tbuckley/cabot-search huggingface dataset:
Abstract 3226: The apoptotic mechanism of MT-6, a mitotic inducer, in human ovarian cancer cells
Authors: Chen Mei-Chuan
Journal: Cancer Research (2017)

Abstract Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of SKOV3 ovarian cancer cells with submicromolar IC50 values. MT-6-treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in SKOV3 cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6-induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future. Citation Format: Chen Mei-Chuan. The apoptotic mechanism of MT-6, a mitotic inducer, in human ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3226. doi:10.1158/1538-7445.AM2017-3226
Abstract 3158:In vivoacquired resistance to an emibetuzumab analogue inMET-amplified gastric xenografts can be overcome by a MET-targeting antibody mixture or PIK3CA/AKT/mTOR inhibition
Authors: Sofie Ellebæk Pollmann, Emanuel Frank Petricoin, Valerie Calvert, Shruti Rao, Simina Boca, Subha Madhavan, Ivan David Horak, Andreas Kjær, Michael Kragh, Thomas Tuxen Poulsen
Journal: Cancer Research (2017)

Abstract Aberrant over-activation of MET receptor tyrosine kinase is involved in driving malignancies such as gastric and non-small cell lung cancer (NSCLC), and in the development of resistance to EGFR-targeting therapeutics. This has led to the development of several MET-targeting agents in the form of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), many of which are in clinical development. However, resistance to MET-targeted agents is an emerging problem. This study aims to understand mechanisms underlying resistance development to an analogue of emibetuzumab, a mAb targeting MET. Upon long term in vivo treatment, emibetuzumab-resistant tumors and cell lines were generated, isolated, and characterized to investigate their acquired resistance mechanisms. Extensive reverse phase protein array and network analysis were used to characterize the proteomic profiles of three resistant cell lines, revealing three distinct resistance profiles, one involving activation of the PI3Kinase/AKT/mTOR pathway. We further show, how these resistance mechanisms can be overcome by treatment with other targeting therapeutics both in vitro and in vivo. Two of the models demonstrated in vivo sensitivity to Sym015, a novel mixture of two mAbs targeting non-overlapping epitopes of MET, partly due to ADCC, indicating that Sym015 can overcome acquired resistance to emibetuzumab. The third model demonstrated a marked increase in PI3Kinase/AKT/mTOR pathway activation. This activation translated into induced cancer cell and tumor growth, which could be inhibited by agents targeting PI3Kinase, AKT, or mTOR. This study thus points to treatment of patients with acquired resistance to single targeting MET mAbs with PI3Kinase/AKT/mTOR-targeting agents or a MET-targeting antibody mixture such as Sym015. Citation Format: Sofie Ellebæk Pollmann, Emanuel Frank Petricoin, Valerie Calvert, Shruti Rao, Simina Boca, Subha Madhavan, Ivan David Horak, Andreas Kjær, Michael Kragh, Thomas Tuxen Poulsen. In vivo acquired resistance to an emibetuzumab analogue in MET-amplified gastric xenografts can be overcome by a MET-targeting antibody mixture or PIK3CA/AKT/mTOR inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3158. doi:10.1158/1538-7445.AM2017-3158
Abstract 1142: Novel target discovery for glioblastoma using chemical biology fingerprinting
Authors: Darren Finlay, Pedro Aza-Blanc, Harshil Dhruv, Alexey Eroshkin, Craig Hauser, Jeff Kiefer, Seungchan Kim, Tao Long, Robert G. Oshima, Sen Peng, Gil Speyer, Michael Berens, Kristiina Vuori
Journal: Cancer Research (2017)

Abstract The most common adult brain tumor is Glioblastoma Multiforme (GBM), an extremely aggressive cancer with only scant treatment options. Even with standard of care most patients present with a recurrence and the median survival is only circa 15 months. The need, therefore, for new therapeutic targets and treatment options is pressing. Here we describe here a multipronged approach to identifying said targets. We present an established methodology for the isolation and culture of patient derived GBM samples that retain the “stem-like” fraction thought to underlie resistance and recurrence. Furthermore we show genomically that these samples represent specific subtypes of the disease yet still form distinct groups in unbiased clustering analysis. Thus we have multiple representative patient derived cultures that are suitable for our drug discovery and chemical biology analyses. Using a process we term Chemical Biology Fingerprinting (CBF) we utilize small focused, and clinically relevant, chemical collections in order to identify patterns of chemovulnerabilities across multiple samples. This allows an unbiased yet cancer relevant sub-stratification and the identification of agents, and therefore targets, which may be relevant for GBM patient subtypes. Indeed our use of the highly annotated NCI CTD2 Informer Set of chemicals allows ready drug-to-target mapping and facilitates data sharing across the CTD2 network. Moreover, already defined subgroups can be clustered to find agents, or groups of agents, that show selective activity against traditional classifications (e.g. proneural, mesenchymal etc.). Finally our strategy is permissive for the identification of “exceptional responders”. That is, individual patient samples that respond to a specific drug whilst most samples are refractory. In sum we demonstrate generation of patient derived models and identify specific, and novel, drugs that may be relevant for specific GBM subtypes. Supported by NIH U01CA168397 Citation Format: Darren Finlay, Pedro Aza-Blanc, Harshil Dhruv, Alexey Eroshkin, Craig Hauser, Jeff Kiefer, Seungchan Kim, Tao Long, Robert G. Oshima, Sen Peng, Gil Speyer, Michael Berens, Kristiina Vuori. Novel target discovery for glioblastoma using chemical biology fingerprinting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1142. doi:10.1158/1538-7445.AM2017-1142
Review of Lydia S. Dugdale, Dying in the 21st Century: Towards a New Ethical Framework for the Art of Dying Well
Authors: Anthony P. Smith
Journal: The American Journal of Bioethics (2017)

"Review of Lydia S. Dugdale, Dying in the 21st Century: Towards a New Ethical Framework for the Art of Dying Well." The American Journal of Bioethics, 17(8), pp. W1–W2
Abstract 1355: Linking AP/MS-derived protein-protein interaction networks and pairwise sgRNA screens defines new KRAS effectors in non-small cell lung cancer
Authors: Marcus R. Kelly
Journal: Cancer Research (2017)

Abstract The KRAS oncogene is mutated in over one fourth of human cancers. Despite decades of work studying known effector pathways, no drugs in clinical use specifically target KRAS-mutant tumors. Uncharacterized feedback mechanisms and parallel pathways have stymied the treatment of KRAS-mutant tumors in patients, and the KRas protein does not easily accommodate the binding of inhibitory small molecules. These challenges demand better characterization of the physical and genetic relationships between Ras regulators and effectors. To that end, we used tandem affinity purification of Kras, Hras and Nras and twelve proteins with known regulatory or effector roles to generate a high-confidence protein-protein interaction (PPI). Interactions were cross-referenced with public PPI, genetic susceptibility, and patient data to assemble a physical PPI map annotated with important functional determinants. The final map contains 287 genes and 990 physical interactions among them. This map was used to construct a library of &amp;gt;1000 sgRNAs covering &amp;gt;100 genes of probable relevance to the Ras pathway. This library was screened for pairwise genetic effects in a dual sgRNA vector system to identify quantitative changes in the growth of the A549 NSCLC line. We will present the quantitative results of this screen and additional validation studies on several previously undescribed regulators and effectors of the Ras proteins. In particular, we highlight unknown interactions between KRAS and the cell adhesion regulator RADIL, and the specificity of Ras-family protein interaction with the Raf and Ral GEF family proteins. These data underscore the limitations of our current understanding of Kras-driven cancers and reveal their genetic vulnerabilities. Citation Format: Marcus R. Kelly. Linking AP/MS-derived protein-protein interaction networks and pairwise sgRNA screens defines new KRAS effectors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1355. doi:10.1158/1538-7445.AM2017-1355
Abstract 2313: Promoting caspase-8-dependent apoptosis signaling using 17-beta-hydroxywithanolides
Authors: Alan D. Brooks, Ya-ming Xu, E. M. Kithsiri Wijeratne, Curtis J. Henrich, Poonam Tewary, Leslie Gunatilaka, Thomas J. Sayers
Journal: Cancer Research (2017)

Abstract We have previously reported that withanolide E (WE), a steroidal lactone from Physalis peruviana, was highly active in sensitizing various human carcinoma cell lines to TRAIL-mediated apoptosis. Therefore, over 100 natural and semi-synthetic withanolides were evaluated for their ability to promote caspase-8-dependent cancer cell death. Our studies identified several withanolides that were 4-8 fold more potent than WE in sensitizing the renal carcinoma cells and melanoma cells to caspase-8-dependent apoptosis in response to either TRAIL or the TLR3 ligand poly (I:C). All active withanolides were 17-beta-hydroxywithanolides (17-BHW). The highly active 17-BHWs were more efficient than withanolide E at reducing cellular levels of both cFLIPL and cFLIPS and enhancing caspase-8 activation. Furthermore, immunoprecipitation of the TRAIL death-inducing signaling complex (DISC), or the related ripoptosome, demonstrated enhanced levels of both FADD and RIP1 in these macromolecular apoptosis signaling complexes following treatment with active 17-BHWs. The 17-BHWs used in this work were obtained by the application of an efficient method of plant biomass production involving our innovative and patented soil-less aeroponic cultivation of P. crassifolia and P. peruviana and by chemical modification of natural withanolides produced by these plants. Preliminary structure activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition, acetoxylation at C-18, an alpha orientation of the side-chain lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as apoptosis sensitizers. This suggests that the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, which could lead to the identification of highly active natural product-based sensitizers of cancer cells to caspase-8-dependent apoptosis. The cellular molecular target(s) of active 17-BHWs are currently under further investigation. Funded by FNLCR Contract HHSN261200800001E. Citation Format: Alan D. Brooks, Ya-ming Xu, E. M. Kithsiri Wijeratne, Curtis J. Henrich, Poonam Tewary, Leslie Gunatilaka, Thomas J. Sayers. Promoting caspase-8-dependent apoptosis signaling using 17-beta-hydroxywithanolides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2313. doi:10.1158/1538-7445.AM2017-2313
Abstract 569: Dexamethasone inhibits T-cell proliferation through a CTLA-4 mediated pathway
Authors: Marsha-Kay N. Hutchinson, Amber J. Giles, Heather M. Sonnemann, Caitlin M. Reid, Deric M. Park, Mark Gilbert
Journal: Cancer Research (2017)

Abstract BACKGROUND: The use of corticosteroids for therapeutic benefit has to be weighed against the risks of adverse consequences associated with these drugs. Brain tumor patients in particular, are routinely prescribed dexamethasone (a glucocorticoid) to reduce edema associated with their lesion. Checkpoint blockade, a type of immune therapy, is currently being investigated as a potential treatment for brain tumors. However, glucocorticoid signaling has been shown to attenuate the immune response through several mechanisms including the repression of transcription of genes controlling pro-inflammatory cytokines and chemokines. HYPOTHESIS: Here, we propose that dexamethasone’s ability to upregulate inhibitory T-cell molecules such as CTLA-4 and PD-1 might be an additional immunosuppressive mechanism. METHODS: Healthy donor T cells were tested for response to dexamethasone. T cell proliferation, cell cycle analysis, apoptosis, and protein expression were assessed with flow cytometry. Protein expression was also measured with Western blots. Transcriptional changes were assessed with qPCR. A monoclonal antibody, ipilimumab, was used to block CTLA-4 binding. RESULTS: Unexpectedly, dexamethasone did not elicit a direct lymphotoxic effect on T cells as measured by absolute cell number. However, we found that dexamethasone significantly reduced T cell entry into the cell cycle, but did not impact cells already undergoing mitosis. Checkpoint molecules CTLA-4 and PD-1 were increased with dexamethasone treatment when cells are stimulated. Blockade of CTLA-4 with Ipilimumab resulted in a substantial reversal of cell cycle entry inhibition that was induced by dexamethasone. CONCLUSIONS: These results suggest that dexamethasone impairs T cell expansion by inhibiting cell cycle entry. Upregulated CTLA-4 expression contributes to cell cycle entry blockade which is reversed by inhibiting CTLA-4 with ipilimumab. These findings indicate that administration of ipilimumab before dexamethasone diminishes the negative proliferative effect on anti-tumor T cells suggesting that when needed, corticosteroids can be used after immune checkpoint blockade has been established. Citation Format: Marsha-Kay N. Hutchinson, Amber J. Giles, Heather M. Sonnemann, Caitlin M. Reid, Deric M. Park, Mark Gilbert. Dexamethasone inhibits T-cell proliferation through a CTLA-4 mediated pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 569. doi:10.1158/1538-7445.AM2017-569
Abstract 4709: Induction of enhanced tumor-specific immunity by Hsp90 targeted photodynamic therapy (Hsp90-PDT) combined with immune checkpoint inhibition
Authors: Kensuke Kaneko, Takuya Osada, Timothy A. Haystead, Michael A. Morse, Herbert K. Lyerly
Journal: Cancer Research (2017)

Abstract Background: Immunotherapy has become an emerging anti-cancer therapy, as immune checkpoint blockade with PD-1 or PD-L1 inhibition have been active against multiple cancer types. Nonetheless, there remain many non-responders, suggesting that combinations may improve activity, particularly combinations which can target tumors and have low toxicity. Methods &amp; Results: We have developed a novel Hsp90 targeted photodynamic therapy (Hsp90-PDT), which causes local anti-tumor responses. Hsp90-PDT can be combined with immune checkpoint blockade to generate potent anti-tumor effects. We synthesized well characterized PDT agent, verteporfin (VP) tethered to a HSP90 small molecule inhibitor, to create a Hsp90-PDT agent (Hsp90i-VP). We first compared the uptake of VP and Hsp90i-VP into the breast cancer cell lines (E0771-OVA) in vitro. Hsp90i-VP showed stronger incorporation than VP when the compounds were added 3μM or less in concentration. We next performed in vitro and vivo PDT with Hsp90i-VP and laser exposure (690 nm wavelength). Killing efficiency of VP and Hsp90i-VP was analyzed by MTT assay, which showed increased killing in a dose dependent manner for both photosensitizers (0-30µM) and laser (0-120J/cm2). Next, we treated E0771-OVA tumor-bearing C57BL/6 mice with Hsp90i-VP (25nmol/mouse) administration alone, laser irradiation (240J/cm2) alone, or the combination of Hsp90i-VP and laser. Suppression of the tumor growth was confirmed only in Hsp90i-VP and laser group. In addition, induction of tumor-specific immune response by PDT was confirmed by ELISA, where the elevation of anti-OVA antibody was seen only in PDT group. Furthermore, combination treatment of Hsp90-PDT and anti-PD-L1 mAbs was able to enhance cytotoxic T-cell response and suppress tumor growth significantly even with relatively PDT-resistant cell line. Conclusions: Hsp90-PDT showed a significant ability to induce antigen-specific immune response in both in vitro and in vivo. These results suggest that Hsp90-PDT can play an important role in anti-cancer immune therapy. Our future plan is to investigate the effect of local photodynamic therapy combined with various types of checkpoint inhibitor in breast cancer models. Citation Format: Kensuke Kaneko, Takuya Osada, Timothy A. Haystead, Michael A. Morse, Herbert K. Lyerly. Induction of enhanced tumor-specific immunity by Hsp90 targeted photodynamic therapy (Hsp90-PDT) combined with immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4709. doi:10.1158/1538-7445.AM2017-4709
Abstract 233: Cardiac Dysfunction Is Associated with Diminished Cardiac Neuropeptide Expression in Patients Undergoing Coronary Artery Bypass Surgery
Authors: Leena Pradhan-Nabzdyk, Asma Ejaz, Frank W LoGerfo
Journal: Circulation Research (2012)

Background: Neuropeptide Y (NPY) and its receptors, NPY1R, NPY2R, and NPY5R, Substance P (SP) and its receptor Neurokinin 1R (NK1R) and calcitonin gene related peptide (CGRP), are important regulators of cardiac physiology, including: vasomodulation, cardiomyocyte hypertrophy, ischemia-induced angiogenesis, modulation of Protein Kinase C activity and calcium homeostasis.[[Unable to Display Character: ]] Objective: To determine the relationship between cardiac function and neuropeptide expression in human subjects. Methods: 38 consecutive patients undergoing elective, on pump, coronary artery bypass surgery (CABG) for coronary artery occlusive disease were studied. A Transesophageal Echo was performed immediately following induction of anesthesia and Left Ventricular Ejection Fraction (LVEF) was determined by AHA criteria as Normal, &gt;55% (NLVEF, n = 26) or Low, &lt;50% (LLVEF, n = 12). Patients with HbA1c&gt;6.0 were considered diabetic. Right atrial tissue was obtained at the time of cannulation and the mRNA expression of Pre-Pro-NPY, NPY1R, NPY2R, NPY5R, Pre-Pro-SP, NK1R and CGRP was determined with qRT-PCR. Data are expressed as fold change relative to the NLVEF group. Results: The results of this study are summarized in the table below. Conclusions: 1. There is a strong association of LLVEF with diminished expression of SP, NK1R and NPY5R, with a similar trend for NPY2R. 2. LLVEF was not associated with HbA1c or diabetes status. 3. The consequences of diminished cardiac neuropeptide expression, the mechanisms involved, the relationship to cardiac autonomic neuropathy, with or without diabetes, warrant priority as an investigational initiative.
Abstract 4215: Cancer-related fatigue and physical activity vary by age for black women with a history of breast cancer
Authors: Melody A. Swen, Amandeep Mann, Raheem Paxton, Lorraine T. Dean
Journal: Cancer Research (2017)

Abstract Purpose: Cancer-related fatigue is the most discomforting symptom among women with a history of breast cancer. Black women are more likely to experience risk factors for cancer-related fatigue, like physical inactivity and obesity, yet cancer-related fatigue studies have not explicitly focused on Black women. This cross-sectional analysis assesses cancer-related fatigue and physical activity among Black female breast cancer survivors. Methods: In May and July of 2012, 266 members of the Sisters Network, Inc completed an online survey on: demographics, cancer history and treatment, fatigue using the 13-item Function Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, and engagement in ≥150 minutes per week of physical activity (CDC guideline). Multiple linear regression assessed relationships between fatigue and physical activity. Results: The average participant was 54 (SD=9) with a FACIT score of 13.63, indicating “severe fatigue”. Fatigue was greater (p=0.02) among the 56% of women meeting physical activity guidelines. Multivariable analysis showed that meeting physical activity guidelines (β=-3.01, p=0.01) and higher age group (50-59: -4.75, p=0.001; 60+: -4.38, p=0.01) were associated with greater fatigue. An interaction plot showed that differences in fatigue for those meeting or not meeting physical activity guidelines is largest among Black women under age 50. Conclusions: Meeting physical activity guidelines was associated with greater cancer-related fatigue, which was most pronounced for those under age 50. Interventions for Black breast cancer survivors with cancer-related fatigue should consider physical activities that can be integrated into existing tasks and provide age-appropriate resources to address physical and emotional fatigue domains. Keywords: breast cancer; fatigue; age; Black/African-American; physical activity Citation Format: Melody A. Swen, Amandeep Mann, Raheem Paxton, Lorraine T. Dean. Cancer-related fatigue and physical activity vary by age for black women with a history of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4215. doi:10.1158/1538-7445.AM2017-4215
Republished: Nicotine and health
Journal: BMJ (2014)

Nicotine, an alkaloid derived from the leaves of tobacco plants (<i>Nicotiana tabacum</i> and <i>Nicotiana rustica</i>) is the primary addictive agent in tobacco products.<sup>1,2</sup> There are different ways of administering the various products including smoking cigarettes, chewing tobacco, holding moist snuff in the mouth, inhaling dry snuff through the nose, inhaling smoke from a waterpipe and inhaling vapour from an electronic cigarette.<sup>3–6</sup> It can be difficult differentiating the effects of nicotine from the many other toxic substances these products also contain. Here we review the pharmacological effects of nicotine but we will not review the well-known harmful effects of cigarettes, where it is primarily the toxins and carcinogens in tobacco smoke rather than the nicotine that cause illness and death.<sup>7</sup> A future article will consider the use of electronic cigarettes.