tbuckley/cabot-search huggingface dataset:
Abstract 4469: Targeting the tri-snRNP complex for triple-negative breast cancer therapy
Authors: Stefanie Chan, Praveen Sridhar, Ying-Jie Lock, Fabio Petrocca
Journal: Cancer Research (2017)

Abstract Triple negative breast cancers (TNBC) account for ~15% of all breast cancers and the majority of breast cancers in women carrying a BRCA1 germline mutation. Due to the inadequacy of existing treatment, here we sought to identify shared genetic dependencies across different TNBC cell lines with the ultimate goal of uncovering novel therapeutic targets. To this end, we performed a targeted siRNA lethality screen across 11 human breast cell lines focusing on 154 genes, which we previously identified as selectively essential to a genetically-defined TNBC progenitor cell line (BPLER) relative to a myoepithelial-like isogenic cell line (HMLER). Thirty genes scored as recurrently and selectively required for survival of progenitor-like (or basal-A) TNBC lines compared to differentiated cell lines. Genes for proteins involved in RNA splicing were prominent shared dependencies among basal-A TNBC cell lines. Of particular note were those associated with the U4/U6.U5 tri-snRNP complex, including PRPF8 and PRPF38A. Transcriptome-wide RNA-seq analysis of the knockdown of either led to widespread intronic retention, expression of immune system genes and aberrant splicing of transcripts involved in protein translation, proteasome function, mitosis and apoptosis, including the TNBC dependency gene MCL1. As the proteasome and mitosis are also established TNBC vulnerabilities, we have identified specific classes of transcripts that are both particularly susceptible to perturbation of tri-snRNP activity and selectively essential for TNBC, making the tri-snRNP complex an attractive target for downstream drug development. Citation Format: Stefanie Chan, Praveen Sridhar, Ying-Jie Lock, Fabio Petrocca. Targeting the tri-snRNP complex for triple-negative breast cancer therapy [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 4469. doi:10.1158/1538-7445.AM2017-4469
Abstract 805: KRASG12Dand TP53R167Hcooperate to induce pancreatic carcinoma in conditional transgenicSus scrofta
Authors: Daniel Principe, Nana Overgaard, Andrew Diaz, Carolina Torres, Ronald McKinney, David Dawson, Laurie Rund, Regina Schwind, Paul J. Grippo, Lawrence Schook
Journal: Cancer Research (2017)

Abstract Although survival has improved in recent years, pancreatic ductal adenocarcinoma (PDAC) remains remarkably virulent with a median survival time of only four months. As there is no effective strategy for the management of PDAC, there is a need for the development of new preclinical strategies. The majority of this work is being done in genetically modified mice, which faithfully recapitulate a variety of pancreatic cancer histotypes. While mice have allowed for unprecedented insight into pancreatic cancer etiology, due to fundamental differences in anatomy and physiology, mouse models of PDAC often fail to accurately predict responsiveness to therapy. As the pig pancreas has more similar anatomical orientation and localization to humans than that of rodents, pigs may serve as a more relevant model for PDAC and other malignancies of the pancreas. As KRAS and TP53 mutations are observed in approximately 95% and 70% of PDAC patients, respectively, we generated Cre/lox transgenic Sus scrofta expressing a LSL-KRASG12D-TP53R167H cassette and administered an Adeno-Cre particle to the pancreas gland parenchyma. This resulted in a mixed histoype of metastatic leiomysarcoma and neoplastic disease of the pancreas. To produce a similar pancreas histoype while avoiding the leiomyosarcoma, we next restricted the Adeno-Cre administration to the main pancreatic duct, which resulted in both PDAC and neuroendocrine carcinoma with no abnormality of the smooth muscle. This serves as the first large animal model of pancreatic carcinogenesis, and given the anatomical/physiological similarity of pigs and humans, may allow for insight into new avenues of research not before possible in rodents. Citation Format: Daniel Principe, Nana Overgaard, Andrew Diaz, Carolina Torres, Ronald McKinney, David Dawson, Laurie Rund, Regina Schwind, Paul J. Grippo, Lawrence Schook. KRASG12D and TP53R167H cooperate to induce pancreatic carcinoma in conditional transgenic Sus scrofta [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 805. doi:10.1158/1538-7445.AM2017-805
Abstract 2612: Anti-Tigit induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity
Authors: Minu K. Srivastava, Rui Yun, Erin Mayes, Janice Yu, Hyun-Bae Jie, Fumiko Axelrod, Ming-Hong Xie, Jorge Monteon, Andrew Lam, May Ji, Yuwang Liu, John Lewicki, Tim Hoey, Austin Gurney, Angie Inkyung Park
Journal: Cancer Research (2017)

Abstract TIGIT (T cell immunoreceptor with Ig and ITIM domains) has been recently described as an inhibitory receptor which blocks CD8 T cell-mediated anti-tumor immune responses. We have generated an anti-mouse TIGIT antibody (313R12) to evaluate drug efficacy and mechanism of action in pre-clinical tumor models. Anti-TIGIT as a single agent promoted an anti-tumor immune response in multiple syngeneic mouse tumor models. Anti-TIGIT enhanced tumor specific T cell responses, particularly of the Th1 type and reduced Th2 type responses and also increased the function of cytotoxic T cells. Furthermore, anti-TIGIT displayed combination activity with immune checkpoint inhibitors anti-PD1 and anti-PDL1 in inhibiting tumor growth, promoting complete tumor rejection and significantly increasing mouse survival in the murine CT26 colon carcinoma model as compared to controls and single agents alone. Mice “cured” with anti-TIGIT/anti-PDL1 or anti-TIGIT/anti-PD1 combination treatments did not form tumors upon subsequent re-challenges with increasing number of CT26 tumor cells, suggesting the existence of immunologic memory. IL2 and tumor-specific IFN-γ production by splenic T cells were increased in mice who responded to combination treatment compared to controls. Additionally, both effector and memory CD8+ T cell frequencies were increased within the total CD8+ T cell population in responding mice. We also demonstrated a systemic increase in tumor-specific CD8 T cells after anti-TIGIT/anti-PDL1 combination treatment compared to controls. Therefore, these results suggest that co-targeting of TIGIT and PD1 or PDL1 may be an effective and durable cancer therapy by increasing T cell-mediated anti-tumor immune responses and promoting long-term immunological memory. Citation Format: Minu K. Srivastava, Rui Yun, Erin Mayes, Janice Yu, Hyun-Bae Jie, Fumiko Axelrod, Ming-Hong Xie, Jorge Monteon, Andrew Lam, May Ji, Yuwang Liu, John Lewicki, Tim Hoey, Austin Gurney, Angie Inkyung Park. Anti-Tigit induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity [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 2612. doi:10.1158/1538-7445.AM2017-2612
Soundings: The turn of the screw
Authors: James Owen Drife
Journal: BMJ (2002)

Paedophilia is an unusual subject for opera. Librettists normally stick to a more wholesome diet of murder, consumption, and suicide. Composer Benjamin Britten's adaptation of Henry James's The Turn of the Screw had its premiere in 1954, when child molestation was thought to be rare. Even today, scholars try to reject the obvious interpretation of James's enigmatic story about two haunted children.

In Sydney Opera House a few weeks ago, evil seemed far away. Outside, ferries hurried back and forth across the harbour, and even inside the auditorium we were conscious of the beauty of the famous sails above our heads. Somewhere in the city, however, an archbishop was facing accusations of interfering with (as people used to say) an altar boy 40 years ago. And I was thinking of the gynaecology clinic back home.

The children in the opera are a boy and a girl. The boy is the centre of attention, perhaps because of Britten's own sexuality, or perhaps because a treble among grown-up singers makes the audience nervous. He dies dramatically in the last act. The girl lives on, and I bet she presents to her doctor 20 years later with chronic pelvic pain.

After three decades in gynaecology I'm starting—I think—to develop an instinct for taking an adequate history from patients with thick case notes. Those whose sex lives began after puberty never take offence at matter of fact questioning. With the others, responses vary.

Some simply tell you, just as matter of factly, about their experience of abuse. If you are the first person to have asked, you cannot suppress a feeling of diagnostic satisfaction, like solving a cryptic crossword. It doesn't last long. Unlike in the movies, catharsis cures nothing—at least, not straight away. But at least you understand.

The difficult cases are those who deny it while instinct tells you differently. I don't believe in suppressed memories but I do know that patients choose when to talk. Sometimes they phone up out of the blue. You wish they had done so years earlier, before losing so many organs to well intentioned surgery.

Their stories can be chilling, even 40 years after the events. The worst aspect, though, is that for some the aftermath of abuse has been not so much chronic disease as a life sentence.
Fibrogenic Potential of PW1/Peg3 Expressing Cardiac Stem Cells
Authors: Elisa Yaniz-Galende, Maguelonne Roux, Sophie Nadaud, Nathalie Mougenot, Marion Bouvet, Olivier Claude, Guillaume Lebreton, Catherine Blanc, Florence Pinet, Fabrice Atassi, Claire Perret, France Dierick, Sébastien Dussaud, Pascal Leprince, David-Alexandre Trégouët, Giovanna Marazzi, David Sassoon, Jean-Sébastien Hulot
Journal: Journal of the American College of Cardiology (2017)
Abstract 3297: Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000-2013
Authors: Fahad Mukhtar, Paolo Boffetta, Harvey A. Risch, Jong Y. Park, Omonigho M. Bubu, Lindsay Womack, Thuan V. Tran, Janice C. Zgibor, Hung N. Luu
Journal: Cancer Research (2017)

Abstract Background. Burkitt’s Lymphoma (BL) has three peaks of occurrence, in children, adults and elderly, at 10, 40 and 70 years respectively. To the best of our knowledge, no study has been conducted to assess predictors of survival in the three age groups. We hypothesized that the predictors of survival may differ by age group. We, therefore, sought to determine the predictors of survival for BL in these three groups: children (&amp;lt;15 years of age), adults (40-70 years of age) and elderly (&amp;gt;70 years of age). Methods. Using the Surveillance, Epidemiology, and End Results (SEER) database covering the years 2000-2013, we identified 797 children, 1,994 adults and 757 elderly patients newly diagnosed with BL. We used Cox proportional hazards regression models to determine prognostic factors for survival for each age group. Results. Five-year relative survival in BL for children, adults and elderly were 90.4%, 47.8%, and 28.9%, respectively. Having at least stage II disease and multiple primaries were associated with higher mortality in the elderly group. In adults, multiple primaries, stage III or IV disease, African American race and bone marrow primary were associated with increased mortality whereas stage IV disease and multiple primaries were associated with worse outcome in children. Conclusion. These findings demonstrate commonalities and differences in predictors of survival that may have implications for management of BL patients. Financial Support: This work was supported by the US National Institutes of Health/National Cancer Institute 1P20CA210300-01 (PI: Shu XO, Tran T/Sub-contract-PI: Luu HN) and the University of South Florida start-up grant (PI: Luu HN). Note: This abstract was not presented at the meeting. Citation Format: Fahad Mukhtar, Paolo Boffetta, Harvey A. Risch, Jong Y. Park, Omonigho M. Bubu, Lindsay Womack, Thuan V. Tran, Janice C. Zgibor, Hung N. Luu. Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000-2013 [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 3297. doi:10.1158/1538-7445.AM2017-3297
Abstract 399: CPTAC phase II final report
Authors: Mathangi Thiagarajan
Journal: Cancer Research (2017)

Abstract National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) is a comprehensive and coordinated effort to accelerate the understanding of the molecular basis of cancer through the application of robust, quantitative, proteomic technologies and workflows. The primary goal for this program is to systematically identify proteins that derive from alterations in cancer genomes and related biological processes, integrate the genomic and proteomic data from analysis of common cancer biospecimen and provide this data with accompanying assays and protocols to the community. The phase II effort managed by the Leidos Biomedical Research Inc. had a goal to procure and qualify a minimum of 100 cases from 3 cancer types (Breast, Ovarian and Colon). Tissues and analytes from the 100 cases were sent to proteomic and genomic characterization centers for analysis. The proteomic data were made available through the Data Coordinating Center (DCC) and the genomic data were made available through NCI’s Genomic Data Commons (GDC). The success from the phase II effort has set precedence for a much larger phase III effort that will focus on additional cancer types and cases. Preliminary analysis results confirm the need for the combination of the genomic and proteomic approaches to produce a more comprehensive inventory of the detectable proteins in a tumor and advance our understanding of cancer biology. Citation Format: Mathangi Thiagarajan. CPTAC phase II final report [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 399. doi:10.1158/1538-7445.AM2017-399
Abstract 4834: 3D modeling of immune cell interactions in breast cancer and prediction of immunotherapy response
Authors: Qi Guo, Stephen Shuford, Brian McKinley, Mary Rippon, Wendy Cornett, Mark O'Rourke, David Schammel, Jeff Edenfield, David L. Kaplan, Hal E. Crosswell, Teresa Desrochers
Journal: Cancer Research (2017)

Abstract While breast cancer has an overall 5-year survival rate of 89%, the rate for patients with stage 4 metastatic disease is only 26%. Immunotherapies have the potential to improve the prognosis for these patients while also providing better treatment options for all breast cancer patients since they have fewer side effects enabling longer treatment times and the use of combination therapies and reduced chances of developing resistance. Currently these treatments are tested in standard 2D cell cultures that are inaccurate in mimicking in vivo drug response or animal models where the immune system differs from humans in numerous ways including T-cell subsets, cytokine receptors, and costimulatory molecule expression. We have developed 3D models of human breast cancer that span the subtypes, ER+, HER2+, and triple negative, incorporate numerous stromal cell types, fibroblasts and adipocytes, and include different immune cells, macrophages and T-cells under either static or perfusion culture systems. These models have been used to examine how tumor cells influence macrophage differentiation using undifferentiated peripheral blood mononuclear cells (PBMCs), how M1 and M2 macrophages influence tumor cell survival and proliferation, how the combination of these cell types influence cytokine secretion, and how the microenvironment affects macrophage invasion. We have also used these complex models to examine response of tumor cells and T-cells to checkpoint inhibitors through standard viability assays and flow cytometry. These models have several potential uses which include the ability to quickly answer whether a particular immunotherapy agent is effective for that particular patient-specific manner and to screen potential novel immunotherapeutic candidates and/or combinations prior to clinical use. Citation Format: Qi Guo, Stephen Shuford, Brian McKinley, Mary Rippon, Wendy Cornett, Mark O'Rourke, David Schammel, Jeff Edenfield, David L. Kaplan, Hal E. Crosswell, Teresa Desrochers. 3D modeling of immune cell interactions in breast cancer and prediction of immunotherapy response [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 4834. doi:10.1158/1538-7445.AM2017-4834
Abstract 3339: Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation
Authors: Yoku Hayakawa, Mitsuru Konishi, Kosuke Sakitani, Kazuhiko Koike, Timothy Wang
Journal: Cancer Research (2017)

Abstract Within the gastrointestine, nerves help to regulate both normal and neoplastic stem cell dynamics. Several previous studies suggested that cholinergic nerve signaling plays an important role in gastrointestinal cancer development, but the exact underlying mechanism has not been clarified. In this study, we examined the role of muscarinic acetylcholine receptor subtype 3 (M3R) in gastric homeostasis and cancer development by using mouse models and human cancer cell lines. In situ hybridization revealed M3R expression in gastric stem cell zone, and its expression was markedly upregulated in gastric cancer cells. We knocked out M3R in Lgr5+ gastric stem cells in Lgr5-CreERT; M3Rflox/flox mice, and found that deletion of M3R inhibited clonal expansion of Lgr5+ cells in regenerative states. In a gastric tumor model of Mist1-CreERT; Apcflox/flox mice, knockout of M3R dramatically suppressed tumor growth. RNA sequencing analysis of these tumors revealed that several important pathways were significantly inhibited in M3R knockout samples, including YAP/TAZ pathway. We established M3R-expressing gastric cancer cell lines, and western blotting, luciferase assay, and RT-PCR analysis confirmed that acetylcholine (ACh) agonist activates YAP pathway through M3R. YAP is upregulated in approximately half of gastric cancer patients, and its expression is significantly associated with disease stage and histological form. This M3R-YAP axis activates the gastric stem cell niche and offers a compelling target for tumor treatment and prevention. Note: This abstract was not presented at the meeting. Citation Format: Yoku Hayakawa, Mitsuru Konishi, Kosuke Sakitani, Kazuhiko Koike, Timothy Wang. Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation [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 3339. doi:10.1158/1538-7445.AM2017-3339
Abstract 1837: High Ras activity promotes neoplasia in pancreatic ductal cells
Authors: Kanchan Singh, Melissa A. Pruski, Wasim A. Dar, Kishore Polireddy, John S. Bynon, Mamoun Younes, Anirban Maitra, Craig D. Logsdon, Jennifer M. Bailey
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy and is the third leading cause of cancer-related deaths in the United States. Next generation sequencing efforts have revealed KRAS mutations occur in over 99% of pancreatic ductal adenocarcinomas and are thought to be the initiating mutation for pancreatic cancer. Despite the high prevalence of KRAS mutations in pancreatic cancer patients, murine models expressing endogenous levels of mutant Kras in pancreatic cells do not develop PDAC. A number of publications have revealed that acinar cells are more sensitive to early neoplastic lesion formation in the presence of Kras mutations than ductal cells. In these models, a second genetic hit (loss of tumor suppressor TP53, SMAD4 or CDKN) is required for the development of invasive PDAC, including transforming pancreatic ductal cells. Recent data has revealed a novel role for high levels of Ras activity in acinar cells in the tranformation of this cell type to PDAC (Ji, B., 2009). We hypothesized based on other preliminary data that high levels of Ras activity would transform ductal cells. To test this hypothesis, we studied the role of constitutively active high levels of Kras activity in acinar and ductal cells by expressing an inducible KrasG12V allele in Ptf1a:CreERT2 (acinar cell specific) and Hnf1b:CreERT2 (ductal cell specific) mice. Similar to previously published work, high levels of Ras activity in acinar cells resulted in PDAC and a remarkably low survival time of 10 days after mice were injected with tamoxifen. Mice with elevated Ras activity in ductal cells needed to be euthanized two weeks after tamoxifen injection and manifested a cancer cachexic phenotype. Histological analysis of these mice revealed high grade oncocytic intraductal neoplasia and the phenotype extended throughout the pancreatobiliary ducts. Western blot analysis of human PDAC and Cholangiocarcinoma tissue revealed similar levels of Ras activity to our murine models, confirming human equivalent high Ras expression to both animal models. Oncocytic tumors are characterized by an abundance of mitochondria. Thus, we are currently studying metabolic alterations and mitochondria accumulation in ductal and acinar cells expressing high Ras activity. Our goal is to determine how mitochondrial alterations play a role in progression or inhibition of tumors in ductal vs acinar cells. Citation Format: Kanchan Singh, Melissa A. Pruski, Wasim A. Dar, Kishore Polireddy, John S. Bynon, Mamoun Younes, Anirban Maitra, Craig D. Logsdon, Jennifer M. Bailey. High Ras activity promotes neoplasia in pancreatic ductal 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 1837. doi:10.1158/1538-7445.AM2017-1837