tbuckley/cabot-search huggingface dataset:
Abstract KP03: NOVEL IMMUNOTHERAPEUTICS FOR OVARIAN CANCER
Authors: Mary L. Disis
Journal: Clinical Cancer Research (2017)

Abstract In the last decade we have seen significance advances in the understanding of how the immune system modulates the ovarian tumor microenvironment and cancer growth. A number of studies have shown that high levels of tumor infiltrating adaptive immune system cells (B-cells and T-cells) found in ovarian cancer are associated with a favorable prognosis, especially if there is evidence of reduced regulatory T-cells. Robust T-cell tumor infiltration (TIL) is associated with PD-L1 upregulation. Almost half of ovarian cancers demonstrate enhanced PD-L1 expression on tumor cells and/or tumor infiltrating immune system cells. Immune checkpoint inhibitor monoclonal antibodies block receptors such as PD-1 and PD-L1 which suppress T-cell function. The largest study of immune checkpoint inhibition in ovarian cancer evaluated the blockade of PD-L1 using avelumab. In this phase I/II study 124 patients with recurrent disease, considered chemotherapy refractory, were treated with 10mg/kg avelumab every 2 weeks (65% of patients with 3 or greater salvage regimens). The overall response rate was 10% with a stable disease rate of 44% resulting in a disease control rate of 54%. Overall survival at 12 months was 44%. Clinical response did not correlate with either PDL-1 expression on tumor or immune infiltrating cells or BRCA mutation status. A randomized trial of avelumab in combination with pegylated liposomal doxorubicin in cisplatin refractory ovarian cancer has been initiated. Pre-clinical studies have shown that clinical responses to immune checkpoint inhibitor therapy in ovarian cancer may be enhanced by increasing Type I T-cell infiltration concurrent with therapy. Clinical strategies aimed at increasing TIL include the use of vaccines immunizing against ovarian cancer antigens to stimulate T-cells trafficking to tumor. Specific chemotherapy may result in increased TIL as some cytotoxic agents have been shown to modulate both the level and phenotype of TIL in ovarian cancer. An alternate approach is to suppress alternate pathways of tumor immune escape such as depletion of macrophage or inhibition of the IDO pathway to enhance immune activation. Several promising combination immunotherapy strategies are currently being evaluated in ovarian cancer. Citation Format: Mary L. Disis, MD. NOVEL IMMUNOTHERAPEUTICS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP03.
Abstract 335: Activation of BKCa Channels With Rottlerin Greatly Improves Cardiac Functional Improvement Following Surgical Ischemia Associated With Cardioplegic Arrest.
Authors: Richard T Clements, Brenda Cordeiro
Journal: Circulation Research (2013)

Introduction: BKCa channels are thought to provide protection during ischemic insults in the heart. Rottlerin, has been implicated as a potent BKCa activator, however this has not been firmly established. The purpose of this study was two fold: 1) assess the specificity of rottlerin for BKCa channels and 2) investigate the efficacy of BKCa channel activation as a cardioprotective agent during cardioplegia/reperfusion (CP/R). Methods: Wild type and BKCa knock-out mice with and without rottlerin (only administered in CP) were subjected to an isolated heart model of CP/R. Hearts were perfused for 30 min at 37C (baseline), followed by intermittent cold crystalloid cardioplegia (intermittent St Thomas II, 10C), and normothermic, normoxic, reperfusion for 30 min. In additional studies, mechanism of rottlerin-induced cardioprotection was investigated using H9c2 cells subjected to in vitro CP/reoxygenation and assessed for mitochondrial membrane potential (TMRE) and ROS (DCFDA) production. Results: CP and 30 min reperfusion decreased LVDP (58.7 +/- 5 % baseline, n=8 ), +/- dP/dt ( 71.1+/- 6.4, 59.2 +/-6.6, % baseline respectively) and coronary flow (CF) (66.8+/-7.4, %baseline) in wild type mice. Rottlerin, (100 (n=3), 500 nM (n=5)) delivered in the CP solution dose dependently increased the recovery of LV function and CF to near baseline levels (500 nM rottlerin, LVDP: 94.1+/- 2.3, +/-dPdt: 99.6 +/- 7.2, 111.0+/- 15.0, % baseline, and CF: 128.9 +/-30.0 %baseline ). BKCa KO hearts treated with (n=4)or without (n=3) 500nM rottlerin, were similar to wt CP hearts, showing no improved cardioprotection (BKCa KO + 500 nM rott: LVDP: 57.7+/- 4.0, +/-dP/dt 69.5 +/-12.0, 59.8+/- 4.9, and CF 73 +/- 6.7). H9c2 cells subjected to in vitro CP/R, displayed reduced mitochondrial membrane potential (39% +/-.09 % decrease relative to control, p&lt;.01) and increased ROS generation (50%+/-.04 increase, p&lt;.01), both of which were dose dependently normalized by rottlerin (100 nM-1 uM) (minimum n=8). Conclusions: Activation of BKCa channels profoundly rescues ischemic damage associated with CP, likely via mitochondrial effects on improved mitochondrial membrane potential and reduced ROS generation.
The Big Bang
Authors: Geoffrey Rubin
Journal: JAMA Cardiology (2017)

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 Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Cardiology journal
Abstract 334: Complementary Atherosclerosis Prophylaxis in Patients After Coronary Bypass Surgery
Authors: Günter Siegel, Karl Winkler, Martin Malmsten, Annette Schmidt, Elke Zimmermann, Eugeny Ermilov, Sören Just
Journal: Circulation Research (2012)

Background and purpose: Atherosclerotic coronary arteries can be well-treated with innovative medicaments, through PCI or by aortocoronary bypasses. Some of the stents and bypasses close again in spite of blood-thinning. We examined in a clinical pilot study of 8 patients who had undergone a CABG operation whether atherosclerosis prophylaxis can be practised through an additional phytochemical approach with ginkgo (EGb 761, 2 × 120 mg/d). Furthermore, our trial aimed to inquire whether the bypasses remain open. Methods: As a biomarker for plaque development, atherosclerotic nanoplaque formation and size were monitored by laser ellipsometry (patent EP 0 946 876). Lipoproteins, cytosolic SOD, oxLDL, and [cAMP] and [cGMP] were determined by established methods. Results: After 2-month medication, the decrease in nanoplaque formation amounted to 11.9 ± 2.5% (p &lt; 0.01) and in nanoplaque size to 24.4 ± 8.1% (p &lt; 0.02), after 5 years 25.0 ± 3.7% (p &lt; 0.01) and 45.8 ± 9.5% (p &lt; 0.01), respectively. A multiple correlation between nanoplaque reduction and the risk factors oxLDL/LDL, Lp(a) and cGMP yielded an estimate of their relative contribution to nanoplaque diminution (34.7%, 43.3%, 22.0%). In the 5 year follow-up examination using high-resolution CT, all arterial and 86.7% of the venous bypasses were open, whereby the increase in blood nucleotides seemed to have played a prominent role. Conclusion: Ginkgo may be used as complementary drug with potentially preventive character after coronary-artery bypass graft.
Signal transduction pathways in non-small cell lung cancer: Characterization of adenocarcinoma and squamous cell carcinoma histologic subtypes
Authors: C. Denise Ching, Valerie Calvert, Emanuel Petricoin, Lance Liotta, Mary Beth Moore, David Harpole, H. Kim Lyerly
Journal: Cancer Research (2004)

1155  Protein functions are intertwined with their cellular, tissue and physiologic context. They exist in a continuous flux of expression levels and activity, forming interconnecting circuits of protein-protein interactions occurring both inside and outside cells. Proteins provide packets of information through binding partner modifications such as phosphorylation, cleavage or changes in conformation. Phosphorylation plays an integral role in regulating protein function, controlling many cellular processes including metabolism, transcription, cell cycle progression, cell movement, apoptosis and differentiation. Cancer is a reflection of dysregulation of these intercellular communications, with defective or hyperactive signal pathways resulting from genetic defects being selected for during carcinogenesis. Reverse phase protein microarrays present an ideal opportunity for real time analysis of the information flow through the protein network by comparing the relative abundance of total (activated and non-activated) protein versus phosphorylated (activated) protein. Characterizing and profiling levels of activation of protein pathways in normal states, and then understanding how these pathways are deranged under the influence of disease processes, can in turn provide targets for therapeutic drug discovery. To further elucidate the pathways dysregulated in non-small cell lung cancer (NSCLC) we performed laser capture microdissection to obtain pure populations of tumor cells from 6 human specimens of NSCLC (3 adenocarcinoma/3 squamous cell carcinoma) collected at Duke University Medical Center. Approximately 12,000 microdissected cells were lysed in 30 μL. 100 nL of each lysate was arrayed onto nitrocellulose-coated glass slides to create reverse phase microarrays to study the expression and phosphorylation of dozens of signaling pathways, including growth factor receptor signaling, TGF-β receptor signaling, T cell receptor signaling, cell survival and apoptosis control. Preliminary results reveal signaling seen in key phospho-specific endpoints such as ERK, ERB2, p38, GSK3β, PDGF, Caspases, BAD, STAT1, EGFR and NFKB. These data will ultimately be correlated with tumor type and patient outcome. This pilot study reports preliminary findings of a study set that will include 50 adenocarcinoma and 50 squamous cell lung cancer samples. Carcinogenesis is a complex succession of events that occurs over decades; a unique combination of mutations individual to each patient. Our ability to identify and characterize signal transduction pathway derangements through protein microarrays represents a potential to personalize cancer treatment, opening the doorway for new combinatorial or targeted therapies. The impact this could have in treating NSCLC, a disease with dismal 5-year survival rates, is of unquestionable value.
Physician Speech and Firearm Safety
Authors: Theodore T. Lee, Gregory D. Curfman
Journal: JAMA Internal Medicine (2017)

To provide the highest-quality medical care, physicians must be able to communicate openly with their patients and provide advice in conformance with professional standards of care. Although states have the power to regulate many aspects of medical practice, laws that interfere with speech by preventing physicians from discussing specific subjects with patients are constitutionally suspect. In 2017, the US Court of Appeals for the Eleventh Circuit struck down key provisions of a Florida law that prohibited physicians from speaking with their patients about firearm safety as a violation of the First Amendment. We discuss this case, Wollschlaeger v Governor, Florida, and the implications of the ruling. Although courts may rule that physician "gag laws," such as the one in Florida, are unconstitutional, this area of the law remains unsettled. Legislative mandates that interfere with medical practice may decrease the quality of care by substituting politics and legislative judgment for medical expertise.
The challenge of defining exacerbation in bronchiectasis
Authors: Miguel Ángel Martínez-García, Luis Máiz-Carro
Journal: European Respiratory Journal (2017)

One of the most difficult aspects of the study of chronic respiratory diseases is the concept of exacerbation. Defining the limits of each patient's normal daily variations in symptoms, and the minimum time beyond these limits that can be considered the start of an acute process of the disease, poses a challenge that is often insuperable. It is also just as difficult to establish the specific parameters that must be used to define an exacerbation; parameters that are usually grouped as symptoms and/or factors involving the use of health resources or a need for treatment. Nevertheless, in the case of bronchiectasis, and other respiratory diseases, exacerbations (particularly severe exacerbations) have a demonstrable negative impact on a patient's prognosis [1–4] and entail great expense [5, 6], and so their identification, and therefore their definition, is crucial to any early detection and treatment. Ideally, such a definition should present a perfect diagnostic value and, as regards bronchiectasis, be based on reproducible objective measurements linked to inflammation/bronchial infection (biomarkers) and their consequences (acute clinical symptoms). At the moment, however, this approach is not viable for various reasons: we do not have any available biomarkers with sufficient diagnostic value, although there have been some promising studies in this respect [7]; we do not have any sufficiently specific objective measurements for the key symptoms in exacerbations; and, finally, we need to know a patient's previous inflammatory/infectious state in order to quantify the change caused by the supposed exacerbation. Furthermore, there is a significant problem here as a review of the literature reveals a wide range of definitions of bronchiectasis, depending on the studies analysed and the mixture of objective and subjective criteria, making it impossible to compare their results. A worldwide consensus has been reached in the definition of exacerbation in bronchiectasis for research purposes <http://ow.ly/SD2P30bFBjX>
Dual-imaging assessment of ultrasonography and mammography in nipple discharge patients: A cohort study.
Authors: Bo Li, Yihe Yang
Journal: Journal of Clinical Oncology (2017)

e12079 Background: Nipple discharge (ND) is a common complaint of women. There is no consensus on clinical approach in these patients. We investigated the diagnostic ability of combination of ultrasound (US) and mammogram (MG) in Chinese ND patients without palpable mass. Methods: 827 patients with ND as only chief complaint presented in the First Hospital of China Medical University (Shenyang, China) between 2008 and 2015 were included. Palpable mass, physiological NP and/or elevated PRL were excluded. All patients underwent dual-imaging examinations of US and MG. Indication of surgical excision included 1) BI-RADS categories 4b, 4c, 5 in either US or MG, and/or 2) US suspected papilloma. Patients met surgical indications served as study arm (N = 742). Patients did not meet surgical indications but underwent surgery served as control arm (N = 85). Reason of surgery in the control group were patients’ choices and surgeons’ clinical judgment. Histological diagnosis provided by surgery were analyzed. In our institution, breast cancer, papilloma, and/or papilloma with atypical dysplasia were regarded as histological indication of surgery. Chi-square tests were applied. Results: Histology revealed 88 (11.9%) breast cancer in the study arm and 0 breast cancer in the control arm ( p= 0.0008); 167 (22.5%) papilloma with atypical dysplasia in the study arm and 12 (13.6%) papilloma with atypical dysplasia in the control arm ( p= 0.08); 335 (45.1%) papilloma without atypical dysplasia in the study arm and 27 (30.7%) papilloma without atypical dysplasia in the control arm ( p= 0.02). A total of 590 (79.5%) in the study arm and 39 (44.3%) in the control arm met histological indication of surgical intervention ( p&lt; 0.00001). Conclusions: This dual-imaging assessment of US and MG is sensitive in detecting breast cancer in ND without palpable mass patients. It showed diagnostic ability in detecting papilloma with/without atypical dysplasia, but needs further improvement.
Development and validation of the HCV-MOSAIC risk score to assist testing for acute hepatitis C virus (HCV) infection in HIV-infected men who have sex with men (MSM)
Authors: Astrid M Newsum, Ineke G Stolte, Jan TM van der Meer, Janke Schinkel, Marc van der Valk, Joost W Vanhommerig, Anne Buvé, Mark Danta, Arjan Hogewoning, Maria Prins
Journal: Eurosurveillance (2017)

Current guidelines recommend hepatitis C virus (HCV) testing for HIV-infected men who have sex with men (MSM) with ongoing risk behaviour, without specifying the type of risk behaviour. We developed and validated the HCV-MOSAIC risk score to assist HCV testing in HIV-infected MSM. The risk score consisted of six self-reported risk factors identified using multivariable logistic regression using data from the Dutch MOSAIC study (n = 213, 2009–2013). Area under the ROC curve (AUC), sensitivity, specificity, post-test-probability-of-disease and diagnostic gain were calculated. The risk score was validated in case–control studies from Belgium (n = 142, 2010–2013) and the United Kingdom (n = 190, 2003–2005) and in cross-sectional surveys at a Dutch sexually transmitted infections clinic (n = 284, 2007–2009). The AUC was 0.82; sensitivity 78.0% and specificity 78.6%. In the validation studies sensitivity ranged from 73.1% to 100% and specificity from 56.2% to 65.6%. The post-test-probability-of-disease ranged from 5.9% to 20.0% given acute HCV prevalence of 1.7% to 6.4%, yielding a diagnostic gain of 4.2% to 13.6%. The HCV-MOSAIC risk score can successfully identify HIV-infected MSM at risk for acute HCV infection. It could be a promising tool to improve HCV testing strategies in various settings.
Development of an in vivo TEM-1 PET test for clinical screening applications.
Authors: Sara ES Lange, Alexander Zheleznyak, Matthew Studer, Daniel John O'Shannessy, Suzanne E Lapi, Brian Andrew Van Tine
Journal: Journal of Clinical Oncology (2015)

e21511 Background: Soft tissue sarcomas (STS) encompass over 50 subtypes, each with independent biology and tumor heterogeneity. The complexity of the treatment of STS has led to the need for in vivo clinical biomarker tests that can be used prior to patient selection and during therapy. Tumor endothelial marker-1 (endosialin, TEM-1) is a cell surface marker expressed by tumor cells, stroma, and vessels. Currently MORAb-004 (Ontuxizumab), an anti-TEM-1 humanized monoclonal antibody, is in clinical trials in STS. Development of a positron emission tomography (PET) imaging technique for clinical in vivo TEM-1 expression may allow for stratification of patients into high- and low-expressing TEM-1 tumors and enhance clinical outcomes seen with Ontuxizumab. Methods: A panel of 12 cell lines were characterized for high and null TEM-1 expression via immunohistochemistry and fluorescence-activated cell sorting. Cell lines with high and null TEM-1 expression were xenografted into mice. Ontuxizumab was labeled with 89Zr, evaluated for immuno-reactivity preservation, and injected into murine models. In vivo PET experiments were performed to demonstrate clinical utility of Ontuxizumab. Results: Characterization of 12 established cell lines revealed clear differences in TEM-1 expression. One high expressing (RD-ES) and one null expressing (LUPI) Ewing’s cell line were xenografted and assessed with 89Zr-labeled Ontuxizumab. PET imaging post-injection at days 3, 5, and 6 revealed that TEM-1 was highly expressed and detectable in vivo in RD-ES xenografts while LUPI xenografts displayed lack of expression and lower radiopharmaceutical uptake. Background PET activity was minimal, observed only in clearance organs. In vivo biodistribution studies confirmed high radiopharmaceutical uptake in tumor relative to normal organs. Conclusions: Expression of TEM-1 has been established in many types of sarcoma. Identification of high and null expressing lines allowed for successful in vivo experiments using radiolabeled anti-TEM1 antibody, Ontuxizumab. Clinically reliable PET imaging of tumor associated TEM-1 in patients may allow for stratification of patients into cohorts that will attain the greatest benefit from anti-TEM-1 therapy.
Abstract TMEM-022: LYSOPHOSPHATIDIC ACID IN OVARIAN CANCER EPITHELIAL–TO–MESENCHYMAL TRANSITION
Authors: Vermont P Dia
Journal: Clinical Cancer Research (2017)

Abstract Lysophosphatidic acid (LPA) is a bioactive phospholipid found in elevated concentrations in ovarian cancer (OVCA) patients. The objective of this study was to define the mechanism of action by which LPA contributes to ovarian carcinogenesis focusing on epithelial-to-mesenchymal transition (EMT) and role of human macrophages. THP-1 human macrophages and A27801AP human OVCA cells were used and treated with LPA up to 40 µM for 24 h. In THP-1 human macrophages, LPA treatment led to a dose-dependent increase in IL-1β secretion from 333.5 pg/mL (untreated) to 581.9, 661.8 and 1270.1 pg/mL for 10, 20 and 40 µM LPA treatment. We then used the conditioned medium (CM) from THP-1 macrophages to determine the effect on A27801AP OVCA cells. LPA-treated THP-1 CM increased the expression of EMT transcription factors p65, Slug and Snail as compared to non-LPA-treated THP-1 CM and resting OVCA cells. When A27801AP OVCA cells were treated with LPA alone, 20 µM LPA led to the same significant increase in the expression of EMT transcription factors p65, Slug and Snail. In addition, LPA treatment reduced the expression of the epithelial marker E-cadherin while increasing the expression of mesenchymal markers N-cadherin and vimentin which might be associated with increased phosphorylation of extracellular regulated kinase 1/2. The data show the role of LPA in modifying not only OVCA cells but also macrophages that can be found in the tumor microenvironment to promote progression of OVCA by promoting EMT. Citation Format: Vermont P Dia, Ph D. LYSOPHOSPHATIDIC ACID IN OVARIAN CANCER EPITHELIAL–TO–MESENCHYMAL TRANSITION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-022.