tbuckley/cabot-search huggingface dataset:
Abstract 1281: T790M gatekeeper mutation emerges via de novo at the early stages of erlotinib treament in PC9 non-small cell lung cancer cells
Authors: Sujin Kim, Angela KJ Park, Jeonghee Cho
Journal: Cancer Research (2019)

Abstract The emergence of the T790M gatekeeper mutation in the Epidermal Growth Factor Receptor (EGFR) gene is an important mechanism that can lead to the acquired resistance to EGFR-targeted tyrosine kinase inhibitors used in a subset of non-small cell lung cancer (NSCLC) patients harboring activating mutations. Here we investigated the paths leading to the acquisition of the T790M mutation by establishing an erlotinib resistant PC9 cell model harboring ectopically introduced EGFR cDNA. We detect the emergence of T790M mutation within the EGFR cDNA in a subset of erlotinib resistant PC9 cell models through Sanger sequencing and droplet digital PCR-based methods, confirming that T790M mutation can emerge via de novo events following treatment with erlotinib. In addition, we show that the de novo T790M bearing erlotinib resistant PC9 cells are sensitive to the 3rd generation EGFR-targeted drug, WZ4002. Furthermore, GFP-based competition cell proliferation assays reveal that PC9 cells ectopically expressing EGFR mutant become more dominantly resistant to erlotinib than parental PC9 cells by acquiring T790M mutation. Taken together, we believe that our findings expand upon the previous notion of evolutionary paths of T790M development, providing an important clue to designing a therapeutic strategy to overcome drug resistance. Citation Format: Sujin Kim, Angela KJ Park, Jeonghee Cho. T790M gatekeeper mutation emerges via de novo at the early stages of erlotinib treament in PC9 non-small cell lung cancer cells [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 1281.
Abstract 14194: Shortness of Breath Predicts Acute Coronary Syndrome in Women Only
Authors: Holli A DeVon, Anne G Rosenfeld, Alana Steffan, Mohamud Daya
Journal: Circulation (2013)

Introduction: Patients presenting to the emergency department (ED) with chest pain and/or associated symptoms suggestive of acute coronary syndromes (ACS) present a diagnostic conundrum. We hypothe...
Capita should compensate doctors for pensions debacle
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The BMA must lobby NHS England and the government to investigate and compensate doctors who have become ill or have been unable to retire as a result of Capita’s pension “failings,” representatives said at the BMA’s annual meeting this week.

Delegates unanimously passed a motion on 24 June calling for action against Capita because of its “catastrophic failings in dealing with GP pension contributions.”

The motion said that the contract with the private company should be terminated and investigations should be held to assess its effects on doctors.

A tax amnesty should also be declared …
Abstract 2989: An all-in-one transcriptome-based assay to identify therapy-related biomarkers in lung cancer
Authors: Klaas Kok, Jiacong Wei, Anna A. Rybczynska, Pei Meng, Martijn M. Terpstra, Anthonie J. van der Wekken, Jeroen T. Hiltermann, Ed Schuuring, Harry J. Groen, Anke van den Berg
Journal: Cancer Research (2019)

Abstract Background. In the past decade, treatment of advanced stage lung cancer patients guided by somatic aberrations has become routine practice. Different molecular tests are being applied to detect all targetable mutations and fusions. However, in most cases tissue biopsies are small, hampering multiple independent diagnostic tests. To optimize diagnostic testing we developed an all-in-one transcriptome-based assay. Methods. We have developed a targeted next generation sequencing protocol that uses total RNA as input and is based on the Single Primed enrichment Technology (SPET). We included 11 cell lines, four frozen biopsies, 12 pleural effusion samples and 32 FFPE samples with in total 41 known mutations (including EGFR n=15; KRAS n=11; BRAF n=2; PIK3CA n=3 ), 21 fusion genes (including ALK n=15; ROS n=3) and 3 cases of MET exon14 skipping. Results. We confirmed presence of 32 out of 41 mutations, 19 out of 23 fusions and all three cases of exon skipping by our assay. Besides confirming the fusions, we were also able to identify the fusion gene partner for all detected fusion transcripts. For the samples for which we failed to detect the mutations or fusions, the read depth of the target region was less than four, indicating low expression, low tumor content or insufficient unique reads. Independent RNA-based ddPCR on six unconfirmed mutations were all positive, albeit with low numbers of mutant droplets in some cases. One of three undetected fusions was positive in a NanoString fusion gene detection assay. For one of two negative cases, the fusion was most likely false positive by FISH, as this patient was FISH-break positive for both ALK and RET, which is never reported before. Conclusions. This study proved feasibility of this targeted all-in-one transcriptome-based assay for simultaneous detection of mutations and fusions even in relatively small FFPE tissue biopsies. Moreover, we were able to detect the fusion partner genes in all positive cases. We expect that for routine diagnostic testing using an enrichment for tumor cell-rich areas of recently prepared FFPE blocks, the success rate of the all-in-one transcriptome approach will reach similar sensitivity as currently used diagnostic tests. Citation Format: Klaas Kok, Jiacong Wei, Anna A. Rybczynska, Pei Meng, Martijn M. Terpstra, Anthonie J. van der Wekken, Jeroen T. Hiltermann, Ed Schuuring, Harry J. Groen, Anke van den Berg. An all-in-one transcriptome-based assay to identify therapy-related biomarkers in 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 2989.
A Multicenter Trial of Vena Cava Filters in Severely Injured Patients
Authors: Kwok M. Ho, Sudhakar Rao, Stephen Honeybul, Rene Zellweger, Bradley Wibrow, Jeffrey Lipman, Anthony Holley, Alan Kop, Elizabeth Geelhoed, Tomas Corcoran, Philip Misur, Cyrus Edibam, Ross I. Baker, Jenny Chamberlain, Claire Forsdyke, Frederick B. Rogers
Journal: New England Journal of Medicine (2019)

Whether early placement of an inferior vena cava filter reduces the risk of pulmonary embolism or death in severely injured patients who have a contraindication to prophylactic anticoagulation is not known.In this multicenter, randomized, controlled trial, we assigned 240 severely injured patients (Injury Severity Score >15 [scores range from 0 to 75, with higher scores indicating more severe injury]) who had a contraindication to anticoagulant agents to have a vena cava filter placed within the first 72 hours after admission for the injury or to have no filter placed. The primary end point was a composite of symptomatic pulmonary embolism or death from any cause at 90 days after enrollment; a secondary end point was symptomatic pulmonary embolism between day 8 and day 90 in the subgroup of patients who survived at least 7 days and did not receive prophylactic anticoagulation within 7 days after injury. All patients underwent ultrasonography of the legs at 2 weeks; patients also underwent mandatory computed tomographic pulmonary angiography when prespecified criteria were met.The median age of the patients was 39 years, and the median Injury Severity Score was 27. Early placement of a vena cava filter did not result in a significantly lower incidence of symptomatic pulmonary embolism or death than no placement of a filter (13.9% in the vena cava filter group and 14.4% in the control group; hazard ratio, 0.99; 95% confidence interval [CI], 0.51 to 1.94; P = 0.98). Among the 46 patients in the vena cava filter group and the 34 patients in the control group who did not receive prophylactic anticoagulation within 7 days after injury, pulmonary embolism developed in none of those in the vena cava filter group and in 5 (14.7%) in the control group, including 1 patient who died (relative risk of pulmonary embolism, 0; 95% CI, 0.00 to 0.55). An entrapped thrombus was found in the filter in 6 patients.Early prophylactic placement of a vena cava filter after major trauma did not result in a lower incidence of symptomatic pulmonary embolism or death at 90 days than no placement of a filter. (Funded by the Medical Research Foundation of Royal Perth Hospital and others; Australian New Zealand Clinical Trials Registry number, ACTRN12614000963628.).
Abstract 380: Tumor suppressor retinoblastoma status as a predictor of ATR inhibitor sensitivity
Authors: Caterina Mancusi, John Hartley, Sibylle Mittnacht
Journal: Cancer Research (2019)

Abstract Inhibitors of the Ataxia Telangiectasia and Rad3 related protein kinase (ATR) are increasingly entering clinical trials as single agents or in combination with inhibitors of poly (ADP-ribose) polymerases (PARPs), DNA-damaging chemotherapy or radiotherapy. However, and despite promise of broad utility and cancer selectivity, compelling results have remained an exception, underscoring the need to identify responsive patient population and tumour types. Based on in vitro testing in an extended cancer cell line panel we found that deleterious mutation of RB1 is significantly associated with hypersensitivity to multiple clinically relevant ATR inhibitors. Cancer cell lines with deleterious RB1 mutation displayed significantly enhanced cell death following ATR inhibitor treatment compared to a histotype matched cancer cell line groups with RB1 normal status and depletion of RB1 gene in RB1 normal cancer cell lines using siRNA, increased sensitivity to ATR inhibition accompanied by increased cells death. Deletion or deleterious mutation of RB1 is frequent in small cell lung cancers, cancers of neuroendocrine origin, and a considerable portion of triple negative breast and urinary tract cancers, cancers of the nervous system, sarcoma and chronic lymphatic leukemia. The data obtained document a link between RB1 status and ATR inhibitor sensitivity and argue that focus on cancer types with RB1 mutation or 13q14 involvement, where RB1 is encoded, should be considered in the design and analysis of trials involving ATR inhibitors. Citation Format: Caterina Mancusi, John Hartley, Sibylle Mittnacht. Tumor suppressor retinoblastoma status as a predictor of ATR inhibitor sensitivity [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 380.
Abstract 4305: AMPK-RUNX2-mTORC2 axis involved in EMT of MDA-MB-231 breast cancer cells
Authors: Aramati Bindu Reddy, Meher B. Gayatri, Suresh Chava
Journal: Cancer Research (2019)

Abstract Metformin is one of the most widely used biguanides for the treatment of type 2 diabetes, whose role as a potent anti-cancer drug has emerged in recent times. Its function as an anti-tumor agent is attributed to its ability to inhibit mTORC1, which is a key player in regulating cell proliferation. However, the use of metformin as an anti-cancer drug is hampered by several limitations. Hence, in order to elucidate the detailed mechanistic properties of metformin in cell growth and metastasis, we investigated the effect of metformin on mTORC2 activity in MDA-MB-231 cells. We report a novel mechanism by which metformin can increase the activity of mTORC2 in a Runx2-dependent fashion, which requires AMPK mediated stabilization of RUNX2. Furthermore, we found that mTORC2 and RUNX2 have a feed forward relation whereby the knockdown of rictor, a key component in activating mTORC2, resulted in loss of RUNX2 through GSK3-β-mediated ubiquitination of RUNX2. Since both mTORC2 and RUNX2 have been found to be involved in activating the EMT, metformin treatment may contribute to this activation by stabilizing AMPK-RUNX2-mTORC2 axis. These results demonstrate that metformin-induced mechanisms can influence metastasis even if they inhibit cell growth, but the genetic heterogeneity of the malignancy may govern cell fate. Citation Format: Aramati Bindu Reddy, Meher B. Gayatri, Suresh Chava. AMPK-RUNX2-mTORC2 axis involved in EMT of MDA-MB-231 breast cancer cells [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 4305.
The Prospects for Biodegradable Zinc in Wound Closure Applications
Authors: Jeffrey Jones D. Venezuela, Sean Johnston, Matthew Simon Dargusch
Journal: Advanced Healthcare Materials (2019)

Abstract Zinc is identified as a promising biodegradable metal along with magnesium and iron. In the last 5 years, considerable progress is made on understanding the mechanical properties, biodegradability, and biocompatibility of zinc and its alloys. A majority of these studies have focused on using zinc for absorbable cardiovascular and orthopedic device applications. However, it is likely that zinc is also suitable for other biomedical applications. In this work, the prospects for zinc in the fabrication of wound closure devices such as absorbable sutures, staples, and surgical tacks are critically assessed, with the aim of inspiring future research on biodegradable Zn for this medical application.
Abstract 4728: IFNγ signaling drives EZH2 degradation to induce MHC-II expression in melanoma
Authors: Jamaal L. James, Susan R. Opalenik, Abigail Toren, Rebecca S. Cook, Justin M. Balko
Journal: Cancer Research (2019)

Abstract Background: The molecular mechanisms governing anti-PD-1 resistance in melanoma are not fully understood. Suboptimal transcriptional and molecular response to interferon-gamma (IFNγ) is commonly identified in tumors with intrinsic or acquired resistance to anti-PD-1. Epigenetic regulators have been shown to reprogram IFNγ responses in some cases, though the mechanism is not clear. The ability of melanoma cells to express MHC-II is a positive clinical predictor to anti-PD-1 therapy, and MHC-II is induced only on cells with robust IFNγ responses. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator with both methyltransferase-dependent and -independent function, can suppress IFNγ target genes and is frequently overexpressed in melanoma. However, the mechanisms whereby EZH2 interacts with the IFNγ pathway and its role in melanoma-specific MHC-II expression is not known. Methods: HLA-DR (MHC-II)-proficient (A375, SKMEL28 and SKMEL5) and -deficient (CHL-1 and MEWO) melanoma cell lines were stimulated with IFNγ for up to 48h, and the modulation of EZH2 protein and function were studied temporally. To test the role of EZH2 in MHC-II (HLA-DR) expression in IFNγ responses, genetic (siRNA) and chemical (GSK343) EZH2 inhibition was utilized. Results: EZH2 was highly expressed in all cell lines tested, regardless of HLA-DR-proficiency. In 2 out of 3 HLA-DR-inducible melanoma cell lines, EZH2 protein expression was downregulated (4-24 hrs) in response to IFNγ stimulation, without effects on EZH2 mRNA expression or downstream tri-methylated H3K27 expression. Blocking proteosomal degradation with MG-132 reversed the IFNγ-induced decrease in EZH2 expression in HLA-DR-proficient cell lines. After siRNA knockdown of EZH2, SKMEL28 cells increased constitutive HLA-DR expression, while A375 cells became more sensitive to IFNγ-induced HLA-DR upregulation. In addition, IFNγ-induced HLA-DR was increased in A375 cells with EZH2 inhibition using GSK343. Conclusion: This work demonstrates a potential role for EZH2 in suppressing IFNγ responses, including the induction of MHC-II, in melanoma cells. EZH2 is subject to proteosomal degradation in MHC-II-inducible cell lines, which, in part, contributes to the expression of MHC-II. Citation Format: Jamaal L. James, Susan R. Opalenik, Abigail Toren, Rebecca S. Cook, Justin M. Balko. IFNγ signaling drives EZH2 degradation to induce MHC-II expression in melanoma [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 4728.
Abstract 17887: Cystein-rich Angiogenic Protein 61 Promotes Vascular Smooth Muscle Cell Calcification Via Metalloproteinase Activation
Authors: Hae-young Lee, Hyun-Joo Cho, Yeon-Yee Yoon, Byung-Hee Oh, Hyo-Soo Kim
Journal: Circulation (2012)

Cystein-rich angiogenic protein 61 (CYR61, CCN1) was reported to be regulated by angiotensin II in vascular smooth muscle cells (SMCs) of Cystein-rich angiogenic protein 61 (CYR61, CCN1) was report...
Abstract 138: TNBC induces immune suppressive tumor microenvironments through microRNAs
Authors: Beichu Guo, Melvin Kantono, Wei Sun
Journal: Cancer Research (2019)

Abstract Metastatic breast cancer is the second leading cause of cancer-related deaths for US women. The triple negative breast cancer subtype (TNBC) is one of the major contributors to breast cancer mortality, among all types of breast cancer. There are no effective treatments available for metastatic tumors. Therefore, identifying and targeting novel tumorigenesis pathways will facilitate developing effective therapeutic approaches that could ultimately lead to effective treatment for breast cancer, particularly metastatic cancer and TNBC. Our results demonstrate that miR-146a promotes tumorigenesis and metastasis of breast cancer. We found that miR-146a was markedly overexpressed in TNBC cell lines. Notably, miR-146a deficiency in a spontaneous mammary tumor model leads to reduced tumor growth and metastasis. Notably, miR-146a shifts the polarization of macrophages into immunosuppressive phenotypes. Our studies suggest that miR-146a may contribute to tumor development through modulation of tumor microenvironments. Note: This abstract was not presented at the meeting. Citation Format: Beichu Guo, Melvin Kantono, Wei Sun. TNBC induces immune suppressive tumor microenvironments through microRNAs [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 138.
Cholangioscopy-guided lithotripsy for difficult bile duct stone clearance in a single session of ERCP: results from a large multinational registry demonstrate high success rates
Authors: Amit P. Maydeo, Rungsun Rerknimitr, James Y. Lau, Abdulrahman Aljebreen, Saad K. Niaz, Takao Itoi, Tiing Leong Ang, Jörg Reichenberger, Dong Wan Seo, Mohan K. Ramchandani, Benedict M. Devereaux, Jong Kyun Lee, Mahesh K. Goenka, Randhir Sud, Nam Q. Nguyen, Rakesh Kochhar, Joyce Peetermans, Pooja G. Goswamy, Matthew Rousseau, Surya Prakash Bhandari, Phonthep Angsuwatcharakon, Raymond S. Y. Tang, Anthony Y. B. Teoh, Majid Almadi, Yun Nah Lee, Jong Ho Moon
Journal: Endoscopy (2019)

Abstract Background Peroral cholangioscopy (POCS) can be useful for difficult bile duct stone clearance. Large prospective multinational data on POCS-guided lithotripsy for clearing difficult bile duct stones in a single session of endoscopic retrograde cholangiopancreatography (ERCP) are missing. Methods Patients with difficult bile duct stones (defined as one or more of: largest stone diameter ≥ 15 mm, failed prior attempt at stone clearance, impacted, multiple, hepatic duct location, or located above a stricture) were enrolled at 17 centers in 10 countries. The principal endpoint was stone clearance in a single ERCP procedure using POCS. Results 156 patients underwent 174 sessions of POCS-guided electrohydraulic or laser lithotripsy. Stone clearance had failed in a previous ERCP using traditional techniques in 124/156 patients (80 %), while 32 /156 patients (21 %) were referred directly to POCS-guided therapy based on preprocedural assessment of the difficulty of stone clearance. In 101/156 patients (65 %), there were impacted stones. POCS-guided stone clearance was achieved in a single POCS procedure in 125 /156 patients (80 %, 95 % confidence interval [CI] 73 % – 86 %), and was significantly more likely for stones ≤ 30 mm compared with &gt; 30 mm (odds ratio 7.9, 95 %CI 2.4 – 26.2; P = 0.002). Serious adverse events occurred in 3/156 patients (1.9 %, 95 %CI 0.4 % – 5.5 %), and included pancreatitis, perforation due to laser lithotripsy, and cholangitis (n = 1 each), all resolved within 1 week. Conclusion POCS-guided lithotripsy is highly effective for clearance of difficult bile duct stones in a single procedure and successfully salvages most prior treatment failures. It may also be considered first-line therapy for patients with difficult choledocholithiasis to avoid serial procedures.
Abstract 18322: The Impact of Obesity on Survival in Fontan Conversion Patients
Authors: Lindsay R Freud, Gregory Webster, Sabrina Tsao, Barbara J Deal
Journal: Circulation (2013)

Introduction: The negative cardiovascular effects of obesity are well described in adult patients. By increasing both pulmonary and systemic vascular resistance, we hypothesized that obesity would be particularly deleterious in the setting of single ventricle physiology. Our aim was to assess the impact of obesity on mid-term survival in patients following Fontan conversion to extracardiac total cavopulmonary connections. Methods: We analyzed the pre-operative body mass index (BMI) of consecutive patients undergoing Fontan conversion at our institution from 1994-2012. Raw BMI values were converted to standardized percentiles and Z-scores to enable comparison to published norms. Overweight and obese were defined as BMI &gt;85%ile and &gt;95%ile for patients &lt;20 years, and BMI 25-30 kg/m 2 and ≥30 kg/m 2 for patients ≥20 years. Transplant-free survival at most recent follow-up was assessed with Kaplan-Meier analyses. Results: We evaluated 139 patients with a median age of 24.1 years (3-47) at the time of Fontan conversion surgery. In 49 patients &lt;20 years of age, mean BMI was significantly lower compared to the normal population with a Z-score of -0.5 (p-value 0.02). In the 90 patients ≥20 years, mean BMI was significantly elevated with a Z-score of +0.4 (p-value &lt;0.001). The prevalence of overweight or obese patients rose from 29% among patients &lt;20 years to 40% among those ≥20 years. At median follow-up of 7.6 years following surgery (age 31.8 years), obese patients had significantly lower transplant free-survival compared to non-obese patients (p-value 0.006; see figure). Conclusion: During mid-term follow-up of patients following Fontan conversion, obesity is associated with significantly shorter transplant-free survival. While this study is retrospective, it offers a strong negative association between obesity and mortality in single ventricle survivors and underscores the importance of weight management in these patients.