could be addressed with additional diagnostic procedures. We suggest, that in certain populations such as those seen in public hospitals, the screening topic may be worth revisiting as it may detect lung cancer at earlier stages where it can be effectively treated.
Genetically tailored magnetosomes used as MRI probe for molecular imaging of brain tumor
Authors: M. Boucher, F. Geffroy, S. Prévéral, L. Bellanger, E. Selingue, G. Adryanczyk-Perrier, M. Péan, C.T. Lefèvre, D. Pignol, N. Ginet, S. Mériaux
Journal: Biomaterials (2016)
Abstract 1891: Butyric acid reverts DRP1-mediated cell proliferation and migration in colorectal cancer cells
Authors: Dhanir M. Tailor, Eun Ryeong Hahm, Shivendra V. Singh, Rana P. Singh
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) is fourth most commonly diagnosed cancer in the world and more than 1 million new cases diagnosed annually. Human gastro-intestinal (GI) tract carries more than 100 billion microbial cells of over 1000 different species. These gut microbiota have direct correlation with dietary habits and health. Butyric acid (BA) is the byproduct of anaerobic microbial fermentation inside the GI tract that could reach up to 20 mM, and has been shown to inhibit the growth of various cancers. Recently, we observed that BA induced G2/M phase arrest and apoptosis, and down regulated the expression of DRP1. Further, we evaluated the effect of DRP1 expression on cell proliferation and migration and its response to BA treatment. DRP1 overexpression increased cell proliferation rate by 20% when compared to control vector transfected HCT116 cells. BA treatment (1 mM) for 12 h to DRP1 overexpressed cells reverted cell proliferation by 11% and induced cell cycle arrest in S and G2/M phase, BA caused significant G2/M arrest in control cells. DRP1 overexpression led to pro-survival signaling including activation of ERK1/2 and Akt, and concomitantly decreased the levels of cell cycle inhibitory and pro-apoptotic molecules including p53, p21 and Bax. BA treatment reverted the pro-survival signaling and induced the expression of p53 and p21 as well as enhanced the interaction between DRP1 and p53. DRP1 also led to an increase in cell migration and invasion by 28% and 40%, respectively which was associated with decreased expression of E- cadherin. In presence of BA, DRP1 overexpressing cells loss their ability to migrate up to 70% and increased the expression of E-cadherin. These results suggest that regulation of DRP1-dependent mitochondrial fission mediated the cell proliferation and migration and thus could be a novel target to regulate colon cancer growth, progression and metastasis. BA is product of anaerobic fermentation of dietary fibers which is directly related to the nutritional practices of individuals; thus healthy dietary practices may help to reduce the incidence of colorectal cancer. Citation Format: Dhanir M. Tailor, Eun Ryeong Hahm, Shivendra V. Singh, Rana P. Singh. Butyric acid reverts DRP1-mediated cell proliferation and migration in colorectal cancer 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 1891. doi:10.1158/1538-7445.AM2015-1891
Genetic profiles of hereditary nonpolyposis colorectal cancer.
Authors: C. Therklidsen, G. Jonsson, I. Bernstein, M. Nilbert
Journal: Journal of Clinical Oncology (2011)

469 Background: With the aim to identify genetic markers of hereditary nonpolyposis colorectal cancer (HNPCC), we applied tiling BAC array-based comparative genomic hybridization (aCGH) to 46 HNPCC-associated colorectal cancer. Methods: 32 k iling BAC arrays were used to generate high-density genomic profiles. Tumors were selected through a case-control design with half of the tumors derived from individuals with disease-predisposing mismatch repair gene mutations and the reminder from phenotypic HNPCC families without identified mutations. In addition, an equal number of sporadic tumors were used for comparison. Results: Tumors with disease-predisposing germline mutations showed frequent gains of chromosomes 1p (39%), 17 (43%), 19 (57%) and 22q (30%). HNPCC associated tumors without mutations did as a group have more complex alterations with the most frequent changes being gains of 20q (70%), 19 (35%), 17 (26%) and loss of 18 (39%). Gains of 1p and 20q and loss of chromosome 18 were identified as significant discriminators between HNPCC tumors with/without germline MMR gene mutations. Conclusions: The aCGH profiles of HNPCC-associated colorectal cancer suggest that specific gains and losses may be used to distinguish between tumors with/without germline mismatch repair gene mutations. No significant financial relationships to disclose.
Rome was not built in one day: Underlying biological and cognitive factors responsible for the emergence of agriculture and ultrasociality
Authors: Jason Grotuss, Sarah Jean Beard
Journal: Behavioral and Brain Sciences (2016)

Abstract Agriculture represented a major transition in human evolution, but the appearance of ultrasociality must have included previous steps. We argue that ultrasociality would not have suddenly emerged with agriculture, but rather developed from pre-existing cognitive and social mechanisms. Discussions must include necessary depth about the historical origins of human ultrasociality, and agriculture's aftereffects on large-scale social organization.
T-Cell Immunotherapy with a Chimeric Receptor Against CD38 Is Effective in Eliminating Myeloma Cells
Authors: Keichiro Mihara, Joyeeta Bhattacharyya, Akira Kitanaka, Akihiro Ihara, Akira Sakai, Yoshiaki Kuroda, Hideki Asaoku, Yoshihiro Takihara, Akiro Kimura
Journal: Blood (2011)
The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy
Authors: Constantin d’Ydewalle, Daniel M. Ramos, Noah J. Pyles, Shi-Yan Ng, Mariusz Gorz, Celeste M. Pilato, Karen Ling, Lingling Kong, Amanda J. Ward, Lee L. Rubin, Frank Rigo, C. Frank Bennett, Charlotte J. Sumner
Journal: Neuron (2016)
Abstract 478: EWS/FLI1 transcription is modulated by the PI3K pathway via SP1 in Ewing sarcoma
Authors: Chiara Giorgi, Alexander Boro, Laura A. Lopez-Garcia, Beat W. Schaefer, Felix K. Niggli
Journal: Cancer Research (2015)

Abstract Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and it is characterized by the presence of the balanced t(11;22)(q24;q12) translocation in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. ES belongs to small-round-blue-cell tumors and it is a very aggressive osteolytic cancer with early tendency for development of metastasis. Mostly it affects bones such as pelvis, femour and ribs but can also arise in soft tissues, mainly in adults. EWS/FLI1 is an essential oncogenic component of ES development which is necessary for tumor cell maintenance, through inappropriate regulation of target genes that are crucial for the fully malignant phenotype. Therefore, EWS/FLI1 represents an attractive therapeutic target. Screening of a small library of 153 targeted compounds has identified inhibitors of the PI3K pathway as main modulators of EWS/FLI1 activity and surprisingly this was due to an effect of the compound on EWS/FLI1 transcription. Indeed, treatment of four different ES cell lines with BEZ235 (PI3K-mTOR inhibitor) resulted in downregulation of EWS/FLI1 by 50% expression with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (-2239/+67) using various deletion constructs identified two 14bp minimal elements, named Del2 and Del23 region, as being important for EWS/FLI1 transcription. Based on in silico prediction and on in vivo data, we were able to predict 4 transcription factor candidates to bind this region and being responsive to PI3K regulation. Among these, SP1 was identified as modulator of EWS/FLI1 gene expression by siRNA. Various approches such as qRT-PCR, Western Blot and Immunofluorescence confirmed a reduction of EWS/FLI1 in Ewing cells when PI3Kαγδ and SP1 were depleted; Electrophoretic Mobility Shift Assay (EMSA) and Chromatine Immuno Precipitation (ChIP) both confirmed that the transcription factor SP1 is indeed binding to Del23 region of the EWS/FLI1 promoter. In summary, our results provide the very first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer a molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition. Citation Format: Chiara Giorgi, Alexander Boro, Laura A. Lopez-Garcia, Beat W. Schaefer, Felix K. Niggli. EWS/FLI1 transcription is modulated by the PI3K pathway via SP1 in Ewing sarcoma. [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 478. doi:10.1158/1538-7445.AM2015-478
Pathway Dependence on the Tyrosine Kinase TYK2 and Its Mediator STAT1 In T-Cell Acute Lymphoblastic Leukemia
Authors: Takaomi Sanda, Jeffrey W Tyner, Alejandro Gutierrez, Vu N Ngo, Richard Moriggl, Yebin Ahn, Jason M Glover, Bill H Chang, Stephanie G Willis, Louis M. Staudt, Brian J Druker, A. Thomas Look
Journal: Blood (2010)
Results of the AIEOP-BFM ALL 2000 Study for Childhood Acute Lymphoblastic Leukemia IN AIEOP High Risk Patients.
Authors: Valentino Conter, Maria Grazia Valsecchi, Maurizio Aricò, Carmelo Rizzari, Rosanna Parasole, Chiara Messina, Giulio De Rossi, Elena Barisone, Luca Lo Nigro, Nicola Santoro, Ottavio Ziino, Franco Locatelli, Andrea Pession, Anna Maria Testi, Concetta Micalizzi, Andrea Biondi, Giuseppe Basso, Daniela Silvestri, Giuseppe Masera
Journal: Blood (2009)
Inhibition of Angiogenesis by a Novel Neutralizing Antibody Against Human Vascular Endothelial Growth Factor Receptor 3 (VEGFR-3).
Authors: Hao Chen, Xiu-Yun Ding, Yuan Gao, Fei-Yao Ren, Hui Li, Jian-En Gao, Qi-Hong Sun
Journal: Blood (2005)
Activated T Cell-Mediated Immunotherapy with a Chimeric Receptor Against CD38 in B-Cell Malignancies.
Authors: Keichiro Mihara, Kazuyoshi Yanagihara, Misato Takigahira, Takahiro Ochiya, Chihaya Imai, Akira Kitanaka, Yoshihiro Takihara, Akiro Kimura
Journal: Blood (2007)