tbuckley/cabot-search huggingface dataset:
Diabetes, Metformin, and Breast Cancer in Postmenopausal Women
Authors: Rowan T. Chlebowski, Anne McTiernan, Jean Wactawski-Wende, JoAnn E. Manson, Aaron K. Aragaki, Thomas Rohan, Eli Ipp, Virginia G. Kaklamani, Mara Vitolins, Robert Wallace, Marc Gunter, Lawrence S. Phillips, Howard Strickler, Karen Margolis, David M. Euhus
Journal: Journal of Clinical Oncology (2012)

Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials.In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes.Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2.Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.
Report from the Fifth National Cancer Institute Mouse Models of Human Cancers Consortium Nervous System Tumors Workshop
Authors: D. H. Gutmann, C. D. Stiles, S. W. Lowe, G. E. Bollag, F. B. Furnari, A. Charest
Journal: Neuro-Oncology (2011)

Cancers of the nervous system are clinically challenging tumors that present with varied histopathologies and genetic etiologies. While the prognosis for the most malignant of these tumors is essentially unchanged despite decades of basic and translational science research, the past few years have witnessed the identification of numerous targetable molecular alterations in these cancers. With the advent of advanced genomic sequencing methodologies and the development of accurate small-animal models of these nervous system cancers, we are now ideally positioned to develop personalized therapies that target the unique cellular and molecular changes that define their formation and drive their continued growth. Recently, the National Cancer Institute convened a workshop to advance our understanding of nervous system cancer mouse models and to inform clinical trials by reconsidering these neoplasms as complex biological systems characterized by heterogeneity at all levels.
Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice
Authors: Takashi Nomiyama, Diego Perez-Tilve, Daisuke Ogawa, Florence Gizard, Yue Zhao, Elizabeth B. Heywood, Karrie L. Jones, Ryuzo Kawamori, Lisa A. Cassis, Matthias H. Tschöp, Dennis Bruemmer
Journal: Journal of Clinical Investigation (2007)

Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. During immune responses, tissue infiltration by macrophages is dependent on the expression of osteopontin, an extracellular matrix protein and proinflammatory cytokine that promotes monocyte chemotaxis and cell motility. In the present study, we used a murine model of diet-induced obesity to examine the role of osteopontin in the accumulation of adipose tissue macrophages and the development of insulin resistance during obesity. Mice exposed to a high-fat diet exhibited increased plasma osteopontin levels, with elevated expression in macrophages recruited into adipose tissue. Obese mice lacking osteopontin displayed improved insulin sensitivity in the absence of an effect on diet-induced obesity, body composition, or energy expenditure. These mice further demonstrated decreased macrophage infiltration into adipose tissue, which may reflect both impaired macrophage motility and attenuated monocyte recruitment by stromal vascular cells. Finally, obese osteopontin-deficient mice exhibited decreased markers of inflammation, both in adipose tissue and systemically. Taken together, these results suggest that osteopontin may play a key role in linking obesity to the development of insulin resistance by promoting inflammation and the accumulation of macrophages in adipose tissue.
Lymphokine-activated killer cell phenomenon. III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer cells.
Authors: E A Grimm, R J Robb, J A Roth, L M Neckers, L B Lachman, D J Wilson, S A Rosenberg
Journal: The Journal of Experimental Medicine (1983)

Purified interleukin 2 (IL-2) was found to be sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer (LAK) cells. The LAK activation factor was directly and consistently associated with IL-2 activity using classic protein purification techniques, adsorption to IL-2-dependent cell lines, and inhibition with anti-Tac antibody. As yet, no other cytokines have been found that perform the same role.
A Phase 1 Clinical Study of Intravenous Administration of PV701, an Oncolytic Virus, Using Two-Step Desensitization
Authors: Scott A. Laurie, John C. Bell, Harold L. Atkins, Joanne Roach, Michael K. Bamat, James D. O'Neil, M. Scot Roberts, William S. Groene, Robert M. Lorence
Journal: Clinical Cancer Research (2006)

Abstract Purpose: In a previous phase 1 study, adverse events, especially flu-like symptoms, were observed mainly following the first i.v. bolus dose of PV701, an oncolytic Newcastle disease virus. Desensitization to adverse events of subsequent doses occurred, allowing a 10-fold increase in the maximum tolerated dose for these doses. Although one-step desensitization (a single desensitizing dose with higher subsequent doses) addressed the tolerability of high repeat doses, additional testing was required to further improve tolerability of the initial dose. This study tested the hypothesis that two-step desensitization, using two dose increments before high repeat doses, would be well tolerated. Experimental Design: Sixteen adults with incurable solid tumors were enrolled. Cycles consisted of six PV701 doses over 2 weeks followed by a 1-week rest. Doses 1 to 2 were 1 and 12 × 109 plaque-forming units (pfu)/m2, respectively, whereas doses 3 to 6 were escalated by cohort from 24 to 120 × 109 pfu/m2. Results: No dose-limiting toxicities were observed, permitting dose escalation through cohort 4 (1, 12, 120, 120, 120, 120 × 109 pfu/m2). Mild flu-like symptoms were common following the first infusion, diminished with repeated dosing, and were less pronounced than those seen previously. Tumor regression was observed in a patient with anal carcinoma who enrolled with stable disease following palliative radiotherapy. Four patients with clearly progressing cancer before enrollment had disease stabilization of ≥6 months. Conclusions: This novel two-step desensitization improved patient tolerability compared with the previous regimen. Toxicities were predictable and manageable. PV701, the first oncolytic virus to enter phase 1 i.v. testing, continues to show single-agent activity, warranting planned phase 2 trials.
Role of private sector in United Kingdom healthcare system Commentary: Cooperation should be based on what the public wants and needs from its healthcare system
Authors: Y. Doyle, A. Bull, J. Keen
Journal: BMJ (2000)

Since 1948 the private sector has viewed itself as complementary to the NHS.Before the NHS was set up in 1948 health care was provided by charities and voluntary hospitals, private medical clubs, occupational medical services and works clubs, fee for service insurance, friendly societies, public medical services (which were funded by subscription), and medical fees paid on an ad hoc basis.The structured health insurance sector initially developed between 1940 and 1947 with the instigation of the London based Hospital Services Plan (now PPP Healthcare) and the amalgamation of several regional schemes into British United Provident Association (BUPA).
Gene Therapy for the Respiratory Manifestations of Cystic Fibrosis
Authors: Robert J. Korst, Noel G. McElvaney, Chin-Shyan Chu, Melissa A. Rosenfeld, Andrea Mastrangeli, John Hay, Steven L. Brody, N. Tony Eissa, Claire Danel, H. Ari Jaffe, Ronald G. Crystal
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The major manifestations are on the airway epithelial surface, with purulent mucus, recurrent infections, chronic inflammation, and loss of lung function. Consequent to mutations in both parental genes, airway epithelial cells have insufficient CFTR function. Because this can be corrected in vitro by transfer of the normal CFTR gene into airway epithelial cells, it is reasonable to hypothesize that the respiratory manifestations of CF could be prevented by transfer of the normal human CFTR cDNA to the airway epithelium in vivo. Over the past 6 years, our laboratory has developed a strategy to accomplish this goal using a replication deficient E1−E3− recombinant adenovirus (Ad) serotype 5 vector containing the normal human CFTR cDNA (AdCFTR). Studies with experimental animals demonstrate that with administration of such a vector to the airways, the human CFTR cDNA could be transferred to the airway epithelium, with expression of the human CFTR cDNA for at least 6 weeks. Extensive preclinical studies in vitro and in vivo demonstrated that the risks to humans were sufficiently low to initiate a Phase I trial using the AdCFTR vector to treat the respiratory manifestations of CF in humans. Following approval by the National Heart, Lung, and Blood Institute Institutional Review Board, the National Institutes of Health Biosafety Committee, the National Institutes of Health Recombinant DNA Advisory Committee, and the Food and Drug Administration, we initiated the first human trial of gene therapy for CF on April 17, 1993. The clinical study is still ongoing, with safety and efficacy data being evaluated, but there is clear evidence that it is feasible to transfer and express the normal CFTR cDNA to the airway epithelium in vivo in individuals with CF.
Metabolomics: A Global Biochemical Approach to Drug Response and Disease
Authors: Rima Kaddurah-Daouk, Bruce S. Kristal, Richard M. Weinshilboum
Journal: The Annual Review of Pharmacology and Toxicology (2008)

Metabolomics is the study of metabolism at the global level. This rapidly developing new discipline has important potential implications for pharmacologic science. The concept that metabolic state is representative of the overall physiologic status of the organism lies at the heart of metabolomics. Metabolomic studies capture global biochemical events by assaying thousands of small molecules in cells, tissues, organs, or biological fluids-followed by the application of informatic techniques to define metabolomic signatures. Metabolomic studies can lead to enhanced understanding of disease mechanisms and to new diagnostic markers as well as enhanced understanding of mechanisms for drug or xenobiotic effect and increased ability to predict individual variation in drug response phenotypes (pharmacometabolomics). This review outlines the conceptual basis for metabolomics as well as analytical and informatic techniques used to study the metabolome and to define metabolomic signatures. It also highlights potential metabolomic applications to pharmacology and clinical pharmacology.
Evidence for altered hepatic matrix degradation in genetic haemochromatosis
Authors: D K George, G A Ramm, L W Powell, L M Fletcher, N I Walker, L L Cowley, D H G Crawford
Journal: Gut (1998)

Background —Altered matrix degradation contributes to fibrosis in some liver diseases but the role of matrix degradation in fibrogenesis associated with genetic haemochromatosis has not previously been addressed. Aims —To measure serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and matrix metalloproteinases (MMP), MMP-1, MMP-2, and MMP-3 in patients with haemochromatosis and control subjects. Patients —Forty patients with haemochromatosis and 19 healthy control subjects. Ten of the 40 patients were studied before and after venesection therapy. Methods —Serum levels of TIMP-1, MMP-1, MMP-2, and MMP-3 were measured by enzyme immunoassay and correlated to hepatic iron concentration and degree of histological fibrosis. Results —Serum TIMP-1 was increased in patients with haemochromatosis compared with controls (163 (30) versus 123 (28) ng/ml, p&lt;0.0002). Mean serum TIMP-1 concentration of patients with haemochromatosis without fibrosis was significantly higher than in controls (153 (16) versus 123 (28) ng/ml, p=0.03). Serum TIMP-1 concentration correlated with both hepatic iron concentration and hepatic iron index ( r =0.42, p&lt;0.01; r =0.42, p&lt;0.01). Serum MMP-2 concentrations correlated with increasing degree of fibrosis in patients with haemochromatosis ( r =0.38, p=0.01). The mean MMP-1:TIMP-1, MMP-2:TIMP-1 and age/sex matched MMP-3:TIMP-1 ratios were significantly lower in patients with haemochromatosis than controls (0.11 (0.06) versus 0.2 (0.14), p=0.02; 3.32 (0.9) versus 3.91 (0.81), p=0.05; and 0.26 (0.12) versus 0.47 (0.27), p=0.007, respectively). Following venesection, MMP-2 and MMP-3 concentrations increased by 11% (p=0.03) and 19% (p=0.03), respectively. Conclusions —This study provides the first evidence of an alteration in matrix degradation in haemochromatosis that may be a contributing factor to hepatic fibrogenesis in this disease.
Medical Marriages: Promises and Problems
Authors: Sally R. Kelly
Journal: JAMA (1997)

<h3>To the Editor.</h3> —Isn't the assessment of medical marriages in the Resident Forum article by Dr Sotile and Ms Sotile<sup>1</sup>a clarion call for action? Affirming that positive marital relationships correlate with "better, more productive" residents than those "whose marriages are foundering," the authors state that "more than 60% [of medical students] divorce within 10 years [after] residency." According to the authors, "medical training is not a time for growth [in a marriage]; it is a time for personal survival without, one hopes, damaging the relationship." Something is very wrong here. We call on the medical profession to reject the idea that palliative measures are an acceptable standard of care for medical marriages. With the Sotiles, we believe a strong, positive marriage is one of the more effective assets for success, both in medical training and in medical practice. Shouldn't we address the underlying causes rather than merely palliate
Chest Pain in Patients Seen in Emergency Clinics
Authors: herbert Berger
Journal: JAMA (1977)

<h3>To the Editor.—</h3> Unfortunately, few emergency rooms possess clinicians of the diagnostic caliber of Dr Kleiger ("Chest Pain in Patients Seen in Emergency Clinics," 236:595, 1976). Instead, the emergency room is often staffed by surgically-oriented physicians who are interested in fractures and lacerations. In community hospitals, the emergency room is handled by interns, most of whom emanate from foreign schools and function at various levels of competency. Language barriers are common. Therefore, I have preached that chest pain is an emergency to be preceded only by an arterial hemorrhage. Electrocardiograms are not to be taken, x-ray films not ordered, and no enzyme studies nor extensive history and physical examination done. Such patients should be given lidocaine intravenously or intramuscularly in the emergency room and should be conducted at once to the intensive care unit. While this procedure will certainly admit some patients who do not need it, the error in
Phase I Trial of Preoperative Doxorubicin-Based Concurrent Chemoradiation and Surgical Resection for Localized Extremity and Body Wall Soft Tissue Sarcomas
Authors: Peter W.T. Pisters, Shreyaskumar R. Patel, Victor G. Prieto, Peter F. Thall, Valerae O. Lewis, Barry W. Feig, Kelly K. Hunt, Alan W. Yasko, Patrick P. Lin, Marc G. Jacobson, Michael A. Burgess, Raphael E. Pollock, Gunar K. Zagars, Robert S. Benjamin, Matthew T. Ballo
Journal: Journal of Clinical Oncology (2004)

The primary objective of this phase I trial was to define the maximum-tolerated dose of continuous-infusion doxorubicin administered with standard preoperative radiation for patients with localized, potentially resectable soft tissue sarcomas of the extremities or body wall.Twenty-seven patients with radiographically resectable intermediate- or high-grade soft tissue sarcomas were treated. Preoperative external-beam radiation was administered in 25 2-Gy fractions (total dose, 50 Gy). Concurrent continuous-infusion doxorubicin was administered by an initial bolus (4 mg/m(2)) and subsequent 4-day continuous infusion (12.5, 15.0, 17.5, or 20.0 mg/m(2)/wk). Radiographic restaging was performed 4 to 7 weeks after chemoradiation, and patients with localized disease underwent surgical resection.Chemoradiation was completed as an outpatient procedure in 25 patients (93%). The maximum-tolerated dose of continuous-infusion doxorubicin combined with standard preoperative radiation was 17.5 mg/m(2)/wk; at this dose level, seven (30%) of 23 patients had grade 3 dermatologic toxicity. Macroscopically complete resection (R0 or R1) was performed in all 26 patients who underwent surgery. Among 22 patients who were treated with doxorubicin 17.5/mg/m(2)/wk with concurrent radiation and subsequent surgery, 11 patients (50%) had 90% or greater tumor necrosis, including two patients who had complete pathologic responses.Preoperative doxorubicin-based chemoradiation appears safe and feasible. The maximum-tolerated dose of continuous-infusion doxorubicin with standard preoperative radiation was 17.5 mg/m(2)/wk. Pathologic response rates with this regimen are encouraging.
Angiotensin-Converting Enzyme Insertion/Deletion Genotype, Exercise, and Physical Decline
Authors: Stephen B. Kritchevsky, Barbara J. Nicklas, Marjolein Visser, Eleanor M. Simonsick, Anne B. Newman, Tamara B. Harris, Ethan M. Lange, Brenda W. Penninx, Bret H. Goodpaster, Suzanne Satterfield, Lisa H. Colbert, Susan M. Rubin, Marco Pahor
Journal: JAMA (2005)

Physical performance in response to exercise appears to be influenced by the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) genotype in young adults, but whether this relationship could help explain variation in older individuals' response to exercise has not been well studied.To determine whether the ACE genotype interacts with significant physical activity to affect the incidence of mobility limitation in well-functioning older adults.The Health Aging and Body Composition (Health ABC) Cohort Study, conducted in the metropolitan areas of Memphis, Tenn, and Pittsburgh, Pa. A total of 3075 well-functioning community-dwelling adults aged 70 through 79 years were enrolled from 1997 to 1998 and had a mean of 4.1 years of follow-up.Incident mobility limitation defined as the report of difficulty walking a quarter of a mile (0.4 km) or walking up 10 steps on 2 consecutive semiannual interviews (n = 1204).Physically active participants (those reporting expending > or =1000 kcal/wk in exercise, walking, and stair climbing) were less likely to develop mobility limitation regardless of genotype. However, activity level interacted significantly with the ACE genotype (P = .002). In the inactive group, the ACE genotype was not associated with limitation (P = .46). In the active group, those with the II genotype were more likely to develop mobility limitation after adjusting for potential confounders compared with those with ID/DD genotypes (adjusted rate ratio, 1.45, 95% confidence interval, 1.08-1.94). The gene association was especially strong among participants reporting weightlifting. Exploration of possible physiological correlates revealed that among active participants, those with the II genotype had higher percentage of body fat (P = .02) and more intermuscular thigh fat (P = .02) but had similar quadriceps strength as those with ID/DD.Among older individuals who exercised, those with the ACE DD or ID genotypes were less likely to develop mobility limitation than those with the II genotype. Regardless of genotype, individuals who exercised were less likely to develop mobility limitation than those who did not exercise.
Toward a second-person neuroscience
Authors: Leonhard Schilbach, Bert Timmermans, Vasudevi Reddy, Alan Costall, Gary Bente, Tobias Schlicht, Kai Vogeley
Journal: Behavioral and Brain Sciences (2013)

Abstract In spite of the remarkable progress made in the burgeoning field of social neuroscience, the neural mechanisms that underlie social encounters are only beginning to be studied and could – paradoxically – be seen as representing the “dark matter” of social neuroscience. Recent conceptual and empirical developments consistently indicate the need for investigations that allow the study of real-time social encounters in a truly interactive manner. This suggestion is based on the premise that social cognition is fundamentally different when we are in interaction with others rather than merely observing them. In this article, we outline the theoretical conception of a second-person approach to other minds and review evidence from neuroimaging, psychophysiological studies, and related fields to argue for the development of a second-person neuroscience, which will help neuroscience to really “go social”; this may also be relevant for our understanding of psychiatric disorders construed as disorders of social cognition.
Allergen-Induced Airway Hyperresponsiveness Mediated by Cyclooxygenase Inhibition is not Dependent on 5-Lipoxygenase or IL-5, but is IL-13 Dependent
Authors: R. Peebles, K. Hashimoto, J.R. Sheller, M.L. Moore, J.D. Morrow, S. Ji, J.A. Elias, K. Goleniewska, J.F. O'Neal, D.B. Mitchell, B.S. Graham, W. Zhou
Journal: Journal of Allergy and Clinical Immunology (2006)
A defect in the formation of uropod‐bearing lymphocytes (hand‐mirror cells) in patients with the wiskott‐aldrich syndrome
Authors: Thomas P. McGraw, James D. Folds, John K. Whisnant, Terry M. Phillips, Sanford A. Stass
Journal: American Journal of Hematology (1981)

Abstract The formation of a uropod by lymphocytes (hand‐mirror cells) represents a morphologic stage of immune activation and motility in lymphocytes. Immune complexes have been previously shown to induce hand‐mirror‐cell (HMC) formation in human lymphocytes and have been associated with increased number of HMC in acute leukemia. We studied the ability of immune complexes to induce HMC in patients with Wiskott‐Aldrich syndrome (WAS), a disease of cellular immune deficiency. Our findings indicate that lymphocytes from patients with WAS adhere to immune complexes but have a defect in their ability to form HMC when compared with normal human lymphocytes. These results support the concept that immune complexes induce HMC formation and that the HMC is related to the normal cellular immune response.