tbuckley/cabot-search huggingface dataset:
Epithelial Membrane Protein-2 Is a Novel Therapeutic Target in Ovarian Cancer
Authors: Maoyong Fu, Erin L. Maresh, Robert A. Soslow, Mohammad Alavi, Vei Mah, Qin Zhou, Alexia Iasonos, Lee Goodglick, Lynn K. Gordon, Jonathan Braun, Madhuri Wadehra
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The tetraspan protein epithelial membrane protein-2 (EMP2) has been shown to regulate the surface display and signaling from select integrin pairs, and it was recently identified as a prognostic biomarker in human endometrial cancer. In this study, we assessed the role of EMP2 in human ovarian cancer. Experimental Design: We examined the expression of EMP2 within a population of women with ovarian cancer using tissue microarray assay technology. We evaluated the efficacy of EMP2-directed antibody therapy using a fully human recombinant bivalent antibody fragment (diabody) in vitro and ovarian cancer xenograft models in vivo. Results: EMP2 was found to be highly expressed in &amp;gt;70% of serous and endometrioid ovarian tumors compared with nonmalignant ovarian epithelium using a human ovarian cancer tissue microarray. Using anti-EMP2 diabody, we evaluated the in vitro response of nine human ovarian cancer cell lines with detectable EMP2 expression. Treatment of human ovarian cancer cell lines with anti-EMP2 diabodies induced cell death and retarded cell growth, and these response rates correlated with cellular EMP2 expression. We next assessed the effects of anti-EMP2 diabodies in mice bearing xenografts from the ovarian endometrioid carcinoma cell line OVCAR5. Anti-EMP2 diabodies significantly suppressed tumor growth and induced cell death in OVCAR5 xenografts. Conclusions: These findings indicate that EMP2 is expressed in the majority of ovarian tumors and may be a feasible target in vivo. Clin Cancer Res; 16(15); 3954–63. ©2010 AACR.
Evidence that the brain of the conscious dog is insulin sensitive.
Authors: S N Davis, C Colburn, R Dobbins, S Nadeau, D Neal, P Williams, A D Cherrington
Journal: Journal of Clinical Investigation (1995)

The aim of this study was to determine whether a selective increase in the level of insulin in the blood perfusing the brain is a determinant of the counterregulatory response to hypoglycemia. Experiments were carried out on 15 conscious 18-h-fasted dogs. Insulin was infused (2 mU/kg per min) in separate, randomized studies into a peripheral vein (n = 7) or both carotid and vertebral arteries (n = 8). This resulted in equivalent systemic insulinemia (84 +/- 6 vs. 86 +/- 6 microU/ml) but differing insulin levels in the head (84 +/- 6 vs. 195 +/- 5 microU/ml, respectively). Glucose was infused during peripheral insulin infusion to maintain the glucose level (56 +/- 2 mg/dl) at a value similar to that seen during head insulin infusion (58 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and similar hypoglycemia; steady state plasma epinephrine (792 +/- 198 vs. 2394 +/- 312 pg/ml), norepinephrine (404 +/- 33 vs. 778 +/- 93 pg/ml), cortisol (6.8 +/- 1.8 vs. 9.8 +/- 1.6 micrograms/dl) and pancreatic polypeptide (722 +/- 273 vs. 1061 +/- 255 pg/ml) levels were all increased to a greater extent during head insulin infusion (P < 0.05). Hepatic glucose production, measured with [3-3H]glucose, rose from 2.6 +/- 0.2 to 4.3 +/- 0.4 mg/kg per min (P < 0.01) in response to head insulin infusion but remained unchanged (2.6 +/- 0.5 mg/kg per min) during peripheral insulin infusion. Similarly, gluconeogenesis, lipolysis, and ketogenesis were increased twofold (P < 0.001) during head compared with peripheral insulin infusion. Cardiovascular parameters were also significantly higher (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog (a) the brain is directly responsive to physiologic elevations of insulin and (b) the response includes a profound stimulation of the autonomic nervous system with accompanying metabolic and cardiovascular changes.
Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice
Authors: J. F. de Groot, G. Fuller, A. J. Kumar, Y. Piao, K. Eterovic, Y. Ji, C. A. Conrad
Journal: Neuro-Oncology (2010)

Patients with recurrent malignant glioma treated with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan have had impressive reductions in MRI contrast enhancement and vasogenic edema. Responses to this regimen, as defined by a decrease in contrast enhancement, have led to significant improvements in progression-free survival rates but not in overall survival duration. Some patients for whom this treatment regimen fails have an uncharacteristic pattern of tumor progression, which can be observed radiographically as an increase in hyperintensity on T2-weighted or fluid-attenuated inverse recovery (FLAIR) MRI. To date, there have been no reports of paired correlations between radiographic results and histopathologic findings describing the features of this aggressive tumor phenotype. In this study, we correlate such findings for 3 illustrative cases of gliomas that demonstrated an apparent phenotypic shift to a predominantly infiltrative pattern of tumor progression after treatment with bevacizumab. Pathologic examination of abnormal FLAIR areas on MRI revealed infiltrative tumor with areas of thin-walled blood vessels, suggesting vascular “normalization,” which was uncharacteristically adjacent to regions of necrosis. High levels of insulin-like growth factor binding protein-2 and matrix metalloprotease-2 expression were seen within the infiltrating tumor. In an attempt to better understand this infiltrative phenotype associated with anti-VEGF therapy, we forced a highly angiogenic, noninvasive orthotopic U87 xenograft tumor to become infiltrative by treating the mice with bevacizumab. This model mimicked many of the histopathologic findings from the human cases and will augment the discovery of alternative or additive therapies to prevent this type of tumor recurrence in clinical practice.
Completeness of Toxicological Analyses
Authors: Peter Goldman
Journal: JAMA (1980)

<h3>To the Editor.—</h3> Based on a survey of toxicological analyses performed by 24 coroners' offices, the recent article by Finkle et al (242:429, 1979) concluded that diazepam is a relatively safe drug. This opinion was based in part on the observation that chemical analysis detected diazepam as the sole agent in only two of 1,239 fatal overdoses where diazepam was detected. Moreover, diazepam was the sole drug detected in addition to ethanol in an additional 5.6% of cases. We are not disagreeing with the conclusion of this investigation, but we do question the validity of this kind of evidence that is so frequently used to implicate or exonerate a drug as a health hazard. The technical limitations of toxicological analysis obviously are an important determinant of whether a drug will be detected in overdosed patients. Thus, drugs that are difficult to measure will be implicated in only a fraction of
Value of 18F-Fluoro-2-Deoxy-<scp>d</scp>-Glucose-Positron Emission Tomography/Computed Tomography in Non–Small-Cell Lung Cancer for Prediction of Pathologic Response and Times to Relapse after Neoadjuvant Chemoradiotherapy
Authors: Christoph Pöttgen, Sabine Levegrün, Dirk Theegarten, Simone Marnitz, Sara Grehl, Roman Pink, Wilfried Eberhardt, Georgios Stamatis, Thomas Gauler, Gerald Antoch, Andreas Bockisch, Martin Stuschke
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To determine the value of combined positron emission tomography/computed tomography (PET/CT) during induction chemotherapy (CTx) followed by chemoradiotherapy (CTx/RTx) for non–small-cell lung cancer to predict histopathologic response in primary tumor and mediastinum and prognosis of the patient. Experimental Design: Fifty consecutive patients with locally advanced non–small-cell lung cancer received induction therapy and, if considered resectable, proceeded to surgery (37 of 50 patients). Patients had at least two repeated 18F-2-fluoro-2-deoxy-d-glucose (FDG)-PET/CT scans either before treatment (t0) or after induction CTx (t1) or CTx/RTx (t2). Variables from the PET/CT studies [e.g., lesion volume and corrected maximum standardized glucose uptake values (SUVmax,corr)] were correlated with histopathologic response (graded as 3, 2b, or 2a: 0%, &amp;gt;0-10%, or &amp;gt;10% residual tumor cells) and times to failure. Results: Primary tumors showed a percentage decrease in SUVmax,corr during induction significantly larger in grade 2b/3 than in grade 2a responding tumors (67% versus 34% at t1, 73% versus 49% at t2; both P &amp;lt; 0.005). SUVmax,corr at t2 was significantly correlated with histopathologic response in tumors smaller than the median volume (7.5 cm3; r = −0.54, P = 0.02). In the mediastinal lymph nodes, SUVmax,corr values at t2 predicted an ypN0 status with a sensitivity and specificity of 73% and 89%, respectively (SUVmax,corr threshold of 4.1, r = −0.54, P = 0.0005). Freedom from extracerebral relapse was significantly better in grade 2b/3 patients (86% at 16 months versus 20% in 2a responders; P = 0.003) and in patients with a greater percentage decrease in SUVmax,corr in the primary tumor at t2 in relation to t0 than in patients with lesser response (83% at 16 months versus 43%; P = 0.03 for cutoff points between 0.45 and 0.55). Conclusions: SUVmax,corr values from two serial PET/CT scans, before and after three chemotherapy cycles or later, allow prediction of histopathologic response in the primary tumor and mediastinal lymph nodes and have prognostic value.
Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects
Authors: Javier Traba, Miriam Kwarteng-Siaw, Tracy C. Okoli, Jessica Li, Rebecca D. Huffstutler, Amanda Bray, Myron A. Waclawiw, Kim Han, Martin Pelletier, Anthony A. Sauve, Richard M. Siegel, Michael N. Sack
Journal: Journal of Clinical Investigation (2015)

Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity.We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation.In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting.Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease.ClinicalTrials.gov NCT02122575 and NCT00442195.Division of Intramural Research, NHLBI of the NIH.
Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis
Authors: Na Liu, Nian-Yong Chen, Rui-Xue Cui, Wen-Fei Li, Yan Li, Rong-Rong Wei, Mei-Yin Zhang, Ying Sun, Bi-Jun Huang, Mo Chen, Qing-Mei He, Ning Jiang, Lei Chen, William CS Cho, Jing-Ping Yun, Jing Zeng, Li-Zhi Liu, Li Li, Ying Guo, Hui-Yun Wang, Jun Ma
Journal: The Lancet Oncology (2012)
Economic Evaluation of Genomic Test–Directed Chemotherapy for Early-Stage Lymph Node–Positive Breast Cancer
Authors: Peter S. Hall, Christopher McCabe, Robert C. Stein, David Cameron
Journal: JNCI Journal of the National Cancer Institute (2011)

Multi-parameter genomic tests identify patients with early-stage breast cancer who are likely to derive little benefit from adjuvant chemotherapy. These tests can potentially spare patients the morbidity from unnecessary chemotherapy and reduce costs. However, the costs of the test must be balanced against the health benefits and cost savings produced. This economic evaluation compared genomic test–directed chemotherapy using the Oncotype DX 21-gene assay with chemotherapy for all eligible patients with lymph node–positive, estrogen receptor–positive early-stage breast cancer. We performed a cost–utility analysis using a state transition model to calculate expected costs and benefits over the lifetime of a cohort of women with estrogen receptor–positive lymph node–positive breast cancer from a UK perspective. Recurrence rates for Oncotype DX–selected risk groups were derived from parametric survival models fitted to data from the Southwest Oncology Group 8814 trial. The primary outcome was the incremental cost-effectiveness ratio, expressed as the cost (in 2011 GBP) per quality-adjusted life-year (QALY). Confidence in the incremental cost-effectiveness ratio was expressed as a probability of cost-effectiveness and was calculated using Monte Carlo simulation. Model parameters were varied deterministically and probabilistically in sensitivity analysis. Value of information analysis was used to rank priorities for further research. The incremental cost-effectiveness ratio for Oncotype DX–directed chemotherapy using a recurrence score cutoff of 18 was £5529 (US $8852) per QALY. The probability that test-directed chemotherapy is cost-effective was 0.61 at a willingness-to-pay threshold of £30 000 per QALY. Results were sensitive to the recurrence rate, long-term anthracycline-related cardiac toxicity, quality of life, test cost, and the time horizon. The highest priority for further research identified by value of information analysis is the recurrence rate in test-selected subgroups. There is substantial uncertainty regarding the cost-effectiveness of Oncotype DX–directed chemotherapy. It is particularly important that future research studies to inform cost-effectiveness–based decisions collect long-term outcome data.
Spontaneous haemothorax in a mild haemophiliac.
Authors: R Rasaretnam, D Chanmugam, C Sivathasan
Journal: Thorax (1976)

Spontaneous haemothoraxis is a very rare presenting manifestation in haemophilia, only four previous cases being recorded in the English literature. The clinical features and management of such a case by intercostal tube drainage in a previously unrecognized haemophiliac are described.
CD8 T cells induce T-bet–dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines
Authors: Karine Serre, Adam F. Cunningham, Ruth E. Coughlan, Andreia C. Lino, Antal Rot, Elin Hub, Katrin Moser, Rudolf Manz, Alastair Ferraro, Roger Bird, Kai-Michael Toellner, Jocelyne Demengeot, Ian C. M. MacLennan, Elodie Mohr
Journal: Blood (2012)
Fitness assessment of English league soccer players through the competitive season.
Authors: V. Thomas, T. Reilly
Journal: British Journal of Sports Medicine (1979)

A battery of 26 tests was administered to professional soccer players (n = 31) at 3 points during the competitive season. Significant changes from start to mid-season were limited to improved muscular power, increased resting heart rate (fH), decreased force expiratory flow (FEF) and ankle mobility. No further changes with the duration of the competitive season were observed. Differences between squads were predominantly cardiac function measures at mid-season, and strength, muscular power and limb girths at the end of the season. The First Team squad had consistently less fat and poorer ankle mobility. It seems that mean fitness levels remain relatively stable during the playing season, though the measures significantly discriminating between the top and reserve squads fluctuate.
Norman John Badham Godfrey Malcolm ("Mac") Baker Emanuel Alfred Cachia John Emsley Coates John Costello Alexander Peter Dick John Michael Faccini Thomas John Fairbank John Cedric Goligher Harold Barnett Hewitt John MacDonald ("Angus") Holmes
Authors: G. Badham, C. Hollingsworth, F F Fenech, H M Lenicker, T G G Davies, A O'Carroll, J O Hunter, C. Fisher, J. Fairbank, M S Losowsky, T. Brewin, J Bridger
Journal: BMJ (1998)

died of respiratory failure, pulmonary hypertension, and sarcoidosis on 29
Abstract 4481: Topical application of the dual PDPK1/AKT inhibitor PHT-427 inhibits signaling and growth of human breast cancer cutaneous metastases in mice
Authors: D. Lynn Kirkpatrick, Jenny L.H. Johnson, Robert Lemos, Mena Abdelemelek, Nathan Ihle, Garth Powis
Journal: Cancer Research (2011)

Abstract Despite advances in the treatment of breast cancer between 10 to 15% of patients develop cutaneous metastatic disease (CMD) most frequently on the face, neck and chest wall, usually in later stages of the disease as a harbinger of metastasis that will occur in other organs 1 to 3 years later. CMD is not life threatening but can significantly impact patients’ quality of life and is a cause of anxiety, pain, discomfort, and a portal for infection. CMD could also be a seed for metastases at other sites. Surgery or radiotherapy is used for single or localized CMD. Topical (epicutaneous) therapy with molecularly targeted agents provides an attractive modality for treatment of more widespread breast CMD. PHT-427 is a dual pleckstrin homology (PH) domain inhibitor of PDPK and AKT, two key enzymes of PI3K signaling that is frequently activated in breast cancer. We report here PHT-427's topical activity in CMD. MCF-7 human breast cancer (mutant PIK3CA) 106 cells in 20 μI were injected intradermaly in the flank of estradiol pelleted female nu/nu mice. When tumors reached 40-200 mm3 groups of 5 mice were treated twice a day with 0.1 ml vehicle or vehicle with 50 mg/ml PH-427, applied to a 1 cm patch of skin over the tumor. Mice were housed individually with collars to prevent them ingesting applied drug. After 10 days mice were euthanized 4 hr after the last application and blood, tumor and overlying skin were removed for analyses. Topical PHT-427 gave 89 % inhibition of tumor growth (p = 0.017, 3/5 no measurable tumor). There was no change in body weight and no apparent skin toxicity. Western blotting showed that PHT-427 inhibited p-AKT Thr308/Ser473 in skin and tumor, and decreased total AKT in skin but not tumor. p-PDPK1 Ser241 was inhibited in tumor but not skin, as was the downstream target pPKC Thr410 and pMAPK Thr202/Tyr204. Measurement of PHT-427 by HPL-MS showed very high levels in the skin at the site of application, levels of ∼50 μg/g in tumor and 5.5 μg/ml in plasma. In vitro levels of PHT-427 of 5 μg/ml are required for killing of sensitive cell lines. Thus, topical application of PHT-427 can deliver active drug levels to skin and tumor, inhibiting PDPK1 and AKT, and significantly inhibiting tumor growth without adverse effects on normal skin. Topical PHT-427 could have use in skin conditions driven by PDPK/AKT such as prevention of sun damage and skin cancer, and in the personalized therapy of breast CMD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4481. doi:10.1158/1538-7445.AM2011-4481
The effect of positive end-expiratory pressure on respiratory resistive properties in anaesthetized paralysed humans
Authors: R Cohendy, J Ripart, JJ Eledjam
Journal: European Respiratory Journal (1994)

The respiratory resistive properties of the normal human respiratory system are volume-dependent. The overall flow resistance (Rmax,rs) can be partitioned into airway resistance (Raw) and the additional resistance (delta Rrs) which may result from the viscoelastic properties of the respiratory system, from inequality of time constants (pendelluft), or from both. Because positive end-expiratory pressure (PEEP) increases end-expiratory lung volume and may equalize ventilation within the lungs, the effect of PEEP on Raw, delta Rrs, and their sum (Rmax,rs) was assessed in anaesthetized surgical patients without evidence of lung disease. Fifteen men were studied during paralysis and isoflow isovolume mechanical ventilation, using the end-inflation occlusion method. Ten men were studied with incremental levels of PEEP, up to 16 cmH2O (Group A). Five men were studied without PEEP (Group B). In Group A, Rmax,rs did not change with PEEP. In contrast, Raw decreased and delta Rrs increased significantly. Moreover, there was a linear relationship between PEEP and the contribution of delta Rrs to Rmax,rs. In Group B, Rmax,rs, Raw and delta Rrs, and the contribution of delta Rrs to Rmax,rs did not change. In both groups, atropine elicited a decrease in Rmax,rs, linked to a decrease in Raw, without any notable effect on the static elastance of the respiratory system (Est,rs) or on delta Rrs. We conclude that the overall flow resistance was not affected by PEEP. In contrast, PEEP clearly modified the contribution of its two components. The decrease in Raw with PEEP could have resulted, at least in part, from modification in the basal vagal tone.
Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut
Authors: Susan M. Schlenner, Benno Weigmann, Qingguo Ruan, Youhai Chen, Harald von Boehmer
Journal: The Journal of Experimental Medicine (2012)

Regulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-β–Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3CNS1mut). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut.