tbuckley/cabot-search huggingface dataset:
Quantitative Measurements of Cardiac Phosphorus Metabolites in Coronary Artery Disease by 31P Magnetic Resonance Spectroscopy
Authors: TakahiroYabe, KenichiMitsunami, ToshiroInubushi, MasahikoKinoshita
Journal: Circulation (1995)

Background 31P metabolite measurements in the human heart by magnetic resonance spectroscopy (MRS) have been reported previously. By use of a method in which metabolite content was quantified with reference to a standard located outside the chest, it has become possible to measure the content of phosphocreatine (PCr) and ATP in vivo in the human heart. In this study, PCr and ATP contents were measured by 31P MRS and compared in human myocardium with reversible ischemia or scar diagnosed by exercise thallium scintigraphy. Methods and Results Forty-one subjects with stenosis of the left anterior descending coronary artery (>50%) and 11 healthy control subjects (C) composed the present study group. Patients were divided into two groups on the basis of exercise 201Tl scintigraphy: a reversible 201Tl defect group (RD[+], n=29) who demonstrated redistribution at late image and a fixed 201Tl defect group (RD[−], n=12). While the subjects lay supine within the magnet, 31P MR spectra were obtained from the anterio...
SAT0687 Silicone breast implants and the risk of autoimmune diseases: real world analysis
Authors: A. Watad, V. Rosenberg, S. Tiosano, J.W. Cohen Tervaert, Y. Yavne, Y. Shoenfeld, V. Shalev, G. Chodick, H. Amital
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Previous reports have suggested an association between silicone breast implants (SBIs) and connective tissue disorders. However, several epidemiological studies have produced inconsistent results. <h3>Objectives</h3> To evaluate the association between SBIs and the most clinically relevant auto-immune diseases (ADs) using a large, population based database. <h3>Methods</h3> In this cross-sectional study, we used the computerised databases of Maccabi Healthcare Services (MHS) which include up to 20 years of data on 2 million members. Women with SBIs were identified by procedure and diagnosis codes, clinical breast examinations and mammography referrals. ADs were identified using the International Classification of Diseases 9th revision (ICD-9) codes. SBIs-free women were matched by age group and socio-economic status (SES) in a ratio of 1:4. Multivariable logistic regression and Cox's proportional hazards models were performed. <h3>Results</h3> We included 24,651 SBI recipients and 98 604 matched SBIs free women in our study. The association between SBIs and AD was significant (p<i>&lt;</i>0.05) (adjusted OR 1.21, 95% CI 1.17–1.26). The strongest association with SBIs (OR &gt;1.5, p&lt;0.001) was recorded for systemic sclerosis (SSc) and sarcoidosis (OR of 1.99 and 1.67, respectively). Similar results were calculated when analysis was limited to cancer free women. Multivariable Cox regression model yielded a HR of 1.45 (95% CI 1.21–1.73) for being diagnosed with at least one AD in women with SBI compared to those without. <h3>Conclusions</h3> SBIs seems to be associated with higher likelihood of auto-immune disease diagnosis. <h3>Acknowledgements</h3> None <h3>Disclosure of Interest</h3> None declared
Abstract 17159: Targeting Acute Post-Infarct Inflammation with 11C-Methioinine or 18F-Deoxyglucose Positron Emission Tomography in Mice
Authors: James T Thackeray, Yong Wang, Jens P Bankstahl, Kai C Wollert, Frank M Bengel
Journal: Circulation (2014)

Inflammation of the tissue microenvironment after myocardial infarction (MI) influences subsequent healing/remodeling and has emerged as a target for molecular therapy and imaging. 18F-Deoxyglucose...
Mitigating the Risks of Medicaid Work Requirements
Authors: John Z. Ayanian, Renuka Tipirneni, Susan D. Goold
Journal: New England Journal of Medicine (2018)

Work requirements represent uncharted territory for Medicaid enrollees and their doctors. The effects on health will depend on how well the requirements focus on enrollees who are healthy and able to work and whether effective work-related training and support are implemented.
Abstract 19679: Is Major Bleeding Risk for Oral Anticoagulants Similar Among Newly Initiated Non Valvular Atrial Fibrillation Patients?
Authors: Gregory Y Lip, Xianying Pan, Shital Kamble, Hugh Kawabata, Jack Mardekian, Cristina Masseria, Amanda Bruno, Phatak Hemant
Journal: Circulation (2015)

Aim: The purpose of this study was to compare the risk of first major inpatient/outpatient bleeding event among non valvular atrial fibrillation (NVAF) patients newly initiated with warfarin versus non-vitamin K antagonist oral anticoagulants (NOACs) including apixaban, dabigatran, or rivaroxaban. Methods: Retrospective cohort study was conducted using MarketScan® database from 01/2012 to 12/2013. NVAF patients 18+ years with ≥1 year baseline period were included if they were newly prescribed an oral anticoagulant from 01/01/ 2013 to 12/31/2013. Major bleeding on anticoagulant was defined as inpatients and/or outpatient bleeding on the index drug during the supply duration or within 30 days after the last supply day of the last prescription. A Cox proportional hazards model was used to estimate the hazard ratios (HR) of major bleeding adjusted for age, sex, baseline comorbidities, and comedications. Results: Among 29,338 NVAF patients newly initiated on an oral anticoagulant, 2,402 (8.19%) were on apixaban, 4,173 (14.22%) on dabigatran, 10,050 (34.26%) on rivaroxaban and 12,713 (43.33%) on warfarin. Patients initiating warfarin (72.5±11.9 yrs) and apixaban (69.3±12.3 yrs) were older as compared to rivaroxaban (67.3±12.2 yrs) and dabigatran (66.8±12.1 yrs). Patients initiating warfarin were higher risk as compared to those initiating NOACs in terms of CHA 2 DS 2- VASc score (3.22±1.65) and higher Charlson comorbidity index (CCI) score of 2.37±2.33 (p &lt;0.0001 across all treatments). After adjusting for baseline characteristics, as compared to patients newly initiated on warfarin, patients newly initiated on apixaban or dabigatran had significantly lower risk of major bleeding (Table). Conclusion: Among newly anticoagulated NVAF patients in the real world setting, initiation with apixaban or dabigatran was associated with significantly lower risk of major bleeding compared to initiation on warfarin.
Abstract 4072: Direct transdifferentiation of glioblastoma cells to antigen-presenting cells: A novel immunotherapeutic approach
Authors: Mathew Sebastian, Son B. Le, Changwang Deng, Nagheme Thomas, David D. Tran
Journal: Cancer Research (2018)

Abstract Cell-based immunotherapy has shown encouraging results in solid cancers. However, major limitations of this approach include difficulty with isolation and generation of effective antigen-presenting or immune effector cells and the high cost of cell-based vaccines. In glioblastoma (GBM), the most common and lethal brain cancer in adults, inadequate migration of immune cells across the blood-brain barrier represents another major obstacle to cell-based immunotherapy. One approach to overcome these barriers is to convert GBM cells directly into immune cells of interest. Transdifferentiation, the transformation of one cell type other than stem cells directly into another cell type without an intermediate pluripotent stage, has shown early promise in regenerative medicine, but has had a limited role as a cancer therapy, especially for solid tumors. This is in large part due to the laborious and time-consuming process of identifying master fate determinants of the cell types of interest in the transdifferentiation. To enable this novel application, we have developed and experimentally validated two tandem computational platforms, GeneRep and nSCORE. Applying this novel algorithm to large quantities of published and in-house gene expression datasets, we successfully predicted cell fate determinants of tens of different cell types with several having been validated in transdifferentiation experiments by others and us, such as the conversions of astrocytes to neuronal stem cells, of astrocytes to glioma stem-like cells, of fibroblasts to macrophages, etc. Here, we describe the process of combining a unique core set of hematopoietic stem cell, myeloid, and macrophage or dendritic cell (DC) fate determinants—some have not been described as critical in these cell fates—as predicted and highly ranked by GeneRep-nSCORE to efficiently transdifferentiate GBM cells into functional macrophages or dendritic cells, respectively, while neutralizing their malignant phenotype. This novel transdifferentiation has the potential for transformative impacts in many areas, including DC vaccine immunotherapy and cancer therapy in general, and pioneers the concept that solid tumor cells can be converted into another cell type, and not just any cell type, but one that potentially can elicit a therapeutic response against itself. Citation Format: Mathew Sebastian, Son B. Le, Changwang Deng, Nagheme Thomas, David D. Tran. Direct transdifferentiation of glioblastoma cells to antigen-presenting cells: A novel immunotherapeutic approach [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 4072.
Abstract B37: Prevention of epithelial ovarian cancer by eliciting P4/RIPK1-dependent necroptosis
Authors: Benjamin Bitler, Tomomi Yamamoto, Elise Bales, Zachary Watson, Kian Behbakht, Joshua Johnson
Journal: Clinical Cancer Research (2018)

Abstract High-grade serous epithelial ovarian cancer (HGSOC) is the deadliest gynecologic disease, commonly diagnosed in peri/postmenopausal women. Annually, HGSOC accounts for over 140,000 deaths worldwide. Because we lack effective early detection methods, over 75% of HGSOC are diagnosed at stages III/IV, with abysmal 5-year survival rates of 37/25%, respectively. Recently, progesterone (P4) was observed to promote the elimination of p53-null cells from the fallopian tube by inducing necroptosis, a regulatable form of non-apoptotic cell death. Activation of necroptosis depends on activation of receptor-interacting kinase proteins 1 and 3 (RIPK1 and RIPK3). Several additional factors suggest that P4 may have a key protective role versus HGSOC; protection versus tumorigenesis is reduced at the time of menopause due to decreasing P4 levels. Several studies examining the use of a synthetic progesterone (medroxyprogesterone acetate, MPA) observed decreases in the incidence of HGSOC. Also, MPA had a significant clinical benefit in 20-40% of pretreated ovarian cancer patients. Further, 75% of HGSOC have decreased expression of progesterone receptor (PGR). With lower P4 at menopause, p53 mutated fallopian tube epithelial cells may therefore escape necroptosis and progress to HGSOC. All of the above information led to our hypothesis that activating P4 signaling will induce necroptosis in HGSOC tumor cells. Examining The Cancer Genome Atlas (TCGA) database for regulators of necroptosis, we found that increased expression of the P4 receptor (PGR), necroptosis effectors TNFα, and RIPK1/3 corresponded to significantly higher overall survival in 484 HGSOC cases. Using OVSAHO (BRCA2-deleted) cells, we show that P4 and/or TNFα treatment increases TNFα, RIPK1, and RIPK3 expression. In OVSAHO cells, we observed a significant decrease in cell number following treatment with P4 and/or TNFα. Also, we confirmed that P4 treatment was able to induce a necroptotic response distinct from classical apoptosis. Upon examination of normal fallopian tube tissue, borderline tumors, and advanced HGSOC, we detected expression of necroptosis effectors RIPK1 and 3, suggesting an intact necroptosis pathway. These observations point towards an HGSOC prevention strategy that favors the elimination of “founder” cells by activating necroptosis downstream of P4. These data may be particularly useful for the management of BRCA1/2 mutant patients, as these women experience menopause significantly earlier than noncarriers. Citation Format: Benjamin Bitler, Tomomi Yamamoto, Elise Bales, Zachary Watson, Kian Behbakht, Joshua Johnson. Prevention of epithelial ovarian cancer by eliciting P4/RIPK1-dependent necroptosis. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B37.
Abstract LB-019: Empowering preclinical studies: A systematic and quantitative analysis of biodistribution methods to facilitate clinical translation of new drugs
Authors: Sara Nizzero, Feng Li, Alessandro Venuta, Guodong Zhang, Carlotta Borsoi, Joy Wolfram, Junhua Mai, Haifa Shen, Zheng Li, Elvin Blanco, Mauro Ferrari
Journal: Cancer Research (2018)

Abstract Biodistribution detection methods currently hold a central role in evaluating clinical potential of new drugs and nanomedicine in vivo, either through therapeutic efficacy or toxicity assays. However, the explorative nature of these methods makes it practically difficult to validate them for clinical studies to comply with regulations as determined by the Food and Drug Administration. This work proposes a new systematic comparison of biodistribution methods to facilitate clinical validation and employment in pre-clinical and early stage clinical studies. Several optical methods (detection through IVIS, confocal microscopy, fluorescence emission), direct detection methods (detection through ICP-OES), and radiation-based methods (detection through gamma counter) are systematically tested and validated on cGMP grade microparticles. The classification here proposed quantitatively highlights the advantages and disadvantages of each method, expressing them in terms of: limit of detection, recovery rate, reproducibility, and sensitivity. As a result, this quantitative evaluation of several preclinical biodistribution detection methods leads to a new rational and objective classification of biodistribution methods based on quantitative characteristics, which is essential to facilitate clinical translation of pre-clinical data collection. Their different characteristics and application-specific advantages are also discussed based in light of the results presented. Overall, this work proposes a new and rational quantitative comparison of biodistribution detection methods with the goal to provide a guide to facilitate clinical translation of on-going and future pre-clinical and early-stage clinical studies. Citation Format: Sara Nizzero, Feng Li, Alessandro Venuta, Guodong Zhang, Carlotta Borsoi, Joy Wolfram, Junhua Mai, Haifa Shen, Zheng Li, Elvin Blanco, Mauro Ferrari. Empowering preclinical studies: A systematic and quantitative analysis of biodistribution methods to facilitate clinical translation of new drugs [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 LB-019.
Abstract 3119: Treatment prediction by subset analysis of tumor infiltrating lymphocytes (TILs) in combination therapy with trastuzumab, pertuzumab, and docetaxel for advanced HER2-positive breast cancer
Authors: Koji Takada, Shinichiro Kashiwagi, Yuka Asano, Goto Wataru, Tamami Morisaki, Satoru Noda, Tsutomu Takashima, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2018)

Abstract Background: The trastuzumab, pertuzumab, and docetaxel (TPD) regimen is strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. The immune microenvironment in cancer is involved in many antitumor treatment effects, and tumor-infiltrating lymphocytes (TILs) is being established as a biomarker for therapeutic effect and prognosis. Recently, subset analysis of TILs is also under way. We have previously reported the clinical validity and benefits of evaluating TILs for neoadjuvant chemotherapy (NAC). Chemotherapy with a TPD regimen is garnering attention for its clinical outcomes and impact on cancer microenvironments. In this study, we evaluated the impact of chemotherapy with a TPD regimen, on immune micro environments in HER2-positive breast cancer using immune related proteins as indicators. Methods: The subjects consisted of 30 patients who received the TPD regimen. The expression levels of estrogen receptor (ER), progesterone receptor (PgR), Ki67, CD8, forkhead box protein (FOXP) 3, programmed death (PD) 1, and programmed death ligand (PD-L) 1 were evaluated in biopsy specimens, by immunostaining. We also examined the ratio of CD8 and FOXP3 (CFR). Results: The objective response rate (ORR) in the high CFR group was higher than in the low CFR group (p=0.013). The CD8 positive, high CFR and PD-L1 negative group had significantly longer PFS than the CD8 negative, low CFR and PDL1 positive group (p=0.045, log-rank) (p=0.007, log-rank) (p=0.040, log-rank), respectively. The high CFR group had significantly better OS than the low CFR group (p=0.034, log-rank). Receiver operating characteristic (ROC) analyses showed that, for advanced HER2-positive breast cancer patients, the CFR results [area under the curve (AUC): 0.708] were better than those for the other factors (AUC: CD8=0.681, FOXP3=0.639, PD1=0.528, PD-L1=0.681). Conclusions: This study shows with the TPD regimen, a high CFR leads to a high ORR and long PFS in HER2-positive breast cancer. CFR, therefore, may be one of the important prognostic factors for this disease. Citation Format: Koji Takada, Shinichiro Kashiwagi, Yuka Asano, Goto Wataru, Tamami Morisaki, Satoru Noda, Tsutomu Takashima, Naoyoshi Onoda, Kosei Hirakawa, Masaichi Ohira. Treatment prediction by subset analysis of tumor infiltrating lymphocytes (TILs) in combination therapy with trastuzumab, pertuzumab, and docetaxel for advanced HER2-positive breast cancer [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 3119.
Abstract 741: Targeting trastuzumab and T-DM-1 resistant breast cancer cells with EV20/MMAF, an antibody drug-conjugate against HER3
Authors: Gianluca Sala, Lucia Gandullo, Emily Capone, Maria Elena Diaz-Rodriguez, Daniela D'Agostino, Vincenzo De Laurenzi, Jean-Frederic Sauniere, Stefano Iacobelli, Atanasio Pandiella
Journal: Cancer Research (2018)

Abstract Trastuzumab and its derivative Trastuzumab-emtansine (T-DM1) are drugs approved to treat HER-2+ tumors. Despite the impressive clinical efficacy observed in many patients, intrinsic and acquired resistance to both drugs has emerged as a challenge. The HER-3 receptor is emerging as an attractive molecule in therapeutics because of its overexpression across many human cancers and because of its role in resistance to certain anticancer drugs. We recently showed that the EV20 humanized anti-HER-3 antibody has the ability of selectively and efficiently deliver the plant toxin Saporin to tumor cells. Here, we describe the antitumor activity of a novel ADC derivative of EV20 coupled to the cytotoxic drug monomethyl auristatin F (MMAF). This HER-3/ADC (EV20/MMAF) demonstrated a powerful and target-dependent killing activity in a panel of HER2+ breast cancer cells, including those resistant to trastuzumab and T-DM1 with an IC50 in the pico/nanomolar range. EV20/MMAF mediated potent antitumor activity in mice bearing trastuzumab resistant xenograft models. Notably, we found that the novel conjugate was well tolerated and caused tumor shrinkage in 100% of tumor-bearing mice. In summary, these findings open the possibility to use EV20/MMAF as a novel ADC targeting HER-3 and support its clinical development for malignancies, such as HER-2+ breast cancer, in which HER-3 is frequently overexpressed. Citation Format: Gianluca Sala, Lucia Gandullo, Emily Capone, Maria Elena Diaz-Rodriguez, Daniela D'Agostino, Vincenzo De Laurenzi, Jean-Frederic Sauniere, Stefano Iacobelli, Atanasio Pandiella. Targeting trastuzumab and T-DM-1 resistant breast cancer cells with EV20/MMAF, an antibody drug-conjugate against HER3 [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 741.
Abstract 3054: High-throughput microfluidic Labyrinth for the label-free isolation of circulating tumor cells
Authors: Eric Lin
Journal: Cancer Research (2018)

Abstract Circulating tumor cells (CTCs) present in the blood are the instruments of metastasis and are of high biologic and clinical relevance. Single-cell technologies are playing an increasing role in profiling CTCs in the peripheral blood for detection and real-time monitoring of cancer metastasis. CTCs also help in identifying its distinct drivers. However, current approaches are limited to manual selection of CTCs, which hinders the unbiased comprehensive study of CTCs on a single-cell level. We present a unique label-free microfluidic “Labyrinth” device to isolate CTCs at a high throughput of 2.5mL/min, offering the first biomarker-independent single-cell isolation and genomic characterization platform to study heterogeneous CTC subpopulations in cancer patients. The Labyrinth takes advantage of inertial forces on the microscale in curved geometries to differentially focus cells based on their size. This novel strategy of multicourse path traversing across inner loops to outer loops yielding highest hydrodynamic path length enables focusing of white blood cells (WBCs), leading to high recoveries (&amp;gt; 90%) and efficient separation of WBCs from CTCs, resulting in high purity (~ 200 WBCs/mL), even in whole blood samples without any preprocessing. CTCs were successfully isolated from 56 breast cancer (9.1 CTCs/mL average, range 2-31/mL) and 20 pancreatic cancer (51.6 CTCs/mL average, range 11-115/mL) patients. We detected not only CTCs typically defined by epithelial markers, but also significant numbers of CTCs (&amp;gt;50%) lacking epithelial markers but expressing mesenchymal and cancer stem cell (CSC) markers. Patient samples were then analyzed using single-cell multiplex gene expression. Seventy single cells were successfully recovered and used to identify different subpopulations of CTCs based on their genetic signature, unlike other methods where a positive or negative selection based on protein expression is used. Interestingly, both inter- and intrapatient molecular heterogeneity at the single-cell level in CTCs were observed with cells expressing genes uniquely related to epithelial, MET, and EMT phenotypes. The Labyrinth platform allows a thorough molecular understanding of the heterogeneity among CTCs. This platform also shows CTCs' potential as a biomarker to noninvasively evaluate tumor progression and response to treatment in cancer patients. Citation Format: Eric Lin. High-throughput microfluidic Labyrinth for the label-free isolation of circulating tumor cells [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 3054.