tbuckley/cabot-search huggingface dataset:
Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene <i>WDR1 </i>
Authors: Ariane S.I. Standing, Dessislava Malinova, Ying Hong, Julien Record, Dale Moulding, Michael P. Blundell, Karolin Nowak, Hannah Jones, Ebun Omoyinmi, Kimberly C. Gilmour, Alan Medlar, Horia Stanescu, Robert Kleta, Glenn Anderson, Sira Nanthapisal, Sonia Melo Gomes, Nigel Klein, Despina Eleftheriou, Adrian J. Thrasher, Paul A. Brogan
Journal: The Journal of Experimental Medicine (2016)

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation.
Abstract 511: Rictor/mTORC2 drives formation, progression and therapeutic resistance of HER2-amplified breast cancers
Authors: Meghan M. Morrison, Bayley Jones, Violeta Sanchez, Monica V. Estrada, Donna Hicks, Michelle Williams, Dana Brantley-Sieders, Rebecca Cook
Journal: Cancer Research (2015)

Abstract The phosphatidyl inositol-3-kinase (PI3K)/Akt signaling pathway is aberrantly activated in nearly 60% of breast cancers, through HER2 amplification, PIK3CA mutation, PTEN inactivation, and other alterations. The mTOR complexes mTORC1 and mTORC2 operate as activators (mTORC2) or effectors (mTORC1) of Akt. We found that mRNA upregulation in the mTORC2 cofactors RICTOR and MAPKAP1 correlated with poor survival in breast cancer patients, while upregulation in the mTORC1 cofactor RPTOR did not. Genomic gains of RICTOR and MAPKAP1 occurred more frequently in breast cancers with PI3K pathway alterations than genomic RPTOR gains. Importantly, Rictor protein levels were increased in invasive over non-invasive breast tumors, while Raptor levels were not. RICTOR gene ablation in a transgenic mouse model of HER2-amplified breast cancer delayed tumorigenesis and decreased lung metastasis, Akt-S473 phosphorylation, cell growth and survival. In human HER2-amplified breast cancer cells, Rictor loss, but not Raptor loss, decreased Akt-S473 phosphorylation, reducing cell survival and motility/invasion. Interestingly, Rictor/mTORC2 loss or treatment with a dual mTORC1/2 inhibitor improved lapatinib-induced cell killing in parental and lapatinib-resistant tumor cells to a greater extent than mTORC1 inhibition. Akt re-activation rescued cell survival, but not motility/invasion, in Rictor-depleted cells. However, Rictor loss caused accumulation of the Rac inhibitor RhoGDI2, thus impairing Rac1-dependent invasion. We conclude that HER2-amplified breast cancers use Rictor/mTORC2 to drive Akt-mediated cell survival and Rac1-mediated cellular invasion. These studies support additional studies into mTORC2-specific inhibitors. Citation Format: Meghan M. Morrison, Bayley Jones, Violeta Sanchez, Monica V. Estrada, Donna Hicks, Michelle Williams, Dana Brantley-Sieders, Rebecca Cook. Rictor/mTORC2 drives formation, progression and therapeutic resistance of HER2-amplified breast cancers. [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 511. doi:10.1158/1538-7445.AM2015-511
An Interim Analysis of Phase II, Open Randomized Comparative Trial: Alternate or Multiple-Day Dosing of Palonosetron (PALO) Is Effective and Safe in the Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) in Patients (pts) with Leukemia Receiving High Dose Ara-C (HDAC).
Authors: Gloria Mattiuzzi, Jorge Cortes, Jennifer Cassat, Deborah Blamble, B. Nebiyou Bekele, Miloslav Beran, Gautam Borthakur, Farhad Ravandi, Jan Burger, Hagop Kantarjian
Journal: Blood (2007)
Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis
Authors: Calvin W.L. Chin, Russell J. Everett, Jacek Kwiecinski, Alex T. Vesey, Emily Yeung, Gavin Esson, William Jenkins, Maria Koo, Saeed Mirsadraee, Audrey C. White, Alan G. Japp, Sanjay K. Prasad, Scott Semple, David E. Newby, Marc R. Dweck
Journal: JACC. Cardiovascular imaging (2016)

Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality.Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis.In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up.iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m2 vs. 16.1 ± 3.2 ml/m2 in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m2; 51% of patients), extracellular expansion (iECV ≥22.5 ml/m2; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009).CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936).
Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).
Authors: Stefan Faderl, Alessandra Ferrajolil, William Wierda, Srdan Verstovsek, Farhad Ravandi-Kashani, Guillermo Garcia-Manero, Elihu Estey, Deborah A. Thomas, Steve Kornblau, Monica Kwari, Varsha Gandhi, Hagop M. Kantarjian
Journal: Blood (2004)
225. Activation Signals from CD19-CAR Permit NFAT-Controlled Inducible Expression of Transgenes in PBMCs
Authors: Ryosuke Uchibori, Takeshi Teruya, Soranobu Ninomiya, Hiroyuki Ido, Tomonori Tsukahara, Ken Ohmine, Masashi Urabe, Yasushi Saga, Akihiro Kume, Hiroaki Mizukami, Isabelle Riviere, Michel Sadelain, Renier J. Brentjens, Junichi Mineno, Keiya Ozawa
Journal: Molecular Therapy (2015)

Adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is a promising cell-based anticancer therapy. Although clinical studies of this approach show therapeutic efficacy, additional genetic modification is necessary to enhance the efficacy and safety of CAR-T cells. For example, producing an antitumor cytokine from CAR-T cells can enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects. Therefore, it is important that exogenous gene expression is confined to the tumor locality. Such an approach may lead to therapeutic strategies that are safe and effective. In this study, we aimed to develop a switch promoter driven by activation signals from a CAR. We prepared a switch cassette that was arranged in the order of two modified SV40 early polyA sequences as a background reduction signal, four NFAT-responsive elements, a minimal interleukin-2 (IL-2) promoter, a reporter gene, and a BGH polyA sequence. Transgene expression in peripheral blood mononuclear cells (PBMCs) transduced with the CD19-targeted CAR and switch cassette (PBMCs/CAR/iReporter) was only induced strongly by coculture with CD19-positive target cells. Furthermore, after antigen stimulation, PBMCs/CAR/iReporter produced approximately the same amounts of IL-2 and interferon-γ as PBMCs expressing the CAR only. The cells also showed redirected cytolysis toward CD19-positive, but not CD19-negative, tumor cells. These results indicated that the switch promoter was selectively driven by activation signals from the CAR. Furthermore, transduction with the switch cassette did not affect the original effector activity including IL-2 and IFN-γ production and antitumor activity of CAR-redirected cytotoxic T lymphocytes. In summary, we developed a retroviral vector that incorporates a CAR-derived, activation signal-dependent promoter to drive exogenous gene expression. This switch cassette permits visualization and quantification of the activation status in CAR-expressing PBMCs.
Distinct Human and Viral Interleukin-6 Profiles and Other Viral and Immunologic Abnormalities In KSHV-Associated Multicentric Castleman Disease: Relationship with Disease Activity and Individual Disease Manifestations
Authors: Mark N Polizzotto, Thomas S Uldrick, Victoria Wang, Karen Aleman, Kathleen M Wyvill, Vickie Marshall, Stefania Pittaluga, Deirdre O'Mahony, Denise Whitby, Giovanna Tosato, Seth M. Steinberg, Richard F Little, Robert Yarchoan
Journal: Blood (2011)
Dose-escalated external beam radiotherapy in unresectable hepatocellular carcinoma.
Authors: H. D. Skinner, H. J. Sharp, A. O. Kaseb, M. M. Javle, J. Vauthey, E. K. Abdalla, M. E. Delclos, P. Das, C. H. Crane, S. Krishnan
Journal: Journal of Clinical Oncology (2011)

267 Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Data regarding the use of external beam radiotherapy is limited in patients from populations without endemic viral hepatitis. We examine the outcomes for patients treated with external beam radiotherapy in the modern era at a single institution. Methods: A total of 29 patients with localized HCC treated from 2000 to 2009 were reviewed. Patients with metastatic disease at the time of radiation were excluded. Median radiation dose was 50 Gy (range 30-75 Gy) with a median biologically effective dose (BED) of 80.6 (range 60-138.6). Median tumor size at the time of radiation was 5.2 cm (range 2-25 cm). Results: Median residual tumor following radiation was 80% (range 27%-278%), with a median residual α-fetoprotein of 47% (range 0.8%-8240%). Estimated one-year overall survival (OS) and in-field progression-free survival (PFS) rates for the study population were 56% and 79%, respectively. One year OS in patients treated to a BED &lt;75 was 18% vs. 69% in patients treated to a BED ≥75 (p=0.002). One year in-field PFS rate (60% vs. 88%, p=0.023) and biochemical PFS duration (median 6.5 vs. 1.6 mos., p=0.001) were also significantly improved in patients treated to a BED ≥75. Grade 3 toxicity was seen in only 13.8% of patients. Conclusions: In a population without endemic viral hepatitis, unresectable HCC demonstrates significant response toexternal beam radiotherapy with minimal toxicity. Furthermore, our findings suggest that increased BED is associated with improved survival and local tumor control. No significant financial relationships to disclose.
Myeloma Microenvironment Controls T Regulatory Cell Activity: Potential Target for Therapeutic Interventions.
Authors: Rao H. Prabhala, Paola Neri, Mariateresa Fulciniti, Vanessa A. Therrien, Vidit Munshi, James J. Driscoll, Masood A. Shammas, Teru Hideshima, John F. Daley, Kenneth C. Anderson, Nikhil C. Munshi
Journal: Blood (2006)
Abstract A2-12: Opposing roles of the 19S regulatory and 20S core proteasomal subunits in controlling sensitivity to proteasome inhibitors
Authors: Min Y. Cho, Diego Acosta-Alvear, Martin Kampmann, Thomas Wild, Chuna Ram Choudhary, Jonathan S. Weissman, Peter Walter
Journal: Cancer Research (2015)

Abstract Targeted therapies for cancer are often hindered by the variable genetic makeup within and between tumors. This hurdle makes the identification of therapeutic targets challenging. Genetic susceptibilities found within networks encoded in the genome of a cancer cell can provide such therapeutic opportunities. Essential cellular networks overseeing homeostasis are often rewired in tumors, providing a landscape where synthetic lethal pairs may exist. A prominent example is the susceptibility of multiple myeloma (MM) cells to proteasome inhibitors. Because of their highly secretory nature, the proteasomes of MM cells can be burdened in a load-versus-capacity tug-of-war. This renders MM cells sensitive to proteasome inhibitors. Unfortunately, single agent therapies against the proteasome do not provide a cure, as tumor cells often acquire resistance. Because of this, we sought to understand how MM cancer cells respond and adapt to proteasome inhibition. Utilizing ultra-complex shRNA libraries, we screened several MM cell lines exposed to the proteasome inhibitor bortezomib. In these screens, we identified several genes that either sensitize or protect MM cells towards bortezomib intoxication. Unexpectedly we found that, contrary to knockdown of genes encoding subunits of the 20S core particle of the proteasome, knockdown of genes encoding subunits of the 19S regulatory particle of the proteasome lead to bortezomib desensitization. To understand the nature of this phenotype, we queried proteome changes in bortezomib treated cells where we ablated a single 19S subunit. By performing ubiquitin-remnant profiling and total proteome SILAC experiments, we identified several proteins involved in autophagy and NF-κB signaling as potential mediators of the protective phenotype. We are currently investigating the roles of components of these pathways in tailoring the response towards bortezomib. We surmise that some of these will be amenable for pharmacological targeting in developing novel combination therapies. Citation Format: Min Y. Cho, Diego Acosta-Alvear, Martin Kampmann, Thomas Wild, Chuna Ram Choudhary, Jonathan S. Weissman, Peter Walter. Opposing roles of the 19S regulatory and 20S core proteasomal subunits in controlling sensitivity to proteasome inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-12.
Abstract 3689: Comparative oncology drug discovery for Osteosarcoma in dogs and humans
Authors: Joy M. Fulbright, Kathleen Neville, Melinda Broward, Tyce A. Bruns, Anuradha Roy, Peter McDonald, Megan Ottomeyer, Douglas H. Thamm, Tomoo Iwakuma
Journal: Cancer Research (2015)

Abstract Introduction: The purpose of this study was to identify FDA approved drugs that initiate cell death or growth arrest in canine and human osteosarcoma (OS) cell lines in vitro followed by confirmation of anticancer activity in these cell lines. The ultimate objective of this comparative oncology project is to identify promising agents for the treatment of osteosarcoma in dogs and humans, a disease in which survival rates have remained low and stagnant for the last three decades. Procedures: A library of 2,328 FDA approved drugs was screened for activity in 2 canine and 2 human OS cell lines, as well as in 1 corresponding normal cell line. Cell viability was measure using the Cell Titer-Glo™ Luminescent Cell Viability Assay (Promega). FDA approved drugs meeting pre-determined screening criteria for activity, selectivity, and potency were selected for confirmatory studies. Effects on cell proliferation were confirmed using cell counting using trypan blue exclusion performed over a 10 day period. Effects on cell cycle and apoptosis were performed using propidium iodide staining and flow cytometry. Summary: Nine FDA approved drugs were identified based on activity and selectivity. Auranofin, a FDA approved rheumatoid arthritis agent, was selected for cell proliferation and cell cycle evaluation due to its IC50 value in control cells in comparison to OS cell lines. Auranofin displayed cytostatic effects in canine and human OS cell lines at low doses and drugs appeared to induce G2 arrest in treated cells. Conclusions: Auranofin is an FDA approved drug that demonstrates promising, selective anticancer activity in canine and human OS cell lines. The next steps are to determine whether this agent possesses additive or synergistic activity in combination with anticancer agents that have already demonstrated clinical activity in dogs and humans with OS. In vivo preclinical proof of concept will be determined in mouse xenograft studies and dogs with spontaneous OS for promising drug combinations. Subsequently, we hope to rapidly translate preclinical proof of concept findings to human OS patients. Citation Format: Joy M. Fulbright, Kathleen Neville, Melinda Broward, Tyce A. Bruns, Anuradha Roy, Peter McDonald, Megan Ottomeyer, Douglas H. Thamm, Tomoo Iwakuma. Comparative oncology drug discovery for Osteosarcoma in dogs and humans. [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 3689. doi:10.1158/1538-7445.AM2015-3689
PO43TRI-METHYLATED HISTONE H3K27 LEVELS ARE ASSOCIATED WITH LOCATION, AGE AND SURVIVAL
Authors: H.A. Rogers, T. Mugisa, J. Barron-Hastings, R.J. Chapman, R.G. Grundy
Journal: Neuro-Oncology (2015)

INTRODUCTION: Ependymoma is the second most common malignant paediatric tumour of the central nervous system, accounting for 6-12% of brain tumours. Currently there are few effective adjuvant therapies for paediatric ependymoma and prognosis remains poor. Understanding the underlying biology of ependymoma will help to identify agents that could be used in a more targeted approach to therapy. Recent studies have suggested epigenetic alterations may be important in the development of ependymoma and other paediatric brain tumours. One such modification is the tri-methylation of the lysine 27 residue of histone H3 which represses gene transcription. METHOD: Global levels of tri-methylated histone H3 (H3K27me3) were measured using IHC across a cohort of 292 ependymomas (210 primary, 82 recurrence). Additionally the effects of inhibiting the PRC2 complex was investigated using ependymoma cell lines. RESULTS: Positive staining for H3K27me3 was identified in 72 primary (34%) and 24 recurrences (29%). Positive staining was significantly associated with older age at diagnosis (p < 1x10-7), supratentorial location (p = 8.6x10-5) and a better overall survival (p = 0.035). The clinical potential of the EZH2 inhibitor GSK343 is under investigation using ependymoma cell lines. CONCLUSION: Global H3K27me3 levels were associated with age, location and overall survival in paediatric ependymoma, suggesting it could be used as a potential prognostic marker and therapeutic target.
Clinical and pathological factors predicting long-term disease control with lapatinib and capecitabine for patients with HER2 positive metastastic breast cancer: results from a multicenter retrospective study
Authors: S. Duranti, A. Inno, V. Rossi, M. Turazza, E. Fiorio, A. Fabi, G. Bisagni, J. Foglietta, D. Santini, I. Pavese, A. Zambelli, P. Vici, V. Leonardi, S. Barni, S. Saracchini, G. Bogina, G. Lunardi, F. Marchetti, F. Montemurro, S. Gori
Journal: Annals of Oncology (2015)
Abstract 1543: Wogonin suppresses the production of breast cancer-derived osteolytic factors
Authors: Hyungkeun Kim, Kwang-Kyun Park, Won-Yoon Chung
Journal: Cancer Research (2015)

Abstract Breast cancer is the most frequent cancer in women and the main cause of its mortality is induced by metastasizing to distant organs. Breast cancer primarily metastasizes to the bone, lung, liver and brain, and the bone is the most susceptible to metastasis. When breast cancer metastasizes to the bone, the dominant lesion is osteolytic. This osteolytic bone metastasis is highly associated with the complex interaction between cancer cells and the bone microenvironment. Interleukin-1 beta (IL-1β) and IL-17 act as osteolytic factors and promote osteolytic lesions in breast cancer pateints by increasing osteoclastogenesis and decreasing osteoblastogenesis. Especially, both of IL-1β and IL-17 increase in patients with breast cancer and decrease disease-free survival in cancer patients. Wogonin, one of the major flavonoids in the roots of Scutellaria baicalensis Georgi, has been recognized as a potent anti-cancer agent through increased apoptosis and decreased proliferation. We investigated whether wogonin could reduce the cancer cell-induced osteolysis by controlling interaction between cancer cells and bone-related cells. Wogonin suppressed cell viability, DNA synthesis and migration in MDA-MB 231 cells. Wogonin reduced the secretion of IL-1β and IL-17 in MDA-MB 231 cells. Wogonin at non-cytotoxic concentrations inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, wogonin blocked an increase in RANKL/osteoprotegerin mRNA ratio in the osteoblastic hFOB1.19 cells exposed to MDA-MB 231 cells-derived conditioned medium. Finally, oral administration of wogonin significantly inhibited osteolytic lesions in MDA-MB 231 cells-injected mice. Taken together, these results indicate that wogonin is a promising agent for preventing and treating cancer-cell mediated bone loss. Citation Format: Hyungkeun Kim, Kwang-Kyun Park, Won-Yoon Chung. Wogonin suppresses the production of breast cancer-derived osteolytic factors. [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 1543. doi:10.1158/1538-7445.AM2015-1543
Central Nervous System Integrity in Adult Survivors of Childhood Hodgkin Lymphoma,
Authors: Kevin R. Krull, Noah D. Sabin, Wilburn E. Reddick, Liang Zhu, Gregory T. Armstrong, Daniel M. Green, Deo Kumar Srivastava, Monika L. Metzger, Leslie L. Robison, Melissa M. Hudson
Journal: Blood (2011)
Post-Hematopoietic Stem Cell Transplantation Minimal Residual Disease and Early Relapses in MDS and AML Evolving from MDS
Authors: Moreno Festuccia, Kelsey Baker, Theodore A Gooley, Brenda M. Sandmaier, Joachim Deeg, Brent L Wood, Min Fang, Bart Lee Scott
Journal: Blood (2015)