tbuckley/cabot-search huggingface dataset:
Abstract 4090: Generation of a new mouse to model pancreatic cancer-induced cachexia
Authors: Erin E. Talbert, Katherine J. Ladner, Maria Cecilia Cuitino, Gustavo W. Leone, Denis C. Guttridge
Journal: Cancer Research (2018)

Abstract Of all cancers, pancreatic cancer causes the third most fatalities, and incidence rates of this devastating disease continue to rise. Further, pancreatic cancer presents with the highest incidence of cachexia, a syndrome of weight loss due to depletion of skeletal muscle and adipose tissue. Clinically, cachexia is associated with increased mortality, poor quality of life, poor treatment responses, and increased treatment complications. Although clearly the best way to prevent cachexia is to address the cancer, pancreatic cancer has proven challenging to treat, with a dismal 9% 5-year survival rate. We believe effective anti-cachexia therapy will improve the care of pancreatic cancer patients, but the development of these therapies will require animal models that accurately recapitulate the etiology of pancreatic cancer-induced cachexia. To improve on the current, non-pancreas tumor xenograft models of cachexia, we generated a genetically engineered mouse model (GEMM) of pancreatic cancer, where induction of Kras and loss of the tumor suppressor Pten occurs in the pancreas of postnatal mice, which we refer to as the KPP model. KPP mice progressively lose skeletal muscle and adipose mass as a result of their cancer. We find that KPP mice exhibit histologic features of pancreatic ductal adenocarcinoma and reach endpoint criteria at an average of 107 days of age. Beginning at approximately 75 days of age, KPP mice undergo progressive loss of existing skeletal muscle mass, resulting in decreased muscle function. We also find that muscle loss from KPP mice exhibits a gene expression signature that closely aligns with the gene expression signature in muscle from cachectic pancreatic cancer patients. In summary, we expect KPP mice to serve as a useful model to elucidate the underlying mechanisms of muscle loss in pancreatic cancer-induced cachexia and to evaluate potential anti-cachexia therapies. Citation Format: Erin E. Talbert, Katherine J. Ladner, Maria Cecilia Cuitino, Gustavo W. Leone, Denis C. Guttridge. Generation of a new mouse to model pancreatic cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4090.
Abstract 437: Leveraging new methods in single-cell copy number analysis and clonotype detection to uncover and characterize hidden subclones within standard cell lines
Authors: Enrique I. Velazquez Villarreal, Vijay Kumar, Yifeng Yin, John D. Carpten, David W. Craig
Journal: Cancer Research (2018)

Abstract Single-cell sequencing is an important and powerful tool for improving our understanding of cancer heterogeneity. While previous reports have largely focused on single-cell RNA-seq, we examined the utility of novel approaches for single-cell copy-number analysis and clonotype detection using 10x Chromium™ Technology capable of processing thousands of single cells. In contrast to bulk sequencing, this technology is able to call cell clonotypes down to 1% of 1,000 cell inputs, while providing detection of CNVs down to 100 Kb events on clones consisting of 10 or more cells. As a pilot study, we processed 300 single cells from COLO829 through the system, generating a barcoded short-read library, which was sequenced to a raw depth of approximately 600 million reads. Previous efforts had characterized COLO829 by bulk whole-genome sequencing of tumor/normal cell-line lineages grown and sequenced across four laboratories to help establish tumor/normal reference standards. We used barcode-aware bioinformatic analysis to recover reads derived from single cells, analyzing them in 20 Kb cassettes of reads providing both regional copy number and genome-wide ploidy estimates. This high resolution of CNV detection is enabled by aggregation of reads across cells within the same clone. Somewhat surprisingly, we find the presence of multiple clones within a single cell line growth evident by large-scale copy number changes, in some cases spanning entire chromosome arms. We show an ability to better resolve absolute copy number, whereas previous analysis approaches on bulk sequencing have lagged due to a reliance on indirect inferences. Consideration of prior publications on this cell line are consistent with the undescribed existence of clonal heterogeneity in these, and when considered with these data provide greater insight into copy number-driven events. Overall, our results suggest that single-cell copy number provides unique and important insight into larger-scale events, providing unique and distinct insight into cancer heterogeneity. Citation Format: Enrique I. Velazquez Villarreal, Vijay Kumar, Yifeng Yin, John D. Carpten, David W. Craig. Leveraging new methods in single-cell copy number analysis and clonotype detection to uncover and characterize hidden subclones within standard cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 437.
Role of BMPR2 Alternative Splicing in Heritable Pulmonary Arterial Hypertension Penetrance
Authors: JoyCogan, EricAustin, LoraHedges, BethanyWomack, JamesWest, JamesLoyd, RizwanHamid
Journal: Circulation (2012)

Background—Bone morphogenic protein receptor 2 (BMPR2) gene mutations are the most common cause of heritable pulmonary arterial hypertension. However, only 20% of mutation carriers get clinical disease. Here, we explored the hypothesis that this reduced penetrance is due in part to an alteration in BMPR2 alternative splicing. Methods and Results—Our data showed that BMPR2 has multiple alternative spliced variants. Two of these, isoform-A (full length) and isoform-B (missing exon 12), were expressed in all tissues analyzed. Analysis of cultured lymphocytes of 47 BMPR2 mutation–positive heritable pulmonary arterial hypertension patients and 35 BMPR2 mutation–positive unaffected carriers showed that patients had higher levels of isoform-B compared with isoform-A (B/A ratio) than carriers (P=0.002). Furthermore, compared with cells with a low B/A ratio, cells with a high B/A ratio had lower levels of unphosphorylated cofilin after BMP stimulation. Analysis of exon 12 sequences identified an exonic splice enha...
Opioids vs Nonopioids for Chronic Back, Hip, or Knee Pain
Authors: Wenbao Wang, William Macaulay
Journal: JAMA (2018)

To the Editor Dr Krebs and colleagues1 compared opioid with nonopioid medications in improving pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain. We have several concerns about the study design and generalizability of the results.
Abstract 2550: Generation of CAR-iPS-T cells expressing CD8β
Authors: Tatsuki Ueda, Shoichi Iriguchi, Yohei Kawai, Atsutaka Minagawa, Hiroyuki Miyoshi, Seitaro Terakura, Yasushi Uemura, Knut Woltjen, Yuzo Kodama, Hiroshi Seno, Yasumichi Hitoshi, Tetsuya Nakatsura, Koji Tamada, Shin Kaneko
Journal: Cancer Research (2018)

Abstract Chimeric antigen receptor (CAR) is an artificial protein that provides HLA-independent antigen specificity to T cells. CAR-T therapy has shown remarkable clinical responses especially in hematologic malignancies. But this therapy needs cell preparation for each patient. That limits its applicability. We have reported regeneration of T cells from iPSCs (Cell Stem Cell 2013). This technology provides unlimited number of T cells, so CAR-T therapy using iPSCs can broadens its applicability. Regenerated T cells previously described in some reports including ours have some different characters from peripheral T cells. In particular, they express only CD8α, and do not express CD8β. We successfully generate CAR-iPS-T cells expressing CD8β with some modification of differentiation protocols. We assayed the function of CAR-iPS-T cells in view of the difference between CD8β positive and negative iPS-T cells. We found CD8β positive CAR-iPS-T cells showed enhanced function to suppress tumor progression compared with CD8β negative CAR-iPS-T cells in subcutaneous xenograft model. In vivo kinetics study revealed that CD8β positive CAR-iPS-T cells have superior function to traffic to target expressing tumor site and enhanced sustainability in vivo compared with CD8β negative CAR-iPS-T cells. These findings indicate that CD8β positive CAR-iPS-T cells may be a potent cell source for iPSC-based cancer immunotherapy. Citation Format: Tatsuki Ueda, Shoichi Iriguchi, Yohei Kawai, Atsutaka Minagawa, Hiroyuki Miyoshi, Seitaro Terakura, Yasushi Uemura, Knut Woltjen, Yuzo Kodama, Hiroshi Seno, Yasumichi Hitoshi, Tetsuya Nakatsura, Koji Tamada, Shin Kaneko. Generation of CAR-iPS-T cells expressing CD8β [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2550.
Opioid Prescribing Limits for Acute Pain — Striking the Right Balance
Authors: Margaret Lowenstein, David Grande, M. Kit Delgado
Journal: New England Journal of Medicine (2018)

Although prescribing limits seem like a commonsense approach to restricting exposure to opioids, adoption of these policies is outpacing the evidence, and opioid prescribing for acute pain is not a one-size-fits-all situation.
Abstract CT104: Evaluation of peripheral T cell subset proliferation as a pharmacodynamic assay to guide the development of anti-CTLA-4 and PD-1 antibody combinations in patients with solid tumors
Authors: Paul De Souza, Agnieszka Malczewski, Igor Proscurshim, Guojun Yuan, Elisabeth Coart, Christopher Dupont, Mariana Manrique, Elise Drouin, Ana Gonzalez, Meg Carini, Olga Shebanova, Jean-Marie Cuillerot
Journal: Cancer Research (2018)

Abstract The combination of anti-CTLA-4 and anti-PD-1 antibodies has demonstrated significant clinical efficacy in metastatic melanoma, but also significant toxicities. Pharmacodynamic (PD) markers are important tools in optimizing the safety and efficacy of anti-CTLA-4/anti-PD-1 combinations, but have remained elusive to date. To test the hypothesis that blockade of both CTLA-4 and PD-1 together results in increased expression of the proliferation marker Ki67 in CD4+ T cells, we studied two dose regimens of ipilimumab in combination with nivolumab in patients with advanced or metastatic solid tumors, using a validated assay. Subjects received either 1.0 mg or 0.3 mg /kg of ipilimumab every 6 weeks in combination with nivolumab 3mg/kg every 2 weeks for a maximum of 12 weeks (2 cycles). A total of 9 subjects were enrolled at the 1.0 mg/kg of ipilimumab cohort and 12 subjects in the 0.3 mg/kg cohort. Highly statistically significant increases of 4.56 fold (range 3.35-6.20) from baseline at cycle 1 day 8 post-treatment (p &amp;lt; 0.001) in cohort 1, and 3.13 fold (range 2.31-4.33) from baseline at cycle 1 day 8 post-treatment (p &amp;lt; 0.001) in cohort 2, in Ki67 expression were observed in CD4+ T cells. The absolute increase in Ki67 expression was also observed to be dose dependent numerically. Significant increases in Ki67 expression were also observed in CD8+ T cells, regulatory T cells, and natural killer T (NKT) cells following treatment. These results identify and support Ki67 expression as a PD biomarker in the context of CTLA-4 and PD-1 blockade. More work is required to correlate these finding with clinical outcomes in order to establish a benchmark biomarker assay for anti-CTLA-4 and anti-PD-1 combinations. (ACTRN12617001059358) Citation Format: Paul De Souza, Agnieszka Malczewski, Igor Proscurshim, Guojun Yuan, Elisabeth Coart, Christopher Dupont, Mariana Manrique, Elise Drouin, Ana Gonzalez, Meg Carini, Olga Shebanova, Jean-Marie Cuillerot. Evaluation of peripheral T cell subset proliferation as a pharmacodynamic assay to guide the development of anti-CTLA-4 and PD-1 antibody combinations in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT104.
Abstract 426: Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport
Authors: Shan-Shan Zhang, Shaohua Xiao, Ying Fu, Wassim A Basheer, Rachel Baum, Robert Naami, Edmund Naami, TingTing Hong, Robin M Shaw
Journal: Circulation Research (2017)

Traditionally, the role of Connexin 43 (Cx43, encoded by GJA1) has been studied in the context of forming gap junctions to mediate cell-cell communication. Cx43 has been implicated in multiple non-canonical roles including metabolic health. It was recently found that GJA1 mRNA undergoes alternative translation to generate truncated C-terminal isoforms, of which GJA1-20k is the most abundant. We examined the relationship between GJA1-20k and mitochondria. Using live cell imaging and organelle markers, we report that, unlike full length GJA1-43k, GJA1-20k has a powerful tropism for mitochondria of all the cell types examined. Mitochondrial enrichment of GJA1-20k was confirmed using biochemical fractionation in transfected cells. High-resolution imaging and immunogold electron microscopy revealed that GJA1-20k is enriched at the interface between mitochondria and microtubules suggesting a role in mitochondrial trafficking. The interaction between GJA1-20k and the microtubules was further confirmed using co-immunoprecipitation. Exploring function, we found that exogenous GJA1-20k is sufficient to rescue mitochondrial localization to the cell periphery upon exposure to hydrogen peroxide, effectively limiting network fragmentation with oxidative stress. Furthermore, we found that the GJA1-20k microtubule-binding domain is unnecessary for mitochondrial localization, but is essential for mediating mitochondrial trafficking and maintaining the integrity of the mitochondrial network and its localization at the cell periphery upon oxidative stress. GJA1-20k enriches in mitochondria and facilitates microtubule-based mitochondrial trafficking, preserving organelle network integrity upon oxidative stress. GJA1-20k provides a means by which otherwise traditional Cx43 can play diverse non-canonical roles. GJA1-20k has therapeutic potential to prevent mitochondrial fragmentation in situations of cellular stress.
Abstract 4904: PD-L1 pathway activation as an escape mechanism of resistance to MEK inhibitor treatment in human colorectal cancer models
Authors: Stefania Napolitano, Nunzia Matrone, Valentina Belli, Vincenzo De Falco, Erika Martinelli, Scott Kopetz, Fortunato Ciardiello, Teresa Troiani
Journal: Cancer Research (2018)

Abstract Molecular mechanisms driving acquired resistance to anti-EGFR therapies in mCRC is complex and biochemically converge to activate the EGFR-RAS-MAPK pathway. In order to understand the mechanism underlying MEKi resistance, SW48 MEKi resistant cell lines (SW48-MR) have been established by in vivo selection. To expand our results, another CRC cell line sensitive to MEK blockade, such as HCT116, has been generated: HCT116-MR. Microarray analysis showed that several genes involved in the PD-L1 pathway were up regulated in SW48-MR versus SW48. Moreover, genes overexpressed in MEKi-resistant tumor were related to the gene signature of CMS4 subtype of CRC. In particular all the pathways that were up regulated in CMS4 tumors were up regulated in the resistant cell line, as confirmed by Western blot and Immunofluorescence analysis. The regulation of PD-L1 expression is regulated by multiple signaling pathways, including JAK/STAT. STAT3 gene is also up regulated in MEKi-resistant tumors. Inhibition of STAT3 expression by siRNA reduced PD-L1 expression and restored MEKi sensitivity. Moreover, a direct correlation has been demonstrated between EGFR and PD-L1. Exogenous activation of EGFR by TGFα stimulation in MEKi sensitive HCT 116 cell lines induced PD-L1 overexpression and resistance to MEKi. Once demonstrated the EGFR role in modulation of PD-L1 expression and subsequently development of acquired resistance to MEKi, we further evaluated the potential mechanism(s) responsible for EGFR activation. One major mechanism is the specific ligand stimulation. Gene expressions analysis revealed that all EGFR ligands were up regulated in MEKi resistant tumors compared to parental tumors. Moreover, we will perform an ELISA assay to confirm this data. To extend these in vitro findings, we will perform an in vivo study using MC38 and CT26 MEKi resistant syngeneic models that we have previously generated. These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with other agents and provide an additional therapeutic strategy via modulation of host immune responses in CMS4 CRC tumors. Citation Format: Stefania Napolitano, Nunzia Matrone, Valentina Belli, Vincenzo De Falco, Erika Martinelli, Scott Kopetz, Fortunato Ciardiello, Teresa Troiani. PD-L1 pathway activation as an escape mechanism of resistance to MEK inhibitor treatment in human colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4904.
Abstract 17950: High-Dose Edoxaban Regimen versus Warfarin in Patients With Atrial Fibrillation and Established Coronary Artery Disease: Insights From the ENGAGE AF-TIMI 48 Trial
Authors: Thomas A Zelniker, Christian T Ruff, Stephen D Wiviott, Jean-Jacques Blanc, Francesco Nordio, Michele F Mercuri, Hans Lanz, Elliott M Antman, Eugene Braunwald, Robert P Giugliano
Journal: Circulation (2017)

Introduction: Concerns regarding less protection from MI with dabigatran vs. warfarin in pts with AF have been raised. The relative efficacy and safety profile of edoxaban compared to warfarin in p...
Abstract 4935: High-throughput immune-oncology screen identifies EGFR inhibitors as potent enhancers of CTL antigen-specific tumor cell killing
Authors: Patrick H. Lizotte, Troy Luster, Megan E. Cavanaugh, Luke J. Taus, Abha Dhaneshwar, Naomi Mayman, Aaron Yang, Mark Bittinger, Paul Kirschmeier, Nathanael S. Gray, David A. Barbie, Pasi A. Janne
Journal: Cancer Research (2018)

Abstract As immune checkpoint blocking antibodies increasing become foundational therapies for the treatment of cancer, there is a pressing need to identify compounds that synergize with checkpoint blockade as the basis of combinatorial treatment regimens. We have developed a screening assay in which a luciferized tumor cell line expressing a model antigen is co-cultured with a transgenic CD8+ T cell specifically recognizing the model antigen in a H-2b-restricted manner. The target tumor cell/T cell assay was screened with a small molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells in an antigen-dependent manner. The EGFR inhibitor Erlotinib was the top hit that enhanced T cell killing of tumor cells. Subsequent experiments with Erlotinib and additional EGFR inhibitors validated the screen result. EGFR inhibitors increase both basal and IFN-γ-induced antigen processing and presentation of MHC class-I, which enhanced recognition and lysis by CD8+ cytotoxic T lymphocytes. The tumor cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen utilizing the same target tumor cell/T cell assay identified sgRNAs targeting EGFR as sensitizing tumor cells to T cell-mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in the MC38 syngeneic colon cancer model that was superior to PD-1 blockade or EGFR inhibition alone, further validating EGFR inhibitors as immunomodulatory agents that enhance PD-1 checkpoint blockade. This novel target tumor cell/T cell assay can be screened in high-throughput with small molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds AND target genes, respectively, that enhance or inhibit T cell recognition and killing of tumor cells. Citation Format: Patrick H. Lizotte, Troy Luster, Megan E. Cavanaugh, Luke J. Taus, Abha Dhaneshwar, Naomi Mayman, Aaron Yang, Mark Bittinger, Paul Kirschmeier, Nathanael S. Gray, David A. Barbie, Pasi A. Janne. High-throughput immune-oncology screen identifies EGFR inhibitors as potent enhancers of CTL antigen-specific tumor cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4935.
Concerns about clinical governance of crematorium medical referees
Authors: David Chappel, Imogen Stephens
Journal: BMJ (2018)

We share Luce and Smith’s disappointment at the recent announcement of another deferral of the introduction of medical examiners in the community.1 This is risky because over half of all deaths occur out of hospital, and Shipman exploited weaknesses in the current system that will remain unchanged. The system is already showing fragility—for example, finding a …
Abstract 5418: GATA3 zinc-finger mutation induces transcriptional reprogramming in breast cancer through gain and loss of function
Authors: Motoki Takaku, Sara A. Grimm, John D. Roberts, Kaliopi Chrysovergis, Page Myers, Charles M. Perou, Paul A. Wade
Journal: Cancer Research (2018)

Abstract Recent large-scale breast cancer genomic profiling identified frequent mutations in a pioneer transcription factor, GATA3. The expression of GATA3 is a prominent marker of luminal breast tumors, and loss of GATA3 expression is associated with aggressive tumor phenotypes. In addition, GATA3 mutations are frequently found in these luminal tumors. However, the clinical and molecular outcomes of GATA3 mutations are poorly understood. Our novel classification scheme of GATA3 mutations defines distinct clinical features of breast tumors with mutations in the second GATA3 zinc-finger (ZnFn2): frequent observation in luminal B subtype and worse prognosis than other GATA3 mutant cases. To dissect the molecular impacts of these ZnFn2 mutations, we generated a GATA3 mutant breast cancer cell clone by CRISPR-Cas9 gene editing. An engineered ZnFn2 mutant cell line manifested increased tumor growth as xenografts and more aggressive phenotypes in vitro. The ZnFn2 mutation led to loss of GATA3 binding and decreased expression at a subset of genes, including progesterone receptor (PR). The mutant cells also exhibited gain of GATA3 binding at other loci, correlated with increased expression of mesenchymal marker genes. Decreased expression of PR and impaired response to progesterone were crucial for cancer-promoting functions in GATA3 ZnFn2 mutant cells. Downregulation of PR and its downstream genes was also observed in the clinical gene expression data. These results illuminate tumor-promoting functions of GATA3 ZnFn2 mutations in breast cancer. Citation Format: Motoki Takaku, Sara A. Grimm, John D. Roberts, Kaliopi Chrysovergis, Page Myers, Charles M. Perou, Paul A. Wade. GATA3 zinc-finger mutation induces transcriptional reprogramming in breast cancer through gain and loss of function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5418.