tbuckley/cabot-search huggingface dataset:
207. Optimal Activation of Both CD28 and 4-1BB in CAR-Targeted T Cells Results in Enhanced Tumor Eradication
Authors: Zeguo Zhao, Sjoukje J.C. van der Stegen, Maud Condomines, Fabiana Perna, Gertrude Gunset, Jason Plotkin, Michel Sadelain
Journal: Molecular Therapy (2015)

Chimeric Antigen Receptors (CARs) are a novel drug class, consisting of engineered receptors for antigen that redirect and reprogram T-cell function. We have shown in both xenogeneic tumor models as well as in leukemia patients, that CD19-targeted T-cells are capable of inducing complete remission of relapsed or refractory B cell malignancies. The inclusion of appropriate co-stimulation is essential for the potency, quality and durability of the CAR T cell response. Here we show that the co-stimulatory domain incorporated within the CAR dictates the kinetics of in vivo anti-tumor response and T-cell accumulation. Additionally, expression of co-stimulatory ligands complementary to the second-generation CAR provides an optimal balance of cytolytic activity and T-cell accumulation resulting in superior anti-tumor function. The combination of 19-28z CAR with 4-1BBL was associated with activation of the endogenous Interferon-β (IFNβ) pathway in an IRF7-dependent manner. This enabled very small T-cell doses to eradicate systemic established leukemia in a xenogeneic model. The unexpected role of the IRF7/IFNβ pathway provides insight into the synergy behind co-stimulatory molecules in T cell activation and a novel mechanism through which engineered T cells can increase tumor control.
AAV-Mediated Anterograde Transsynaptic Tagging: Mapping Corticocollicular Input-Defined Neural Pathways for Defense Behaviors
Authors: Brian Zingg, Xiao-lin Chou, Zheng-gang Zhang, Lukas Mesik, Feixue Liang, Huizhong Whit Tao, Li I. Zhang
Journal: Neuron (2016)
Adoptive Immunotherapy with Donor Lymphocyte Infusions after T-Cell Depleted Allogeneic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia.
Authors: Renee M.Y. Barge, Eva Steel, Ingrid Starrenburg, Floor Beaumont, Willem M. Smit, Martyn Ronald Schaafsma, Ward Posthuma, Willem E. Fibbe, Frederik Falkenburg, Roelof Willemze
Journal: Blood (2005)
Autologous vs Allogeneic Cell Transplantation for Mantle Cell Lymphoma (MCL): Outcomes over a 10-Year Period at City of Hope.
Authors: Leslie L. Popplewell, A. Nademanee, Nora Carter, Jasmine Zain, Amrita Krishnan, Roberto Rodriguez, Neil M. Kogut, Nayana Vora, Arturo Molina, Stephen J. Forman
Journal: Blood (2004)
OC-013 Clinical utility of faecal calprotectin in diagnosing inflammatory bowel disease during first presentation to the gastroenterology clinic: a novel investigative algorithm: Abstract OC-013
Authors: A Walkden, A Clark, R Dart, K Kingstone, G Brydon, J Satsangi, I D R Arnott, C W Lees
Journal: Gut (2010)

<h3>Introduction</h3> Faecal calprotectin (FC) has been shown to distinguish reliably between functional and inflammatory bowel diseases (IBD) in a number of studies of patients with established gastrointestinal disease. However, it is a poor screening test for colorectal cancer. Presently, diagnostic algorithms incorporating FC at first presentation to the gastroenterology clinic are lacking. <h3>Methods</h3> This study aimed to determine the optimal use of FC, in conjunction with serum markers, in the initial diagnostic workup of patients aged 16–50 years. Patients &gt;50 years were excluded, as they require colonoscopy to exclude malignancy. Detailed clinical, laboratory, endoscopic and radiological parameters were collected. Patients with a prior GI diagnosis were excluded. All stool samples were analysed in the same laboratory using the same FC assay (Calpro ELISA). ROME III and Lennard-Jones criteria were used. Patients were followed up for a minimum of 12 months. <h3>Results</h3> The Edinburgh FC Register comprises data on 7512 patients (2005–2008) from across Lothian. 1838/7512 were managed at 2 Edinburgh teaching hospitals, and aged 16–50 years at time of FC; 851 were excluded, mostly due to pre-established diagnosis of IBD. 987 (mean±SD age 33.5±9.0 years; 64.8% female) met the strict inclusion criteria. In patients presenting primarily with bloody diarrhoea (n=68), median FC was 690 μg/g (IQR: 72–2323), in contrast to watery diarrhoea (n=325, FC 30 μg/g (20–90), p&lt;0.0001), or abdominal pain (n=271; FC 25 μg/g (20–85), p&lt;0.0001). 193/987 (19.6%) were ultimately diagnosed with organic disease with median FC of 180 μg/g (37–1292), 113/987 (11.4%) with IBD (FC 990.0 (225–2190)) and 605/987 (61.3%) with a functional disorder (FC 20 (20–50)). FC was influenced by NSAID use, but not by age, sex or smoking. ROC analysis of FC in discriminating organic disease and IBD from functional disorders gave an area under the curve of 0.80 (95% CI 0.76 to 0.84) and 0.93 (95% CI 0.90 to 0.96), respectively. Further detailed analysis suggested the following model: FC&lt;70 μg/g with normal blood parameters and no alarm symptoms/signs – no further investigation; FC&gt;50 μg/g with bloody diarrhoea OR raised CRP/low albumin – combined radiological and endoscopic evaluation. <h3>Conclusion</h3> In this study, the largest on the clinical utility of FC, we were able to develop clear investigative strategies in adults &lt;50 years, dependent on FC and other clinical/laboratory parameters. This simple algorithm could be rolled out into primary care facilitating timely and appropriate triage of new patients and minimising diagnostic delay in IBD.
The Presence Of Leukemogenic Mutational Events In Paroxysmal Nocturnal Hemoglobinuria Suggests That Clonal Architecture Of Bone Marrow Failure Is Similar To Myelodysplastic Syndrome
Authors: Wenyi Shen, Bartlomiej P. Przychodzen, Michael J. Clemente, Brittney Dienes, Tetsuichi Yoshisato, Masashi Sanada, Kenichi Yoshida, Seishi Ogawa, Jaroslaw P. Maciejewski, Hideki Makishima
Journal: Blood (2013)
Abstract 4287: Talimogene laherparepvec activates systemic T-cell-mediated anti-tumor immunity
Authors: Julia Piasecki, Jim Rottman, Tiep Le, Rafael Ponce, Courtney Beers
Journal: Cancer Research (2015)

Abstract Talimogene laherparepvec is an investigational oncolytic immunotherapy based on a modified herpes simplex virus type-1 (HSV-1) immunotherapy designed to selectively replicate in tumors and to initiate an anti-tumor immune response. Intralesional administration of talimogene laherparepvec is intended to result in oncolysis within injected tumors. Iterative replication of virus within permissive tumor tissue results in lytic cell destruction and local release of progeny virus and tumor derived antigens. GM-CSF, a product of the viral transgene, is also produced locally such that it can recruit and stimulate antigen presenting cells which, in addition to relevant tumor-derived antigens, are required for the initiation of a systemic antitumor immune response. The talimogene laherparepvec-induced immune mediated mechanism of action in both the virus-injected and distant tumors have yet to be fully understood therefore, we evaluated viral replication, tumor cell lysis, and the changes in immune cell populations in both the injected and distant tumors using syngeneic contralateral tumor models. Animals received a single intratumoral dose of the murine surrogate of talimogene laherparepvec (OncoVEXmuGM-CSF), which induced regression in the majority of virus-injected tumors and tumor growth inhibition/regression in the contralateral (uninjected) tumors. HSV-1 antigen was only detected by IHC in the virus-injected tumor and not the contralateral tumor (and no other tissues). Virally-mediated tumor destruction (oncolysis) was also localized to only the virus-injected tumor. In preliminary experiments, morphometric analysis of the tumor tissue revealed that the percent area of CD3+ and CD8+ lymphocytes were significantly increased in both the virus-injected and contralateral tumors compared to the formulation control mice. In addition, the percent area occupied by CD103+ cells (a marker found on potent cytotoxic T cell stimulating dendritic cells) was increased in the virus-injected tumor compared to the contralateral tumor and the tumors in the control animals. Although cellular infiltration was increased in both virus-injected and contralateral tumors and was inversely correlated with tumor volume, the decreased volume of injected tumors was attributed to viral oncolysis. Taken together these data supports that talimogene laheparepvec activates a systemic T cell mediated anti-tumor immune response. Citation Format: Julia Piasecki, Jim Rottman, Tiep Le, Rafael Ponce, Courtney Beers. Talimogene laherparepvec activates systemic T-cell-mediated anti-tumor immunity. [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 4287. doi:10.1158/1538-7445.AM2015-4287
PBSC Mobilization by the Chemokine GROβ Alone and in Combination with G-CSF in Mice Demonstrates the Same Inter-Strain Variability in Mobilization Response as G-CSF and Is Dependent upon Differences in Neutrophil Pro-MMP-9 Content and Release.
Authors: Louis M. Pelus, Huimin Bian, Andrew G. King, Seiji Fukuda
Journal: Blood (2005)
Abstract 1431: Id4 inhibits cancer metastasis through EMT regulation in lung cancer
Authors: Szu-Hua Pan, Yuan Ling Hsu, Pei-Fang Hung, Chia-Jen Wang, Chi-Chung Wang
Journal: Cancer Research (2015)

Abstract Lung cancer is the leading cause of cancer related deaths worldwide. Delayed diagnosis and early metastasis are the major unsolved obstacles for most physicians in treating lung cancer patients. Thus, identifying novel metastatic genes and their action mechanisms involved in lung cancer progression and metastasis may provide new insights into the pathogenesis and management of lung cancer treatment. In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we identified a panel of 589 genes whose expression was correlated with cell invasiveness. And Inhibitor of DNA binding 4 (Id4) was one of these candidates. In this study, we demonstrate that the expression of Id4 was inversely associated with cell invasiveness in different lung cancer cell lines. Through manipulating the expression of Id4, we found that the expression of Id4 not only attenuate cell migration and invasion in vitro, but also affect the regulation of Epithelial-mesenchymal transition (EMT), a critical step for cancer metastasis. Additionally, we demonstrated that the expression Id4 was inversely correlated with lung cancer metastasis in vitro and in vivo and the reason Id4 affects metastasis probably is the regulation of EMT procession. Our data showed that Id4 could regulate EMT pathway by controlling the expression of Slug, a well-known EMT regulator, and recovering promoter activity of E-cadherin. Collectively, Id4 is a tumor suppressor in lung cancer, it can down-regulate EMT by reversing E-cadherin expression that represses by Slug. How to translate this research result for clinical application and develop potential therapeutic strategy for lung cancer treatment is our work in the future. Citation Format: Szu-Hua Pan, Yuan Ling Hsu, Pei-Fang Hung, Chia-Jen Wang, Chi-Chung Wang. Id4 inhibits cancer metastasis through EMT regulation in lung cancer. [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 1431. doi:10.1158/1538-7445.AM2015-1431
EBMT Risk Score for Pre Transplant Risk Assessment in Patients with Multiple Myeloma.
Authors: Zartash Gul, Hasan Khan, Qaiser Bashir, Nina Shah, Simrit Parmar, Yvonne T Dinh, Chitra M. Hosing, Uday R. Popat, Partow Kebriaei, Paolo Anderlini, Elizabeth J Shpall, Sergio Giralt, Richard E. Champlin, Muzaffar H. Qazilbash
Journal: Blood (2012)
5-hydroxytryptamine synthesized in the aorta-gonad-mesonephros regulates hematopoietic stem and progenitor cell survival
Authors: Junhua Lv, Lu Wang, Ya Gao, Yu-Qiang Ding, Feng Liu
Journal: The Journal of Experimental Medicine (2016)

The in vitro or ex vivo production of transplantable hematopoietic stem cells (HSCs) holds great promise for the treatment of hematological diseases in the clinic. However, HSCs have not been produced from either embryonic or induced pluripotent stem cells. In this study, we report that 5-hydroxytryptamine (5-HT; also called serotonin) can enhance the generation of hematopoietic stem and progenitor cells (HSPCs) in vitro and is essential for the survival of HSPCs in vivo during embryogenesis. In tryptophan hydroxylase 2–deficient embryos, a decrease in 5-HT synthesized in the aorta-gonad-mesonephros leads to apoptosis of nascent HSPCs. Mechanistically, 5-HT inhibits the AKT-Foxo1 signaling cascade to protect the earliest HSPCs in intraaortic hematopoietic clusters from excessive apoptosis. Collectively, our results reveal an unexpected role of 5-HT in HSPC development and suggest that 5-HT signaling may be a potential therapeutic target for promoting HSPC survival.
Different Cooperating Mutation Patterns of Receptor Tyrosine Kinases/Ras/JAK2 between De Novo AML1-ETO and CBFβ-MYH11 Acute Myeloid Leukemia.
Authors: Der-Cherng Liang, Lee-Yung Shih, Chein-Fuang Huang, Chang-Liang Lai, Ya-Tzu Chang, Tung-Huei Lin, Jin-Hou Wu, Ming-Chung Kou, Tung-Liang Lin, Chao-Ping Yang, Hsu-Che Liu
Journal: Blood (2007)
222. The LCR-Free Y-Globin Lentiviral Vector Combining Two HPFH Activating Elements Corrects Murine Thalassemic Phenotype In Vivo
Authors: Panayotis Antoniou, Eleni P. Papanikolaou, Maria Georgomanoli, Ekati Drakopoulou, Nicholas P. Anagnou
Journal: Molecular Therapy (2016)

The β-thalassemias result from reduced or absent expression of the β-chain of hemoglobin (α2β2; HbA) causing precipitation of excess α-chains and eventually apoptosis. Thus, factors that reduce the degree of chain imbalance such as an innate ability to increase fetal hemoglobin (HbF;α2γ2), as in the HPFH phenotype, have an ameliorating effect on the disease. Hence, gene therapy of β-thalassemia based on γ-globin addition via viral vectors, displays a considerable advantage. In this study, we assessed the efficiency of our previously generated LCR-free γ-globin self inactivating vector GGHI (Papanikolaou et al. Hum Gene Ther 2012) to correct the thalassemic phenotype in vivo in the Hbth3/+ C57BL/6J mouse model (thal3 model). Recipient mice aged about 12 weeks, were treated with the myelosuppresant factor busulfan, while donor mice, of the same age and of the opposite gender, were treated with 5-fluorouracil, prior to transplantation. Total bone marrow was isolated from 5-fluorouracil-treated donors and was transduced with GGHI in X-VIVO™ medium containing cytokines (mIL-1a, mIL-3, mIL-6 and mSCF) at an MOI=30, employing the spinoculation method. The transduced cells were then transplanted via tail vein intravenous injection to the recipients. To evaluate the therapeutic effect of GGHI, blood was collected from recipient mice prior and post transplantation for 4 months and, hemoglobin levels (g/dl), hematocrit and total red blood cell count were assessed by a hematological analyzer. The expression of human γ-globin in peripheral blood was assessed by flow cytometry using an anti-HbF monoclonal antibody. Our results documented that transplanted thalassemic mice (n=4) with GGHI-corrected hemopoietic stem cells, exhibited an increase in hematocrit values by 22.3% (ranging from 24.5% to 35.7%, p=0.02) with a concomitant increase in hemoglobin levels, reaching an average of 11.1 g/dl in transplanted mice vs 8.8 g/dl to those prior to transplantation, which corresponds to a 25.5% increase (p=0.008). Human γ-globin was detected in the peripheral blood of all transplanted animals by flow cytometry and ranged from 20 to 45%. Transduction efficiency in these experiments was estimated to be 35-50% as assessed in vitro in CFUs by PCR for vector-specific sequences. In summary, these results demonstrate for the first time that viral-mediated globin gene transfer via an LCR-free γ-globin lentiviral vector in hemopoietic stem cells effectively corrects a severe hemoglobin disorder.
Abstract 3823: Dysregulation of bone morphogenetic protein 2 serves as a candidate molecular marker in human renal cell carcinoma
Authors: Yozo Mitsui, Hiroshi Hirata, Naoko Arichi, Miho Hiraki, Hiroaki Yasumono, Inik Chang, Shinichiro Fukuhara, Soichiro Yamamura, Varahram Shahryari, Guoren Deng, Sharanjot Saini, Shahana Majid, Yuichiro Tanaka, Rajvir Dahiya, Hiroaki Shiina
Journal: Cancer Research (2015)

Abstract Introduction and Objective Bone morphogenetic protein-2 (BMP-2) has been shown to function as a tumor suppressor with several different cancers, while its expression level is down-regulated by CpG hypermethylation. We hypothesized that impaired regulation of BMP-2 through epigenetic pathways is associated with the pathogenesis of renal cell carcinoma (RCC). Methods To test our hypothesis, CpG methylation of the BMP-2 gene was analyzed using 2 RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. Results BMP-2 mRNA expression was significantly enhanced in the RCC cells by 5-aza-2′-deoxycitidie treatment. The prevalence of BMP-2 promoter methylation was significantly higher, while BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in the tumors. There was also a significant association of BMP-2 mRNA expression with tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after a radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression effectively induced p21WAF1/CIP1 and p27KIP1 expression, and cellular apoptosis in RCC cells. Conclusion This is the first study to show inactivation of the BMP-2 gene via epigenetic pathways in RCC. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be useful as a molecular marker for designing improved diagnostic and therapeutic strategies for RCC. Citation Format: Yozo Mitsui, Hiroshi Hirata, Naoko Arichi, Miho Hiraki, Hiroaki Yasumono, Inik Chang, Shinichiro Fukuhara, Soichiro Yamamura, Varahram Shahryari, Guoren Deng, Sharanjot Saini, Shahana Majid, Yuichiro Tanaka, Rajvir Dahiya, Hiroaki Shiina. Dysregulation of bone morphogenetic protein 2 serves as a candidate molecular marker in human renal cell 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 3823. doi:10.1158/1538-7445.AM2015-3823
Comparable Outcomes in Secretory (SM) Versus Non-Secretory (NSM) Multiple Myeloma (MM) with Autologous Hematopoietic Stem Cell Transplantation (AuHCT).
Authors: Shaji Kumar, Waleska S. Pérez, Mei-Jie Zhang, Christopher N. Bredeson, Martha Q. Lacy, Gustavo Milone, Donna Reece, David H. Vesole, Parameswaran Hari
Journal: Blood (2007)
Carfilzomib Induces Differentiation of Mesenchymal Stromal Cells Toward Osteoblast Via Activation of β-Catenin/TCF Signaling
Authors: Yu Chen, Saad Z Usmani, Bo Hu, Xenofon Papanikolaou, Christoph Heuck, Joshua Epstein, Bart Barlogie, Ya-Wei Qiang
Journal: Blood (2012)
Long-Term Results of Donor Lymphocyte Transfusions for the Treatment of Relapse After Allogeneic Transplantation for Chronic Myelogenous Leukemia - Is There a Role for Immunotherapy in CML?.
Authors: Hans-Jochem Kolb, Dagmar Bund, Helga Schmetzer, Christoph Schmid, Raymund Buhmann, Johanna Tischer, Georg Ledderose
Journal: Blood (2009)
PWE-047 Evaluation of PEG-IFN in an ethnically diverse HBV-infected population: 50% of treated patients derive long-term benefit
Authors: R Ghani, A Javaid, R Marley, J Lindsay, P T Kennedy, G R Foster
Journal: Gut (2010)

<h3>Introduction</h3> Historically pegylated-interferon (PEG-IFN) was reserved for HBeAg+ disease, where seroconversion represented a well defined treatment outcome with reported rates of up to 32%.<sup>1</sup> It has recently been shown to benefit a small proportion of patients with HBeAg- disease although patient groups who will benefit remains unclear. The Royal London Hospital treats a large ethnically diverse HBV infected population, thus represents an ideal setting to evaluate the influence of ethnicity on response. <h3>Methods</h3> Chronic HBV patients completing treatment with PEG-IFN between 2005 and 2008 were included. A total of 34 patients received PEG-IFN alfa-2a (180 μg once weekly) for 48 weeks. ALT, HBeAg, anti-HBe and viral load (VL) were recorded at 24 and 48 weeks on treatment, 6 and 24 months post treatment. Patients were divided according to e antigen status; HBeAg+ (Group 1, n=25) and HBeAg-(Group 2, n=9). Treatment success was defined by HBeAg seroconversion for Group 1, and a viral load &lt;80 IU/ml and ALT normalisation (&lt;40 IU/l) 6 months after treatment cessation was considered treatment success for HBeAg negative patients (Group 2). <h3>Results</h3> For HBeAg+ve patients (Group 1, n=25, 6 East Asian, 4 Bangladeshi, 5 African 6 other): 4 patients (17%) seroconverted, one of whom became anti-HBs+ on treatment. 28% of patients suppressed viral load and normalised ALT while on treatment. 50% of patients progressed to oral antivirals, 25% of whom then seroconverted. Hence 50% of patients either seroconverted or moved to a disease state where therapy was not required. All ethnic groups had a similar response and no pre-treatment factors influenced outcome. For HBeAg-ve disease (Group 2, n=9, 3 Bangladeshi 2 Pakistani 4 other): 3 patients (33%) met the criteria for treatment success at 48 weeks which was upheld over follow-up, one of whom underwent HBsAg seroconversion. Two patients had a sustained reduction in viraemia and inflammation that led to a decision to withhold further therapy. Four patients (44%) required oral antiviral therapy. Hence 56% of patients were managed by interferon alone. Success was most marked in patients from Bangladesh; all three had a full response. <h3>Conclusion</h3> This study highlights the benefit of PEG-IFN in HBeAg- disease and its potential advantage in certain ethnic groups. Nevertheless, we saw lower seroconversion rates in HBeAg+ patients than previously reported. Our data suggest that a high ALT is not a requisite for treatment success, while baseline VL, fibrosis stage and age were not determinants of treatment outcome. These data suggest that consideration should be given to PEG-IFN as a treatment option, as opposed to the early initiation of lifelong oral antivirals in treating chronic HBV.