tbuckley/cabot-search huggingface dataset:
Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide
Authors: Christopher G. Kanakry, Javier Bolaños-Meade, Yvette L. Kasamon, Marianna Zahurak, Nadira Durakovic, Terry Furlong, Marco Mielcarek, Marta Medeot, Ivana Gojo, B. Douglas Smith, Jennifer A. Kanakry, Ivan M. Borrello, Robert A. Brodsky, Douglas E. Gladstone, Carol Ann Huff, William H. Matsui, Lode J. Swinnen, Kenneth R. Cooke, Richard F. Ambinder, Ephraim J. Fuchs, Marcos J. de Lima, Borje S. Andersson, Ravi Varadhan, Paul V. O’Donnell, Richard J. Jones, Leo Luznik
Journal: Blood (2017)
Percutaneous Therapies for Peripheral Artery Disease
Authors: Mehdi H. Shishehbor, Michael R. Jaff
Journal: Circulation (2016)

Percutaneous therapies for peripheral artery disease continue to evolve with new techniques and devices. Although guidelines-recommended therapies have impacted cardiovascular morbidity and mortality, endovascular interventions have been shown to reduce limb pain, improve quality of life, and prolong walking distance for those with claudication and to reduce amputation rates among those with critical limb ischemia. Novel devices such as drug-eluting stents and drug-coated balloons have improved patency for moderate-length lesions, whereas others allow treatment of heavily calcified and tortuous segments. New adjunctive devices to cross lesions and reduce or modify associated plaque have also been developed, although level 1 data regarding their efficacy are sparse. There has also been a better mechanistic understanding of lower extremity endovascular treatment using tools such as intravascular ultrasound. This information has highlighted the need for better stent size selection for the femoropopliteal arterial segments and larger balloon diameters for the tibial arteries. Moreover, a wound perfusion approach with direct in-line flow, the so-called angiosome approach, and reconstruction of the pedal loop have been advocated for improved wound healing. Technical advances such as the tibiopedal access and reentry methods have allowed crossing of lesions that were considered no option for the endovascular approach in the past. Collectively, there has been increased awareness, interest, and commitment by various specialty societies and organizations to advance the treatment of peripheral artery disease and critical limb ischemia. This is also evident by the recent coalition of 7 professional societies and organizations that represented >150 000 allied health professionals and millions of patients with peripheral artery disease at the 2015 Centers for Medicaid and Medicare Services Medicare Evidence Development and Coverage Analysis Committee meeting. The percutaneous therapies for peripheral artery disease continue to evolve with longer follow-up with randomized data and larger prospective registries. In the future, it is hopeful that we will treat the lower extremity arteries according to segments, taking into account plaque morphology, luminal versus subintimal crossing, location, and stenotic versus occlusive disease. Until then, we must identify the most cost-effective, efficacious, and safe treatment for each patient. The goal of this article is to aid the practicing vascular specialist consider the optimal choices for the management of patients with vascular disease.
Assessing DNA Damage Ex Vivo Induced by Chemotherapy Targeting Topoisomerase Inhibitors in Acute Leukemias.
Authors: Dorota H. Halicka, Fevzi M. Ozkaynak, Karen Seiter, Malgorzata A. Kajstura, Delong Liu, Toshiki Tanaka, Frank Traganos, Zbigniew Darzynkiewicz
Journal: Blood (2006)
Engraftment and Survival Following Non-Myeloablative Allogeneic Peripheral Blood Hematopoietic Cell Transplantation for Malignant Diseases Is Affected by CD8+ T-Cell Dose.
Authors: Thai M. Cao, Judith A. Shizuru, Ruby M. Wong, Kevin Sheehan, Ginna G. Laport, Keith E. Stockerl-Goldstein, Laura J. Johnston, Monic J. Stuart, Janic M.Y. Brown, F. C. Grumet, Robert S. Negrin, Robert Lowsky
Journal: Blood (2004)
Abstract 1992: Evidence for modulation of FoxM1 by p21 in ovarian cancer
Authors: Jill Madden, Jeremy Chien
Journal: Cancer Research (2015)

Abstract The oncogenic transcription factor forkhead box M1 (FoxM1) is overexpressed in many cancers, including 84% of ovarian cancer and plays a role in DNA repair, mitotic checkpoint, cell proliferation, and cancer drug resistance. Similar to Her2 in breast cancer, the constitutive expression of FoxM1 makes it a plausible gene target for novel anti-cancer therapies, but the regulation of FoxM1 has yet to be elucidated. Evidence suggests FoxM1 up-regulation is a result of TP53 mutations, however, no TP53 response element has been found within the FoxM1 promoter, thus there is likely another molecule mediating p53-induced FoxM1 overexpression. We hypothesize that cyclin-dependent kinase inhibitor 1a, p21, is involved in the regulation of FoxM1 by p53 in ovarian cancer. To test this hypothesis, we knocked down p21 expression with siRNA and shRNA in two wild-type p53 cancer cell lines, NCI-H23 and A2780. Knock down of p21 resulted in a mirrored increase in FoxM1 protein level in both cell lines as detected by Western blot. The addition of nutlin-3 (10 μM), a p53 stabilizer, to these p21 knocked down cell lines restored some p21 expression 24 hour post-treatment, which led to a subsequent decrease in FoxM1 levels compared to the corresponding DMSO-treated p21 knock down. These results suggest p21 is a negative regulator of FoxM1 in cancer cell lines. To further investigate this pathway, the same two cancer cell lines were treated with the FoxM1 inhibitor thiostrepton (10 μM) and protein levels were measured over a time course of 48 hours. FoxM1 protein levels were reduced following 8 hours, a time point where p21 protein levels peaked. This finding was further support by qRT-PCR analysis of A2780 ovarian cancer cell mRNA collected 0, 6, 8, 9, 10, 11, and 12 hours following thiostrepton (10 μM) treatment. In this experiment, p21 mRNA levels peaked 6 hours post-treatment, with FoxM1 mRNA levels reduced at 8 hours post-treatment, relative to control. Although thiostrepton has been shown to directly bind and inhibit the transcription of FoxM1, these results suggest that thiostrepton may also induce p21, potentiating FoxM1 inhibition. Thiostrepton has previously been shown to induce cancer cell death and reduce tumor burden, therefore further supporting FoxM1 as a potential drug target as well as encouraging the need to understand regulators involved in this pathway. Citation Format: Jill Madden, Jeremy Chien. Evidence for modulation of FoxM1 by p21 in ovarian 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 1992. doi:10.1158/1538-7445.AM2015-1992
Agonist and Antagonist Effects of Diadenosine Tetraphosphate, a Platelet Dense Granule Constituent, on Platelet P2Y1, P2Y12 and P2X1 Receptors
Authors: Hung Chang, Ivan B Yanachkov, Alan D Michelson, YouFu Li, Marc R Barnard, George E Wright, Andrew L Frelinger
Journal: Blood (2008)
Egress of CD19+CD5+ Cells Into Peripheral Blood Following Treatment with the Bruton Tyrosine Kinase Inhibitor, PCI-32765, in Mantle Cell Lymphoma Patients
Authors: Betty Y Chang, Michelle Francesco, Padmaja Magadala, Min Mei Huang, Marcel Spaargaren, Joseph J. Buggy, Laurence Elias
Journal: Blood (2011)
666. Oncolytic Herpes Virotherapy Induces a Paracrine Death Signal Causing Synergistic Antitumor Efficacy with Aurora A Kinase Inhibition
Authors: Leslee Sprague, Mark Currier, Tilat Rizvi, Brooke Nartker, Chun-Yu Chen, Pin-Yi Wang, Brian Hutzen, Meghan Franczek, Jeffrey Ecsedy, Joe Conner, Nancy Ratner, Timothy Cripe
Journal: Molecular Therapy (2016)

Aurora A Kinase (AURKA) inhibition with the investigational agent alisertib results in abnormal mitotic progression and the induction of apoptosis in multiple tumor cell lines. Cell cycle arrest is a strategy employed by a variety of viruses, including herpes simplex virus (HSV), to bolster viral reproduction. We previously demonstrated the anti-tumor efficacy of oncolytic HSV and alisertib as monotherapies in models of malignant peripheral nerve sheath tumor (MPNST). We then proceeded to test alisertib and the oncolytic HSV Seprehvir in combination, finding a synergistic anti-tumor effect between the two therapies. Considering this, we hypothesized that alisertib potentiates Seprehvir infection, leading to more rapid and robust viral proliferation with concomitant tumor regression. However, our efforts to quantify enhanced viral infection with combination therapy have uncovered no significant differences in Seprehvir viral growth kinetics witih or without alisertib therapy. Therefore, the synergistic tumor response of Seprehvir combined with alisertib in vitro or in vivo is not due to augmented viral infection. We then hypothesized that Seprehvir infection potentiates the anti-tumor effect of alisertib. In line with this hypothesis, there is a signficant decrease in tumor cell proliferation in alisertib-treated tumor cells that are exposed to soluble factors released by Seprehvir-infected cells. Furthermore, by UV inactivation of Seprehvir conditioned media, we demonstrate that these soluble death signals are not replication competent virus released by infected cells. Taken together, our results suggest a novel mechanism through which Seprehvir-infected cells release a paracrine signal to surrounding cells promoting cell death and increasing the anti-tumor activity of alisertib therapy.
Abstract 5455: Surface accumulation of receptor tyrosine kinases upon treatment with tyrosine kinase inhibitors and resulting enhancement of activity upon treatment cessation
Authors: Anne-Mette Bjerregaard, Michael V. Grandal, Camilla Frohlich, Trine Lindsted, Christina Egebjerg, Ivan D. Horac, Michael Kragh, Mikkel W. Pedersen
Journal: Cancer Research (2015)

Abstract Receptor tyrosine kinases (RTKs) constitute the largest family of structurally related oncogenes and are often involved in the initiation, maintenance and/or metastasis of various human cancers. The genes encoding RTKs are frequently amplified, fused, mutated, or the ligands are expressed at high levels, causing abnormal activation and downstream signaling. Two major types of drugs have been used with success to treat cancers with abnormal RTK activation, recombinant monoclonal antibodies (mAbs) and small molecule inhibitors of the tyrosine kinases (TKIs). TKIs have proven most successful against cancers driven by gene fusions or mutations, whereas mAbs dominate in cancers driven by gene amplifications or ligand-mediated RTK activation. Recent studies show that the two types of treatment modalities may often be synergistic, but the reason for this is not well characterized. Here, we demonstrate that surface levels of various RTKs increase in cancer cell lines upon treatment with TKIs specific for the individual RTKs. The effect was most pronounced in cell lines with amplification or autocrine ligand production and occurred at inhibitor concentrations suboptimal for inhibition of growth. Removal of the TKIs resulted in an increase in RTK activity and cancer cell proliferation as a result of the increased RTK levels. MAbs, especially mAb mixtures, when given in combination with the TKIs were found to prevent RTK accumulation and led to enhanced efficacy. Due to the increased number of receptors, the combination also resulted in enhancement of secondary effector functions, such as ADCC. In conclusion, our results demonstrate that in certain contexts TKI treatment leads to RTK accumulation and that this accumulation has the potential to enhance tumor growth. Antibody mixtures, when given together with the TKIs, can prevent RTK accumulation and even enhance the TKI activity. Citation Format: Anne-Mette Bjerregaard, Michael V. Grandal, Camilla Frohlich, Trine Lindsted, Christina Egebjerg, Ivan D. Horac, Michael Kragh, Mikkel W. Pedersen. Surface accumulation of receptor tyrosine kinases upon treatment with tyrosine kinase inhibitors and resulting enhancement of activity upon treatment cessation. [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 5455. doi:10.1158/1538-7445.AM2015-5455
Preclinical Mechanistic Studies Investigating Neutrophil and Lymphoid Cell Depletion By IMGN529, a CD37-Targeting Antibody-Drug Conjugate (ADC)
Authors: Jutta Deckert, Jose F. Ponte, Jennifer A. Coccia, Leanne Lanieri, Sharon Chicklas, Yong Yi, Krystal Watkins, Rodrigo Ruiz-Soto, Angela Romanelli, Robert J. Lutz
Journal: Blood (2014)
Ultraviolet Radiation and Kaposi Sarcoma Incidence in a Nationwide US Cohort of HIV-Infected Men
Authors: Elizabeth K. Cahoon, Eric A. Engels, D. Michal Freedman, Mary Norval, Ruth M. Pfeiffer
Journal: JNCI Journal of the National Cancer Institute (2016)

Although ultraviolet radiation (UVR) is established as both an inducer of herpes simplex virus reactivation and as the primary risk factor for many common skin cancers, its relationship with human herpes virus 8 (HHV8) infection or risk of Kaposi sarcoma (KS) is unknown.Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the association between ambient UVR, history of nonmelanoma skin cancer (NMSC; as a biomarker of personal cumulative UVR dose), and incidence of first primary KS in a nationwide US cohort of white and African American male veterans infected with HIV between 1986 and 1996 (prior to the widespread availability of treatment) using Cox regression. All statistical tests were two-sided.Based on discharge records, there were 422 newly diagnosed KS cases among 17 597 HIV-infected veterans. Cohort members with prior NMSC had a statistically significantly increased risk of KS (HR = 8.64, 95% CI = 6.23 to 11.96) in the total population. Risk of KS was higher for quartile 4 vs 1 among the total population (HR = 1.49, 95% CI = 1.02 to 2.16, Ptrend UVR quartile [coded 1 to 4] = .02) and among whites (HR = 1.75, 95% CI = 1.11 to 2.78, Ptrend = .009), but not among African Americans (HR = 1.23, 95% CI = 0.71 to 2.15, Ptrend = .23).KS risk was elevated among HIV-infected men with NMSC diagnosis and in those living in locations with high ambient UVR at time of HIV diagnosis. Our novel findings suggesting that UVR exposure may increase KS risk warrant further investigation.
Abstract 3569: Inhibition of the TRPM7 kinase domain inhibits breast cancer cell migration and invasion and tumor metastasis
Authors: Tamer S. Kaoud, Xuemei Xie, Jihyun Park, Clint D.J. Tavares, Shreya Mitra, Micael Cano, Rachel M. Sammons, Mohamed F. Radwan, Chandra Bartholomeusz, Kevin N. Dalby
Journal: Cancer Research (2015)

Abstract TRPM7 (transient receptor potential melastatin 7) is a non-selective cation channel fused to protein kinase domain at the C-terminal whose activity is linked to the control of actomyosin contractility. TRPM7 mediates adhesion and migration of breast cancer cells and promotes breast tumor metastasis. The lack of cell-permeable inhibitors of the kinase domain represents a barrier to understand the kinase function. Herein, we discovered the first small molecule (KD-1) that targets TRPM7 kinase activity. Mg2+ starvation, which promotes TRPM7 kinase activity, induces phosphorylation of eEF2. Treatment of Mg2+-starved HEK293 cells with KD-1 decreased eEF2 phosphorylation, consistent with TRPM7 kinase activity suppression in-cells. KD-1 decreased the binding of Myosin IIB to TRPM7 in HEK293 and MDA-MB-231 cells. And when MDA-MB-231 cells were treated with increasing doses of KD-1, no change in cell viability was seen. Interestingly, KD-1 inhibited MDA-MB-231 cells migration and invasion that is reportedly regulated by TRPM7 kinase activity. Finally, the bioluminescent signals (to assess metastasis) were significantly lower in KD-1-treated mice (25 and 50 mg/kg/day) than in mice treated with vehicle control (P ≤ 0.05, 2-sided t-test.). in conclusion, inhibition of TRPM7 kinase activity may reduce or block breast tumor progression and/or metastasis. Citation Format: Tamer S. Kaoud, Xuemei Xie, Jihyun Park, Clint D.J. Tavares, Shreya Mitra, Micael Cano, Rachel M. Sammons, Mohamed F. Radwan, Chandra Bartholomeusz, Kevin N. Dalby. Inhibition of the TRPM7 kinase domain inhibits breast cancer cell migration and invasion and tumor metastasis. [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 3569. doi:10.1158/1538-7445.AM2015-3569
Safety and efficacy of self-assembling bubble carriers stabilized with sodium dodecyl sulfate for oral delivery of therapeutic proteins
Authors: Po-Yen Lin, Er-Yuan Chuang, Yi-Hsuan Chiu, Hsin-Lung Chen, Kun-Ju Lin, Jyuhn-Huarng Juang, Ching-Hua Chiang, Fwu-Long Mi, Hsing-Wen Sung
Journal: Journal of Controlled Release (2016)
52. Gorilla Adenovirus Vectors for Molecular Therapeutics and Vaccines
Authors: Douglas E. Brough
Journal: Molecular Therapy (2015)

Adenovirus vectors built from gorilla adenovirus are showing superior performance characteristics for molecular vaccines. These new adenovectors (GC Ads) are built from virus isolated from gorilla, and have been cloned and engineered to be replication-defective. GC Ads grow efficiently to high titer on cell lines GenVec has characterized, banked and filed with regulatory agencies for scalable manufacturing. They can be deleted of multiple regions (e.g., E1, E3, and E4) to provide space for multiple transgene cassettes, provide multiple blocks to eliminate replication competent virus and to ensure safer transgene delivery. These new adenovectors have been shown to not be recognized by human sera from either the United States or from Africa. A single intramuscular injection of these GC Ads can induce durable immune responses to encoded antigen. For example, intramuscular injection of GC Ads expressing RSV fusion (F0) glycoprotein induced neutralizing antibody titers that were durable > 24weeks, and protected the lung and nose against RSV challenge at even low doses of immunization in cotton rats. A single intramuscular administration of GC Ads expressing the malaria antigen CSP generated CD8 T cell and antibody responses to CSP that were greater than those generated with Ad5 in mice. In a mouse malaria challenge model the GC Ad regimen was more protective than Ad5. A single intramuscular administration of GC Ads expressing two HSV antigens, UL19 and UL47, resulted in high level cellular responses that were protective against intravaginal HSV2 challenge in mice and the CD8 T cell responses were shown to be durable, 26 weeks. Moreover, repeat administration of the same GC Ad resulted in a boost of antigen-specific immune response. Unlike other adenoviral vectors, homologous prime boost regimens with these GC Ads resulted in a boost of the CD8 T cell responses at all doses and intervals tested. These new GC Ads based on gorilla adenoviruses show generation of strong, durable T cell and neutralizing antibody responses to multiple antigens from a single administration that can be further enhanced by repeat administration. Based on these data, the platform shows great promise for development of a broad array of immunotherapeutic and molecular vaccine product candidates.
Abstract 799: Protein kinase C ϵ cooperates with Pten deficiency to regulate NF-κB pathway in prostate cancer progression
Authors: Rachana Garg, Jorge Blando, Carlos J. Perez, Fernando J. Benavides, Marcelo G. Kazanietz
Journal: Cancer Research (2015)

Abstract Prostate cancer is one of the most commonly diagnosed malignancies and the second leading cause of cancer-related deaths among men in the United States. Protein kinase C epsilon (PKCϵ), a member of the PKC family of phorbol ester/diacylglycerol receptors, has emerged as an oncogenic kinase and shown to be up-regulated in human prostate cancer specimens. We recently demonstrated that PKCϵ is an upstream regulator of NF-κB activation in prostate cancer (JBC, 287:37570-37582, 2012) and that transgenic overexpression of PKCϵ in mice prostate under the control of the probasin promoter (PB-PKCϵ) leads to hyperplasia and PIN lesions but was insufficient to drive neoplastic changes (Cell Cycle, 10:268-277, 2011). Notably, when we intercrossed PB-PKCϵ mice with mice haploinsufficient for Pten, another common genetic alteration in human prostate cancer, the resulting compound mutant mice (PB-PKCϵ;Pten+/- mice) developed fully invasive adenocarcinoma with elevated NF-κB levels. In the present study, we aim to delineate the mechanism underlying the observed cooperativity between PKCϵ overexpression and Pten deficiency and to explore the consequences of this cooperativity on the transcription factor NF-κB signaling, a pathway known to be highly dysregulated in prostate tumorigenesis. To this end, we stably overexpressed PKCϵ in mouse prostate epithelial lines that are either heterozygous (P8) or homozygous (CaP8) for Pten deletion. We observed a striking synergism between PKCϵϵ overexpression and Pten loss in conferring enhanced proliferative, migratory and invasive phenotype. Moreover, LPS or TNFα stimulation of these cells led to increased NF-κB activation as evident from the elevated IκBα phosphorylation, NF-κB nuclear translocation and transactivation of a NF-κB luciferase reporter. These effects were much more pronounced in CaP8 cells. Of note, PKCϵ overexpression and Pten loss also cooperates to augment levels of the NF-κB regulated gene, COX-2. Stable overexpression of PKCϵ and Pten depletion in “normal” immortalized RWPE1 cells also resulted in significant enhancements in TNFα-induced NF-κB activation and COX-2 induction. Furthermore, NF-κB inhibition by parthenolide significantly retarded the growth of CaP8-PKCϵ tumors in athymic nude mice. Overall, our results identify NF-κB as a mediator of PKCϵ oncogenesis in prostate cancer, particularly in the context of Pten loss. Citation Format: Rachana Garg, Jorge Blando, Carlos J. Perez, Fernando J. Benavides, Marcelo G. Kazanietz. Protein kinase C ϵ cooperates with Pten deficiency to regulate NF-κB pathway in prostate cancer progression. [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 799. doi:10.1158/1538-7445.AM2015-799
Assessment of Quality of Life in the NCRI Spirit 2 Study Comparing Imatinib with Dasatinib in Patients with Newly-Diagnosed Chronic Phase Chronic Myeloid Leukaemia
Authors: Alexander M. Labeit, Mhairi Copland, Leanne M. Cork, Corinne A. Hedgley, Letizia Foroni, Wendy L. Osborne, Gemma Gills, Jane F. Apperley, Tessa L. Holyoake, Ruth V. Bescoby, Christopher Pocock, Thomas Zwingers, Philippa Burnell, Jenny L. Byrne, John H. McCullough, John M. Goldman, Richard E. Clark, Stephen G. O'Brien
Journal: Blood (2015)
Outcome of Intramuscular Anti-D In Children with Chronic Immune Thrombocytopenia (ITP) and Severe Thrombocytopenia: A Case-Control Study,
Authors: Nongnuch Sirachainan, Usanarat Anurathapan, Ampaiwan Chuansumrit, Duantida Songdej, Pakawan Wongwerawattanakoon, Sakara Hutspardol, Pimpun Kitpoka
Journal: Blood (2011)