tbuckley/cabot-search huggingface dataset:
Abstract 543: Preclinical combination strategies to enhance the efficacy of the anti-PD-1 antibody pembrolizumab
Authors: Elaine M. Pinheiro, Marlene Hinton, Ruban Mangadu, Mingmei Cai, Uyen Phan, Michael Nebozhyn, Heather Hirsch, Andrey Loboda, Sarah Javaid, Yaolin Wang, Venkataraman Sriram, Joseph H. Phillips, Terri McClanahan, Brian Long
Journal: Cancer Research (2016)

Abstract Pembrolizumab (MK-3475), a humanized monoclonal IgG4 antibody against programmed death receptor 1 (PD-1), has shown activity in multiple types of cancer. Although pembrolizumab is showing a dramatic impact in patients that respond, a large fraction of patients do not respond to single agent therapy. Combination approaches may be the key to improving response rates in these patients. One of the challenges is how best to tailor combination strategies to provide maximal benefit to patients. How we prioritize new combinations will require an understanding of which mechanism is best for which tumor. To elucidate mechanisms that may create an immunogeneic tumor microenvironment and enhance the antitumor activity of PD-1 blockade, we have tested combination strategies with muDX400, a murine anti-PD-1 antibody. The murine preclinical syngeneic tumor models selected for these studies had varied tumor microenvironment compositions and displayed a range of responses to therapy with single agent anti-PD-1. Here we show enhanced anti-tumor activity when PD-1 blockade is combined with conventional chemotherapies, small molecule therapies and additional immunotherapy approaches that target multiple steps in the immune-oncology pathway. Pre and post treatment tumors from these models were extensively characterized by gene expression profiling, whole exome sequencing, flow cytometry and immunohistochemistry analysis. Molecular and cellular correlates of response to anti-PD-1 as a single agent and in combination with these agents were evaluated. These data support potential combination strategies that could either increase efficacy or expand the patient population in which pembrolizumab will demonstrate benefit. Citation Format: Elaine M. Pinheiro, Marlene Hinton, Ruban Mangadu, Mingmei Cai, Uyen Phan, Michael Nebozhyn, Heather Hirsch, Andrey Loboda, Sarah Javaid, Yaolin Wang, Venkataraman Sriram, Joseph H. Phillips, Terri McClanahan, Brian Long. Preclinical combination strategies to enhance the efficacy of the anti-PD-1 antibody pembrolizumab. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 543.
Iron Status Independently Associates With Bone Mineral Density At Population Level. Insights From The Val Borbera Study
Authors: Nicola Martinelli, Michela Traglia, Fabiana Busti, Marcella Sirtori, Natascia Campostrini, Cinzia Sala, Ginevra Biino, Corrado Masciullo, Michela Corbella, Daniele Manna, Giorgio Pistis, Annalisa Castagna, Oliviero Olivieri, Daniela Toniolo, Clara Camaschella, Domenico Girelli
Journal: Blood (2013)
P0851 : Effectiveness of sofosbuvir and ribavirin for genotype 2 and 3 HCV among non-cirrhotic, cirrhotic, and post-transplant patients at 3 US medical centers
Authors: M. Leise, B. Rodriguez, S. Pungpapong, B. Aqel, A. Chervenak, T. Werner, J. Murphy, T.M. Henry, K. Ryland, A. Keaveny, H. Vargas, K. Watt
Journal: Journal of Hepatology (2015)
Cyclophosphamide, epirubicin, and 5-fluorouracil versus epirubicin plus paclitaxel in node-positive early breast cancer patients: A randomized, phase III study of Gruppo Oncologico Nord Ovest-Mammella Intergruppo Group
Authors: L. Del Mastro, M. Costantini, A. Durando, A. Michelotti, S. Danese, E. Aitini, N. Olmeo, P. Pronzato, M. Venturini
Journal: Journal of Clinical Oncology (2008)

516 Background: This trial is aimed at comparing the efficacy and tolerability of 2 regimens of adjuvant therapy for patients (pts) with node-positive breast cancer. Methods: Women with operable, N+ breast cancer and less than 10 involved axillary nodes were eligible. Therapy was as follows: Arm 1 (CEF): cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2 and 5-fluorouracil 600 mg/m2 given every 3 weeks for 6 cycles; Arm 2 (ET): epirubicin 90 mg/m2, paclitaxel 175 mg/m2 3-hour infusion given every 3 weeks for 4 cycles. Tamoxifen (20 mg/die) was given to all pts with ER and/or PgR positive tumor. Primary endpoint was overall survival (OS) and secondary endpoints were event free survival (EFS) and tolerability. The study was designed to detect a hazard ratio of 0.80, assuming an alpha error of 0.05 (two sided) and a power of 0.80. This required 500 pts per arm. Results: From Nov 1996 to Jan 2001, 1,055 pts were randomized: 520 pts received CEF and 535 ET regimens. Main pts characteristics were age <50 years (35% and 42% in arm 1 and 2, respectively); N+1–3 (68% and 69%); ER and PgR negative status (24% and 19%). Pts treated with CEF experienced more frequently nausea/vomiting (85% in arm 1 and 76% in arm 2, p=0.0001), mucositis (46% vs 37%, p=0.003) and leukopenia (52% vs 40%, p=0.0002). Toxicities occurring more frequently in ET arm were anemia (17% vs 25% in arm 1 and 2, respectively, p=0.006); fever (7% vs 15%, p=0.0001); myalgia (1% vs 19%, p=0.0001); neurotoxicity (6% vs 38%, p <0.0001) and allergic reaction (1% vs 5%, p=0.03). Among 412 premenopausal pts, chemotherapy-induced amenorrhea occurred in 51% of pts treated with CEF and in 45% of pts treated with ET (p=0.16). The median follow-up in surviving pts was 8.2 years. At Dec 2007, 223 deaths and 344 events were recorded. The 5-year EFS was 71% and 70% in arm 1 and 2 respectively; 10-year EFS was 46% in both arms. The 5-year OS was 89% and 88% in arm 1 and 2, respectively; the 10-year OS was 72% (95% CI: 66–78) and 76% (95% CI: 71–80) (p=0.8). Conclusions: CEF for 6 cycles and ET for 4 cycles are associated with a different toxicity profile. At 5- and 10 years, no significant difference in OS and EFS was observed between CEF and ET regimens. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb
Abstract 282: Pan-RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4 and 6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1
Authors: Shih-Hsun Chen, Youyan Zhang, Robert D. Van Horn, Tinggui Yin, Lysiane Huber, Teresa F. Burke, Xueqian Gong, Wenjuan Wu, Shripad Bhagwat, Sean Buchanan, Richard P. Beckmann, Ramon V. Tiu, Sheng-Bin Peng
Journal: Cancer Research (2016)

Abstract KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, including melanoma, lung, colorectal, and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor currently in phase I clinical trial, has been shown to inhibit cell proliferation of RAS- or BRAF-mutant tumor cells in vitro and xenograft tumor growth in vivo. An unbiased screen for compounds that synergize with LY3009120 in RAS/BRAF mutant cancers identified inhibitors of CDK4 among the top hits. In this study, we found that combined inhibition of RAF and CDK4 and 6 by LY3009120 and abemaciclib cooperatively reduced viability of tumor cells with KRAS, NRAS or BRAF mutation in vitro. In animal models, the LY3009120 and abemaciclib combination exhibited synergistic regression of tumor growth in multiple xenograft models with KRAS, NRAS, or BRAF mutation. Molecular mechanistic analysis revealed that pan-RAF inhibitor treatment suppressed the cyclin D1 upregulation which was mediated through CDK4 and CDK6 inhibition by abemaciclib, and the combination treatment cooperatively demonstrated more complete inhibition of RB phosphorylation. These results were further verified by CDK4 and CDK6 siRNA knockdown and another CDK4 and CDK6 selective inhibitor palbociclib. Importantly, the more complete phospho-RB inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combinational treatment led to more significant cell cycle G0/G1 arrest and apoptosis of tumor cells. These preclinical findings suggest that the combinational inhibition of RAF and CDK4 and CDK6 signaling by LY3009120 and abemaciclib is synergistic and should be further studied compared to single agents in the treatment of cancer in patients with KRAS, NRAS or BRAF mutations. Citation Format: Shih-Hsun Chen, Youyan Zhang, Robert D. Van Horn, Tinggui Yin, Lysiane Huber, Teresa F. Burke, Xueqian Gong, Wenjuan Wu, Shripad Bhagwat, Sean Buchanan, Richard P. Beckmann, Ramon V. Tiu, Sheng-Bin Peng. Pan-RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4 and 6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 282.
Acquired Pure Red Cell Aplasia Associated with Clonal T-Cell Receptor (TCR) Gene Rearrangements with and without Pathologic Features of T-Cell Large Granular Lymphocytic Leukemia (T-LGLL).
Authors: Grzegorz S. Nowakowski, William G. Morice, Ayalew Tefferi, Robert E. Phyliky
Journal: Blood (2004)
TNF activation of NF-κB is essential for development of single-positive thymocytes
Authors: Louise V. Webb, Steven C. Ley, Benedict Seddon
Journal: The Journal of Experimental Medicine (2016)

NF-κB activation has been implicated at multiple stages of thymic development of T cells, during which it is thought to mediate developmental signals originating from the T cell receptor (TCR). However, the Card11–Bcl10–Malt1 (CBM) complex that is essential for TCR activation of NF-κB in peripheral T cells is not required for thymocyte development. It has remained unclear whether the TCR activates NF-κB independent of the CBM complex in thymocyte development or whether another NF-κB activating receptor is involved. In the present study, we generated mice in which T cells lacked expression of both catalytic subunits of the inhibitor of κB kinase (IKK) complex, IKK1 and IKK2, to investigate this question. Although early stages of T cell development were unperturbed, maturation of CD4 and CD8 single-positive (SP) thymocytes was blocked in mice lacking IKK1/2 in the T cell lineage. We found that IKK1/2-deficient thymocytes were specifically sensitized to TNF-induced cell death in vitro. Furthermore, the block in thymocyte development in IKK1/2-deficient mice could be rescued by blocking TNF with anti-TNF mAb or by ablation of TNFRI expression. These experiments reveal an essential role for TNF activation of NF-κB to promote the survival and development of single positive T cells in the thymus.
Abstract 3110: MASH1 expression in high grade astrocytoma may demonstrate a potential model for prognosis that may lead to a molecular target for future therapy
Authors: David E. Tacha, Jillian Tyrrell, Margaret Lobo
Journal: Cancer Research (2016)

Abstract Introduction: A large U.S. study showed that 25% of patients diagnosed with grade 3 astrocytoma survived for 5 years or more after diagnosis. Unfortunately, the outlook is even worse for patients diagnosed with GBM, as most patients live for less than a year. Achaete-scute complex homolog 1 (ASCL1, MASH1) is a proneural transcription factor that has an essential role in the formation of multiple neuronal lineages. Recent studies have shown that the upregulation of MASH1 and inhibition of the Notch signaling pathway characterize progressive astrocytoma. Proneural proteins have been shown to regulate stem-cell proliferation and differentiation. The convergence with oncogenic pathways combined with the overexpression in glioblastoma has been shown to correlate with poor clinical outcome and has identified these transcription factors as promising therapeutic targets. Recently, a MASH1 mouse monoclonal antibody has been developed. Most studies have shown MASH1 to be a specific marker of neuroendocrine carcinomas; however, only one immunohistochemical study on astrocytoma using a polyclonal antibody has been reported. This study examined MASH1 expression in grade 1-4 astrocytoma cases. Materials and Methods: Formalin-fixed paraffin-embedded tissue microarrays consisting of samples of normal brain and astrocytomas [grade 1 (n = 22), grade 2 (n = 34), grade 3 (n = 16) and glioblastoma (n = 35)] were evaluated by immunohistochemical analysis using a monoclonal MASH1 antibody. A value of &amp;gt;1% staining was scored as positive. Results: MASH1 stained 61.7% (66/107) of astrocytomas (grades 1-4). In grade 1 astrocytoma, MASH1 was expressed in 31.8% versus 85.3% in grade 2, 68.7% in grade 3 and 54.3% in grade 4 (p ∼ 0.0028). Conclusion: MASH1 is highly expressed in astrocytoma. There was a variable and progressive increase of MASH1 expression in grade 1 versus grade 2-4 astrocytoma; and thus, may demonstrate a potential model for prognosis that may lead to future target therapeutic strategies. Citation Format: David E. Tacha, Jillian Tyrrell, Margaret Lobo. MASH1 expression in high grade astrocytoma may demonstrate a potential model for prognosis that may lead to a molecular target for future therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3110.
Vincristine Sulfate Liposomes Injection (Marqibo®) Facilitates Durable Remissions and Potentially Curative Hematopoietic Stem Cell Transplantation in Adults with Advanced, Relapsed and/or Refractory Acute Lymphoblastic Leukemia
Authors: Gary J. Schiller, John Lister, Leonard T. Heffner, Stuart L. Goldberg, Lloyd E. Damon, Jeffrey A. Silverman, Steven R. Deitcher
Journal: Blood (2011)
The Efficacy of Oncolytic Adenovirus Is Mediated by T-cell Responses against Virus and Tumor in Syrian Hamster Model
Authors: Xiaozhu Li, Pengju Wang, Hang Li, Xuexiang Du, Mingyue Liu, Qibin Huang, Yaohe Wang, Shengdian Wang
Journal: Clinical Cancer Research (2016)

Oncolytic adenoviruses (Ad) represent an innovative approach to cancer therapy. Its efficacy depends on multiple actions, including direct tumor lysis and stimulation of antiviral and antitumor immune responses. In this study, we investigated the roles of T-cell responses in oncolytic adenoviral therapy.An immunocompetent and viral replication-permissive Syrian hamster tumor model was used. The therapeutic mechanisms of oncolytic Ad were investigated by T-cell deletion, immunohistochemical staining, and CTL assay.Deletion of T cells with an anti-CD3 antibody completely demolished the antitumor efficacy of oncolytic Ad. Intratumoral injection of Ad induced strong virus- and tumor-specific T-cell responses, as well as antiviral antibody response. Both antiviral and antitumor T-cell responses contributed to the efficacy of oncolytic Ad. Deletion of T cells increased viral replication and extended the persistence of infectious virus within tumors but almost abrogated the antitumor efficacy. Preexisting antiviral immunity promoted the clearance of injected oncolytic Ad from tumors but had no effect on antitumor efficacy. Strikingly, the repeated treatment with oncolytic Ad has strong therapeutic effect on relapsed tumors or tumors insensitive to the primary viral therapy.These results demonstrate that T cell-mediated immune responses outweigh the direct oncolysis in mediating antitumor efficacy of oncolytic Ad. Our data have a high impact on redesigning the regimen of oncolytic Ad for cancer treatment. Clin Cancer Res; 23(1); 239-49. ©2016 AACR.
Use of novel radiosensitizers and radiation-specific miRNAs to modulate radiation response in non-small cell lung adenocarcinoma (NSCLC).
Authors: C. Acharya, K. A. Higgins, B. Balakumaran, A. Pappadake, N. Khodarev, W. Barry, W. Kim, R. R. Weichselbaum, A. Potti
Journal: Journal of Clinical Oncology (2010)

e17519 Background: Tumor response to radiotherapy in NSCLC remains markedly heterogeneous. Few successful radiosensitivity predictive assays exist that can be applied to individualize radiotherapeutic options. Methods: Using Bayesian regression analysis, a 52-gene expression signature that predicts sensitivity to external beam radiotherapy was developed and independently validated. On the basis of the signature, using Connectivity Map, novel candidate radiosensitizers were identified and tested in vitro by cell proliferation assays on predicted radioresistant NSCLC cell lines at three different radiation doses (3, 5 and 7 Gy). Cisplatin was used as a clinically relevant control. Furthermore, a systemic computational approach was developed to identify potential radiation-specific miRNAs, which were later transiently expressed and validated in vitro using the aforementioned NSCLC cell lines. Results: The 52-gene expression signature accurately predicted radiosensitivity in vitro and in individuals treated with radiation or chemoradiation independent of tissue. Tumor cell-specific novel agents, such as ethacrynic acid and docosahexaenoic acid have shown to radiosensitize NSCLC cell lines in a drug and radiation dose-indepependent manner. Finally, radiation-specific miRNAs (hsa-let-7b, hsa- let-7i and hsa-miR30a), which were shown to regulate RAS signaling pathway as evidenced from Western analyses, significantly radiosensitize (p<0.001 for all three miRNAs with respect to mock transfected controls) NSCLC cell lines. Conclusions: Comprehensive genomic analysis using gene expression signatures and miRNA data provides opportunities to better understand the mechanisms underlying radiation response and provides novel therapeutic opportunities in NSCLC. No significant financial relationships to disclose.
Abstract 4587: Dynactin dysregulation-induced increase in EGFR on basal-like breast cancer cells
Authors: Gautam Chaudhuri, Smita Misra
Journal: Cancer Research (2016)

Abstract Aggressive triple-negative basal-like breast cancer (BLBC) cells are often characterized with overabundance of the epidermal growth factor receptor (EGFR). Major objective of our research is to explore the possibility that dysregulation of the function of the dynactin complex as a mechanism of over-abundance of EGFR on BLBC cell surface. Our notion is that molecular defects in the dynactin-mediated retrograde EGFR recycling pathway in the BLBC cells causes the accumulation of this receptor on their cell surface making them hyper-responsive to EGF signaling. Our comparative transcriptome analysis between BLBC cells with higher levels of EGFR and the non-BLBC cells with lower levels of EGFR revealed that the expression of dynactin complex subunits 1, 2, 3, 4 and 6 (DCTN1, 2, 3, 4, 6), are significantly reduced in the EGFR-high aggressive BLBC cells. In addition, EGFR-high BLBC cells also have lower levels of two other dynactin-associated proteins, CLIP1 and LRRK1. Interestingly, elevation of surface EGFR levels in BLBC cells are associated with higher levels of the long non-coding RNA PVT1. Six miRNAs are generated from the precursor of PVT1 RNA during cis-splicing. They are miR-1204, miR-1205, miR-1206, miR-1207-3p, miR-1207-5p and miR-1208. We found that relative levels of these miRNAs are significantly higher in EGFR-high BLBC cells and tissues in comparison to the non-aggressive EGFR-low BLBC cells. Bioinformatics analysis followed by experimental validation revealed that miR-1207-5p inhibits DCTN1, DCTN3 and ACTR1A; DCTN2 is inhibited by miR-1205 and miR-1208. MiR-1208 also inhibits DCTN6 and CLIP1 whereas LRRK1 and CAPZA1 are inhibited by miR-1207-3p and miR-1206, respectively. Moreover beta-spectrin (SPTB), a protein associated with dynactin complex, is also inhibited by miR-1205 and miR-1207-3p. Treatment of the cells with the antagomirs of the miRNAs increased the levels of their respective target proteins with concomitant decrease in the surface level of EGFR. Our data suggest that BLBC cells maintain a robust level of EGFR on the cell surface by repressing the retrograde transport of EGFR through the repression of the proteins in the dynactin complex and thus sustain their higher growth rates. This research is supported in part by DOD-CDMRP IDEA Expansion Grant# BC103645 and NIH/NCI grant 1R21CA181920-01 to GC. Citation Format: Gautam Chaudhuri, Smita Misra. Dynactin dysregulation-induced increase in EGFR on basal-like breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4587.
Biogenic amine and metabolite levels in depressed patients with high versus normal hypothalamic-pituitary-adrenocortical activity
Authors: P E Stokes, J W Maas, J M Davis, S H Koslow, R C Casper, P M Stoll
Journal: American Journal of Psychiatry (1987)

The activity of the hypothalamic-pituitary-adrenocortical (HPA) axis is often high in depressive illness. The authors studied 132 depressed patients and 80 healthy control subjects. They report a significant direct association between HPA axis activity and adrenomedullary epinephrine secretion in depressed patients. They also found that depressed patients with high HPA activity tend to have lower CSF levels of 5-hydroxyindoleacetic acid, a serotonin metabolite, and modestly lower levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of epinephrine and norepinephrine, than patients with normal HPA activity. These findings provide potentially important leads for understanding interactions of biogenic amine systems with HPA axis function.
PRM-151 in Myelofibrosis: Durable Efficacy and Safety at 72 Weeks
Authors: Srdan Verstovsek, Ruben A. Mesa, Lynda M Foltz, Vikas Gupta, John O. Mascarenhas, Ellen K. Ritchie, Ronald Hoffman, Richard T. Silver, Marina Kremyanskaya, Olga Pozdnyakova, Robert P. Hasserjian, Elizabeth Trehu, Mohamed E Salama, Hagop M Kantarjian, Jason Gotlib
Journal: Blood (2015)