tbuckley/cabot-search huggingface dataset:
Abstract 4009: Biotinylated estrogens a novel tool for early detection of adduct in ovarian cancer and their carcinogenic effects in cultured human cells
Authors: Kaushlendra Tripathi
Journal: Cancer Research (2018)

Abstract In humans, endogenous estrogens such as Estrone (E1) and 17L-estradiol (E2) regulate many physiological processes including reproduction, primarily in females, and control the growth of certain responsive cells. However, unbalanced estrogen metabolism has been linked to development of several malignant diseases including breast, endometrial and ovarian cancer and has been identified as a risk factor for these cancers. Elevated estrogens exert their carcinogenic effects by at least three different mechanisms; they promote cell proliferation by transcriptional regulation of estrogen responsive genes, cause generation of reactive oxygen species and other free radicals, and directly react with DNA and form potentially mutagenic adducts. The metabolic breakdown of estogens is regulated by a series of reactions mediated by hepatic and peripheral enzymes that balances the induction and reduction of cellular stress. An imbalance in this enzymes and processes can lead to highly reactive catechol estrogen metabolites that can react with DNA, form carcinogenic DAN-adducts and lesions. Although several studies established a connection between estrogen-induced DNA damage and carcinogenesis, the underlying molecular mechanisms have been difficult to study because of the technical challenges in detecting and analyzing the variety of different DNA lesions that are formed by estrogen compounds. Moreover, detection and analysis of these adducts are important to directly monitor estrogen metabolites induced cellular responses in the cells. Towards this, we developed a novel method using biotinylated-estrogens that allows immunodetection of estrogen-induced DNA adducts by Slot-blot and single-cell molecular combing and proximity ligation assays. Using these modified estrogens we first time quantitatively detected these adducts on DNA by immune Slot-blot techniques and on DNA fibers. Furthermore, similar to other environmental carcinogens estrogens activates replication associated DNA damage responses and induces chromosomal instability. Thus, for the first time our studies demonstrate that biotin-labeled estrogens could be a powerful tool to detect estrogen adducts and to probe associated DNA damage responses and cellular responses. Citation Format: Kaushlendra Tripathi. Biotinylated estrogens a novel tool for early detection of adduct in ovarian cancer and their carcinogenic effects in cultured human 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 4009.
Abstract 2101: The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44
Authors: Chunmei Zhao, Benjamin J. Thompson, Kelly Chen, Mathieu Marella, Susan Zimmerman, Trevor Kimbler, Barbara Blouw, Sheryl Garrovillo, Lei Huang, Adrian Radi, Zhongdong Huang, H. Michael Shepard, Sanna Rosengren, Christopher D. Thanos, Daniel C. Maneval
Journal: Cancer Research (2018)

Abstract The abnormal accumulation of hyaluronan in the solid tumor microenvironment is associated with poor prognosis in several human cancers. Hyaluronan often accumulates in the tumor stroma. To understand the role of hyaluronan-accumulating stroma in tumor progression, we engineered a hyaluronan-producing fibroblast cell line 3T3HAS3 by lentiviral transduction of the human hyaluronan synthase 3 gene into Balb/c 3T3 cells. The 3T3HAS3 cells produced significant amounts of hyaluronan in vitro, which bind to the cell surface of the human breast cancer cell line MDA-MB-468. When co-grafted with MDA-MB-468 cells in nude mice, 3T3HAS3 significantly enhanced tumor growth. Immunohistochemical analysis of tumor xenografts showed that MDA-MB-468 cells were surrounded by hyaluronan-accumulating stroma, closely resembling the morphology observed in human breast cancer specimens. Tumor growth of this co-graft model required hyaluronan production from 3T3HAS3 cells, as demonstrated by the delayed tumor growth upon hyaluronan removal by expression of the human PH20 gene in 3T3HAS3 cells, or by systemic administration of PEGylated recombinant human PH20 (PEGPH20). In contrast, neither the expression of CD44, a well-characterized hyaluronan receptor, in tumor and stromal fibroblasts, nor the binding of hyaluronan to CD44 in MDA-MB-468 tumor cells was essential for tumor growth. Small scale screening of signaling changes in xenograft tumors suggested that the AMPK/mTOR pathway may respond to hyaluronan removal by PEGPH20. Collectively, these data demonstrate that the growth of an engineered breast cancer xenograft model with hyaluronan-accumulating stroma is dependent on hyaluronan, and that hyaluronan-CD44 interaction may not be the main mechanism through which hyaluronan promotes tumor progression in certain tumors. Citation Format: Chunmei Zhao, Benjamin J. Thompson, Kelly Chen, Mathieu Marella, Susan Zimmerman, Trevor Kimbler, Barbara Blouw, Sheryl Garrovillo, Lei Huang, Adrian Radi, Zhongdong Huang, H. Michael Shepard, Sanna Rosengren, Christopher D. Thanos, Daniel C. Maneval. The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44 [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 2101.
Abstract 12529: Low Dose Oral Cyclophosphamide Therapy Reduces Atherosclerosis Progression and Promotes Plaque Stability in a Murine Model of Atherosclerosis
Authors: YayoiSato-Okabayashi, ChiemiNishida, DaidaHiroyuki, ShinyaMunakata, HiroshiShimazu, BeateHeissig, KoichiHattori
Journal: Circulation (2014)

Introduction: Atherosclerosis is a chronic inflammatory disease and the primary cause of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions. Extended survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood. The objective of this study was to examine the antiatherosclerotic effects of CPA and the underlying mechanism in a murine model of atherosclerosis. Hypothesis: CPA treatment can alter inflammatory processes pivotal for the development of atherosclerosis, therefore limiting disease progression. Method: Apolipoprotein E deficient (ApoE-/-) mice fed a high fat diet received CPA resuspended in drinking water (37.5 g/kg /day p.o.) or water for 12 weeks, respectively. In an interventional protocol, mice fed a high fat diet received the same dose of CPA or water from week 14 to 18, respectively. Mice were sacrificed at week 12, 14 and 18, and aorta, perip...
Risk of Constrictive Pericarditis After Acute Pericarditis
Authors: MassimoImazio, AntonioBrucato, SilviaMaestroni, DavideCumetti, RiccardoBelli, RitaTrinchero, YehudaAdler
Journal: Circulation (2011)

Background—Constrictive pericarditis (CP) is considered a rare, dreaded possible complication of acute pericarditis. Nevertheless, there is a lack of prospective studies that have evaluated the specific risk according to different etiologies. The aim of this study is to evaluate the risk of CP after acute pericarditis in a prospective cohort study with long-term follow-up. Methods and Results—From January 2000 to December 2008, 500 consecutive cases with a first episode of acute pericarditis (age, 51±16 years; 270 men) were prospectively studied to evaluate the evolution toward CP. Etiologies were viral/idiopathic in 416 cases (83.2%), connective tissue disease/pericardial injury syndromes in 36 cases (7.2%), neoplastic pericarditis in 25 cases (5.0%), tuberculosis in 20 cases (4.0%), and purulent in 3 cases (0.6%). During a median follow-up of 72 months (range, 24 to 120 months), CP developed in 9 of 500 patients (1.8%): 2 of 416 patients with idiopathic/viral pericarditis (0.48%) versus 7 of 84 patients...
Improved Quality of Life After 1 Year With an Invasive Versus a Noninvasive Treatment Strategy in Claudicants
Authors: JoakimNordanstig, CharlesTaft, MarleneHensäter, AngelicaPerlander, KlasÖsterberg, LennartJivegård
Journal: Circulation (2014)

Background—The quality of evidence for invasive revascularization in intermittent claudication is low or very low. This prospective, randomized, controlled study tested the hypothesis that an invasive treatment strategy versus continued noninvasive treatment improves health-related quality of life after 1 year in unselected patients with intermittent claudication. Methods and Results—After clinical and duplex ultrasound assessment, unselected patients with intermittent claudication requesting treatment for claudication were randomly assigned to invasive (n=79) or noninvasive (n=79) treatment groups. Primary end point was health-related quality of life after 1 year, assessed with Medical Outcomes Study Short Form 36 version 1 and Vascular Quality of Life Questionnaire, and secondary end points included walking distances on a graded treadmill. The Medical Outcomes Study Short Form 36 version 1 physical component summary (P<0.001) and 2 Medical Outcomes Study Short Form 36 version 1 physical subscales improv...
Gaining on Pain
Authors: Edward C. Emery, John N. Wood
Journal: New England Journal of Medicine (2018)

A side effect of bortezomib (a drug used to treat multiple myeloma) is neuropathic pain, probably owing to increased sphingolipid synthesis. Fingolimod, a drug used to treat multiple sclerosis, down-regulates a sphingolipid receptor and is a candidate analgesic.
Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
Authors: Alexander Drilon, Sai-Hong Ignatius Ou, Byoung Chul Cho, Dong-Wan Kim, Jeeyun Lee, Jessica J. Lin, Viola W. Zhu, Myung-Ju Ahn, D. Ross Camidge, Judy Nguyen, Dayong Zhai, Wei Deng, Zhongdong Huang, Evan Rogers, Juliet Liu, Jeff Whitten, John K. Lim, Shanna Stopatschinskaja, David M. Hyman, Robert C. Doebele, J. Jean Cui, Alice T. Shaw
Journal: Cancer Discovery (2018)

The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA-C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1-3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA-C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion-positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance.Significance: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1-3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1227-36. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1195.
Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia
Authors: HiromitsuMatsui, TatsuoShimosawa, KanamiItakura, XingGuanqun, KatsuyukiAndo, ToshiroFujita
Journal: Circulation (2004)

Background— Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin (AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM+/−) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia. Methods and Results— Ten-week-old male wild-type (AM+/+) or AM+/− mice were housed under 10% oxygen conditions for 3 to 21 days. In AM+/+ mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was sig...
Abstract 398: Functional coding and noncoding drivers of EMT-mediated acquired drug resistance
Authors: Russell O. Bainer, Catherine Wilson, Marinella Callow, Siyu Feng, Michael Costa, Colin Watanabe, Oleg Mayba, Eva Lin, Scott Martin, Bob Yauch, Richard Bourgon, Christiaan Klijn
Journal: Cancer Research (2018)

Abstract In response to diverse stimuli, tumor cells can undergo a process resembling the epithelial-mesenchymal transition (EMT) observed during development. During this transition, epithelial-like tumor cells acquire mesenchymal-like physiologic features, become more motile and invasive, and acquire insensitivity to many therapeutic agents. While the importance of this phenomenon to cancer treatment and patient outcomes is well known, considerable heterogeneity exists across experimental models of EMT, and diverse mechanisms have been proposed to explain its various associated malignant phenotypes. Consequently, the extent to which these processes are shared uniformly across instances of EMT, as well as their relative importance in treatment contexts, remains unclear. We have used RNAseq, ATACseq, and parallelized high-throughput cell viability screening to identify differences in gene expression levels, chromatin accessibility, and drug sensitivity that correlate with EMT in a series of cell line models. By contrasting these changes across different genetic backgrounds and mechanisms of EMT induction, we are able to identify sets of elements in the transcribed and noncoding genome that are characteristic of different modes of EMT induction. Then, by comparing these candidate sets with observed differences in acquired drug sensitivity in the respective models, we were able to define a set of genetic elements whose biologic activity is likely to influence the efficacy of these compounds. Finally, we used a series of targeted CRISPR-based knockout screens to assess the relative importance of these elements to the viability of isogenic epithelial-like and mesenchymal-like cells, alone and in the presence of multiple therapeutic drugs. Using this approach, we were able to validate known mechanisms of acquired drug resistance and identify new candidate effectors. Notably, we identify multiple candidate noncoding elements containing CTCF binding sites that appear to meaningfully influence cell viability in a drug-specific manner, potentially implicating genome conformational changes in acquired therapeutic resistance. Citation Format: Russell O. Bainer, Catherine Wilson, Marinella Callow, Siyu Feng, Michael Costa, Colin Watanabe, Oleg Mayba, Eva Lin, Scott Martin, Bob Yauch, Richard Bourgon, Christiaan Klijn. Functional coding and noncoding drivers of EMT-mediated acquired drug resistance [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 398.
Disease-free survival pattern in breast cancer patients in India treated in a single institution.
Authors: Basavalinga S. Ajaikumar, Kodaganur Srinivasachar Gopinath, B S Srinath, Ramesh Bilimagga S, Nalini K Rao, Shekhar Patil, Ravi B Diwakar, Shilpa A. Prabhudesai, Kumar G Kallur, Rao M. Raghavendra, H P Shashidhar
Journal: Journal of Clinical Oncology (2012)

e12030 Background: This study elucidates data from a 5 year retrospective study evaluating survival rates and prognostic factors in breast carcinoma patients in a private cancer set up in south India. Methods: 1046 patients who were treated between years 2003 to 2008 were analyzed. Clinical data including stage, histopathology type, age, node positivity, treatment plan, chemotherapy regimen, ER/ PR and Her2 Neu status, type of surgery etc were abstracted in a database. Five year disease free survival, local failure free survival and distant failure free survival was calculated using Kaplan Meier survival curves. Log rank mantel hazel tests were used to compare two survival curves. Results: Local recurrence was seen in 4% and distant metastases in 22% of the study sample. 62% of patients presented with early breast cancer (AJCC Stage I, II and IIIA). 85.6% of early and 73.1% of locally advanced breast cancers were disease free at 5 years (p&lt;0.001).90.6% of early and 82.4% of locally advanced breast cancers had distant failure free survival at 5 years (p=0.001). Local failure free survival was 96.1% in both early and locally advanced breast disease at 5 years.94.9% of her 2 negative and 83.5% Her 2 positive were disease free at 5 years (p=0.001). 5 years progression free survival was 91.5% for breast conservation surgery vs 84.1% for mastectomy with axillary clearance (p=0.01). 75.4% with triple negative status and 80.8% non triple negative receptor status had 5 years DFS. Conclusion: This is a first report of survival patterns of breast cancer patients treated in a single centre in India. High early stage patient numbers and high median disease free survival times could be because of improvement in screening and treatment of breast cancer in a developing country like India.
Abstract 5270: Associations of circulating 25-hydroxyvitamin D3 concentrations with incident, sporadic colorectal adenoma risk according to common vitamin D-binding protein isoforms
Authors: David C. Gibbs
Journal: Cancer Research (2018)

Abstract 25-hydroxyvitamin D3 (25[OH]D3), the main circulating form of vitamin D, is inversely associated with incident, sporadic colorectal adenoma. We investigated whether this association differs by two functional variants in the vitamin D binding protein gene (GC) that encode for common protein isoforms (Gc1s, Gc1f, Gc2) linked to differences in vitamin D metabolism. We pooled data from three US colonoscopy-based case-control studies (418 adenoma cases, 524 polyp-free controls), and estimated 25(OH)D3-adenoma associations, by GC isoforms, using multivariable logistic regression. Consistent with previous studies, mean-adjusted 25(OH)D3 concentrations were lowest among Gc2 homozygotes (20.7 ng/mL, 95% CI: 26.2, 28.0) and highest among Gc1 (combined Gc1s and Gc1f) homozygotes (27.1 ng/mL, 95% CI: 18.6, 22.7). Higher 25(OH)D3 concentrations were inversely associated with colorectal adenoma among those with the Gc2 isoform (per 10 ng/mL increase in 25(OH)D3 odds ratio = 0.71; 95% confidence interval: 0.56, 0.90), but not among those with only Gc1 isoforms (odds ratio = 1.07; 95% confidence interval: 0.87, 1.32) (Pinteraction = 0.03). These novel findings suggest that the vitamin D-incident, sporadic colorectal adenoma association may differ by common GC isoforms, and that those with the Gc2 isoform may particularly benefit from maintaining higher circulating 25(OH)D3 concentrations for adenoma prevention. Citation Format: David C. Gibbs. Associations of circulating 25-hydroxyvitamin D3 concentrations with incident, sporadic colorectal adenoma risk according to common vitamin D-binding protein isoforms [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 5270.
David Oliver: Private practice by NHS doctors—still controversial?
Authors: David Oliver
Journal: BMJ (2018)

The issue of NHS doctors practising privately still sparks heated debate among the profession, press, and public. The ongoing renegotiation of the consultant contract,1 the contested lifting of the pay freeze on NHS staff,234 and the finding that pay has fallen dramatically in real terms for doctors and other NHS staff since 2010,5 have thrown this into sharper relief. Why wouldn’t they want to maximise their earnings potential and better support their families?

And some on the political right argue that, taking into account pensions and automatic increments, public sector workers have done better than the private sector and that UK doctors are high earners by international comparison.6789 The potential in England for swathes of NHS provision to be opened up to private providers after the 2012 Health and Social Care Act leads us to consider where their clinicians might come from.10 …
Transvenous Biventricular Defibrillation Halves Energy Requirements in Patients
Authors: ChristianButter, EckhardMeisel, JuergenTebbenjohanns, LotharEngelmann, EckartFleck, BerndSchubert, StephenHahn, DietrichPfeiffer
Journal: Circulation (2001)

Background Defibrillation thresholds (DFT) with standard implantable cardioverter-defibrillator leads in the right ventricle (RV) may be determined by weak shock field intensity in the myocardium of the left ventricle (LV). Adding a shocking electrode in a coronary vein on the middle of the LV free wall, thereby establishing biventricular defibrillation, substantially reduced defibrillation requirements in animals. We investigated the feasibility of this approach in 24 patients receiving an implantable cardioverter-defibrillator using a prototype over-the-wire temporary LV defibrillation lead. Methods and Results The LV lead was inserted through the coronary sinus, using a guide catheter and guidewire, into a posterior or lateral coronary vein whose location was determined by retrograde venography. Paired DFT testing compared a standard system (RV to superior vena cava plus can emulator [SVC+Can], 60% tilt biphasic shock) to a system including the LV lead. The biventricular system was tested with a dual-s...