tbuckley/cabot-search huggingface dataset:
Abstract 3092: In-situ Kinome wide profiling of Palbociclib treated COLO-205 human tumor xenograft samples
Authors: Geeta Sharma, Subha Vogeti, Wendy Grant, Shuzhen Wu, Christa Dias, Tyzoon Nomanbhoy, Jiangyue Wu, Arwin Aban
Journal: Cancer Research (2015)

Abstract Palbociclib (PD0332991) is a cyclin dependent kinase 4 and 6 inhibitor being developed for treatment of breast cancer. In order to evaluate the kinome-wide impacts of Palbociclib in an in-vivo setting, nude mice inoculated with COLO-205 (human colon carcinoma) cells were administered Palbociclib at different doses (12.5, 75 and 150mg/kg once daily for 3 days. Tumors were collected at various time points after the final dose (1, 3, 6, 12, 24 &amp; 48 hours), lysed and subjected to in-situ kinase profiling using the KinativTM technology. Tumor lysates were probed with an ATP acylphosphate desthiobiotin probe which covalently modifies lysine residues in the kinase active site. Samples are then denatured, trypsinized, and the probe-labeled peptides captured with streptavidin, eluted, and quantitated by targeted mass spectrometry. The presence of an inhibitor bound to the active site of a kinase prevents the probe binding, resulting in the loss of MS signal for peptides from that kinase. In addition, the upregulation or downregulation of kinase proteins can also result in changes in the MS signals in palbociclib versus vehicle-treated samples. A total of 180 kinases were quantified. As expected, direct targets of palbociclib were observed to be inhibited in this study (i.e., kinases inhibited by Palbociclib in Colo205 lysate), including CDK4 &amp;6 as well as ERK5, JNK, CDK16 &amp;17, PIK3C3 and PIP4K2C. The observed inhibition of these targets was both dose and time dependent. Significantly, the MS signals for additional kinases not observed to directly bind Palbociclib in Colo205 lysate were also strongly downregulated in this study. These include CDC2, AurA, AurB, PLK1 and MASTL; kinases critical for cell cycle progression. We hypothesize that the downregulation of these kinases was due to cell cycle arrest in G1 phase. Consistent with this hypothesis, the downregulation of these kinases corresponded well with the inhibition of phosphorylated (Ser780; pRb) as demonstrated by Western Blots of a part of tumor tissue used for the Kinome profiling. Taken together, these results highlight the utility of kinome wide profiling in tumor samples collected from xenograft mice to better understand both pharmacodynamics of target engagement as well as pathway effects elicited by compound treatment. Citation Format: Geeta Sharma, Subha Vogeti, Wendy Grant, Shuzhen Wu, Christa Dias, Tyzoon Nomanbhoy, Jiangyue Wu, Arwin Aban. In-situ Kinome wide profiling of Palbociclib treated COLO-205 human tumor xenograft samples. [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 3092. doi:10.1158/1538-7445.AM2015-3092
Dasatinib Time to and Durability of Major and Complete Cytogenetic Response (MCyR and CCyR) in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Authors: Michele Baccarani, Gianantonio Rosti, Giuseppe Saglio, Jorge Cortes, Richard Stone, Dietger W. Niederwieser, Eric Bleickardt, Ritwik Sinha, Bengt Simonsson
Journal: Blood (2008)
657. Enhancing Therapeutic Efficacy of an Oncolytic Virus with a Beta-1 Integrin Blocking Antibody, OS2966
Authors: Tejaswini Reddy Nallanagulagari
Journal: Molecular Therapy (2016)

Glioblastoma Multiforme (GBM) is a destructive cancer of the central nervous system with poor outlook for its patients, which prompts for development of novel therapeutic approaches such as oncolytic viruses (OVs). OVs are genetically engineered viruses with tumor specific replication and lead to lysis and destruction of cancer cells. Our lab has developed a novel oncolytic Herpes Simplex Virus (oHSV), 34.5ENVE, which expresses the anti-angiogenic protein Vasculostatin. This virus has shown unparalleled antitumor efficacy against intracranial glioma in mice. OV therapy is limited by the activation and infiltration of monocytic cells that promote virus clearance and inhibit tumor destruction. β1 integrins are cell surface molecules involved in cellular proliferation, invasion and inflammation. We revealed that oHSV-induced cysteine-rich 61 protein (CCN1) binds with integrins on the surface of glioma cells and macrophages, triggering antiviral type-I interferon and chemokine responses that increase macrophage infiltration and activation, which causes increased virus clearance in glioblastoma cells and limits oncolytic virus efficacy. To improve OV therapeutic efficacy, we combined oHSV with OS2966, a β1 integrin neutralizing antibody, which has been humanized in anticipation of clinical trials. We hypothesized that OS2966 would mitigate CCN1- β1 integrin induced inflammation and increase oHSV replication. Combination treatment with OS2966 increased oHSV replication and glioma cell killing. Migration assays revealed that treatment with OS2966 strongly inhibited oHSV-induced raw246.7 macrophage cell migration toward infected glioblastoma cells. From our results, we demonstrate that β1 integrins limit oHSV replication. Furthermore, we concluded that OS2966 could rescue CCN1- β1 integrin mediated macrophage and microglia migration toward oHSV infected GBM cells. Our findings show how a β1 integrin neutralizing antibody (OS2966) inhibits the innate immune response triggered upon oHSV treatment. This work suggests that β1 integrin inhibition may be utilized in the development of a novel oHSV therapeutic strategy.
Transforming Evidence Generation to Support Health and Health Care Decisions
Authors: Robert M. Califf, Melissa A. Robb, Andrew B. Bindman, Josephine P. Briggs, Francis S. Collins, Patrick H. Conway, Trinka S. Coster, Francesca E. Cunningham, Nancy De Lew, Karen B. DeSalvo, Christine Dymek, Victor J. Dzau, Rachael L. Fleurence, Richard G. Frank, J. Michael Gaziano, Petra Kaufmann, Michael Lauer, Peter W. Marks, J. Michael McGinnis, Chesley Richards, Joe V. Selby, David J. Shulkin, Jeffrey Shuren, Andrew M. Slavitt, Scott R. Smith, B. Vindell Washington, P. Jon White, Janet Woodcock, Jonathan Woodson, Rachel E. Sherman
Journal: New England Journal of Medicine (2016)

We will address the strategic, organizational, and technical aspects that must be considered through an assessment of the current landscape of data available to clinicians and patients for use in clinical decision making and the opportunities for enhancing the available body of clinical evidence.2. We will work to better identify and describe the landscape of ongoing activities contributing to narrowing the current evidence gap through approaches that leverage and extend the use of the volumes of relevant digital health and health care data to facilitate efficient, streamlined randomized trials and high-quality observational studies.3. We will initiate demonstration projects focused on collaborations seeking to leverage resources created by ongoing projects that use digital data from government sources and private organizations (e.g., health care organizations, payers, providers, and patients).Activities for Building a Strong Foundation for the Implementation of a Learning Health System.
Preclinical Pharmacology and Toxicology of Humanized Anti-B-Cell Antibodies (Anti-CD22 and Anti-CD20) in Cynomolgus Monkeys (CM).
Authors: Puja Sapra, Gary Kikuchi, Ashwini Venkatasamy, Marianne K. Hayes, Christina M. Satterwhite, Darren Warren, Mark D. Walker, David M. Goldenberg, Ivan D. Horak
Journal: Blood (2005)
Abstract 298: Overcoming TGF-β-related immunosuppression for cancer immunotherapy by oncolytic adenovirus co-expressing Interleukin-12 and decorin
Authors: Eonju Oh, Il-Kyu Choi, June Kyu Hwang, Chae-Ok Yun
Journal: Cancer Research (2015)

Abstract Interleukin (IL)-12 has been shown to be one of the most promising antitumor cytokines. The major antitumor activities of IL-12 rely on its ability to promote T helper type 1 (Th1) immune responses and CTL responses. However, immune suppression-dominated microenvironments in advanced tumors hinder the effect of IL-12 gene therapy for cancer. Most tumor cells produce large amounts of transforming growth factor-β (TGF-β), which plays crucial roles of tumor-induced immune suppression. The TGF-β inhibits proliferation of immune cells such as T, NK, and dendritic cells, resulting in suppression of antitumor immunity. Moreover, TGF-β is also known to regulate the maintenance and induction of regulatory T (Treg) cells. Thus, it has been hypothesized that inhibiting TGF-β might be an apt strategy for generating more effective cancer immunotherapy. Therefore, to enhance the efficiency of IL-12-mediated cancer immunotherapy, we generated oncolytic adenovirus co-expressing IL-12 and Decorin (hDCN) (RdB/IL12/hDCN) as suitable therapeutic adjuvant to overcome immune suppression by down-regulation of TGF-β through hDCN. Intratumoral administration of RdB/IL12/hDCN promoted enhanced antitumor effects compared with an oncolytic adenovirus expressing IL-12 or hDCN alone (RdB/IL12 or RdB/hDCN, respectively). We showed markedly elevated levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α and IFN-γ secreting cells in RdB/IL12/hDCN-treated tumors. Moreover, Treg in draining lymph nodes (DLNs) dramatically decreased in mice treated with RdB/IL12/hDCN, suggesting an association with the down-regulation of TGF-β in tumor treated with RdB/IL12/hDCN. Consistent with these data, tumor tissue injected with RdB/IL12/hDCN showed increased infiltration of CD4+ T and CD8+ T cells infiltration. Furthermore, hDCN enhanced viral distribution and tumor penetration, leading to improved virus-mediated cancer gene therapy by overcoming the extracellular matrix barrier within tumor masses. Together, these results provide new insight into the ability of hDCN to eliminate immune suppression and demonstrate that adenovirus co-expressing IL-12 and hDCN is a promising therapeutic tool for cancer treatment than adenovirus expressing IL-12 alone. Note: This abstract was not presented at the meeting. Citation Format: Eonju Oh, Il-Kyu Choi, June Kyu Hwang, Chae-Ok Yun. Overcoming TGF-β-related immunosuppression for cancer immunotherapy by oncolytic adenovirus co-expressing Interleukin-12 and decorin. [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 298. doi:10.1158/1538-7445.AM2015-298
Abstract 4213: Gene therapy for esophageal squamous cell carcinoma using SOCS-1 expressing adenoviral vector
Authors: Hisashi Hara, Rie Nakatsuka, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Hiroshi Miyata, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Tetsuji Naka
Journal: Cancer Research (2015)

Abstract Objective Esophageal squamous cell carcinoma (ESCC) is the major histological form of oesophageal cancer in East Asian countries. Despite recent improvements in multimodality treatment, including surgery, radiotherapy and chemotherapy, the prognosis for patients with ESCC remains unsatisfactory. Therefore, development of novel therapy is urgently required. Suppressor of cytokine signaling-1 (SOCS-1) has been cloned as a negative regulator of various cytokine signaling. Recently, lines of evidences suggest that overexpression of SOCS-1 has been considered as a promising therapeutic approach for treatment of cancer. This study was aimed to evaluate the therapeutic effect of the overexpression of SOCS-1 by adenoviral vector (AdSOCS-1) against ESCC. METHODS By WST-8 assay, cell growth inhibition via infection with various dose of AdSOCS-1 was evaluated in 11 ESCC cell lines in vitro. We also evaluated the induction of apoptosis by overexpression of SOCS-1 in vitro. To evaluate the therapeutic efficacy of AdSOCS-1, ESCC cell line (TE-8) was subcutaneously implanted into the ICR nu/nu mice. In addition, therapeutic efficacy was also assessed using human xenografts subcutaneously transplanted in imuune-deficient mice. Mice were intra-tumorally injection with AdSOCS-1 or control adenovirus vector (AdLacZ) twice a week for 4weeks. RESULTS Among 11 ESCC cell lines, AdSOCS-1, markedly suppressed proliferation of 8 ESCC cell lines in vitro. AdSOCS-1 strongly induced apoptosis in vitro, via inhibiting JAK/STAT3 pathway. In the TE8 xenograft model, the volume of tumors after therapy in AdSOCS-1 group (1,580 ± 1,005mm3) were lower than that in control group (2,690 ± 1,309mm3). Furthermore, compared with AdLacZ, injection with AdSOCS-1 also inhibited the tumor growth of patient derived ESCC xenografts. CONCLUSIONS Our results indicated that overexpression of SOCS-1 inhibited the progression of ESCC both in ESCC cell lines and ESCC xenograft model derived from patient. SOCS-1 can be a promising novel therapeutic approach for intra-lesional therapy in ESCC. Citation Format: Hisashi Hara, Rie Nakatsuka, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Hiroshi Miyata, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Tetsuji Naka. Gene therapy for esophageal squamous cell carcinoma using SOCS-1 expressing adenoviral vector. [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 4213. doi:10.1158/1538-7445.AM2015-4213
Evaluation of anti-CTLA4 treatment in a murine model of intestinal polyposis.
Authors: J. D. Phillips, N. R. Blatner, M. F. Mulcahy, P. Beckhove, D. J. Bentrem, K. Khazaie
Journal: Journal of Clinical Oncology (2011)

10584 Background: Colon cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer death in the United States. Mutations of the APC gene are found in the majority of sporadic cases of polyps and cancer and are the cause of familial adenomatous polyposis. The role of inflammation in the progression of polyps to cancer is well established. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a member of the CD28-B7 immunoglobulin superfamily that mediates non-antigen specific interactions w/ antigen presenting cells and prevents or down-regulates the activation of T-cells in response to a stimulus. Treatment of cancer patients with anti-CTLA-4 antibody (aCTLA4) has shown some promise in melanoma, prostate and ovarian tumors. We have recently observed polyp specific T-cell responses in a mouse model of polyposis and hypothesize that treatment with aCTLA4 will enhance this response, resulting in a reduction of polyps. Methods: Using a well-established murine model of polyposis, APCΔ468, animals were randomized to receive either 100µg monoclonal aCTLA4, 9H10 (BioXCell), or PBS. Intraperitoneal injections were performed every other day for 3 doses. The primary endpoint was number of polyps in the small intestine and large intestine. Animals were sacrificed and polyps were counted by gross inspection at 3-weeks (n=6 for each group) and 6-weeks (n=3 for each group) post injection. Interferon-γ ELISPOT analysis was performed on splenic lymphocytes to evaluate tumor specific immunity. Results: A reduction in small intestinal polyp count was seen in the 3-week aCTLA4 group compared to controls, 48 +/- 13 vs. 100 +/- 12 (p=0.0154). This decrease was sustained at 6-weeks, 46 +/- 6 (p=0.0032). No significant difference was noted in large intestinal polyp counts at 3- or 6-weeks. Preliminary ELISPOT analysis revealed a trend toward increased spots in the aCTLA4 group. Conclusions: Anti-CTLA4 treatment with a monoclonal antibody resulted in a reduction of polyp load in a murine model of intestinal polyposis up to six weeks following treatment. Thus, aCTLA4 may be useful for treatment of intestinal pre-neoplasia. Further studies are needed to assess the immunologic affect of aCTLA4 in the treatment of polyposis and colon cancer.
Abstract 438: Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis of uterine cervical cancer by recruiting myeloid-derived suppressor cells (MDSCs) via CXCL12-CXCR4 axis
Authors: Tomoyuki Sasano, Seiji Mabuchi, Ryoko Takahashi, Hiromasa Kuroda, Kenjiro Sawada, Tadashi Kimura
Journal: Cancer Research (2015)

Abstract Objectives: Granulocyte-colony stimulating factor (G-CSF) is known to induce the myeloid-derived suppressor cells (MDSCs) to stimulate the progression of uterine cervical cancer. The aim of this study was to investigate the role of G-CSF and the MDSCs in the invasion and the metastasis of uterine cervical cancer. Methods: We first established cervical cancer cell lines stably transfected with G-CSF expression vector (ME180-GCSF) or control vector (ME180-control). Then, using mice subcutaneously inoculated with ME180-control or ME180-GCSF cells, the effect of G-CSF on the induction of MDSCs (CD11b+Gr1+ cells) and the metastatic activity of cervical cancer cells. The association of MDSCs infiltration and the clinical outcome was also assessed immunohistochemically using tumor samples obtained from cervical cancer patients. Finally, using MDSCs isolated from the spleen of the ME180-GCSF-bearing mice, we investigated whether the MDSCs facilitate the invasive or metastatic activities of uterine cervical cancer in vitro and in vivo. Results: 1) ME180-GCSF-derived tumors contain greater number of MDSC, more frequently develop lymphovascular space invasion, and developed greater number of metastatic tumors than ME180-control-tumors. 2) Immunohistochemical analyses using human samples revealed that increased MDSC counts were significantly associated with deep stromal invasion and lymphovascular space invasion. 3) MDSCs were recruited into cervical cancer via CXCL12-CXCR4 axis. 4) Coincubation of MDSCs with ME180 cells increased the invasive activity of ME180 cells. 5) The depletion of MDSCs significantly decreased the invasive and metastatic activities of ME180 cells. Conclusions: Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis by recruiting MDSCs. MDSCs and CXCL12-CXCR4 axis might be promising therapeutic targets in patients with uterine cervical cancer. Citation Format: Tomoyuki Sasano, Seiji Mabuchi, Ryoko Takahashi, Hiromasa Kuroda, Kenjiro Sawada, Tadashi Kimura. Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis of uterine cervical cancer by recruiting myeloid-derived suppressor cells (MDSCs) via CXCL12-CXCR4 axis. [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 438. doi:10.1158/1538-7445.AM2015-438
PTU-335 Quality of care in the management of inflammatory bowel disease: how do patients rate their quality of care?: Abstract PTU-335 Table 1
Authors: WY Ding, A Baigent, K Bunger, M Dibb, T Ellis, M Gordon, C Probert, S Subramanian, P Collins
Journal: Gut (2015)

<h3>Introduction</h3> QUOTE-IBD is a validated patient questionnaire that assesses the quality of health care provision in inflammatory bowel disease (IBD) from the patient’s perspective.<sup>1</sup>A series of questions assess health care within eight domains. Each patient scores elements of their health care according to: 1) The importance of that aspect of health care to them, and 2) Their experience as to how well that aspect of the service is delivered. The QUOTE instrument combines the “Importance” and “Performance” scores to generate a “Quality Impact” (QI) score for each domain (range 0 to 10). A QI of less than 9.0 indicates that there is room for improvement. Patients scored health care provision for specialist clinics and GP attendances separately. <h3>Aim</h3> To assess the quality of health care provision from the IBD service in a tertiary centre from patients’ perspective. <h3>Method</h3> The QUOTE-IBD questionnaire was given to consecutive patients in three consecutive IBD clinics. Data were analysed as described by van der Eijk <i><i>et al</i>.</i><sup>1</sup> <h3>Results</h3> 149 consecutive patients were invited to complete the QUOTE-IBD questionnaire with a response rate of 98.7%. 59 patients (40.1%) indicated that they had a diagnosis of Crohn’s disease, and 49 patients (33.3%) a diagnosis of ulcerative colitis (33.3%). 39 patients (26.6%) did not indicate an IBD-subtype. Specialist clinics and GP services had QI scores of &gt; 9.0 for accommodation and cost, with specialist clinics also scoring &gt;9.0 for courtesy. Overall there was a trend for specialist-led clinics to have higher QI scores than GP-based services for IBD care. With the exception of one domain, all QI scores were &gt;8.0. The aspect of health care rated lowest for quality provision was in the domain of provision of information. Subjective feedback supported this latter observation, with requests for information on diet as a common theme. <h3>Conclusion</h3> Patients attending a tertiary IBD service express a high level of satisfaction with their health care. Feedback indicates areas where there is room for improvement, with provision of information deemed the area requiring greatest focus. (Patient information packs have been developed in partnership with the patient panel.) The QUOTE-IBD tool is a valuable resource to enhance patient-centred improvement in the quality of health care in IBD. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> van der Eijk <i>et al</i>. Am J Gastroenterol. 2001;96:3329