tbuckley/cabot-search huggingface dataset:
Abstract 4470: Elucidating the role of drug-linker hydrophobicity in the disposition of antibody-drug conjugates
Authors: Svetlana O. Doronina, Jocelyn R. Setter, Tim D. Bovee, Martha E. Anderson, Mechtild Jonas, Steven Daniho, Heather Kostner, Peter D. Senter, Robert P. Lyon
Journal: Cancer Research (2014)

Abstract The in vitro potency of antibody-drug conjugates (ADCs) is generally proportional to the level of drug loading, with higher drug per antibody levels producing more potent ADCs. However, this intuitive relationship often fails to translate in vivo, presumably because plasma clearance of the ADC also increases with drug loading, resulting in substantially reduced exposure to highly loaded ADCs (Hamblett, KJ et al, Clin. Cancer Res. 2004, 10: 7063-7070). We postulated that this accelerated clearance effect is not purely a function of the number of drugs per antibody, but also of the intrinsic hydrophobicity of each drug-linker. Collectively, drug-linker hydrophobicity and number of drugs per antibody determine the overall hydrophobicity of the ADC. To test this hypothesis, we designed and prepared a series of drug-linkers within the auristatin class that varied in hydrophobicity, and used them to produce a corresponding series of homogeneous 8-loaded ADCs. The pharmacokinetic profiles of these ADCs were determined and found to correlate well with their relative retention times by hydrophobic interaction chromatography. We further postulated that hydrophobicity-driven clearance is likely to be mediated by cells of the mononuclear phagocytic system (MPS). To identify the specific cell populations responsible for accelerated ADC clearance, we performed an immunohistochemistry-based biodistribution study which has provided clear evidence for the cellular sites of hydrophobic ADC clearance which are not operative on native antibodies or hydrophilic ADCs. Using the information gained from these studies, we have successfully prepared a hydrophilic auristatin drug-linker which enables the preparation of ADCs uniformly loaded with 8 drugs per antibody at defined cysteine sites. These ADCs evade clearance by the MPS, maintain native antibody pharmacokinetics, and translate their high in vitro potency into the in vivo setting. Citation Format: Svetlana O. Doronina, Jocelyn R. Setter, Tim D. Bovee, Martha E. Anderson, Mechtild Jonas, Steven Daniho, Heather Kostner, Peter D. Senter, Robert P. Lyon. Elucidating the role of drug-linker hydrophobicity in the disposition of antibody-drug conjugates. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4470. doi:10.1158/1538-7445.AM2014-4470
Relevance of Salt, Water, and Renin to Hypertension in Chronic Renal Failure
Authors: G. S. Stokes, M. K. Mani, J. H. Stewart
Journal: BMJ (1970)

Blood pressure control was examined in 75 patients with end-stage renal failure treated by regular twice-weekly haemodialysis. Dietary sodium was restricted and extracellular fluid was removed by ultrafiltration until blood pressure was normal or signs of salt depletion were observed. Failure of these measures constituted an indication for nephrectomy. Of the 75 patients, 18 were never hypertensive, 46 had hypertension which could be corrected by salt and water depletion, and 11 had persistent hypertension which could not be controlled in this way. Nine of these 11 patients underwent bilateral nephrectomy; in each of the seven in whom the post operative result could be evaluated the blood pressure returned rapidly to normal.Plasma renin activity, measured in 34 subjects, was raised above normal in six out of nine patients whose blood pressure could not be controlled by salt and water depletion and in one of the 11 patients whose blood pressure could be so controlled, but was within the normal range in all nine normotensive patients. The mean level of plasma renin activity in the first group was significantly higher than that of each of the other two groups.There was a significant correlation between hypertension during dialysis and after transplantation, suggesting that, in addition to renin, there is a non-renal factor which predisposes certain patients to hypertension in the presence of salt and water excess.
Mutation of the Angelman Ubiquitin Ligase in Mice Causes Increased Cytoplasmic p53 and Deficits of Contextual Learning and Long-Term Potentiation
Authors: Yong-hui Jiang, Dawna Armstrong, Urs Albrecht, Coleen M Atkins, Jeffrey L Noebels, Gregor Eichele, J.David Sweatt, Arthur L Beaudet
Journal: Neuron (1998)
Type D Personality in Never Depressed Patients at Their First Acute Coronary Syndrome
Authors: Carlo Marchesi, Paolo Ossola, Francesca Scagnelli, Francesca Paglia, Sonja Aprile, Alberto Monici, Matteo Tonna, Giulio Conte, Franco Masini, Chiara De Panfilis, Diego Ardissino
Journal: Psychotherapy and Psychosomatics (2014)
Fetal bone marrow transplants spark hope for genetic diseases
Authors: D. Josefson
Journal: BMJ (1997)

Several infants destined to develop the severe combined immunodeficiency syndrome have had their disease prevented by in utero bone marrow transplantation. The success of the technique may herald a new era in the treatment of some types of genetic disorders.

The technique of fetal bone marrow transplantation was pioneered by Dr Alan Flake of the Children's Hospital of Philadelphia, and two cases are described in recent issues of the New England Journal of Medicine (1996:335:1806-10) and the Lancet (1996;348:1484-7). In both …
Targeting of breast cancer with non-oncology drugs – possible novel therapeutic option for triple-negative breast cancer.
Authors: C Liedtke, K Yan, Y Wu, GN Hortobagyi, WF Symmans, V Valero, M Goette, L Kiesel, L Pusztai
Journal: Cancer Research (2009)

Abstract Abstract #2119 Introduction: Triple-negative breast cancer (TNBC) is defined by lack of ER, and PR expression and normal HER2 expression. It is characterized by aggressive biological presentation and unfavorable outcome. It is associated with frequent lack of response to current chemotherapy agents. Recently, 392 drugged genes that serve as targets for 1557 both oncologic and non-oncologic drugs were identified from the pharmacologic database DrugBank (Lauss et al. Pharmacogenomics 2007). In this study, we compared expression levels of these known drug targets between TNBC and receptor-positive cancers. Methods: Gene expression profiles were obtained from fine needle biopsies of newly diagnosed early stage breast cancer before any therapy (n=133, MDACC dataset). Differential expression of these genes was validated in a second independent data set (n=286, Rotterdam dataset) and in a panel of cell lines (n=19). In order to assess the functional relevance of known drug targets overexpressed in TNBC we performed in vitro experiments. Cell lines were treated with various concentrations of selected drugs alone or in combination with paclitaxel. Results: We mapped 675 U133A probe sets representing 347 unique drug targets to the Affymetrix U133A Genechip. 44 drug targets were overexpressed in TNBC compared to non-TNBC in the MDACC dataset. Thirty-three of these (75%) were also overexpressed among TNBC compared to non-TNBC in the Rotterdam dataset. Glutathione-S-transferase pi (GSTpi, target of clomipramine) was the most highly and consistently overexpressed target in human TNBC and in estrogen- and HER2-receptor-negative breast cancer cell lines. The GSTpi overexpressing (and triple negative) human mammary cell line HBL-100 showed dose-dependent inhibition of growth after 144 hrs of incubation with clomipramine, whereas growth of the GSTpi-low expressing (non-triple negative) breast cancer cell lines MCF-7 and SKBR3 was not inhibited by this drug. Treatment with clomipramine did not alter sensitivity to paclitaxel in either cell line in vitro. Conclusion: Gene expression analysis indicates that targets for several known drugs are over expressed in TNBC relative to other types of breast cancers. We hypothesize that some of these drugs may influence the behavior of TNBC and may represent future therapeutic options. Further experiments are needed to fully explore the functional implications of these findings; however, our preliminary results suggest that inhibition of GSTpi with clomipramine leads to inhibition of cell growth of TNBC cell lines in vitro. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2119.
The Macula: A Comprehensive Text and Atlas
Authors: W. Ronald Coughlin
Journal: JAMA (1979)

The multiauthored text on macular disorders by Yannuzzi et al is a fine text for any ophthalmology resident or general ophthalmologist. For the most part, each major topic is presented in a concise and adequately comprehensive fashion. The selected fundus photographs and fluorescein angiograms are of excellent quality and serve to highlight the major points. The references selected were likewise appropriate and well chosen. As the authors noted in the introduction, the text was a by-product of a meeting on macular disorders and, as such, was never intended to be encyclopedic by nature. Thus, one cannot be too critical of the topics selected and those omitted from a more classical treatise on macular disorders. The material chosen, the manner of presentation, and the selected references serve as an excellent introduction to the discipline. And for that reason, the text as a whole warrants favorable recommendation.
Israel loses minister over health insurance
Authors: J Siegel-Itzkovich
Journal: BMJ (1994)

The Israeli health minister, Haim Ramon, has resigned in protest at the ruling Labour party's withdrawal of support for his national health insurance bill. The prime minister, Yitzhak Rabin, who until recently was an enthusiastic supporter of the legislation, has disowned both the bill and Ramon, bowing under pressure from the Histadrut (the General Labour Federation). The prime minister is trying to conserve his political might so that he can successfully conclude negotiations with the Palestine Liberation Organisation over autonomy.

The bill, which would grant a universal “basket of health services” to the entire Israeli population of five million in exchange for a 4.8% tax on income, was the result of five years' work by health professionals and politicians. National health insurance …
Laetrile: End Play Around the FDA
Authors: GERALD M. ROSEN
Journal: Annals of Internal Medicine (1979)

We consider here some of the legal and political background behind today's laetrile controversy. First, we provide a brief historical review of our present food and drug legislation and discuss details of these laws with respect to attempts by laetrile's backers to use the courts in the legalization of this compound. We analyze one case, Rutherford v. United States, that was won in the lower courts by the advocates of laetrile and conclude that the courts may have allowed emotionalism to interfere with the process of rational decision-making. On a larger scale, this emotionalism manifests itself as political pressure that may bring about changes in our food and drug legislation. These changes could loosen restrictions on the effectiveness requirement and result in the sacrifice of consumer protection in favor of making available more drugs, some of them ineffective, from which the patient may choose for treatment.
The Incubation Period of Pneumonia
Authors: E. M. Callender
Journal: BMJ (1904)

ALTHOUGH the pneumococcus (Fraenkel) does not conform to Koch's postulates, there is, I take it, little or no doubt in the minds of most physicians that it is the specific micro-organism of acute pneumonia.The same micro-organism is almost constantly found in the mouth, but seldom, if ever, in the nasal passages and cavities in health.In acute inflam- maatory affections of these passages and cavities it is, I believe, very generally present; in fact, it is probably the cause of many of these inflammations as well as of at least some cases of acute otitis media.ISeveral endeavours have been made to fix a more or less
Doctors on the March — Burke and Hare, 1970? — Dumb-Dumb Dodo
Authors: John Lister
Journal: New England Journal of Medicine (1970)

EVER since the Health Service began there have been recurring disputes between the Government and the medical and dental profession on rates of pay. It was hoped that this source of disagreement would have been permanently eliminated when the Government and the professions accepted the recommendation of the Royal Commission on Doctors' and Dentists' Remuneration1 that an independent review body be set up to advise upon the correct rates of pay in both professions and report from time to time directly to the Prime Minister. This review body, under the Chairmanship of Lord Kindersley, has been making recommendations for several . . .
Acute Severe Mitral Regurgitation from Papillary Muscle Dysfunction in Acute Myocardial Infarction
Authors: TSUNG O. CHENG, TALI BASHOUR, PAUL C. ADKINS
Journal: Circulation (1972)

A patient with acute severe mitral regurgitation resulting from papillary muscle dysfunction which developed on the third day of acute myocardial infarction underwent early successful mitral valve prosthetic replacement with concomitant aortocoronary saphenous vein bypass. The concept of acute severe mitral regurgitation due to an infarcted papillary muscle which has not actually ruptured and an aggressive approach to such a catastrophic event early in the course of acute myocardial infarction are emphasized. The risk is well worth the gratifying result obtained in our patient who successfully underwent such a combined operative procedure for one of the early complications of acute myocardial infarction.
Animals in Research
Authors: Janna Koch
Journal: JAMA (1988)

<h3>To the Editor.—</h3> My daughter is alive today because of animal research. Lilah was the world's smallest pacemaker recipient at the age of 1 month and is with us today seven years later. Therefore, I have a very personal interest in the debate on the use of animals in biomedical research and am extremely grateful to those researchers—and those animals—who were involved in developing the procedures that have saved her life. But Lilah's medical needs continue and we wait for new procedures to be developed to ensure that she will have a future. Researchers must be able to continue to use animals in their research for Lilah's sake as well as for all of the others with medical conditions who wait for cures and treatments. As one of those to whom this means everything, I would like to provide my thanks and encouragement to all of those who speak out
Hypertension Resulting From Hydronephrosis
Authors: Henry M. Wise
Journal: JAMA (1975)

ACTIVATION of the renin-angiotensin system occurs only rarely as a consequence of ureteral obstruction as compared to the frequent clinical experience involving arterial occlusion. Multiple case reports have appeared in the literature describing hypertension associated with renal obstruction. In the unique case described in this report, carcinoma of the ureter caused severe obstruction, with high circulating plasma renin activity and associated hypertension. No vascular abnormality could be demonstrated by arteriography. <h3>Report of a Case</h3> A 45-year-old woman had been in excellent health until one month before admission to the hospital, when severe headaches had developed. Blood pressure was 180/110 mm Hg, the only abnormal finding. One year earlier, at the time of a routine physical examination, she had been normotensive. There was no familial history of cardiovascular disease or hypertension. Hemoglobin value was 14.3 gm/100 ml; the hematocrit reading, 43%. Blood urea nitrogen level was 16 mg/100 ml; creatinine level,
The Use of LSD in Psychotherapy: Transactions of a Conference on Lysergic Acid Diethylamide (LSD-25), April 22, 23, and 24, 1059, Princeton, N. J
Authors: Louis L. Lunsky
Journal: JAMA (1960)

Contributors to this volume include psychiatrists, psychologists, ethnologists, and sociologists. The purpose of the volume, as outlined in the introduction, is to promote effective communication by the give-and-take of lively discussions. Unfortunately, meaningful communication is infrequently achieved in this volume. The discussions are tangential and lack coherence. The experiments which are described by the members of this symposium lack a sound design. They really are subjective evaluations and are not substantiated. One of the participants expressed it aptly by commenting that one finds only the impressions of the doctor's unconscious mind in the productions of the volunteers. The volume contains some cogent and succinct ideas, but they are lost in the morass of confusion. The volume is of questionable value.
Preconditioning of isolated rabbit cardiomyocytes: induction by metabolic stress and blockade by the adenosine antagonist SPT and calphostin C, a protein kinase C inhibitor
Authors: S. Armstrong, J. M Downey, C. E Ganote
Journal: Cardiovascular Research (1994)

Journal Article Preconditioning of isolated rabbit cardiomyocytes: induction by metabolic stress and blockade by the adenosine antagonist SPT and calphostin C, a protein kinase C inhibitor Get access Stephen Armstrong, Stephen Armstrong Department of Veterans Affairs Medical Center and Department of Pathology, East Tennessee State University, James H Quillen College of Medicine, PO Box 19540A<Johnson City, TN 37614, USA: S Armstrong, C E Ganote; Department of Physiology, University of South Alabama, Mobile, Alabama, USA: J M Downey. Correspondence to Dr Ganote. Search for other works by this author on: Oxford Academic PubMed Google Scholar James M Downey, James M Downey Department of Veterans Affairs Medical Center and Department of Pathology, East Tennessee State University, James H Quillen College of Medicine, PO Box 19540A<Johnson City, TN 37614, USA: S Armstrong, C E Ganote; Department of Physiology, University of South Alabama, Mobile, Alabama, USA: J M Downey. Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles E Ganote Charles E Ganote Department of Veterans Affairs Medical Center and Department of Pathology, East Tennessee State University, James H Quillen College of Medicine, PO Box 19540A<Johnson City, TN 37614, USA: S Armstrong, C E Ganote; Department of Physiology, University of South Alabama, Mobile, Alabama, USA: J M Downey. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 28, Issue 1, January 1994, Pages 72–77, https://doi.org/10.1093/cvr/28.1.72 Published: 01 January 1994 Article history Received: 11 June 1993 Accepted: 03 September 1993 Published: 01 January 1994
Muscle activity pattern in Olympic lifting: latissimus dorsi and pectoralis major - an EMG study
Authors: Mohan C Narayana
Journal: British Journal of Sports Medicine (2010)

An electromyography study was conducted to identify the response of latissimus dorsi (LD) and pectoralis major (PM) during the Olympic style of weightlifting, that is, two types of lifting were included in the study. ‘Snatch’ and ‘Clean &amp; Jerk’ in various loads from 20 kg, 40%, 60% and 80% of lifter's maximum lifts were studied. The electrical signal of the muscles (EMG) was recorded using a multichannel recorder (Sensor medic R 612; The Netherlands). The signal conditioning was made through a couple (direct/average EMG type 9852A), preamplifier (type 820) and amplifier (type 412). The gain of amplification was selected according to the level of activity of the particular muscle. The activity of the LD was for a long duration in phase I and II for both the Olympic lifts. In 2nd phase of C &amp; J there was 100% activity at all loads. In 3rd and 4th phase the duration of activity came down remarkably. Duration of activity of PM was very short in phases II and IV for both the Olympic lifts. Second and 3rd phase showed considerably long duration. In phase V, the activity was moderate for C &amp; J. Study shows remarkably high electrical activity of LD in phase I of both the lifts and in phase II it was maintained. PM showed very short response in all the phases especially in phase I and IV where it was considerably short. The pattern of electrical activity at all loads and in all the phase was identical.
Excess Lactate: An Index of Reversibility of Shock in Human Patients.
Authors: Max H. Weil
Journal: Annals of Internal Medicine (1964)

s1 April 1964Excess Lactate: An Index of Reversibility of Shock in Human Patients.Max H. Weil, M.D., F.A.C.P., George Broder, M.D., Frank Cramer, B.S.Max H. Weil, M.D., F.A.C.P.Search for more papers by this author, George Broder, M.D.Search for more papers by this author, Frank Cramer, B.S.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-60-4-711_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Excerpt"Excess lactate," an indicator of oxygen debt, has been studied as a metabolic index of the severity of the shock state in human patients. Serial hemodynamic and metabolic measurements were performed in 56 patients who had hypotension and clinical features of shock due to blood or fluid loss, myocardial infarction, overwhelming infection, and pulmonary embolization. Lactic and pyruvic acid concentrations were measured in arterial blood and the "excess lactate" (XL) was calculated as defined by Huckabee. Eighty-two per cent of patients in whom XL was in the normal range, that is less than 1 mM/liter, survived. Survival decreased to 60%... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Los Angeles, California PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 April 1964Volume 60, Issue 4Page: 711-711KeywordsAttentionBloodHemodynamicsHypotensionLactatesLactic acidMyocardial infarctionOxygenPulmonary diseasesShock Issue Published: 1 April 1964 PDF downloadLoading ...
Lung Function Changes in Workers Exposed to Cobalt Compounds
Authors: Violaine Verougstraete, Alex Mallants, Jean-Pierre Buchet, Bert Swennen, Dominique Lison
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

The objective of the study was to examine the influence of cobalt exposure on lung function changes in workers from a cobalt-producing plant in a health monitoring program implemented between 1988 and 2001. A total of 122 male workers with at least 4 (median = 6) lung function tests (FEV(1) and FVC) during the follow-up period were assessed longitudinally. Cobalt exposure significantly decreased over the follow-up period, as reflected by the measurements in air and urine. The possible association of spirometric changes with cobalt exposure was examined by a random coefficients model, taking into account other potential influential variables, such as smoking, age, previous respiratory illness, exposure to other lung toxicants, or the presence of glutamate in position 69 in the HLA-DP beta-chain, an HLA polymorphism possibly associated with hard-metal-induced lung diseases. The main finding of the follow-up study was that cobalt exposure contributed to a decline in FEV(1) over time, and only in association with smoking. No influence of glutamate in position 69 in the HLA-DP beta-chain polymorphism was detected. Although the amplitude of the additional FEV(1) decrement associated with smoking exposure was relatively small (< 20%) compared with the expected decline in a non-cobalt-exposed smoker, the results indicate that further efforts to reduce cobalt exposure and to encourage workers to quit smoking are still warranted.