tbuckley/cabot-search huggingface dataset:
Abstract 4752: Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner in <i>EGFR</i>L858R/T790M-positive non-small-cell lung cancer
Authors: Chia-Chi Hsu, Bin-Chi Liao, Wei-Yu Liao, Aleksandra Markovets, Daniel Stetson, Kenneth Thress, Chih-Hsin Yang
Journal: Cancer Research (2019)

Abstract Osimertinib is current recommended treatment for EGFR T790M-positive NSCLC following progression on prior EGFR tyrosine kinase inhibitor therapy. However, acquired resistance to osimertinib therapy inevitably developed after a period of effective treatment. We had a patient of EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually developed resistance. Plasma cell-free DNA analysis disclosed exon-16-skipping HER2 (HER2Δ16) in one osimertinib treated patient. HER2Δ16 was regarded as an oncogenic driver in breast cancer and has never been reported in lung cancer before. Therefore, it’s intriguing to investigate the role of HER2Δ16 in osimertinib resistance in NSCLC. The purpose of this study is to explore the mechanism of HER2Δ16-mediated resistance to osimertinib and to explore strategies to overcome the resistance. We constructed and established H1975 cells stably expressing either vehicle, WT-HER2 or HER2Δ16. We observed that without osimertinib treatment, there was no difference in cell growth and the response to EGF-stimulation. However, when treated with osimertinib, H1975-HER2Δ16 cells were more resistant under normal and EGF-stimulating conditions compared to vehicle or WT-HER2 expressing cells. Moreover, osimertinib treatment in H1975-HER2Δ16 cells had less inhibitory effect on phosphor-ERK and phosphor-AKT compared to vehicle or H1975-WT-HER2 cells. Interestingly, co-treatment of osimertinib with Src-kinase inhibitor, dasatinib, failed to reverse the resistance, indicating that HER2Δ16-driven osimertinib-resistance was independent of Src-kinase. Finally, we revealed that combination of osimertinib with the HER2 small molecular inhibitor, afatinib, can suppress cell growth in H1975-WT-HER2 and H1975-HER2Δ16 cells. In summary, we have shown that HER2Δ16, may be a resistance mechanism to osimertinib in EGFR mutated NSCLC and that HER2Δ16-driven resistance was Src-kinase independent. Moreover, we found the HER2Δ16-driven resistance could be rescued by combination of osimertinib with afatinib. Citation Format: Chia-Chi Hsu, Bin-Chi Liao, Wei-Yu Liao, Aleksandra Markovets, Daniel Stetson, Kenneth Thress, Chih-Hsin Yang. Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner in EGFRL858R/T790M-positive non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4752.
BMA is urged to seek legal advice for doctors on refusing to work because of system failures
Authors: Abi Rimmer
Journal: BMJ (2019)

Doctors have called on the BMA to obtain legal guidance for doctors on whether they can refuse to work when system failures, such as understaffing or IT breakdowns, mean that patient safety cannot be guaranteed.

Representatives at the association’s annual meeting in Belfast on 26 June voted in favour of a motion that also called for guidance for doctors on their contractual and regulatory position if they …
Abstract 1241: Characterization of a newly developed anti-TIGIT monoclonal antibody by double staining of T cells and NK cells by IHC and FACS
Authors: Weimin Qi, Joseph Chu, Lily Luo, Tatiana Scoggin, Kim Dickinson
Journal: Cancer Research (2019)

Abstract T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory domain (TIGIT) is a newly identified surface protein expressed in regulatory, memory, naturalkiller (NK), and activated T cells. Several studies indicate that mouse TIGIT is a vital immunomodulator that can control the activities of both NK and T cells and plays an important role in transplantation tolerance and tumor immune surveillance. In this study, we generated a mouse monoclonal antibody, clone: BC41, by immunizing a recombinant human TIGIT, corresponding to an extra cellular domain. The protein was injected into BALB/c mice for three times and then the splenocytes were electro fused with mouse myeloma cells. The TIGIT-specific hybridoma cells were screened and a TIGIT-specific clone, named as BC41, was selected. The BC41 antibody was characterized by Western blot and immunohistochemistry. In immunoblots, TIGIT was able to detect a 26 kda protein corresponding to human TIGIT on over-expressed cells and native protein in human spleen lysates. Moreover, the BC41 was able to bind mouse TIGIT. FACS result showed that the BC41 antibody bond specifically to CD3/CD28+ T cells. We further analyzed the antibody binding profile by Immunohistochemistry on human T cells and NK cells by double staining. BC41 was able to bond portion of CD8 T cells (EOMES+), Treg cells (FOXP3+), PD1+ T cells and NK (CD57+) cells. Our results demonstrated that the antibody is TIGIT-specific and can be applied for detecting and analyzing tumor-infiltrating cells profile in transplantation and tumor immunotherapy. Citation Format: Weimin Qi, Joseph Chu, Lily Luo, Tatiana Scoggin, Kim Dickinson. Characterization of a newly developed anti-TIGIT monoclonal antibody by double staining of T cells and NK cells by IHC and FACS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1241.
Abstract 11756: Higher Body Mass Index is Associated with Left Ventricular Structural Change Even in Early Childhood
Authors: Kenji Harada, Tomohiro Abe, Yukiko Harada
Journal: Circulation (2012)

Background: Left ventricular (LV) hypertrophy is an independent risk factor for adverse cardiovascular outcomes. Adulthood obesity is associated with concentric LV hypertrophy, but there is little ...
Abstract 12710: Cyclic GMP Enhancing Therapy Promotes Titin Phosphorylation and Corrects High Cardiomyocyte Passive Stiffness in Diastolic Heart Failure
Authors: Nazha Hamdani, Bishu G Kalkidan, Jolanda van der Velden, Ger J Stienen, Margaret M Redfield, Wolfgang A Linke
Journal: Circulation (2011)

Myofiber passive stiffness is lowered by phosphorylation of the giant sarcomeric protein titin, with beneficial effects on diastolic function. Titin can be phosphorylated by cGMP-activated protein ...
Safety and efficacy of abivertinib (AC0010), a third-generation EGFR tyrosine kinase inhibitor, in Chinese patients with EGFR-T790M positive non-small cell lung cancer (NCSLC).
Authors: Qing Zhou, Lin Wu, Luo Feng, Tongtong An, Ying Cheng, Jianying Zhou, Junling Li, Ji Feng Feng, Li Zhang, Baohui Han, Walson Xu, Lvyu Zhu, Li Xu, Xiao Xu, Feng Roger Luo, Yi-Long Wu
Journal: Journal of Clinical Oncology (2019)

9091 Background: Abivertinib (AC0010) is a potent, selective third-generation EGFR tyrosine kinase inhibitor (TKI) that demonstrated clinical efficacy and manageable adverse events (AEs) in the phase 1 portion of the study in Chinese patients with EGFR T790M+ NSCLC. Here we report the results from patients enrolled to the phase 2 portion of the study (NCT02330367). Methods: The study enrolled locally advanced or metastatic NSCLC patients who were ≥ 18 years, progressed with the prior EGFR-TKI therapy, and must have T790M+ in tumor based on the central laboratory test. All patients received the recommended phase 2 doses of 300 mg twice daily [BID]. Results: As of March 5, 2018, 227 patients received treatment, majority of patients had adenocarcinoma (n = 220, 97%) with the median age of 59 years, 65% (n = 148) patients were female, most patients were non-smoker (n = 171, 75%), ECOG performance status of 1 (n = 162, 71%). The median treatment duration was 21 week. The treatment-related adverse events (AEs) were reported for 96.9% (n = 220) patients, mostly of grade 1 or 2 severity. The most common drug-related grade 3/4 AE (≥2%) was ALT increase (7.0%), AST increase (4.8%), diarrhea (4.4%), interstitial lung disease (4.0%), neutrophil count decrease (3.5%), and there was no drug-related grade 5 AEs. Among 209 response evaluable patients, per investigator’s assessment, 90.0% (n = 188) patients had tumor size reduction, the objective response rate (Complete Response + Partial Response [PR]) was 50.2% (n = 105; 95% CI 43.3%, 57.2%); 37.8% (n = 79) had stable disease, and the disease control rate was 88% (95% CI 82.9%, 92.1%). The median duration of response and progression-free survival estimated by Kaplan-Meier was 7.5 months (95% CI 6.0, 9.2) and was 7.5 months (95% CI 6.0, 8.8), respectively. Conclusions: Abivertinib demonstrated the clinical efficacy with manageable side-effects in patients with EGFR T790M+ NSCLC. Therefore, abivertinib could be a suitable treatment for patients with EGFR T790+ disease who have progressed on an EGFR-TKI. Clinical trial information: NCTNCT02330367.
Genetics of blood lipids among similar to 300,000 multi-ethnic participants of the Million Veteran Program
Authors: Derek Klarin, Scott M. Damrauer, Kelly Cho, Yan Sun, Tanya M. Teslovich, Jacqueline Honerlaw, David R Gagnon, Scott L. Du Vall, Jin Li, Gina M. Peloso, Mark Chaffin, Aeron M. Small, Jie Huang, Hua Tang, Julie A. Lynch, Yuk-Lam Ho, Dajiang J. Liu, Connor A. Emdin, Alexander H. Li, Peter Wilson
Journal: Nature Genetics (2018)
Routine HIV Screening During Intake Medical Evaluation at a County - Jail Fulton County, Georgia, 2011-2012
Authors: Anne Spaulding, Chava J. Bowden, Bryan I. Kim, Mario C. Mann, Lesley Miller, Genetha R. Mustaafaa, Ryan P. Kyle, Michelle Leon, Mary V. Mbaba, Lauren C. Messina, Sharne Hampton, Robin MacGowan, Laurie Reid, Andrew Margolis, Lisa Belcher
Journal: MMWR Morbidity and Mortality Weekly Report (2013)
Abstract 11033: Monoarterial Cardiovascular Screening: A 10-year Follow-up Study. San Valentino Cardiovascular Screening Project
Authors: Gianni Belcaro
Journal: Circulation (2012)

The cardiovascular screening method developed for the Cardiovascular Screening project in San Valentino has used for more than 20 years, high-resolution ultrasound scanning of both carotid and femo...
Abstract 5057: Single cell RNA sequencing reveals altered natural killer-like, effector CD8+ T lymphocytes in smokers
Authors: Suzanne N. Martos, Michelle R. Campbell, Marie A. Iannone, Gary S. Pittman, Ma Wan, Douglas A. Bell
Journal: Cancer Research (2019)

Abstract Tobacco smoke exposure is a risk factor for many human diseases and the global disease burden attributed to smoking remains substantial. In addition to DNA damage, smoking-induced epigenetic changes may contribute to etiology of complex smoking-associated diseases. Smoking alters the epigenome and transcriptome of human blood leukocytes. However, interpretation of bulk genomic approaches is limited because changes could indicate altered distribution of cell (sub)populations or changes in expression within (sub)populations. To characterize smoking-related gene expression changes in primary immune cells, we performed single cell RNA sequencing on human peripheral blood mononuclear cells (PBMCs) from smokers (n=4) and nonsmokers (n=4). Transcriptomes of 45,965 cells (78,183 reads per cell) revealed an altered population of Natural Killer (NK)-like T lymphocytes in smokers. Compared to NK cells, the NK-like T cell cluster had elevated expression of CD8A, CD8B, CD3D, CD3E, CD3G, CD6, and CD2, indicative of CD8+ T lymphocytes. Relatively rare in nonsmokers (2.2%), the transcriptionally unique subset of CD8+ T cells comprised 8.7% of PBMCs in smokers. Among CD8+ T cell subtypes, the increase in NK-like CD8+ T cells (Mann-Whitney p = 0.03) corresponded with a decrease in Naïve CD8+ T cells (p = 0.03). We did not observe changes in the frequencies of two additional CD8+ T cell clusters or in the overall frequency of CD8+ T cells. Mass cytometry of a 26-antibody leukocyte panel confirmed no differences in the frequencies of total CD8+ T (CD3+/CD8+/CD56-), total NKT (CD3+/CD56+) or CD8+ NKT (CD3+/CD8+/CD56+) cells between smokers and nonsmokers. This suggests smoking is associated with an increased number of CD8+ T cells that share characteristics with NK cells, but are not NKT cells. Consistent with an NK-like phenotype, altered effector CD8+ T cells had elevated expression of genes reported to be upregulated in T cells reprogrammed to NK-like cells. Compared to other effector CD8+ T cells, altered effector CD8+ T cells had reduced IL7R and increased FCGR3A (CD16), IFNG (interferon gamma), GZMB (granzyme B), and PRF1 (perforin) expression. In mice, granzyme B and perforin expressing CD8+ T cells contribute to the development of atherosclerotic plaques. Our data highlights a potential link between smoking-induced functional changes in human CD8+ T cells and atherosclerosis and /or immune surveillance in cancer. Citation Format: Suzanne N. Martos, Michelle R. Campbell, Marie A. Iannone, Gary S. Pittman, Ma Wan, Douglas A. Bell. Single cell RNA sequencing reveals altered natural killer-like, effector CD8+ T lymphocytes in smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5057.
Abstract 878: IGFBP2 is required to activate EGFR-DNA-PKcs pathway to protect esophageal adenocarcinoma cells from acidic bile salts-induced DNA damage
Authors: Zhangjian Zhou, Heng Lu, Shoumin Zhu, Ahmed Gomaa, Zheng Chen, Jin Yan, Wael El-Rifai, Chengxue Dang, Dunfa Peng
Journal: Cancer Research (2019)

Abstract The incidence of esophageal adenocarcinoma (EAC) is rising rapidly in the US and Western countries. The development of Barrett’s esophagus (BE) and its progression to EAC have been linked to gastroesophageal reflux disease (GERD). Exposure of BE and EAC cells to acidic bile salts (ABS) in GERD conditions induces high levels of DNA damage. In this study, we investigated the role of insulin-like growth factor binding protein 2 (IGFBP2) in regulating ABS-induced DNA double-strand breaks (DSBs). Immunohistochemistry analysis demonstrated frequent overexpression of IGFBP2 in EACs (31/57). Treatment of EAC cells with ABS, to mimic GERD conditions, induced high levels of IGFBP2 expression. Knocking down endogenous IGFBP2 in FLO1 cells (with constitutive high levels of IGFBP2) led to a significant increase in DNA DSBs and apoptosis, following transient exposure (20 min) to ABS. On the other hand, overexpression of exogenous IGFBP2 in OE33 cells (with low endogenous levels of IGFBP2) had a protective effect against DSBs and apoptosis. Using western blotting and immunofluorescence assays, we found that IGFBP2 is required for ABS-induced nuclear accumulation and phosphorylation of EGFR and DNA-PKcs, which are required for DNA damage repair activity. Using co-immunoprecipitation assay, we detected IGFBP2 forms complex with EGFR and DNA-PKcs and co-localizes with EGFR and DNA-PKcs in nucleus, following acidic bile salts treatment. We also demonstrated, using cycloheximide (CHX) chase assay, that IGFBP2 promotes EGFR protein stability in response to ABS exposure. In summary, our data indicate that IGFBP2 protects EAC cells against ABS-induced DNA damage and apoptosis through stabilization and activation of EGFR - DNA-PKcs signaling axis. Citation Format: Zhangjian Zhou, Heng Lu, Shoumin Zhu, Ahmed Gomaa, Zheng Chen, Jin Yan, Wael El-Rifai, Chengxue Dang, Dunfa Peng. IGFBP2 is required to activate EGFR-DNA-PKcs pathway to protect esophageal adenocarcinoma cells from acidic bile salts-induced DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 878.
Abstract 15271: In vivo RNA Profiling of Pulmonary Endothelial Cells Links BRCA1 to the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Sanna Vattulainen, Joonas Aho, Molong Li, Mikko Helenius, Samuel Myllykangas, Juha Koskenvuo, Tero-Pekka Alastalo
Journal: Circulation (2012)

Rationale: Endothelial cell (EC) dysfunction plays a key role in the pathogenesis of pulmonary arterial hypertension (PAH). To avoid EC culture or whole lung samples, we have, for the first time, u...
Abstract 4131: Overcoming aryl hydrocarbon receptor mediated tumor immunosuppression
Authors: Jeremy Tchaicha, Silvia Coma, Meghan Walsh, Jill Cavanaugh, Marta Sanchez-Martin, X. Michelle Zhang, Alfredo Castro, Jeff Ecsedy, Mark Manfredi, Karen McGovern
Journal: Cancer Research (2019)

Abstract Checkpoint inhibitors (CPIs) have become the cornerstone of immune-based oncology therapy; still many cancer patients do not benefit from these agents. Resistance to checkpoint inhibitors is due in part to the presence of immunosuppressive molecules which prevent immune activation despite T cell checkpoint inhibition. Aryl Hydrocarbon Receptor (AHR) is a transcription factor that mediates the immune response in multiple innate and adaptive immune cells subsequent to binding of a diverse set of endogenous and exogenous ligands. One such AHR agonist is kynurenine. Kynurenine, metabolized from tryptophan by indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), binds to AHR and leads to a net immunosuppressive tumor microenvironment. Given that kynurenine can be synthesized by both IDO1 and TDO2 and that AHR is activated by endogenous ligands other than kynurenine, AHR inhibition provides a novel approach to reverse immunosuppression in a broad range of tumor types. We demonstrated that AHR antagonism affects multiple immune cell types and can lead to pro-inflammatory phenotypes in human T cells and myeloid cells in vitro and in murine tumor models. AHR antagonism inhibits growth in the B16-IDO, CT26 and MC38 models and reverses the immunosuppressive microenvironment as indicated by changes in T cell and myeloid cell populations. Immune signature changes characterized via Nanostring in multiple tumor models treated with AHR antagonists were also assessed. Oral dosing of AHR antagonists led to tumor growth inhibition as a single agent and increased anti-tumor activity when combined with checkpoint inhibitors. In addition, beneficial anti-tumor activity occurred with AHR antagonists combined with chemotherapy or with radiation therapy in syngeneic mouse tumor models. Our data indicate that reversing AHR-mediated immune suppression in the tumor microenvironment drives anti-tumor activity alone and in combination with other therapeutic modalities. Overall, our data demonstrates that AHR is an attractive target for reversing immune suppression in tumors. Therefore, we are developing AHR antagonists and translational insights to treat patients most likely to benefit from this approach. Citation Format: Jeremy Tchaicha, Silvia Coma, Meghan Walsh, Jill Cavanaugh, Marta Sanchez-Martin, X. Michelle Zhang, Alfredo Castro, Jeff Ecsedy, Mark Manfredi, Karen McGovern. Overcoming aryl hydrocarbon receptor mediated tumor immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4131.
Hospital Readmission Rates in Medicare Advantage and Traditional Medicare
Authors: Orestis A. Panagiotou, Amit Kumar, Roee Gutman, Laura M. Keohane, Maricruz Rivera-Hernandez, Momotazur Rahman, Pedro L. Gozalo, Vincent Mor, Amal N. Trivedi
Journal: Annals of Internal Medicine (2019)

Background: Medicare's Hospital Readmissions Reduction Program reports risk-standardized readmission rates for traditional Medicare but not Medicare Advantage beneficiaries. Objective: To compare readmission rates between Medicare Advantage and traditional Medicare. Design: Retrospective cohort study linking the Medicare Provider Analysis and Review (MedPAR) file with the Healthcare Effectiveness Data and Information Set (HEDIS). Setting: 4748 U.S. acute care hospitals. Patients: Patients aged 65 years or older hospitalized for acute myocardial infarction (AMI) (n = 841 613), congestive heart failure (CHF) (n = 1 458 652), or pneumonia (n = 2 020 365) between 2011 and 2014. Measurements: 30-day readmissions. Results: Among admissions for AMI, CHF, and pneumonia identified in MedPAR, 29.2%, 38.0%, and 37.2%, respectively, did not have a corresponding record in HEDIS. Of these, 18.9% for AMI, 23.7% for CHF, and 18.3% for pneumonia resulted in a readmission that was identified in MedPAR. However, among index admissions appearing in HEDIS, 14.4% for AMI, 18.4% for CHF, and 13.9% for pneumonia resulted in a readmission. Patients in Medicare Advantage had lower unadjusted readmission rates than those in traditional Medicare for all 3 conditions (16.6% vs. 17.1% for AMI, 21.4% vs. 21.7% for CHF, and 16.3% vs. 16.4% for pneumonia). However, after standardization, patients in Medicare Advantage had higher readmission rates than patients in traditional Medicare for AMI (17.2% vs. 16.9%; difference, 0.3 percentage point [95% CI, 0.1 to 0.5 percentage point]), CHF (21.7% vs. 21.4%; difference, 0.3 percentage point [CI, 0.2 to 0.5 percentage point]), and pneumonia (16.5% vs. 16.0%; difference, 0.5 percentage point [95% CI, 0.4 to 0.6 percentage point]). Rate differences increased between 2011 and 2014. Limitation: Potential unobserved differences between populations. Conclusion: The HEDIS data underreported hospital admissions for 3 common medical conditions, and readmission rates were higher among patients with underreported admissions. Medicare Advantage beneficiaries had higher risk-adjusted 30-day readmission rates than traditional Medicare beneficiaries. Primary Funding Source: National Institute on Aging.