tbuckley/cabot-search huggingface dataset:
Abstract 6323: Identification of genomic alterations related to treatment progression in RWD
Authors: Nayan Chaudhary, Patricia Luhn, Gunther Jansen, Ciara Metcalfe, Marc Hafner
Journal: Cancer Research (2020)

Abstract Real-world data (RWD) are potentially a highly valuable resource to accelerate drug discovery and improve clinical practice. In particular, datasets combining clinical outcomes and comprehensive genomic profiling (CGP) could uncover new mechanisms of resistance and identify new patient populations for targeted therapies. Here, we used a de-identified clinico-genomic database (CGDB) from routine clinical care based on a clinical EHR-derived data from Flatiron Health linked to tumor sequencing results from Foundation Medicine to assess how prevalence of genomic alterations changes following progression on targeted therapies in the metastatic setting. One of the main challenges we faced is the lack of systematic and longitudinal genomic testing: among the patients receiving a specific treatment, some had a CGP performed prior to treatment, others only around the end of the line of therapy, but only a handful had multiple tests. We therefore established a methodology to assess changes in alteration prevalence and tested how our results are sensitive to cohort building parameters such as timing of testing, duration of therapy, or prior lines of treatment. Our approach successfully recovered three established cases of therapeutic resistance: (1) EGFR T790M in non-small cell lung cancer patients treated with erlotinib or gefitinib; (2) AR alterations following hormonal therapies in prostate cancers; and (3) ESR1 mutations in hormone-receptor positive breast cancer patients progressing on endocrine therapies other than fulvestrant. We delved into the latter case and identified differences in the type of ESR1 mutation that occurred following endocrine therapies if CDK4/6 inhibitors were co-administered or not. On one hand, RWD lack randomization and can thus be subject to confounding variables but on the other hand, RWD have the advantage of including a larger number of patients in a real-world setting compared to clinical trials. Our analysis shows that real-world CGDB can recapitulate the expected emergence of mutations following specific lines of treatment. Our study is a proof of concept of usage of RWD to assess how prevalence of genomic alterations changes following treatment. Our method allowed us to assess differences between patient cohorts and generate novel hypotheses on treatment-related changes in genomic profiles, which can ultimately lead to new drug indications. Citation Format: Nayan Chaudhary, Patricia Luhn, Gunther Jansen, Ciara Metcalfe, Marc Hafner. Identification of genomic alterations related to treatment progression in RWD [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6323.
Abstract 1536: MiRNA expression profile of exosomes derived from breast cancer cells following induction of the epithelial-to-mesenchymal transition
Authors: Christian A. Showalter, Yinan Huang, Monica M. Burdick
Journal: Cancer Research (2020)

Abstract Breast cancer-derived exosomes are small extracellular vesicles that play a crucial role in the metastatic progression of breast cancer due to their ability to transport a variety of biologically active molecules (e.g., miRNAs) to local and distant sites in the body. The molecular cargo transported by breast cancer-derived exosomes alters the transcriptome of recipient cells at these sites to stimulate pro-metastatic events, including the epithelial-to-mesenchymal transition (EMT). Importantly, the molecular cargo loaded into exosomes can vary depending on cell state. However, it is unclear whether the expression of miRNAs in breast cancer-derived exosomes is altered following inducement of the EMT. Regulation of exosomal miRNAs following the EMT may enhance the ability of circulating tumor cells to target specific tissue sites or improve formation and maintenance of metastatic tumors compared to miRNAs packaged into exosomes secreted from cancer cells without induction of the EMT. To address this knowledge gap, we hypothesized that the EMT alters expression of miRNAs in exosomes derived from EMT-induced MDA-MB-468 breast cancer cells. To induce the EMT, MDA-MB-468 cells were treated with exogenous epidermal growth factor. MDA-MB-468 cells treated with epidermal growth factor exhibited greater mRNA expression of the mesenchymal marker Vimentin compared to non-treated MDA-MB-468 cells by qRT-PCR. Subsequently, exosomes were isolated from the conditioned cell culture medium of MDA-MB-468 cells, with and without induction of the EMT, using ExoQuick exosome isolation reagent. Molecular size analysis of isolated exosomes revealed that they were similar in size to the typical size range reported for exosomes (40 - 150nm). Moreover, a common exosomal marker protein, CD9, was enriched in the MDA-MB-468-derived exosome fractions compared to whole cell lysates by Western blot. Furthermore, next generation sequencing and bioinformatic analysis were performed to determine the miRNA expression profiles of these exosomes. Results from this study reveal expression of miRNAs in breast cancer cell-derived exosomes before and after activation of the EMT and may indicate how exosomes secreted from advanced stage breast cancer enhance metastatic tumor progression. Citation Format: Christian A. Showalter, Yinan Huang, Monica M. Burdick. MiRNA expression profile of exosomes derived from breast cancer cells following induction of the epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1536.
Abstract 3268: Anti-tumor effect of VSIG4 in conversion of immunosuppressive type II macrophage <i>via</i> repolarization
Authors: Hye Jeong Kim, Sunhee Hwang, Seung-Hyun Lee, HyunTae Son, Joong Won Lee, Byoung S. Kwon
Journal: Cancer Research (2020)

Abstract V-set and immunoglobulin domain-containing 4 (VSIG4) is a B7 family-related protein which includes PDL1, VISTA and CTLA4 ligand. The known functions of VSIG4 are a receptor for complement iC3b and C3b to inhibit complement activity and negative regulation of proliferating T cell. Although VSIG4 is highly expressed in tissue-resident macrophage and tumor-associated macrophage (TAM), the mechanism of the signal transduction is not fully elucidated. Here we investigate the pivotal roles of anti-VSIG4 therapeutic antibody in TAM and tumor microenvironment. Anti-VSIG4 antibody engagement altered a broad range of type II macrophage (M2) transcriptome which related to immune-tolerance and increased the proliferation of cytotoxic CD8+T cells. Anti-VSIG4 antibody induced phosphorylation of JNK and p38MAPK and in consequence, decreased the expression of M2 marker CD14, CSF-1R and CD163 while type I macrophage (M1) marker CD86 and CD40 were increased. Furthermore, anti-VSIG4 antibody treatment to TAM in ovarian cancer patients, results in secretion of inflammatory cytokines and chemokines in a similar way to M1 macrophages. In the CD34+-based humanized mouse model, stimulation of VSIG4 attenuated tumor growth and promoted infiltration of IFN-gamma-producing CD8+ T cells into tumor tissue. Adopted transfer of differentiated M2 macrophages to immune-deficient NSG mice confirmed M2 conversion into M1 macrophage phenotype with anti-VSIG4 antibody. Our finding suggests that anti-VSIG4 antibody directly act on TAM and induce repolarization of TAM to tumor suppressive M1 macrophages, leading to a CD8+ T cell proliferation and tumor suppression. Overall, targeting the VSIG4 would be an advantageous candidate in cancer therapeutics. Citation Format: Hye Jeong Kim, Sunhee Hwang, Seung-Hyun Lee, HyunTae Son, Joong Won Lee, Byoung S. Kwon. Anti-tumor effect of VSIG4 in conversion of immunosuppressive type II macrophage via repolarization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3268.
Abstract 6080: IL1RAP augments Cysteine metabolism and drives oxidative stress adaptation and lung metastasis in Ewing sarcoma
Authors: Hai-Feng Zhang, Amal M. El-Naggar, Hongwei Cheng, Anna Prudova, Alberto Delaidelli, Jian-Zhong He, Gian Luca Negri, Michael Lizardo, Tianqing Yang, Gregg Morin, Wei Li, Dimiter S. Dimitrov, Poul H. Sorensen
Journal: Cancer Research (2020)

Abstract The high oxidative stress cancer cells experience during the metastatic cascade is an important determinant of metastasis. How cancer cells adapt to those stressful conditions remains elusive. Here our global translatome and proteome analyses have uncovered novel signatures exploited by oncogene-transformed cells to adapt and survive oxidative stress. We revealed that various oncoproteins promote the expression of the IL1RAP to alleviate oxidative stress and facilitate stress adaptation. Mechanistically, IL1RAP controls Cysteine metabolism, a key substrate and determinant of antioxidant glutathione synthesis. CTH, a crucial enzyme for de novo Cysteine synthesis and redox regulation, was identified as a key functional mediator of IL1RAP. Moreover, global interactome analysis uncovered IL1RAP as a novel component and enhancer of the System Xc− transporter (SLC7A11), which is involved in Cystine uptake. Thus, IL1RAP enhances Cysteine supply via both uptake and biogenesis. IL1RAP depletion rendered Ewing sarcoma cells susceptible to oxidative stress and ferroptosis in vitro, and dramatically mitigated local invasion and lung metastasis in mice. In patients with Ewing sarcoma, high-expression of IL1RAP in the tumors correlated with poor event-free survival. Therefore, we have defined a novel pro-metastatic mechanism driven by IL1RAP-mediated Cysteine metabolism and redox regulation. Citation Format: Hai-Feng Zhang, Amal M. El-Naggar, Hongwei Cheng, Anna Prudova, Alberto Delaidelli, Jian-Zhong He, Gian Luca Negri, Michael Lizardo, Tianqing Yang, Gregg Morin, Wei Li, Dimiter S. Dimitrov, Poul H. Sorensen. IL1RAP augments Cysteine metabolism and drives oxidative stress adaptation and lung metastasis in Ewing sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6080.
Abstract 5594: Inmune gene expression by nCounter in mucinous adenocarcinoma lung cancer
Authors: Ruth Román Lladó, Cristina Aguado Esteban, Ana Giménez-Capitán, Ueda Daisuke, Masaoki Ito, Yasuhiro Tsutani, Yoshihiro Miyata, Cristina Teixidó, Noemí Reguart, Morihito Okada, Sonia Rodríguez, Ariadna Balada, Erika Aldeguer, Santiago Viteri Ramirez, Maria Gonzalez Cao, Andrés Aguilar, Rafael Rosell, Miguel Angel Molina Vila
Journal: Cancer Research (2020)

Abstract Introduction: Although immune checkpoint inhibitors have become a standard of care for multiple cancer types; currently used biomarkers, such as PD-L1 expression, MSI or TMB, fail to identify all responders. In addition, little is known about markers of response to immunotherapy in some infrequent histological subtypes, such as mucinous adenocarcinoma of the lung. Gene expression signatures incorporating not only PD-L1 but also other immune modulators can have a better predictive power, particularly in these histological subtypes. Methods: A cohort of 165 baseline samples from with stage I-IV non-small cell lung cancer (NSCLC) patients was retrospectively analyzed, 55 stage I-IIIA mucinous adenocarcinomas (MA), 31 stage I-IIIA nonmucinous adenocarcinomas (NMA) and 79 stage IIIB-IV NMAs. RNA was extracted from FFPE tumor samples and the expression levels of a 7-gene immune signature (CD4, CD8A, FOXP3, GZMM, INFG, CD274 and PDCD1) were determined using a nCounter panel. Krustal-Wallis test was used for statistical comparisons. Results: No significant differences were observed in the expression levels of FOXP3 and PDCD1 (codifying forkhead box P3 and PD-1) between the three groups analyzed. In contrast, GZMM, IFNG and CD4 expression (codifying granzyme M, interferon gamma and CD4) was significantly higher in early stage MA compared to stage I-IIIA or stage IIIB-IV NMA. CD8A expression was significantly higher in early stage tumors, independently of the presence of mucinous component. In addition, the levels of CD274 mRNA (codifying PD-L1) were significantly higher in early stage MA compared to advanced stage NMA. Finally, among the stage I-IIIA MA, 27/55 (49%) were KRAS-mutant, but they did not show significant differences with KRAS-wt MAs in the expression of any of the genes tested. Conclusions: Mucinous adenocarcinoma of the lung shows a different pattern of expression of immune-related genes, which may influence response to immunotherapy. Citation Format: Ruth Román Lladó, Cristina Aguado Esteban, Ana Giménez-Capitán, Ueda Daisuke, Masaoki Ito, Yasuhiro Tsutani, Yoshihiro Miyata, Cristina Teixidó, Noemí Reguart, Morihito Okada, Sonia Rodríguez, Ariadna Balada, Erika Aldeguer, Santiago Viteri Ramirez, Maria Gonzalez Cao, Andrés Aguilar, Rafael Rosell, Miguel Angel Molina Vila. Inmune gene expression by nCounter in mucinous adenocarcinoma lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5594.
Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial
Authors: Toby Richards, Ravishankar Rao Baikady, Ben Clevenger, Anna Butcher, Sandy Abeysiri, Marisa Chau, Iain C Macdougall, Gavin Murphy, Rebecca Swinson, Tim Collier, Laura Van Dyck, John Browne, Andrew Bradbury, Matthew Dodd, Richard Evans, David Brealey, Stefan D Anker, Andrew Klein
Journal: The Lancet (2020)

Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes.In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants.Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints.Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery.UK National Institute of Health Research Health Technology Assessment Program.
Abstract 5340: Novel small-molecule antagonists of the PD1/PD-L1 axis
Authors: Romain Magnez, Natascha Leleu-Chavain, Morgane Tardy, Hassiba El Bouazzati, Fréderique Klupsch, Christian Bailly, Régis Millet, Bruno Quesnel, Xavier Thuru
Journal: Cancer Research (2020)

Abstract Immuno-therapy has become a leading strategy to fight cancer. Over the past few years, immuno-therapies using checkpoint inhibitor monoclonal antibodies (mAbs) against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) have demonstrated improved survival compared with chemotherapy. We describe the identification and characterization of an innovative series of synthetic compounds (named PyrDLones, patented) endowed with nanomolar activity against PD-L1. PyrDLones properties were characterized using several biophysical techniques including microscale thermophoresis (MST) and fluorescence resonance energy transfer (FRET) measurements. In vitro, selected small molecules demonstrate a high affinity for human PD-L1, potently disrupt the PD-L1:PD-1 interaction (&amp;lt;2nM), and inhibit Src homology region 2 domain-containing phosphatase (SHP2) recruitment to PD-1 (&amp;lt;4nM). As a result, upon binding to and inhibiting PD-L1, these molecules reactivate proliferation of CTL-L2 cells expressing PD-1 (EC50=44nM). More than 150 molecules have been synthesized and a dozen of highly potent “PD-L1 silencing compounds” have been identified, based on in vitro measurements. Structure-activity relationships have been defined and an in silico drug-target model supporting the mechanism of action has been built. Experiments are on-going to delineate further the molecular mechanism of action of the PyrDLones (drug-induced PD-L1 dimer formation), the cellular consequences of the PD-L1 silencing (reactivation of cytotoxic T cells in the tumor microenvironment) and to characterize their activity in vivo. In summary, we have discovered a novel series of potent, small molecule PD-L1 antagonists, amenable to the design of orally active drugs for immuno-therapy of cancers. Citation Format: Romain Magnez, Natascha Leleu-Chavain, Morgane Tardy, Hassiba El Bouazzati, Fréderique Klupsch, Christian Bailly, Régis Millet, Bruno Quesnel, Xavier Thuru. Novel small-molecule antagonists of the PD1/PD-L1 axis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5340.
Upper Airway Surgery for Obstructive Sleep Apnea
Authors: Meghna P. Mansukhani, Eric J. Olson, Sean M. Caples
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 5005: Impact of H3.3K27M mutation on diffuse intrinsic pontine glioma's resistance to treatment
Authors: Quentin Bailleul, Mélanie Arcicasa, Audrey Hochart, Andria Rakotomalala, Marie Castets, Eddy Pasquier, Pierre-Olivier Angrand, Eric Adriaenssens, Xuefen Le Bourhis, Pierre Leblond, Samuel Meignan
Journal: Cancer Research (2020)

Abstract Diffuse Intrinsic Pontine Glioma is one of the worst pediatric brain tumors regarding prognosis due notably to intrinsic cell resistance to radio and chemotherapy. One of the main characteristics of DIPG cells is the presence of a mono-allelic mutation on the lysine 27 of histone H3 (H3K27M). This mutation inhibits the trimethylation of this lysine that leads to strong modifications of gene expression. Until now, even though this mutation seems to be a driver event in tumorigenesis, its role in cell resistance to treatment has not been deciphered, due to a lack of relevant cellular models. This way, in order to evaluate the role of the mutation on resistance to treatment, we first induced the mutation in three H3K27-unmutated pediatric glioma cell lines. In parallel, using the CRISPR/Cas9 technology, we are establishing DIPG cellular models in which the mutation will be reversed. By gene trapping approach, we aim to restore an H3F3Awt/wt genotype. After validation, these models would result in original tools to study the impact of H3K27M mutation in DIPG cells resistance to treatment. For the model of induction, the transfected cell lines exhibit the mutation accompanied by a loss of H3K27me3 mark and H3.3 overexpression. For now, we showed an increased cell growth due to the mutation in two cell lines, under normoxia as well as under hypoxia. On contrary there was no impact on resistance to chemotherapy or ionizing radiation. In the third cell line, we didn't observe any impact on cell growth, but an increase of cell radioresistance. Concerning the mutation reversion, our preliminary results show homologous recombination at the right locus in the genome, and some clones present a loss of the mutation confirmed by sequencing. After the removal of resistance cassette by action of a recombinase protein, we will be able to evaluate the biological effects of mutation reversion. To sum up, these different models would allow us to decipher cellular and molecular mechanism induced by the H3.3K27M mutation in DIPG cells including resistance to treatment, and thus, to possibly identify putative therapeutic targets. Citation Format: Quentin Bailleul, Mélanie Arcicasa, Audrey Hochart, Andria Rakotomalala, Marie Castets, Eddy Pasquier, Pierre-Olivier Angrand, Eric Adriaenssens, Xuefen Le Bourhis, Pierre Leblond, Samuel Meignan. Impact of H3.3K27M mutation on diffuse intrinsic pontine glioma's resistance to treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5005.