tbuckley/cabot-search huggingface dataset:
Abstract 3732: Detecting germline PTEN mutations among at-risk cancer patients: An age and gender-specific cost effectiveness analysis
Authors: Joanne Ngeow, Chang Liu, Ke Zhou, Kevin Frick, David B. Matchar, Charis Eng
Journal: Cancer Research (2015)

Abstract Introduction Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumours. One-quarter of patients diagnosed with CS have pathogenic germline PTEN mutations, which increase risks of breast, thyroid, uterine, renal and other cancers. PTEN testing and regular, intensive cancer surveillance allow for early detection and treatment of these cancers for mutation positive patients and their relatives. Individual CS-related features, however, occur commonly in the general population, making it challenging for clinicians to identify CS-like patients to offer PTEN testing. Methods: We calculated the cost per mutation detected and analyzed the cost-effectiveness of performing selected PTEN testing among CS-like patients using a semi-quantitative score [PTEN-Cleveland Clinic (CC) score] compared with existing diagnostic criteria. In our model, first-degree relatives of the patients with detected PTEN mutations are offered PTEN testing. All individuals with detected PTEN mutations receive cancer surveillance. Findings: CC score at a threshold of 15 (CC15) allows costs ranging from $3,720 to 4,573 to detect one PTEN mutation, which is the lowest among different strategies tested. At a cost-effectiveness threshold of $100,000/Quality Adjusted Life Year (QALY), CC15 is the optimal strategy for female patients older than 50 years while CC10 is the optimal strategy for female patients younger than 50 years old and male patients of all ages. These results are robust in one-way sensitivity analyses. In probabilistic sensitivity analysis, CC10 and CC15 are the optimal strategies in 73% and 21% of the simulations respectively at a willingness to pay $100,000/QALY. Conclusion: CC score as a clinical risk calculator is a cost-effective pre-screening method to identify CS-like patients for PTEN germline testing. Citation Format: Joanne Ngeow, Chang Liu, Ke Zhou, Kevin Frick, David B. Matchar, Charis Eng. Detecting germline PTEN mutations among at-risk cancer patients: An age and gender-specific cost effectiveness analysis. [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 3732. doi:10.1158/1538-7445.AM2015-3732
Human CD34+ Cells Rapidly Mobilized by AMD3100 Repopulate NOD/SCID Mice with Equivalent Efficiency as CD34+ Cells Mobilized by G-CSF.
Authors: David A. Hess, Jesper Bonde, Timothy P. Craft, Louisa Wirthlin, John F. DiPersio, Steven M. Devine, Jan A. Nolta
Journal: Blood (2004)
A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy
Authors: Erhao Zhang, Hanmei Xu
Journal: Journal of Hematology & Oncology (2017)

Adoptive cell therapy using chimeric antigen receptor (CAR)-engineered T cells has emerged as a very promising approach to combating cancer. Despite its ability to eliminate tumors shown in some clinical trials, CAR-T cell therapy involves some significant safety challenges, such as cytokine release syndrome (CRS) and "on-target, off-tumor" toxicity, which is related to poor control of the dose, location, and timing of T cell activity. In the past few years, some strategies to avoid the side effects of CAR-T cell therapy have been reported, including suicide gene, inhibitory CAR, dual-antigen receptor, and the use of exogenous molecules as switches to control the CAR-T cell functions. Because of the advances of the CAR paradigm and other forms of cancer immunotherapy, the most effective means of defeating the cancer has become the integration therapy with the combinatorial control system of switchable dual-receptor CAR-T cell and immune checkpoint blockade.
Abstract 938: Circulating biomarkers of gut barrier function: Correlates and responses to calcium supplementation among sporadic colorectal adenoma patients in a dose-response randomized controlled trial
Authors: Baiyu Yang, Roberd M. Bostick, Andrew T. Gewirtz, Hao Quang Tran, Veronika Fedirko
Journal: Cancer Research (2015)

Abstract Gut barrier dysfunction contributes to several gastrointestinal disorders, including inflammatory bowel diseases and colorectal cancer, but factors associated with intestinal hyperpermeability have rarely been assessed in human populations, and there is very limited clinical trial evidence on whether gut barrier function may be modified by dietary factors. To address these gaps, we 1) evaluated factors associated with baseline circulating biomarkers of gut barrier function, and 2) tested the effect of calcium on these biomarkers over a 4-month treatment period among patients with previous colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial (n = 193). Patients were randomized to placebo (n = 66), 1.0 g calcium (n = 64), or 2.0 g calcium (n = 63) daily. Circulating levels of anti-flagellin and anti-lipopolysaccharide (LPS) immunoglobulins (Igs) as markers of colonic hyperpermeability were measured at baseline and at 4-month follow-up via ELISA. At baseline, mean levels of anti-flagellin and anti-LPS IgA but not IgG were higher among men and those with a larger body mass index (BMI), a larger waist circumference, and higher levels of plasma C-reactive protein. Mean anti-flagellin IgG levels were higher among those with higher proinflammatory cytokine scores. We did not observe effects of calcium on anti-flagellin or anti-LPS Igs: the relative change of a combined permeability score (defined as the sum of the optical densities of all biomarkers) from baseline to follow-up was 0.07 (95% confidence interval [CI] -0.13, 0.27) for each treatment group relative to the placebo group (p-values ≥ 0.5). Our results suggest that 1) men and those with a larger BMI or waist circumference may have greater gut permeability, 2) markers of gut permeability and systemic inflammation may be directly associated with one another, and 3) supplemental calcium administered for 4 months may not modify circulating levels of biomarkers of gut barrier function. Citation Format: Baiyu Yang, Roberd M. Bostick, Andrew T. Gewirtz, Hao Quang Tran, Veronika Fedirko. Circulating biomarkers of gut barrier function: Correlates and responses to calcium supplementation among sporadic colorectal adenoma patients in a dose-response randomized controlled trial. [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 938. doi:10.1158/1538-7445.AM2015-938
A combination of histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC and AML cells with constitutively active mutant FLT-3 tyrosine kinase
Authors: K. N. Bhalla, P. George, R. Gutti, P. Bali, J. Tao, F. Guo, C. Sigua, Y. Li, P. Cohen, P. Atadja
Journal: Journal of Clinical Oncology (2004)

6541 Background: We have reported that treatment with histone deacetylase inhibitors, LAQ824 and LBH589 (Novartis Pharma AG), and hsp90 inhibitor 17-AAG attenuates the levels of Bcr-Abl and FLT-3, as well induces apoptosis of human CML-BC and AML cells. In these studies we determined the antileukemia activity of the combination of LBH589 and 17-AAG. Methods: K562 (CML-BC), MV4–11 (AML cells with the activating length mutation of FLT-3) and primary AML (with FLT-3 mutation) were exposed to 0.1 to 2.0 uM 17-AAG and/or 5 to 100 nM LBH589 for 24 to 48 hours. Following this, the cell cycle status and apoptosis (by flow cytometry), as well as the expressions of p21, hsp70, p-FLT-3, FLT-3, p-AKT, p-ERK1/2 and p-STAT5 (by Western analyses) were determined. Results: LBH589 treatment induced p21 levels and mediated cell cycle G1 phase accumulation as well as apoptosis of MV4–11 and K562 cells. In MV4–11 cells, this was associated with marked attenuation of the protein levels of p-FLT-3, FLT-3, p-AKT, p-ERK1/2 and p-STAT5, as well as the DNA binding activity of STAT5. Furthermore, co-treatment with LBH589 and the FLT-3 kinase inhibitor PKC412 (Novartis Pharma AG) exerted synergistic cytotoxic effect against MV4–11 cells. In K562 cells, exposure to LBH589 attenuated Bcr-Abl, p-AKT, p-ERK1/2 and p-STAT5. Treatment with 17-AAG or LBH589 inhibited the chaperone association of hsp90 with FLT-3 and Bcr-Abl in MV4–11 and K562 cells, respectively, resulting in polyubiquitylation and proteasomal degradation of FLT-3 and Bcr-Abl. Significantly, co-treatment with LBH589 and 17-AAG induced more apoptosis of MV4–11 and K562 cells that either agent alone. The combination also attenuated the levels of mutant T315I Bcr-Abl and induced apoptosis of Gleevec-refractory primary CML-BC,as well as induced more apoptosis of primary AML cells with FLT-3 mutations. Conclusions: These studies demonstrate that the combination of LBH589 and 17-AAG may be highly effective in attenuating p-FLT-3 and Bcr-Abl, as well as inducing apoptosis of CML-BC and AML cells with FLT-3 mutations. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Corp. Novartis Corp.
Detection of Fusarium-specific T cells in hematologic patients with invasive fusariosis
Authors: Daniela Vallerini, Fabio Forghieri, Ivana Lagreca, Giovanni Riva, Patrizia Barozzi, Chiara Quadrelli, Monica Morselli, Paola Bresciani, Angela Cuoghi, Valeria Coluccio, Monica Maccaferri, Ambra Paolini, Elisabetta Colaci, Roberto Marasca, Franco Narni, Monica Cellini, Anne Beauvais, Jean-Paul Latgè, Luigina Romani, Lorenzo Iughetti, Patrizia Comoli, Daniele Campioli, Tommaso Trenti, Mario Luppi, Leonardo Potenza
Journal: Journal of Infection (2016)
Upper Gastrointestinal Bleeding In Patients with Haemophilia In Iran: Prevalence of Helicobacter Pylori Infection.
Authors: Roya Dolatkhah, Manouchehr Khoshbaten, Iraj Asvadi Kermani, Zohreh Sanaat, Mohammad Reza Bonyadi, Morteza Ghojazadeh, Kamran Alimoghaddam, Touraj Asvadi Kermani
Journal: Blood (2010)
Six Amino Acid Residues in a 1200 Å2 Interface Mediate Binding of Factor VIII to An IgG4 Inhibitory Antibody.
Authors: Jasper C. Lin, Jason T. Schuman, Shelley M. Nakaya, Vasudha Kaushik, Marc Jacquemin, Arthur R. Thompson, Kathleen P. Pratt
Journal: Blood (2008)
Abstract 1038: Cell-based screening identifies gene expression signature correlated with sensitivity to PI3K-mTOR dual inhibitor BEZ235
Authors: Jing Zhang, Sheng Guo, Zhengzheng Bao, Limei Shang, Xiao Wen, Jean-Pierre Wery, Jinying Ning
Journal: Cancer Research (2015)

Abstract The PI3K-mTOR pathway is one of the major signaling cascades that promote tumor growth and cell survival. Multiple inhibitors targeting this important axis are currently under clinical investigation for cancer treatment and some are under preclinical development. Here we examined the anti-proliferation activity of BEZ235, a PI3K and mTOR dual inhibitor, in 243 human cancer cell lines of different caner types. We identified 35 lines that are sensitive to the inhibitor with IC50 values less than 0,04uM and 57 insensitive lines with IC50 values more than 0.4uM. We compared gene expression of the two groups by Affymetrix U219 arrays. With a p-value cutoff set at 0.00001, we identified 14 genes that are differentially expressed. These genes include epithelial membrane glycoprotein EPCAM and serine threonine kinase 31 (STK31). Furthermore, the mutation status of tubulin tyrosine ligase TTL is significantly correlated with sensitivity to BEZ235. These results suggested a potential genomic signature that could be predictive of response to BEZ235 and provided information that may help selecting patients that are likely to receive clinical benefit. Citation Format: Jing Zhang, Sheng Guo, Zhengzheng Bao, Limei Shang, Xiao Wen, Jean-Pierre Wery, Jinying Ning. Cell-based screening identifies gene expression signature correlated with sensitivity to PI3K-mTOR dual inhibitor BEZ235. [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 1038. doi:10.1158/1538-7445.AM2015-1038
Abstract 2540: A new mathematical model and software, to enable improved quantification and interpretation of combinatorial drug effects
Authors: Giovanni Y. Di Veroli, Duncan I. Jodrell, Frances M. Richards, Ian Goldlust
Journal: Cancer Research (2015)

Abstract Drug combinations are used commonly to treat patients with cancer. Combination studies are conducted in vitro, to support advancement to in vivo and/or clinical research. In order to interpret in vitro data, mathematical models and numerical methods are used to quantify degrees of drug synergism. Several traditional approaches exist but they have been questioned with regard to how resulting synergy or antagonism levels should be interpreted. Our aim was to develop a robust method to analyse in vitro drug combination data, avoiding the issues related to traditional models and methods. To facilitate its implementation, software to enable rigorous and systematic assessment of combinations in vitro was also developed. We have derived a new mathematical model to identify synergy distributions based on drug combination dose response surfaces. Our new model and the classical Bliss, Loewe and HSA models were incorporated into the newly developed Combenefit software. Combenefit enables systematic quantification of high-throughput screening data, incorporating statistical assessment, metrics to describe synergy distributions and advanced graphical visualisation. Using multiple simulations of combination data with expected outcomes, our approach showed that it always provided appropriate evaluation while classical models failed to do so. We showed how our new model is in principle better aligned with in vivo requirements of identifying combinations which provide improvements compared to single agents. We then proceeded to analyse a large high-throughput combination screen. We first demonstrated that dataset assessment is strongly model-sensitive. We then demonstrated that our new model identified the best combinations in terms of dose response, thus confirming our simulated cases. Therefore, we have developed a new mathematical model that solves fundamental issues of model relevance that are encountered with classical models in the context of drug combinations. The newly developed Combenefit software enables easily performing rigorous and systematic quantification of in vitro combinations based on this novel approach. (Combenefit is freely available on our institutional website http://www.cruk.cam.ac.uk/combenefit). The resulting procedure is robust and better aligned with our perception of in vivo requirements. Citation Format: Giovanni Y. Di Veroli, Duncan I. Jodrell, Frances M. Richards, Ian Goldlust. A new mathematical model and software, to enable improved quantification and interpretation of combinatorial drug effects. [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 2540. doi:10.1158/1538-7445.AM2015-2540
The aryl hydrocarbon receptor controls cell-fate decisions in B cells
Authors: Bharat Vaidyanathan, Ashutosh Chaudhry, William T. Yewdell, Davide Angeletti, Wei-Feng Yen, Adam K. Wheatley, Christopher A. Bradfield, Adrian B. McDermott, Jonathan W. Yewdell, Alexander Y. Rudensky, Jayanta Chaudhuri
Journal: The Journal of Experimental Medicine (2016)

Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody-secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool. In this study, we show that an environmental sensor, the aryl hydrocarbon receptor (AhR) is highly induced upon B cell activation and serves a critical role in regulating activation-induced cell fate outcomes. We find that AhR negatively regulates class-switch recombination ex vivo by altering activation-induced cytidine deaminase expression. We further demonstrate that AhR suppresses class switching in vivo after influenza virus infection and immunization with model antigens. In addition, by regulating Blimp-1 expression via Bach2, AhR represses differentiation of B cells into plasmablasts ex vivo and antibody-secreting plasma cells in vivo. These experiments suggest that AhR serves as a molecular rheostat in B cells to brake the effector response, possibly to facilitate optimal recall responses. Thus, AhR might represent a novel molecular target for manipulation of B cell responses during vaccination.
Dysregulation of mitotic checkpoint proteins Chfr and Aurora A in HTLV-I-infected T-cells
Authors: Mariko Tomita, Chie Ishikawa, Minoru Toyota, Takashi Tokino, Naoki Mori
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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Human T-cell leukemia virus type-I (HTLV-I) is the etiologic agent for adult T-cell leukemia (ATL) which shows various chromosomal aberrations, including aneuploidy and chromosomal instability. These abnormalities may be due to dysregulation of mitotic checkpoint proteins. Checkpoint with fork head-associated and ring finger (Chfr) is an early mitotic checkpoint gene that delays transition to metaphase in response to mitotic stress. Chfr protein, which has E3 ubiquitine ligase activity, interacts with mitotic kinase Aurora A and degrades Aurora A by ubiquitine-proteasome system. Overexpression of Aurora A transforms NIH3T3 fibroblasts and induces aneuploidy. Here we found that expression of Chfr is lost in HTLV-I-infected T-cell lines which express HTLV-I transforming protein Tax. Suppression of Chfr expression was associated with overexpression of Aurora A in these cells. Decreased expression of Chfr and overexpresion of Aurora A were also observed in primary ATL cells comparing to peripheral blood mononuclear cells (PBMCs) from healthy donors. Inducing Tax expression in JPX-9 cells, which are expressing Tax under control of the metallothionein promoter, did not affect the expression levels of Chfr and Aurora A. The 5’ CpG island of Chfr was aberrantly methylated and the methyltransferase inhibitor 5-aza-dC restored expression of Chfr in HTLV-I-infected T-cell lines, indicating that abnormal methylation in the promoter of Chfr gene inhibited the expression of this gene. Moreover, introduction of Chfr expression plasmid into HUT-102, an HTLV-I-infected T-cell line which does not express Chfr, reduced the cell growth, suggesting that loss of Chfr expression in HTLV-I-infected T-cell lines enhanced growth of the cells. To elucidate the role of overexpressed Aurora A in HTLV-I-infected T-cell lines, cells were treated with Aurora kinase inhibitor. Aurora kinase inhibitor reduced the cell viability of primary ATL cells, but did not affect that of PBMCs from healthy donors. Although the Tax-negative T-cell lines treated with Aurora kinase inhibitor underwent suppression of cell division, Aurora kinase inhibitor induced apoptosis without suppression of cell division in Tax-positive HTLV-I-infected T-cell lines. Moreover, induction of Tax protein in JPX-9 cells reduced the cell number without suppression of cell division by treatment with Aurora kinase inhibitor. These results suggest that Tax may affect cell fate after treatment of Aurora kinase inhibitor. Our findings in this study suggested that loss of Chfr and overexpression of Aurora A might contribute malignant growth and anti-apoptosis of HTLV-I-infected T-cells and these molecules are good therapeutic targets of ATL.
Abstract 5036: Tumor-induced activation of the Wnt/β-catenin/TCF4 pathway in dendritic cells promotes immune tolerance
Authors: Yuan Hong, Indumathi Manoharan, Amol Suryawanshi, Santhakumar Manicassamy
Journal: Cancer Research (2015)

Abstract Tumors actively suppress host antitumor immune response and this represents a fundamental barrier to successful cancer immunotherapy. However, the molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that Wnt ligands in the tumor microenvironment activate the β-catenin/TCF4 pathway within dendritic cells (DCs) rendering them tolerogenic and able to suppress host antitumor immunity against melanoma. This was because Wnt/β-catenin/TCF4 signaling in DCs induced retinoic acid synthesizing enzymes, which induced T regulatory responses and suppressed effector T cells. Consistent with this observation, DC-specific deletion of key downstream mediators of canonical Wnt signaling (Wnt co-receptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6), β-catenin and transcription factor 4 (TCF4)) in mice markedly delayed melanoma growth and enhanced host anti-tumor immunity. Likewise, pharmacological inhibition of the Wnt/β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and effector T cell responses. Hence, Wnt/β-catenin/TCF4 pathway links together DCs, Tregs and the retionoic acid pathway, and is an important target for anticancer immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: Yuan Hong, Indumathi Manoharan, Amol Suryawanshi, Santhakumar Manicassamy. Tumor-induced activation of the Wnt/β-catenin/TCF4 pathway in dendritic cells promotes immune tolerance. [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 5036. doi:10.1158/1538-7445.AM2015-5036