tbuckley/cabot-search huggingface dataset:
Evaluation of Utility of Pharmacokinetic Studies in Phase I Trials of Two Oncology Drugs
Authors: Kehua Wu, Larry House, Jacqueline Ramírez, Michael J. Seminerio, Mark J. Ratain
Journal: Clinical Cancer Research (2013)

Abstract Purpose: There are many phase I trials of oncology drug combinations, very few of which report clinically significant pharmacokinetic interactions. We hypothesized that the utility of such pharmacokinetic drug–drug interaction (DDI) studies is low in the absence of a mechanistic hypothesis. Experimental Design: We retrospectively reviewed 152 phase I (two drug) combination studies published between 2007 and 2011. Results: Only 28 (18%) studies had an implicit or explicit rationale, either inhibition/induction of a drug-metabolizing enzyme or transporter, cosubstrates for the same enzyme or transporter, potential for end-organ toxicity, or protein binding. Only 12 (8%) studies demonstrated a statistically significant DDI, on the basis of change in clearance (or area under the curve) of parent drug and/or active metabolite. There was a strong association between a rationale and a demonstrable drug interaction, as only 2% of studies without a rationale demonstrated a DDI, compared with 32% of studies with a rationale (Fisher exact test; P &amp;lt; 10−6). Conclusion: DDI studies should not be routinely performed as part of phase I trials of oncology combinations. Clin Cancer Res; 19(21); 6039–43. ©2013 AACR.
Detecting dic(9;20)(p13.2;p11.2)-positive B-cell precursor acute lymphoblastic leukemia in a clinical setting using fluorescence in situ hybridization
Authors: V Zachariadis, J Schoumans, I Öfverholm, G Barbany, E Halvardsson, E Forestier, B Johansson, M Nordenskjöld, A Nordgren
Journal: Leukemia (2013)
LESIONS OF THE EXTREMITIES ASSOCIATED WITH DIABETES MELLITUS
Authors: FREDERICK A. COLLER
Journal: JAMA (1925)

It is a truism that persons with diabetes mellitus are prone to develop infection and that the feet are frequently involved. It is also well known that gangrene of the extremities is a common complication of this  disease. These two factors, infection and arterial occlusion, produce in the extremity, and particularly in the lower extremity, a variety of lesions that it is important to recognize from the standpoints of prognosis and treatment. A series of fifty-two cases of diabetes mellitus with associated lesions of the extremities has been observed in the University Hospital during the last four years. The cases were unselected and represent 8 per cent, of all cases of diabetes mellitus seen during this time. This incidence is probably higher than would be found in ordinary practice. It is our purpose in this communication to analyze and classify the cases in this series and to discuss the diagnosis,
The Diagnosis and Treatment of Depression in the Old
Authors: Max Fink
Journal: JAMA (1988)

To the Editor.—  A letter by Kushnir 1 testifies to the resolution of a depressive disorder in a 102-year-old woman by three drug trials and 40 days of treatment. It is unclear why the physician eschewed the use of electroconvulsive therapy in such a case when the first drug trial failed. The successful and safe use of electroconvulsive therapy in elderly depressed patients, including those with syndromes of pseudodementia, is well documented. 2-6 The risks of repeated drug trials, and the use of new drug treatments with limited experience, does a disservice to elderly patients who often are more rapidly and more safely treated by modified electroconvulsive therapy than by antidepressant drugs.
Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin
Authors: Michael J. Liguori, Mark G. Anderson, Stanley Bukofzer, James McKim, Jeffrey F. Pregenzer, Jacques Retief, Brian B. Spear, Jeffrey F. Waring
Journal: Hepatology (2005)

Idiosyncratic drug toxicity, defined as toxicity that is dose independent, host dependent, and usually cannot be predicted during preclinical or early phases of clinical trials, is a particularly confounding complication of drug development. An understanding of the mechanisms that lead to idiosyncratic liver toxicity would be extremely beneficial for the development of new compounds. We used microarray analysis on isolated human hepatocytes to understand the mechanisms underlying the idiosyncratic toxicity induced by trovafloxacin. Our results clearly distinguish trovafloxacin from other marketed quinolone agents and identify unique gene changes induced by trovafloxacin that are involved in mitochondrial damage, RNA processing, transcription, and inflammation that may suggest a mechanism for the hepatotoxicity induced by this agent . In conclusion, this work establishes the basis for future microarray analysis of new compounds to determine the presence of these expression changes and their usefulness in predicting idiosyncratic hepatotoxicity. Supplementary material for this article can be found on the Hepatology website ( http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html ). (Hepatology 2005;41:177–186.)
Analytical subcellular fractionation of human heart: a comparison of left and right ventricle with hypertrophic obstructive myopathic tissue
Authors: D. H. FITCHETT, G. WELLS, T. J. PETERS
Journal: Cardiovascular Research (1979)

Enzymic microanalysis in combination with analytical subcellular fractionation by density gradient centrifugation has been used to compare left ventricular myocardium (papillary muscle from patients with rheumatic mitral valve disease) and right ventricular myocardium (infundibulum resected from patients with Tetralogy of Fallot). In addition the subcellular pathology of left ventricular out-flow tract tissue from patients with hypertrophic obstructive cardiomyopathy was investigated. In the non-cardiomyopathic tissue the principal organelles have been characterised by their enzymic content. Increased activities of sarcolemma enzymes (5'-nucleotidase, Na+, K+-activated Mg2+-dependent ATPase) and of lysosomal enzymes (N-acetyl-β-glucosaminidase) were found in the right ventricular infundibular myocardium compared with left ventricle papillary muscle. Increased lysosomal integrity was noted in right ventricular extracts. Density gradient centrifugation experiments indicated that the density of the lysosomes and sarcoplasmic reticulum was greater in the right ventricle. In hypertrophic obstructive myopathic tissue, compared with non-myopathic left ventricular papillary muscle, increased activities of certain mitochondrial enzymes (Mg2+-dependent ATPase, monoamine oxidase), sarcolemma, lysosomal, and sarcoplasmic reticulum enzymes were noted. Subcellular fractionation studies showed a small increase in median density of the sarcolemma. By analogy with the hereditary cardiomyopathic hamster it is suggested that the primary lesion in human hypertrophic obstructive cardiomyopathy may reside in the sarcolemma. Changes in the other organelles could be secondary to the sarcolemmal changes.
Abstract 5262: The role of Bcl-2 in colon cancer metastatic progression
Authors: Wang Wang, Chandrakanth Are, Michael G. Brattain
Journal: Cancer Research (2011)

Abstract Colon cancer is the second most lethal malignancy in the United States. The majority of deaths are related to metastasis, for which no effective therapies are currently available. While much is known about oncogenic initiation of colon cancer, the mechanisms by which cancer cells survive and metastasize in spite of the cellular stresses associated with this process require further investigation. Recent studies indicated that deregulation of apoptosis contributes to metastasis, and deregulation of Bcl-2 family members, which control the mitochondrial-dependent apoptosis pathway, is correlated with cancer progression. We have initiated these studies using a unique othotopic implant model based on closely related colon cancer cell lines. HCT116 and HCT116b cells were isolated from the same primary colon tumor and both bear the H1047R PIK3CA mutation and form progressively growing invasive orthotopic primary tumors. However, only HCT116 cells exhibit metastatic potential. Interestingly, we found that Bcl-2 is highly expressed in HCT116 cells, but not in HCT116b cells. Overexpression of exogenous Bcl-2 in HCT116b cells, and complementary studies by shRNA mediated stable knockdown and overexpression of dominant negative forms of Bcl-2 molecule in metastatic HCT116 cells indicated that Bcl-2 is essential for their ability to withstand external stress. Current studies in our orthotopic model demonstrated that HCT116b tumors bearing exogenous Bcl-2 associated with increased cell survival and reduced center necrosis. Future study will determine whether this significant alteration in the expression of Bcl-2 associates with the distal metastatic capability of colon cancer. 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 5262. doi:10.1158/1538-7445.AM2011-5262
Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma.
Authors: E Samojlik, J D Veldhuis, S A Wells, R J Santen
Journal: Journal of Clinical Investigation (1980)

We evaluated the comparative effects of aminoglutethimide (AG) on androgen and estrogen levels estrone ([E1], estradiol [E2], plasma dehydroepiandrosterone-sulfate [DHEA-S], testosterone [T], dihydrotestosterone [DHT], delta 4-androstenedione [delta 4-A]), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin in postmenopausal patients with breast cancer randomly allocated to either AG treatment or bilateral surgical adrenalectomy as a control group. In response to either treatment, the plasma levels of E1 fell 62-75% (P less than 0.001) and urine E1 85.7-88.7% (P less than 0.001) in all study days over a 12-wk period. Similarly, the concentrations of E2 in plasma and urine fell 40-72% without statistically significant differences between the two treatment modalities. The relatively weak androgen, DHEA-S, was reduced by 92% (877.3 +/- 184.6 to 71.8 +/- 14.5 ng/ml) at 12 wk in women treated with AG, but suppressed nearly 99% (1,151 +/- 262 to 5.8 +/- 3.3 ng/ml) in adrenalectomized women. At all time points after treatment, the DHEA-S levels were significantly higher in patients receiving AG. Plasma concentrations of the potent androgens, T and DHT, were also relatively preserved during AG treatment. T levels were never significantly reduced by AG, and DHT concentrations were decreased only at the 4th wk to a maximum of 20%. delta 4-A levels fell 56% in response to this drug only on the 12th wk of therapy (basal, 0.79 +/- 0.09 ng/ml; 12 wk, 0.35 +/- 0.07 ng/ml). In marked contrast, all androgens fell significantly at each time period in response to surgical adrenalectomy, with an 81% maximum suppression of T, 73% of DHT, and 97% of delta 4-A. In response to estrogen suppression, plasma levels of FSH, LH, and prolactin did not change significantly throughout the treatment period in either therapy group. To examine possible contributions of the postmenopausal ovary to hormone levels during therapy, data from surgically castrate and spontaneously menopausal women were evaluated separately. No significant differences between the two groups were observed for E1, E2, T, DHT, DHEA-S, delta 4-A, LH, FSH, and prolactin. We conclude that equivalent and highly significant estrogen suppression occurs with either AG or surgical adrenalectomy although androgen secretion is preserved during AG treatment but not after surgical adrenalectomy. The combined effects of estrogen deprivation associated with androgen preservation might be significant in the therapeutic action of AG in hormone-responsive neoplasms.
The Psychedelic Plague and Polypsychotropia
Authors: Patrick T. Donlon
Journal: JAMA (1971)

Mankind has experienced numerous plagues throughout history. Often the morbidity seriously hampered the functioning of the stricken society. Most frequently, the physicians of antiquity were unable to successfully treat or prevent the spread of the plagues. They had to experience the anguish and frustration of observing the disease run its natural course. Multiple causative factors were responsible for the origins of the plagues. Among them were such social problems as population overcrowding and inadequate sanitation. Thus any treatment program would have required both the recognition and correction of the social causative factors as well as development of medical cures for those who became diseased. In the past decade the Western world has experienced a new plague. It too has placed a great social and financial burden on society. This plague differs notably from previous ones in two ways. First, the noxious agent is not an infectious disease but a series
Blood Coagulation Changes during Mid-trimester Abortion Induced by Prostaglandin F2 
Authors: M. H. H. Badraoui, J. Bonnar, K. Hillier, M. P. Embrey
Journal: BMJ (1973)

Serial studies on the coagulation system were made during second-trimester abortion induced by extra-amniotic, intra-amniotic, vaginal, and intravenous prostaglandin F<sub>2</sub>α. No significant changes were found in the prothrombin time, partial thromboplastin time, or levels of fibrin-fibrinogen degradation products. An increase in the activity of factor X occurred with all routes of administration; the activity of factor VIII increased during extra-amniotic, vaginal, and intravenous administration; factor V activity increased during extra-amniotic and vaginal administration; and the activity of factor VII-X complex increased slightly at the time of abortion with all methods. The findings suggest that though prostaglandin induction of second-trimester abortion produces changes in the coagulation system the effects are much less than those which accompany induction of abortion by hypertonic saline or abdominal delivery in late pregnancy.
Plasma and lipoprotein cholesterol and triglyceride concentrations in the Pima Indians: distributions differing from those of Caucasians.
Authors: B V Howard, M P Davis, D J Pettitt, W C Knowler, P H Bennett
Journal: Circulation (1983)

Plasma and lipoprotein cholesterol and triglyceride concentrations were measured in Pima Indians, a genetically homogeneous population with a high prevalence of obesity and diabetes and a low frequency of coronary heart disease. The data for nondiabetic Pima Indians were compared with those of U.S. Caucasians measured during the Lipid Research Clinics Prevalence Study. Plasma total and low-density lipoprotein (LDL) cholesterol levels in Pima men older than 30 years of age and in women over 25 were lower than those of U.S. Caucasians, and in men the total and LDL cholesterol levels did not increase with age. In Pima male subjects of all ages high-density lipoprotein (HDL) cholesterol levels were lower than that in Caucasian male subjects, and in Pima female subjects HDL cholesterol levels averaged 11 mg/dl lower than those in female Caucasian subjects. On the other hand, plasma triglyceride levels in Pima male subjects up to 35 years of age and in female subjects up to 55 years old were higher than those of Caucasians. Comparison of plasma cholesterol and triglyceride levels in Pima male and female subjects showed the same relationships as those in Caucasians (i.e., higher in male subjects until the older age groups), but Pima male and female subjects had similar HDL cholesterol levels. There was a strong negative correlation between obesity and HDL cholesterol levels in Pimas. Obesity appeared to account for the lower HDL cholesterol levels in Pima male subjects compared with that in Caucasian male subjects, but obesity could not explain the lack of differences between the sexes in HDL levels in the Pimas. Triglyceride levels correlated positively with obesity in the Pimas, but the relationship was not as strong as that reported for Caucasians. The results indicate that there are differences in lipoprotein distributions between Pimas and U.S. Caucasians; the relationship between lipoprotein levels and the incidence of coronary disease in the Pimas must be determined.
Nightmares and Hobbyhorses: Swift, Sterne, and Augustan Ideas of Madness
Authors: Lester S. King
Journal: JAMA (1975)

In a somewhat uneven but nevertheless stimulating fashion, the author concerns himself with "madness," melancholy, and insanity and their relations to literature and culture of the early 18th century. The criteria of madness and the theories of mental disorder during this period are abundantly discussed, with major attention devoted to Swift and Sterne, together with many minor figures. There are numerous comments on philosophers and physicians, especially Locke and Willis, Descartes and Hobbs, Sydenham, Charleton, Cheyne, and a liberal sprinkling of lesser figures. This is definitely not a history of 18th century medical psychology, nor of medical history, nor yet of literature, but a combination that will illuminate all of them and integrate the study of literature into the cultural milieu—the "age of reason" and the "scientific revolution." The first chapter, discussing abnormal psychology in England, is an overview of both medical and literary ideas and serves to set the
Reactivity of tixocortol pivalate-positive patients in intradermal and oral provocation tests
Authors: L. RÄSÄNEN, M.-L. TUOMI, L. YLITALO
Journal: British Journal of Dermatology (1996)

Pivalone/tixocortol pivalate commonly yields positive reactions in the patch test series. The clinical relevance of these positive reactions was investigated in more detail. In the standard patch test series 5.6% (73 of 1306) of the patients were positive to corticosteroids, 5.2% to 0.1% tixocortol pivalate in ethanol (Pivalone nasal spray diluted 1:10) and 2.3% to 1% hydrocortisone butyrate in ethanol. Some of the patients were tested in parallel with Pivalone and 1% tixocortol pivalate in petrolatum. The former test reagent yielded some false-positive reactions, whereas with the latter, some allergic responses were missed. Intradermal tests with the succinate esters of hydrocortisone, methylprednisolone and prednisolone were performed with 52 patients positive to Pivalone. Of these 76.9% (40 of 52) were positive in the intradermal tests; 38 to hydrocortisone, 35 to methylprednisolone and 30 to prednisolone. Twelve patients who had been positive in the intradermal tests were challenged orally with corticosteroids and they all showed positive reactions to hydrocortisone, methylprednisolone or prednisolone. The patients developed localized reactions at the sites of previous eczema or positive skin tests or diffuse erythema or exanthema. The oral doses of hydrocortisone eliciting positive delayed skin reactions ranged from 20 to 200 mg. Reactivity to tixocortol pivalate is closely related to sensitivity to hydrocortisone, methylprednisolone and prednisolone, but high oral doses of these corticosteroids may be required to produce allergic symptoms.
THE RELATIONSHIP OF VARIOLA AND VACCINIA
Authors: P. M. ASHBURN
Journal: JAMA (1913)

The relationship of variola and vaccinia has been discussed since Jenner's day, but no satisfactory explanation found. Yet there is an explanation so simple, complete and satisfactory that as thorough an investigation of the literature as I have been able to make in Manila in three months does not reveal any evidence in opposition, and does yield an amount of support that seems almost to constitute proof. <h3>I. BASIC FACTS</h3> 1. Small-pox contagion or inoculation gives rise in man to small-pox, a highly contagious, generalized disease of considerable mortality, characterized ordinarily by a preemptive stage, and other stages related to the appearance, development and subsidence of the eruption. 2. Passed through monkeys and cattle for a few generations and brought back to man, the virus gives rise to vaccinia, a localized, non-contagious, mild disease, that in itself causes no mortality, though septic complications may cause some. 3. Having, by passage, once
Support for Health-Science Libraries
Authors: Norman Q. Brill
Journal: JAMA (1965)

Critical deficiencies exist in the area of medical communications, especially in medical libraries. Within recent years these defects have been documented very adequately by numerous groups, including the American Medical Association; the Association of American Medical Colleges; the President's Commission on Heart Disease, Cancer and Stroke; the Medical Library Association; and the National Library of Medicine, among others. There seems to be firm agreement that the deficiencies go considerably beyond the frustrations of the medical-school librarian who insists that his budget is too small, or the complaints of the students, teachers, or practitioners who cannot find particular articles they desire. The consensus seems to be that failure to meet the needs of the health-science libraries could indirectly threaten the health efforts of the entire nation. <h3>Pending Legislation</h3> On Jan 19, 1965, Senator Lister Hill and Representative Oren Harris introduced in the Senate and House, respectively, the medical library assistance act
WATERBORNE CHOLERA.An Address delivered before the Forty-fourth Annual Meeting of the American Medical Association, held at Milwaukee, Wis., June 7, 1893.
Authors: ERNEST HART
Journal: JAMA (1893)

<i>Mr. President and Members of the American Medical Association</i>:—The thesis which I am here to present to you is one which has a superficial air of triteness, but it is not our value to be affected by superficialities, and I hope to convince you that although well worn, the subject of the causation and prevalation of cholera is by no means threadbare. At any rate, to such threads of this well worn subject as have survived attrition, there lie attached untold thousands of lives, which it may be yours or mine at any moment to save. My thesis is that cholera death is a violent death, an unnatural death, a preventable death; that the very existence of epidemic cholera, not to say endemic cholera, is a reproach to the nation and to the community in which it exists. Being a violent death, its prevalence is due to ignorance or apathy,
THE RELATION OF THE PHYSICIAN TO SANITATION.CHAIRMAN'S ADDRESS BEFORE THE SECTION ON HYGIENE AND SANITARY SCIENCE, AT THE FIFTY-FIFTH ANNUAL SESSION OF THE AMERICAN MEDICAL ASSOCIATION, AT ATLANTIC CITY, JUNE 7-10, 1904.
Authors: GARDNER T. SWARTS
Journal: JAMA (1904)

On the question of hygiene and sanitation much, if not all, of the practice of medicine rests. The nearer that the individual personally and the nearer the public or masses of individuals collectively live and conduct themselves in accordance with the conditions provided by Nature, so much less will be the need of medical interference. What asepsis is to the surgeon, perfect hygiene is to the medical practitioner. Unfortunately, however, under the stress of accomplishment of great results in every line of effort except that of health, Nature's pristine conditions are forgotten and abuse of all her natural laws follows. In the effort of the ignorant mother to improve on the diet provided by Nature, she seeks to add to the infant's strength by feeding it with all sorts of indigestible foods. The woman of knowledge, striving for social eminence, forces on her infant a diet, scientific
STUDIES ON BLOOD CHANGES IN PNEUMOCOCCUS INFECTIONS
Authors: William C. Stadie
Journal: The Journal of Experimental Medicine (1921)

In the occasional cases of pneumonia which show a decrease in the oxygen capacity of the blood, the decrease is probably due to a formation of methemoglobin. The latter is removed from the circulation, however, as rapidly as it is formed, so that it can seldom be detected even qualitatively, and is probably never a cause of cyanosis.