tbuckley/cabot-search huggingface dataset:
Abstract 3276: Impact of the different treatments on the survival of advanced esophageal squamous cell carcinoma
Authors: Rang Cheng, Fu You Zhou, Neng Chao Wang, Ran Wang, Wei Peng Wang, Xian Zeng Wang, Wen Bin Yue, Jian Wei Zhou, Zhan Hui Miao, Guang Cheng Ding, De Chao Bu, Li Dong Wang
Journal: Cancer Research (2017)

Abstract Esophageal squamous cell carcinoma (ESCC) remains one of the leading cause of cancer-related death in China. Moreover, more than 90% of the ESCC patients have been in the advanced stage when diagnosed, the 5-year survival is very poor even though the medical techniques have been improved in the past decades. Although the accumulated evidences have suggested the crucial role of genetic changes in esophageal carcinogenesis, the target therapy based on these genetic changes is largely in the very beginning, and radical esophagectomy and radiochemotherapy remain the chief choice for ESCC treatment at present. The present study was thus designed to evaluate the efficacy of the present treatment methods in China to provide more information for optimal choice in advanced ESCC treatment. The enrolled 20,712 ESCC patients in this study were from the ESCC database in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University. Of the patients, there were 12,818 males with a mean age of 59.59±8.2 and 7,894 females with a mean age of 60.34±8.3. All the 20,712 patients were confirmed by histopathology as ESCC at II to IV stage (advanced stage) and classified into three groups based on the treatment methods: radical esophagectomy (R0) alone (17,577, 84.8%), R0 plus radiochemotherapy (2,510, 12.1%) and radiochemotherapy alone (625, 3.1%). The followed-up was undertaken until 2016. The SPSS21.0 software and Kaplan-Meier survival analysis and Log Rank test were used to evaluate the efficiency of different treatments. The results demonstrated that the overall median survival time for the three groups was 5.81 years, 4.82 years and 2.85 years, respectively (P&amp;lt;0.001). Moreover, compared with surgery alone, R0 plus radiochemotherapy did not prolong survival of the advanced patients. Obviously, much efforts, especially combined with genetic application are much desirable to improve the survival for the advanced ESCC patients. [Supported by National High-Tech Research and Development Program of China (SQ2015AA0202183), Project for Characteristic and Advantage Discipline of Henan Province (20151208) and Correspondence to: Li Dong Wang, Email: ldwang2007@126.com] Note: This abstract was not presented at the meeting. Citation Format: Rang Cheng, Fu You Zhou, Neng Chao Wang, Ran Wang, Wei Peng Wang, Xian Zeng Wang, Wen Bin Yue, Jian Wei Zhou, Zhan Hui Miao, Guang Cheng Ding, De Chao Bu, Li Dong Wang. Impact of the different treatments on the survival of advanced esophageal squamous cell carcinoma [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 3276. doi:10.1158/1538-7445.AM2017-3276
Abstract 5227: Synthesis of a biotin probe for identification of the ajoene protein targets in cancer cells ajoene protein targets in cancer cells
Authors: Catherine H. Kaschula, Daniel A. Kusza, Georgia Schafer, Arieh A. Katz, Shivendra V. Singh, Roger Hunter
Journal: Cancer Research (2017)

Abstract Garlic (Allium sativum) is a medicinal plant belonging to the lily family which has been used since ancient times for its beneficial health effects which include protection against infections and cancer. There are a cluster of bioactive compounds found in crushed garlic which contain sulfide or polysulfide functional groups. One of these compounds, ajoene, is able to interfere with biological processes by undergoing thiolysis exchange reactions with biological thiols, for example glutathione and cysteine residues on proteins. Importantly, ajoene is cytotoxic to cancer cells in the low micromolar range. We have previously found that ajoene targets multiple proteins in cancer cells and the aim of this project is to identify the specific protein targets of ajoene. To achieve this aim, we have synthesized a “tagged” ajoene analogue containing a biotin functional group. As biotin may alter the biological properties of ajoene, our strategy was to initially synthesize an azide-containing ajoene analogue (called azide-ajoene) using our 4-step synthetic route to ajoene analogues previously published. Azide-ajoene was found to retain cancer cell cytotoxicity similar to that of the parent ajoene. We then treated cancer cells (MDA-MB-231 breast and WHCO1 oesophageal cancer) with azide-ajoene to allow transfer of an azide label to the protein targets during thiolysis exchange with ajoene. We then collected lysate from the treated cells and performed an in vitro click reaction with a separately synthesized biotin-alkyne partner which was synthesized via a series of substitution and amide coupling reactions. Click chemistry covalently links biotin to the ajoene-tagged protein via a triazole linkage; and the feasibility of this method was validated by western blot. The biotinylated protein targets were purified using immobilised streptavidin beads and identified by MALDI-TOF mass spectrometry. It is anticipated that knowledge of the specific ajoene protein targets will provide valuable insights into the cytotoxic mechanism of action of ajoene in cancer cells. Citation Format: Catherine H. Kaschula, Daniel A. Kusza, Georgia Schafer, Arieh A. Katz, Shivendra V. Singh, Roger Hunter. Synthesis of a biotin probe for identification of the ajoene protein targets in cancer cells ajoene protein targets in 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 5227. doi:10.1158/1538-7445.AM2017-5227
Serrated pathway: a paradigm shift in CRC prevention
Authors: Evelien Dekker, Joep Evert Godfried IJspeert
Journal: Gut (2017)

In the prevention of colorectal cancer (CRC), hyperplastic polyps have long been regarded as innocent bystanders and only adenomas were thought to be precursors for CRC. Therefore, focus during colonoscopy was on adenomas only. In the past decade, evidence has accumulated that serrated polyps might progress to cancer as well via the serrated neoplasia pathway. On the one hand, patients with multiple serrated polyps, nowadays classified as having serrated polyposis syndrome, demonstrated an increased risk of CRC development, and small cancers were detected within serrated lesions. On the other hand, a growing body of circumstantial evidence suggests that at least 15% of all CRCs arise through the serrated neoplasia pathway, and an even larger proportion of postcolonoscopy CRCs arise from serrated polyps.1

This growing body of evidence has gradually led to a paradigm shift in both cancer prevention as well as treatment strategies. To reduce the number of postcolonoscopy CRCs and to optimise current clinical care for patients with serrated polyps, several issues are at stake. The new British Society of Gastroenterology (BSG) position statement on serrated polyps in the colon and rectum is therefore timely as well as important.2 It discusses current knowledge on serrated polyps and provides recommendations for daily clinical practice as well as research. We hope that this publication will increase the awareness among clinicians on this topic and will be an incentive for appropriate management of these lesions. In the light of rapidly developing evidence on this topic, we would like to comment on this excellent work of the BSG.

As the terminology of serrated polyps is confusing, and does not help to bring a clear message to the general gastrointestinal practice, the BSG proposes new terminology. We support the proposal of the BSG to simplify the WHO classification slightly by renaming ‘sessile serrated adenomas/polyps’ …
Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in <i>CNTNAP2</i> -deficient mice
Authors: Aslihan Selimbeyoglu, Christina K. Kim, Masatoshi Inoue, Soo Yeun Lee, Alice S. O. Hong, Isaac Kauvar, Charu Ramakrishnan, Lief E. Fenno, Thomas J. Davidson, Matthew Wright, Karl Deisseroth
Journal: Science Translational Medicine (2017)

Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity-based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons. Surprisingly, both of these distinct, real-time, and reversible optogenetic modulations acutely rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2 Using fiber photometry, we discovered that native mPFC PV neuronal activity differed between CNTNAP2 knockout and wild-type mice. During social interactions with other mice, PV neuron activity increased in wild-type mice compared to interactions with a novel object, whereas this difference was not observed in CNTNAP2 knockout mice. Together, these results suggest that real-time modulation of E:I balance in the mouse prefrontal cortex can rescue social behavior deficits reminiscent of autism phenotypes.
Sharing the Process of Diagnostic Decision Making
Authors: John E. Brush, James M. Brophy
Journal: JAMA Internal Medicine (2017)

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Perspectives of survivors, families and researchers on key outcomes for research in acute respiratory failure
Authors: Victor D Dinglas, Caroline M Chessare, Wesley E Davis, Ann Parker, Lisa Aronson Friedman, Elizabeth Colantuoni, Clifton O Bingham, Alison E Turnbull, Dale M Needham
Journal: Thorax (2017)

Background There is heterogeneity among the outcomes evaluated in studies of survivors of acute respiratory failure (ARF). Aim To evaluate the importance of specific outcome domains to acute respiratory distress syndrome (ARDS) survivors, their family members and clinical researchers. Methods Nineteen outcome domains were identified from the National Institutes of Health’s Patient Reported Outcomes Measurement Information System; WHO’s International Classification of Functioning, Disability, and Health; Society of Critical Care Medicine’s Post-Intensive Care Syndrome (PICS); as well as patient, clinician and researcher input. We surveyed ARDS survivors, family members and critical care researchers, 279 respondents in total, using a 5-point scale (strongly disagree, disagree, neutral, agree and strongly agree) to rate the importance of measuring each domain in studies of ARF survivors’ postdischarge outcomes. Measurements and main results At least 80% of patients and family members supported (ie, rated ‘agree’ or ‘strongly agree’) that 15 of the 19 domains should be measured in all future studies. Among researchers, 6 of 19 domains were supported, with researchers less supportive for all domains, except survival (95% vs 72% support). Overall, four domains were supported by all groups: physical function, cognitive function, return to work or prior activities and mental health. Conclusion Patient, family and researcher groups supported inclusion of outcome domains that fit within the PICS framework. Patients and family members also supported many additional domains, emphasising the importance of including patients/family, along with researchers, in consensus processes to select core outcome domains for future research studies.
Abstract 769: Matched-pair comparisons of chemotherapy plus bevacizumab versus chemotherapy alone as third-line treatment or beyond for advanced non-small cell lung cancer
Authors: Binbin Hu, You Lu, Xiaojuan Zhou, Qian Li, Mengmeng Xiang
Journal: Cancer Research (2017)

Abstract Background: The addition of bevacizumab to chemotherapy has proven efficacy as first-line treatment for advanced NSCLC. Whether this combination still be efficient as salvage treatment for NSCLC patients who have not received bevacizumab previously remains unclear. This retrospective matched-pair study was designed to compare the efficacy and safety of chemotherapy plus bevacizumab with chemotherapy alone as third-line treatment or beyond for NSCLC patients. Methods: Patients with stage IV NSCLC who had received single-agent chemotherapy plus bevacizumab after failure of at least two prior regimens were enrolled in this study. Each of them was matched with two patients who had received chemotherapy alone (1:2) by age (within ±5 years), sex, smoking history, histology, EGFR mutation status and number of prior regimens. Tumor response rate, survival and toxicity analyses were performed. Results: Between January 2011 and June 2016, a total of 40 patients who had received chemotherapy plus bevacizumab (chemotherapy-bevacizumab group) were matched with 80 patients who had received chemotherapy alone (chemotherapy-alone group) as third-line treatment or beyond. Objective response rate (ORR) and Disease control rate (DCR) were improved for chemotherapy-bevacizumab compared with chemotherapy alone (ORR, 22.5% v 6.2%, respectively, p= .014; DCR, 62.5% v 40.0%, respectively, p= .032). Progression-free survival was prolonged for chemotherapy-bevacizumab compared with chemotherapy alone (median, 3.9 v 2.5 months, respectively; HR, 0.64; 95%CI, 0.43 to 0.97; p = .032). Incidence of severe (≥ grade 3) adverse events was low and similar across groups. Conclusion: The combination of chemotherapy and bevacizumab can be an efficient alternative salvage treatment for NSCLC patients who have not received bevacizumab previously. But taking this combination as first-line treatment for advanced NSCLC still should be a priority.&amp;lt;!–EndFragment–&amp;gt; Note: This abstract was not presented at the meeting. Citation Format: Binbin Hu, You Lu, Xiaojuan Zhou, Qian Li, Mengmeng Xiang. Matched-pair comparisons of chemotherapy plus bevacizumab versus chemotherapy alone as third-line treatment or beyond for advanced 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 769. doi:10.1158/1538-7445.AM2017-769
Abstract 332: Loss of primary cilia promotes LPA-driven proliferation in glioblastoma
Authors: Yuriy Loskutov
Journal: Cancer Research (2017)

Abstract Glioblastoma is one of the most common brain cancers with a median survival of 13 months. Therapeutic approaches for this type of cancer are very limited, creating an urgent need to develop new strategies for the treatment. Recently several groups reported that glioblastoma have a drastic decrease in primary cilia, suggesting that loss of cilia might be important for glioblastoma biology. The primary cilium is a ubiquitous microtubule based organelle presented on most of human cells. It plays significant role in embryonic development and tissue homeostasis, serving as a hub for multiple signaling cascades including RTK, Sonic Hedgehog, Wnt and Hippo. Here we report that loss of primary cilia in immortalized astrocytes stimulate cell proliferation and drastically change ERK1/2 activation in response to serum. These changes depend on lysophosphotidic acid (LPA), a water-soluble lipid metabolite, implicated in chemotactic and proliferative signaling. The receptor to LPA type 1 tends to accumulate in the primary cilia, indicating its potential role in inhibition/restriction of LPA-dependent mitogenic signaling via dynamic changes in primary cilium. Loss of primary cilia can lead to LPA receptors 1 redistribution to the plasma membrane and switch cellular response for the LPA, allowing it to act as mitogen. Inhibition of LPA receptors with a small molecule inhibitor, Ki16425, is significantly decreasing the growth of glioblastoma PDXs. Overall, our findings clearly indicate that loss of primary cilia is sufficient to severely change mitogen-driven signal transduction and point towards the new therapeutic target for glioblastoma. Citation Format: Yuriy Loskutov. Loss of primary cilia promotes LPA-driven proliferation in glioblastoma [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 332. doi:10.1158/1538-7445.AM2017-332
Abstract 4693: Fc effector bioassays enable faster and quantitative measurement of ADCC and ADCP mechanisms of action
Authors: Zhi-Jie Jey Cheng, Rich Moravec, Aileen Paguio, Denise Garvin, Gopal B. Krishnan, Frank Fan, Mei Cong
Journal: Cancer Research (2017)

Abstract Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) are recognized as important mechanisms of action (MOA) of therapeutic antibodies. Primary peripheral blood mononuclear cells (PBMCs) are routinely used in traditional bioassays to measure potency, stability of antibody drugs in ADCC and ADCP. However these methods are labor intensive and highly variable. Here we report the development of a luciferase-based reporter assay that measures activation of effector cells via cross-linking of Fc receptors with target cell-bound antibodies. We will discuss functional cell-based Fc effector reporter bioassays developed to measure Human FcgRIIIa (V158 and F158 variants), Human FcgRIIa (H131 and R131 variants), Human FcgRI as well as Mouse FcgRIV and FcgRIII. Compared to primary cell-based assays these reporter bioassays are less variable, easier to use and provide more consistent analysis of the important MOAs that are critical to for drug development programs. In qualification studies, performed in accordance with ICH guidelines for antibody screening and characterization, we tested the bioassays for specificity, accuracy, precision and linearity. Citation Format: Zhi-Jie Jey Cheng, Rich Moravec, Aileen Paguio, Denise Garvin, Gopal B. Krishnan, Frank Fan, Mei Cong. Fc effector bioassays enable faster and quantitative measurement of ADCC and ADCP mechanisms of action [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 4693. doi:10.1158/1538-7445.AM2017-4693
Abstract LB-301: PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors
Authors: Fumi Higuchi, Daniel P. Cahill, Hiroaki Wakimoto
Journal: Cancer Research (2017)

Abstract Background: Mismatch repair (MMR) deficiency through MSH6 alteration has been identified in approximately 30% of recurrent high grade gliomas, and represents a key molecular mechanism for the development of acquired resistance to the alkylating agent temozolomide (TMZ). Additionally, glioma progression post-TMZ treatment is frequently accompanied by distinct genomic alterations such as amplification of the MYC locus and resulting signaling activation. There is an urgent need to establish new treatment strategies that do not rely upon MMR to target MMR deficient, TMZ resistant glioma. Methods: We first screened 14 compounds that modulate DNA damage response for their ability to suppress viability of an MSH6 knockdown, TMZ resistant glioma cell line. Efficacy of PLK1 inhibitors and combination with TMZ were assessed in glioblastoma cells lines and patient-derived glioblastoma neurosphere lines engineered with MSH6 silencing, MYC overexpression and controls. Impacts of PLK1 blockade on cell cycle distribution, apoptosis, and DNA damage effects were examined. Results: The compound screening indentified PLK1 selective inhibitor, volasertib, as the most potent inhibitor of proliferation of both MMR intact and deficient glioblastoma cells. PLK1 inhibition induced G2/M cell cycle arrest, DNA damage and caspase-mediated apoptosis in glioblastoma cells, but no detectable toxicity in normal human astrocytes. Importantly, beneficial therapeutic effects of PLK1 inhibitors were not influenced by MMR deficiency due to MSH6 knockdown, whereas PLK1 inhibition had no additive or synergic effect when combined with TMZ. Furthermore, we found that MYC overexpression sensitized glioblastoma cells to PLK1 inhibitors. Conclusions: Selective PLK1 inhibitors are potently cytotoxic to glioblastoma and their action is independent of MMR status of the cells. Cells with deregulated MYC are vulnerable to PLK1 inhibition suggesting genomic MYC alteration as a biomarker for PLK inhibitor sensitivity. Thus PLK inhibitor represents a novel therapeutic option for MMR deficient TMZ resistant recurrent gliomas, particularly those driven by MYC. Citation Format: Fumi Higuchi, Daniel P. Cahill, Hiroaki Wakimoto. PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors [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 LB-301. doi:10.1158/1538-7445.AM2017-LB-301