tbuckley/cabot-search huggingface dataset:
Expression of phosphorylated Stat3, cyclin D<sub>1</sub> and Bcl-xL in extramammary Paget disease
Authors: H.J. Liu, Y. Moroi, T. Masuda, S. Yasumoto, H. Kokuba, S. Imafuku, T. Koga, T. Tetsuya, Y.T. Tu, H. Aburatani, M. Furue, K. Urabe
Journal: British Journal of Dermatology (2005)

Stat3 (Signal transducer and activator of transcription-3) is an oncogene that plays a critical role in regulating fundamental processes associated with malignant transformation and cell survival. It participates in oncogenesis through upregulation of genes encoding apoptosis inhibitors (Bcl-xL) and cell cycle regulators (cyclin D1). The expression of Stat3, Bcl-xL and cyclin D1 protein has not been investigated in extramammary Paget disease (EMPD).To study the expression of phosphorylated Stat3 (p-Stat3), Bcl-xL and cyclin D1 protein in EMPD and to evaluate the relationships among them.Thirty-six tissue samples from 34 patients with primary EMPD were subjected to immunohistochemical staining for p-Stat3, cyclin D1 and Bcl-xL.Thirty-five of 36 specimens were clearly positive for p-Stat3 in EMPD, while 30 of 36 and 32 of 36 were positive for cyclin D1 and Bcl-xL expression, respectively. In all of four invasive EMPD specimens, strong and frequent expression of these three molecules was evident; moreover, two invasive EMPD specimens with lymph nodal metastasis showed very strong nuclear and membranous p-Stat3 staining. Two metastatic lymph node specimens showed very strong nuclear and local membrane p-Stat3 staining. There were significant correlations between p-Stat3 and cyclin D1 expression and between p-Stat3 and Bcl-xL expression.Our study shows that the expression of p-Stat3, cyclin D1 and Bcl-xL may play a pivotal role in the pathogenesis of EMPD.
Problems with current catecholamine hypotheses of antidepressant agents: Speculations leading to a new hypothesis
Authors: Eric A. Stone
Journal: Behavioral and Brain Sciences (1983)

Problems with current hypotheses of catecholamine involvement in antidepressant action are reviewed. The theories examined include those that attribute a key role to increased brain norepinephrine (NE) availability or to the desensitization of brain beta adrenergic receptors. Although these hypotheses are consistent with a great deal of relevant laboratory and clinical data there arc an increasing number of findings that cannot be explained by them. These contradictions include findings on the lag time between pharmacological and therapeutic effects of antidepressants, the actions of propranolol and thyroid hormones on depression, the relationship between cortisol secretion and depression, the net effect of chronic antidepressants on noradrenergic neurotransmission, and the functions of cyclic AMP in the CNS. To reconcile the discordant data in these areas of research, a new formulation, the output hypothesis, which is derived from the foregoing theories, is proposed. The new hypothesis assumes that depression or adverse behavioral effects of stress results when the output of brain cells bearing noradrenergic receptors is too low to meet increased demand resulting from stress or other biologically disruptive events. According to this view antidepressants act by a mechanism akin to adaptation to chronic stress in which there is a prolonged increase in postsynaptic noradrenergic receptor activation in the brain. The prolonged increase is necessary for NE to induce, via the beta adrenoceptor–cAMP system, trophic or long-term metabolic effects that increase the output of catecholamine effector cells to a level commensurate with demand.
DNA methylation-independent loss of RARA gene expression in acute myeloid leukemia
Authors: Annegret Glasow, Angela Barrett, Kevin Petrie, Rajeev Gupta, Manuel Boix-Chornet, Da-Cheng Zhou, David Grimwade, Robert Gallagher, Marieke von Lindern, Samuel Waxman, Tariq Enver, Guido Hildebrandt, Arthur Zelent
Journal: Blood (2007)
Effect of Radiation Therapy on Survival in Patients With Resected Merkel Cell Carcinoma
Authors: Julian A. Kim, Audrey H. Choi
Journal: JAMA Dermatology (2013)

<h3>Importance</h3> Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignant neoplasm that can be highly aggressive and ultimately lethal. However, the cumulatively low incidence rate has made it difficult to accrue patients to prospective randomized trials. <h3>Objective</h3> To determine whether patients with MCC in the Surveillance, Epidemiology, and End Results (SEER) database who received radiation therapy after resection demonstrate improved survival. <h3>Design</h3> The study population consisted of SEER patients with histologically confirmed MCC who underwent surgical resection between January 1, 1998, and December 30, 2006. Cox proprotional hazards regression models were used to determine factors associated with MCC-specific and overall survival. Propensity scoring with matched pairs was used to perform Kaplan-Meier survival analysis comparing patients who underwent surgery plus radiation therapy vs those who underwent surgery alone. <h3>Setting and Participants</h3> National database study of participants at least 20 years old with MCC, matched for age, sex, race/ethnicity, diagnosis period, tumor size, disease stage, surgery of the primary site, type of lymph node surgery, and geographic region. Exclusion criteria included survival of less than 4 months and metastatic disease. <h3>Main Outcomes and Measures</h3> Disease-specific survival and overall survival. <h3>Results</h3> Factors that were independently associated with the use of radiation therapy included marital status, disease stage, and type of lymph node surgery. Factors associated with both MCC-specific and overall survival included age and disease stage. Propensity scoring and matched-pair analysis resulted in 269 matched pairs of patients and demonstrated that patients who received radiation therapy had improved overall survival (<i>P</i> = .03) but not MCC-specific survival (<i>P</i> = .26). <h3>Conclusions and Relevance</h3> The improvement in overall survival among SEER patients who receive radiation therapy following surgical resection of MCC may be a result of selection bias or unmeasured factors and not radiation therapy.
Disclosure of Financial Relationships to Participants in Clinical Research
Authors: Kevin P. Weinfurt, Mark A. Hall, Nancy M.P. King, Joëlle Y. Friedman, Kevin A. Schulman, Jeremy Sugarman
Journal: New England Journal of Medicine (2009)

The authors review the potential goals of disclosing investigators' financial relationships to research participants and discuss the limitations of disclosure in achieving these goals. They note that equity interests are especially problematic and should be limited or avoided rather than simply disclosed.
Trends in tar, nicotine, and carbon monoxide yields of UK cigarettes manufactured since 1934.
Authors: N Wald, R Doll, G Copeland
Journal: BMJ (1981)

The tar, nicotine, and carbon monoxide yields of cigarettes manufactured in the United Kingdom between 1934 and 1979 were studied. Over this period the average tar yield decreased by 49%, the nicotine yield by 31%, the carbon monoxide yield by 11%, all estimated on a sales-weighted basis. The average tar yield decreased progressively after the second world war, owing both to the introduction of filter cigarettes and to changes in the manufacture of plain cigarettes. The average nicotine yield increased initially, decreased by 43% from about 1950 to 1974, but increased again by 9% between 1974 and 1979. The average carbon monoxide yield started to decrease after about 1961; while it decreased substantially in plain cigarettes, the rapid increase in sales of filter cigarettes at this time, at the expense of plain cigarettes, largely offset the reduction in carbon monoxide yield that would otherwise have occurred. As with nicotine, carbon monoxide yield showed a small rise in later years (4% between 1976 and 1979). The trends in tar yield may well explain the reduction in lung cancer in the UK better than has been suspected hitherto. The trends in nicotine and carbon monoxide yields are probably not sufficiently different to distinguish which of them might be the more likely cause of cardiovascular disease.
Benefits of Cardiac Resynchronization Therapy for Heart Failure Patients With Narrow QRS Complexes and Coexisting Systolic Asynchrony by Echocardiography
Authors: Cheuk-Man Yu, Yat-Sun Chan, Qing Zhang, Gabriel W.K. Yip, Chi-Kin Chan, Leo C.C. Kum, LiWen Wu, Alex Pui-Wai Lee, Yat-Yin Lam, Jeffrey Wing-Hong Fung
Journal: Journal of the American College of Cardiology (2006)
Grants for New Hospitals
Authors: R. S. Murley
Journal: BMJ (1955)

Consolidation therapy is used in order to maximize the benefit of first-line therapy and to improve the progression-free and overall survival of patients. In women with advanced epithelial ovarian cancer, tested maintenance and consolidation strategies following first-line chemotherapy include high-dose chemotherapy, radiation therapy, intraperitoneal radionuclides including those linked to an antibody, and biological and immunologic agents. This review focuses on the current understanding of the benefit of radiation therapy and biological agents used as consolidation in women with advanced ovarian cancer. Whole abdominal radiation has given promising results only in the subgroup of patients with pathologic complete response. However, this treatment modality is associated with considerable intestinal toxicity. Single treatment with intraperitoneal radionuclides, either alone (<sup>32</sup>P) or in combination with an antibody (<sup>90</sup>Y-muHMFG1) has not improved survival. Biological agents used for consolidation include, eg, α- and γ-interferon, tanomastat, a matrix metalloprotease inhibitor and oregovomab, a murine antibody that targets CA125. Randomized trials with these agents have not demonstrated any significant improvement in the overall survival of ovarian cancer patients. Currently, two ongoing studies (GOG 218, ICON7) are examining the potential of bevacizumab in the maintenance therapy of advanced epithelial ovarian cancer. Evaluation of new agents is indicated in order to achieve long-term disease-free survival in these patients. Toxicity and ease of administration must be reflected against the benefits of therapy.
Bladder Cancer — Field versus Clonal Origin
Authors: Adrian L. Harris, David E. Neal
Journal: New England Journal of Medicine (1992)

THE paper in this issue of the Journal by Sidransky and his colleagues on the clonal origin of multiple tumors of the bladder1 augments our understanding of genetic changes in the bladder during early neoplasia and has implications for other common cancers. Transitional-cell cancer of the urinary bladder has an incidence rate of 15 in 100,000 and a mortality rate of 4 in 100,000; these rates increase steeply between 50 and 65 years of age and are four to five times higher in men. As with most tumors, the cause of bladder tumors is multifactorial, but exposure to chemical carcinogens . . .
Hodgkinʼs Disease Presenting as a Solitary Thyroid Nodule
Authors: RUTH HARDOFF, RACHEL BAR-SHALOM, MURALEE DHARAN, RAFAEL LUBOSHITSKY
Journal: Clinical Nuclear Medicine (1995)

Two patients with unusual Hodgkin's disease who initially had a painless, solitary, thyroid cold nodule are described. Fine-needle aspiration revealed lymphocytic thyroiditis in one patient and a diagnosis of Hodgkin's disease was made 1 year later. In the second patient, aspiration of the nodule demonstrated a syncytial variant of nodular sclerosis Hodgkin's disease. Both patients underwent radiologic work-up, and surgery of the thyroid was avoided. After chemotherapy, both thyroid nodules disappeared. Thyroid involvement by Hodgkin's disease may be more common than anticipated, and may present atypically as a solitary thyroid nodule. Lymphocytic thyroiditis may accompany the disease and may cause a delay in the diagnosis. Recognition of this entity and the use of fine-needle aspiration may prevent unnecessary thyroid surgery, thus maintaining intact thyroid function after therapy.
Induction of IL-4Rα–dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4–driven murine macrophage proliferation in vivo
Authors: Dominik Rückerl, Stephen J. Jenkins, Nouf N. Laqtom, Iain J. Gallagher, Tara E. Sutherland, Sheelagh Duncan, Amy H. Buck, Judith E. Allen
Journal: Blood (2012)
Management of the Ambulatory Diabetic Patient
Authors: John W. Runyan, David Hurwitz
Journal: New England Journal of Medicine (1954)

WITH the large and ever-increasing diabetic population, it is essential for all physicians to have a working knowledge of the diagnosis and treatment of this disease. Since we are convinced that the diagnosis and management of newly discovered diabetes should be conducted on an ambulatory basis, this paper describes a method used in a large outpatient clinic that can readily be adapted to the handling of private patients.A person with newly discovered diabetes who is told that hospitalization is necessary becomes unduly alarmed about the gravity of his disease. If regulated in the hospital, the regimen often requires major . . .
Longitudinal study of living kidney donor glomerular dynamics after nephrectomy
Authors: Colin R. Lenihan, Stephan Busque, Geraldine Derby, Kristina Blouch, Bryan D. Myers, Jane C. Tan
Journal: Journal of Clinical Investigation (2015)

BACKGROUND. Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors.
Functional heterogeneity of oxygen supply-consumption ratio in the heart
Authors: C Zuurbier
Journal: Cardiovascular Research (1999)

In this review, the regional heterogeneity of the oxygen supply-consumption ratio within the heart is discussed. This is an important functional parameter because it determines whether regions within the heart are normoxic or dysoxic. Although the heterogeneity of the supply side of oxygen has been primarily described by flow heterogeneity, the diffusional component of oxygen supply should not be ignored, especially at high resolution (tissue regions ≪ 1 g). Such oxygen diffusion does not seem to take place from arterioles or venules within the heart, but seems to occur between capillaries, in contrast to data recently obtained from other tissues. Oxygen diffusion may even become the primary determinant of oxygen supply during obstructed flow conditions. Studies aimed at modelling regional blood flow and oxygen consumption have demonstrated marked regional heterogeneity of oxygen consumption matched by flow heterogeneity. Direct, non-invasive indicators of the balance between oxygen supply and consumption include NADH videofluorimetry (mitochondrial energy state) and microvascular PO2 measurement by the Pd-porphyrin phosphorescence technique. These indicators have shown a relatively homogeneous distribution during physiological conditions supporting the notion of regional matching of oxygen supply with oxygen consumption. NADH videofluorimetry, however, has demonstrated large increases in functional heterogeneity of this ratio in compromised hearts (ischemia, hypoxia, hypertrophy and endotoxemia) with specific areas, referred to as microcirculatory weak units, predisposed to showing the first signs of dysoxia. It has been suggested that these weak units show the largest relative reduction in flow (independent of absolute flow levels) during compromising conditions, with dysoxia initially developing at the venous end of the capillary.
New Drugs: Angiotensin converting enzyme inhibitors
Authors: A. Breckenridge
Journal: BMJ (1988)

The development of angiotensin converting enzyme inhibitors is often cited as a prime example of task oriented research. The truth is far from this, and, as so often, chance played a large part in the development of this group of drugs. Some 25 years ago a group of Brazilian pharmacologists was searching for substances that would block the inactivation of bradykinin, a process subsequently shown to take place in man in the pulmonary vascular bed. It was shown that this was also the site for the conversion of angiotensin I to the potent vasoconstrictor angiotensin II, and the two processes were controlled by enzymes that, if not the same, were very similar. It has been appreciated for many years that the renin-angiotensin aldosterone system is important in the control of blood pressure. Most early stratagems to lower blood pressure clinically, however, were based on manipulating the sympathetic nervous system, and attempts to perturb the renin-angiotensin-aldosterone system came much later. The use of effective orally active angiotensin converting enzyme inhibitors depended on translating the experiences of pharmacologists, who were interested primarily in the breakdown of bradykinin, to physiologists, who were interested in the mechanisms of controlling blood pressure, and then using the skills of medicinal chemists and clinical pharmacologists to design and test suitable compounds. A recent review by Ferreira, an important figure in the early development of this subject, details this interesting story.1 There are currently two orally active angiotensin converting enzyme inhibitors available in the United Kingdom, captopril and enalapril. Some 20 compounds that have a similar pharmacological activity are in, various stages of development, several of them having been already given to volunteers and patients. This review will concentrate on the two marketed products because, as will be seen below, a risk-benefit analysis for angiotensin converting enzyme inhibitors can be made only after extensive exposure of patients, and any assessment of new members of the group is difficult. I will therefore compare captopril and enalapril with respect to their pharmacology, relative efficacy, and relative toxicity.
You can't get there from here: Foundationalism and development
Authors: Jedediah W. P. Allen, Mark H. Bickhard
Journal: Behavioral and Brain Sciences (2011)

Abstract The thesis of our commentary is that the framework used to address what are taken by Carey to be the open issues is highly problematic. The presumed necessity of an innate stock of representational primitives fails to account for the emergence of representation out of a nonrepresentational base. This failure manifests itself in problematic ways throughout Carey's book.
Exposure to polycyclic aromatic hydrocarbons among Dutch children.
Authors: J H van Wijnen, R Slob, G Jongmans-Liedekerken, R H van de Weerdt, F Woudenberg
Journal: Environmental Health Perspectives (1996)

We determined the urinary 1-hydroxypyrene (1-HP) concentration and the creatinine-adjusted 1-HP concentration in 644 randomly selected Dutch children, aged 1-6 years and living in five areas with roughly different levels of polycyclic aromatic hydrocarbons (PAHs) in soil and ambient air. The presence of other factors that might influence the exposure to PAHs was studied using a questionnaire. To evaluate the reliability of a single urinary 1-HP determination, measurements were repeated after 3 weeks for approximately 200 children. The mean urinary 1-HP content of the total study population was 2.06 nmol/l. This varied from 1.58 nmol/l in the reference area (Flevoland) to 2.71 nmol/l in the valley of the Geul. Only indoor sources of PAHs showed a small, positive association with urinary 1-HP. The urinary 1-HP concentrations of children from the valley of the Geul were higher (p < 0.01) and those of children from a suburb of Amsterdam were lower (p < 0.01) than those of children from the reference area. The possible ambient environment-related differences were probably too small to be detected in the variations of the intake of PAHs from the daily diet. The reliability of a single 1-HP measurement was low. Similar results were obtained with the creatinine-adjusted data. In one neighborhood built on coal-mine tailings, the urinary 1-HP content in children was weakly but positively associated with the PAH content in the upper soil layer of the garden of their homes. However, this association was not found for the children from the other neighborhood built on coal-mine tailings and with similar PAH levels in soil.
A PATIENT WHO CHANGED MY LIFE
Authors: W. Angus
Journal: BMJ (1996)

The year was 1988. Pamela—not her real name—had just had her first baby, a beautiful healthy little girl. From being vivacious and happy Pamela became morose and tearful. There was no doubt that she had developed postnatal depression. In the days that followed it became apparent that there were underlying fears and anxieties that I had not uncovered. These centred around mistrust and sexual concerns. For the first time I asked the patient if she had been sexually abused as a child. To my …
First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats
Authors: Morando Soffritti, Fiorella Belpoggi, Davide Degli Esposti, Luca Lambertini, Eva Tibaldi, Anna Rigano
Journal: Environmental Health Perspectives (2005)

The Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation has conducted a long-term bioassay on aspartame (APM), a widely used artificial sweetener. APM was administered with feed to 8-week-old Sprague-Dawley rats (100-150/sex/group), at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. The treatment lasted until natural death, at which time all deceased animals underwent complete necropsy. Histopathologic evaluation of all pathologic lesions and of all organs and tissues collected was routinely performed on each animal of all experimental groups. The results of the study show for the first time that APM, in our experimental conditions, causes a) an increased incidence of malignant-tumor-bearing animals with a positive significant trend in males (p < or = 0.05) and in females (p < or = 0.01), in particular those females treated at 50,000 ppm (p < or = 0.01); b) an increase in lymphomas and leukemias with a positive significant trend in both males (p < or = 0.05) and females (p < or = 0.01), in particular in females treated at doses of 100,000 (p < or = 0.01), 50,000 (p < or = 0.01), 10,000 (p < or = 0.05), 2,000 (p < or = 0.05), or 400 ppm (p < or = 0.01); c) a statistically significant increased incidence, with a positive significant trend (p < or = 0.01), of transitional cell carcinomas of the renal pelvis and ureter and their precursors (dysplasias) in females treated at 100,000 (p < or = 0.01), 50,000 (p < or = 0.01), 10,000 (p < or = 0.01), 2,000 (p < or = 0.05), or 400 ppm (p < or = 0.05); and d) an increased incidence of malignant schwannomas of peripheral nerves with a positive trend (p < or = 0.05) in males. The results of this mega-experiment indicate that APM is a multipotential carcinogenic agent, even at a daily dose of 20 mg/kg body weight, much less than the current acceptable daily intake. On the basis of these results, a reevaluation of the present guidelines on the use and consumption of APM is urgent and cannot be delayed.