tbuckley/cabot-search huggingface dataset:
Regulation of the Embryonic Morphogen Nodal by Notch4 Facilitates Manifestation of the Aggressive Melanoma Phenotype
Authors: Katharine M. Hardy, Dawn A. Kirschmann, Elisabeth A. Seftor, Naira V. Margaryan, Lynne-Marie Postovit, Luigi Strizzi, Mary J.C. Hendrix
Journal: Cancer Research (2010)

Abstract Metastatic melanoma is an aggressive skin cancer associated with poor prognosis. The reactivation of the embryonic morphogen Nodal in metastatic melanoma has previously been shown to regulate the aggressive behavior of these tumor cells. During the establishment of left-right asymmetry in early vertebrate development, Nodal expression is specifically regulated by a Notch signaling pathway. We hypothesize that a similar relationship between Notch and Nodal may be reestablished in melanoma. In this study, we investigate whether cross talk between the Notch and Nodal pathways can explain the reactivation of Nodal in aggressive metastatic melanoma cells. We show a molecular link between Notch and Nodal signaling in the aggressive melanoma cell line MV3 via the activity of an RBPJ-dependent Nodal enhancer element. We show a precise correlation between Notch4 and Nodal expression in multiple aggressive cell lines but not poorly aggressive cell lines. Surprisingly, Notch4 is specifically required for expression of Nodal in aggressive cells and plays a vital role both in the balance of cell growth and in the regulation of the aggressive phenotype. In addition, Notch4 function in vasculogenic mimicry and anchorage-independent growth in vitro is due in part to Notch4 regulation of Nodal. This study identifies an important role for cross talk between Notch4 and Nodal in metastatic melanoma, placing Notch4 upstream of Nodal, and offers a potential molecular target for melanoma therapy. Cancer Res; 70(24); 10340–50. ©2010 AACR.
The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice
Authors: Samantha M. Solon-Biet, Aisling C. McMahon, J. William O. Ballard, Kari Ruohonen, Lindsay E. Wu, Victoria C. Cogger, Alessandra Warren, Xin Huang, Nicolas Pichaud, Richard G. Melvin, Rahul Gokarn, Mamdouh Khalil, Nigel Turner, Gregory J. Cooney, David A. Sinclair, David Raubenheimer, David G. Le Couteur, Stephen J. Simpson
Journal: Cell Metabolism (2014)
Gynecologic Oncology: Fundamental Principles and Clinical Practice
Authors: Larry McGowan
Journal: JAMA (1993)

The goal of this second edition is the same as the first: a comprehensive, indeed encyclopedic, account of the state of the art in gynecologic oncology. The format and organizational concepts are basically unchanged, yet an additional 12 chapters have been added, and there has been considerable rearrangement of the author list due to the inevitable attrition since the first edition 11 years ago. Three outstanding clinicians and educators have joined Professor Coppleson as coeditors. This second edition is one of the best written, most comprehensive textbooks of gynecologic oncology available today. The 129 contributors are recognized experts worldwide in their respective fields. This edition supersedes the first in quality and is well worth the price. The book has 93 chapters. The first 13 present fundamental principles as well as specific information on epidemiology, carcinogenesis, quantitative pathology, oncological endocrinology, pharmacology and selection of cytotoxic drugs, and statistics and clinical trials.
South Korean WHO veteran has tough act to follow
Authors: F. Fleck
Journal: BMJ (2003)

Dr Jong-Wook Lee , new director general of WHO, wants to take a fresh look at the organisation 

When Dr Jong-Wook Lee became the new director general of the World Health Organization in July, one of the first things he did was to recruit external consultants to help his team in the daunting task of making the agency work more efficiently.

After 20 years in the organisation—from 1983 as a leprosy expert in the South Pacific to more recent posts as head of WHO's global programme for vaccines and, in 2000, head of WHO's Stop TB programme—he said the time was ripe to take a fresh look at how WHO worked.

“Cynics say that a consultant borrows your watch and then tells you the time,” Dr Lee, aged 58, said in an interview with the BMJ , adding, in his trademark self effacing style: “But maybe from time to time we don't know what time it is and it is nice to be reminded.”

Dr Lee surprised his staff recently by his choice of executive car—an environmentally friendly petrol-electric hybrid and not the traditional gas-guzzling limousine.

He has been at pains to make it clear to staff that he is open to suggestions on ways to improve their work.

It …
Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects.
Authors: M R Knowles, J M Robinson, R E Wood, C A Pue, W M Mentz, G C Wager, J T Gatzy, R C Boucher
Journal: Journal of Clinical Investigation (1997)

To test whether a major contribution of airways epithelial ion transport to lung defense reflects the regulation of airway surface liquid (ASL) ionic composition, we measured ASL composition using the filter paper technique. On nasal surfaces, the Cl- concentration (approximately 125 meq/liter) was similar to plasma, but the Na+ concentration (approximately 110 meq/liter) was below plasma, and K+ concentration (approximately 30 meq/liter) above plasma. The resting ASL osmolarity [2(Na+ + K+); 277 meq/liter] approximated isotonicity. There were no detectable differences between cystic fibrosis (CF) and normal subjects. In the lower airways, the Na+ concentrations were 80-85 meq/liter, K+ levels approximately 15 meq/liter, and Cl- concentrations 75-80 meq/liter. Measurements of Na+ activity with Na(+)-selective electrodes and osmolality with freezing point depression yielded values consistent with the monovalent cation measurements. Like the nasal surfaces, no differences in cations were detected between CF, normal, or chronic bronchitis subjects. The tracheobronchial ASL hypotonicity was hypothesized to reflect collection-induced gland secretion, a speculation consistent with observations in which induction of nasal gland secretion produced hypotonic secretions. We conclude that there are no significant differences in ASL ion concentrations between CF, normal, and chronic bronchitis subjects and, because ASL ion concentrations exceed values consistent with defensin activity, the failure of CF lung defense may reflect predominantly factors other than salt-dependent defensins.
In Vitro Alternatives for Ocular Irritation
Authors: Rodger D. Curren, John W. Harbell
Journal: Environmental Health Perspectives (1998)

The necessity of using animals to test whether new chemicals and products are eye irritants has been questioned with increasing frequency and fervor over the last 20 years. During this time many new nonanimal methods have been proposed as reliable alternatives to the traditional rabbit (Draize) test. To date, however, none of these nonanimal (in vitro) tests have become universally accepted as a complete replacement for the Draize test. To understand why a complete replacement has not been found, one has to first understand the reasonably complex structure of the eye, the standard Draize scoring scale--which is based on a qualitative evaluation of three different tissues--the differences between human and rabbit eyes, the intrinsic variability of the animal test, and the details of the different in vitro tests that have been proposed as replacements. The in vitro tests vary from relatively simple assays using single cells to more sophisticated assays that use discarded animal tissue or artificially constructed human tissue. It is clear that appropriately designed in vitro tests will eventually give more useful mechanistic information about ocular injury from which we can more comfortably predict the risk of human eye irritation from new products and ingredients.
Blinding reviewers to authors' identity does not improve quality
Authors: S. Goldbeck-Wood
Journal: BMJ (1997)

The peer review process is viewed as the arbiter of quality in published research, yet is itself based on little evidence. In Prague last week an international congress on biomedical peer review and global communications debated the value and purpose of peer review.

Reviewers of research manuscripts do not produce better reports if they are blinded to the authors' identity and institution, according to research presented by investigators from the London School of Hygiene and Tropical Medicine and the BMJ …
Case of Subcutaneous Division of the Pronator and Flexor Muscles of the Hand and Fingers
Authors: P. Doubovitski
Journal: BMJ (1841)

emits a fetid sanious discharge; at the very bot- tom of the stump there are several sharp spicula of bone, appareiitly of recent production.His Meneral health is now pretty good.Some time after these notes were taken, I found that the sharp spicular projections at the end of the stump had exfoliated, and that firm sicatrices had formed over it, giving it as nearly as possible the appearance of having been re- moved by an operation.He occasionally felt uneasy sensations, which he referred to the foot which had been lost, but was otherwise in perfect health.
PENICILLIN ANAPHYLAXIS, NONFATAL AND FATAL REACTIONS
Authors: Samuel M. Feinberg
Journal: JAMA (1953)

This paper deals with the problem of immediate, anaphylactic, and, at times, fatal reactions from penicillin. We shall not discuss other types of allergic manifestations. The episodes to be reported here are those that occur immediately after the administration of penicillin and consist of an acute allergic (atopic) reaction, manifested by any or a combination of the following symptoms: urticaria, angioneurotic edema, asthma, emphysema, labored breathing, shock (with profound fall of blood pressure), cyanosis, and unconsciousness. There is evidence that, in persons in whom the reaction is of this type, a true atopic or anaphylactic type of sensitivity has developed as a result of repeated administration of penicillin, that circulating antibodies to this drug have been produced, and that there is the capacity to give an immediate whealing skin reaction to scratch or intradermal tests.  Anaphylactic reactions are profound, dangerous, and even fatal. They are also preventible in most instances.
Renal and Electrolyte Disturbances Associated with Cisplatin
Authors: JON D. BLACHLEY
Journal: Annals of Internal Medicine (1981)

Cisplatin is a coordinate metal complex with significant antineoplastic activity and various adverse effects, including acute and chronic renal insufficiency and renal magnesium wasting. Nephrotoxicity may occur in as many as 50% to 75% of patients receiving the drug, and is apparently due to renal tubular injury. Although controlled, prospective clinical trials are lacking, the available data indicate that the frequency and severity of cisplatin nephrotoxicity may be reduced by slow infusion rates; hydration before, during, and immediately after administration of cisplatin; and concomitant administration of mannitol. Preliminary animal studies indicate that chloride-containing vehicles such as 0.9% sodium chloride may prevent the aquation or hydroxylation of cisplatin and reduce its toxicity. No information is available on the prevention of cisplatin associated renal magnesium wasting. However, frequent measurement of serum cations and appropriate replacement are recommended.
Pneumocystis carinii pneumonia as presenting feature of lymphoma.
Authors: A Manoharan
Journal: BMJ (1982)

thiazides, chlorthalidone, indapamide, as shown by Drs Fonseca and Phear, and now xipamide.We suggest caution in the use of diuretics in the elderly, since not all patients developing the syndrome have such a favour- able outcome-and since other adverse effects, particularly hypokalaemia, postural hypotension, and glucose intolerance of less sinister proportions, may go unrecognised.
Observations on the Clauses and Provisions of Sir James Graham's Medical Bill
Authors: C. T. Carter
Journal: BMJ (1844)

in the sac or membranes of the chord.The sciatic nerve was of its wual size.Mr. Porter then gave the statistics of t*ent-one published cases, from which it appeared a large pro- portion occurred in the sacral region, and then the lumbar, and from the results of these cases he drew the conclusions, that spina bifida is not necessarily fatal, that it does not appear that the results of surgical interference are very encouraging, and that puncture is the only operation which is worthy of trial.
Observations on patients with primary ventricular fibrillation complicating acute myocardial infarction.
Authors: K I Lie, H J Wellens, E Downar, D Durrer
Journal: Circulation (1975)

In order to evaluate the events preceding primary ventricular fibrillation (PVF), continuous tape recording was performed in 262 patients consecutively admitted to the hospital within six hours of infarction in whom antiarrhythmic therapy was withheld. Warning arrhythmias (defined as ventricular ectopic beats occurring with a frequency of more than five beats per minute, in runs, falling in the vulnerable phase of the cardiac cycle or being multiformed) were registered in an equal percentage in patients who did or did not develop PVF. Immediately prior to PVF seven patients showed sinus tachycardia, 10 a sinus rate ranging from 60 to 100 beats per minute and two bradycardia due to complete atrioventricular block. The ventricular ectopic beat initiating PVF had a late coupling interval (QR'/QT larger than or equal to 0.85) in 11 patients and a left bundle branch block configuration as frequent as a right bundle branch block.1) Warning arrhythmias are not considered good criteria for institution of antiarrhythmic therapy in order to prevent PVF. 2) In patients with sinus rhythm there may be an association between heart rate and onset of PVF. 3) The malignancy of a ventricular ectopic beat is not determined by its coupling interval or its configuration.
Hay-Fever Treatment by Dunbar's Remedies (Pollantin).
Authors: George L. Richards
Journal: JAMA (1906)

Fall River, Mass., Aug. 8, 1906. <h3>To the Editor:</h3> —I have read with interest the letter from Dr. Ingals inThe Journal, Aug. 4, 1906, touching the question of the treatment of hay fever with pollantin. I have no contribution to make on the subject of the use of pollantin except reports which have been made to me by my private patients, for I have not personally administered it to them, but as hay-fever patients tell one another everything new in the way of remedies, and usually try them all, whether the physician prescribes them or not, I have found a number of my own patients to have used pollantin without regard to any advice from me, and so far as I know, with entirely negative results. Hay fever seems to me to be a vasomotor neurosis, with a good many causative factors, as it appears all the way from
Effect of Tranquilizers on Medical Morbidity and Mortality in a Mental Hospital
Authors: Allen E. Hussar
Journal: JAMA (1962)

Among 1,324 patients admitted from a psychiatric service to a medical service during an 8-year period, there were 236 deaths. The first 4 years (pretranquilizer Period A, 1952-1955) were compared with the last 4 years (Period B, 1956-1959) when most patients were receiving tranquilizers. While some causes of sickness and death were unaffected, 3 significant differences were found, namely an increased morbidity and mortality from arteriosclerotic heart disease and cancer, an increase in suicides, and the appearance of known complications from drug therapy during Period B. It was not always possible to link these changes to the use of tranquilizers, but it was noted that 90% of the patients who committed suicide during Period B had been receiving tranquilizers.
Trial of thyroxine treatment for biochemically euthyroid patients has been approved
Authors: E H McLaren, C J G Kelly, M A Pollock
Journal: BMJ (1997)

Progress in reducing inpatient mortality from acute myocardial infarction is slowEditor-Brown et al report a substantial increase in the use of beneficial interventions for patients admitted to hospital with acute myocardial infarction in Nottingham from 1982 to 1992. 1 However, they found no change in inpatient mortality adjusted for age and sex.This contrasts with findings in Ontario, Canada, where hospital discharge abstracts show that inpatient mortality fell from 1981 to 1991 2 and has since fallen further (data on request).Brown et al suggest that the disparate results may reflect coding errors in the Ontario administrative data.Our group has assessed the classification of deaths from acute myocardial infarction in inpatients in the Ontario discharge abstracts.Matching Ontario administrative data to data from the GUSTO-I and LATE trials, we found the specificity of the administrative data to be 100% (1403/1403 alive), with overall sensitivity of 94% (104/111 deaths detected). 3he classification of acute myocardial infarction itself is more problematic.The sensitivity of the primary diagnosis of acute myocardial infarction is high, but specificity varies. 4 5There are two common reasons for false positive coding.Firstly, patients may be admitted to a coronary care unit with possible acute myocardial infarction but this diagnosis is ruled out and they are sent home quickly.Alternatively, patients recently admitted to hospital with acute myocardial infarction are readmitted for coronary angiography or with complications other than overt reinfarction, and the code for acute myocardial infarction is wrongly used again.Thus the analysis of outcomes in Ontario excluded both patients with a primary diagnosis of acute myocardial infarction who were discharged in under four days and patients who had been admitted to hospital for acute myocardial infarction in the preceding three months. 2t is therefore doubtful that imprecise coding explains the improving outcomes of acute myocardial infarction in Ontario.Indeed, only systematic coding errors could explain the observed trends in inpatient mortality, and we have found neither evidence nor a rationale for this.Ontario's administrative data do mirror the findings of Brown et al in two respects 2 : admissions for acute myocardial infarction, particularly among elderly patients, increased over the period studied, and inpatient mortality ranged from 16% to 21%, which is much higher than in the large randomised trials of thrombolytic treatment.Thus while the trends in Ontario are more positive than those in Nottingham, we agree with Brown et al that the cardiovascular megatrials have been enrolling skewed patient populations 3 and that progress in the battle to reduce inpatient mortality from acute myocardial infarction remains slow.
Abstract 1031: Sphingolipid metabolism as a therapeutic target in chemotherapy resistant and hormone therapy resistant breast cancer
Authors: Matthew M. Gestaut, James W. Antoon, Adharsh P. Ponnapakam, Liu J, Matthew E. Burow, Maryam Foroozesh, Barbara S. Beckman
Journal: Cancer Research (2010)

Abstract Endocrine- and chemo-resistance are major causes for failure of treatment in recurrent breast cancer. Normal apoptotic pathways targeted by chemotherapeutic agents become altered, diminishing their efficacy and increasing resistance mechanisms. The proapoptotic sphingolipid compound N-Octanoyl-D-erythro-sphingosine (C8-ceramide) mimics endogenous long chain ceramide and is a potent drug in endocrine-/chemo-resistant breast cancer cells. In this study, we examined basal expression levels of modifier enzymes for endogenous ceramide regulation across drug sensitive, chemoresistant and hormone therapy- resistant breast cancer cells lines. Differences were found among UDP-galactose ceramide galactosyltransferase, sphingosine kinase-1, and acid sphingomyelinase gene expression in: MCF-10A, MCF-7, MDA-MB-231 and MCF-7TN-R cell lines. Using C8-ceramide as the lead compound, 8 novel ceramide analogs were synthesized with either enol or amide backbone substitutions and tested for biological activity. The enol substitution was found to be the most potent, with (2S,3R,E)-2-((E)benzylideneamino)octadec-4-ene1,3-diol (Analog C) displaying the greatest reduction in proliferation. Analog B appeared to be the most potent cytotoxic drug in MCF-7 and MDA-MB-231 cell lines with IC50 values of 6.2uM and 3.0 uM respectively. In the cytotoxicity assay MCF-7TN-R cell line, Analog A appeared to be the most potent with an IC50 of 2.4uM. The clonogenic proliferation assay provided very different, yet promising results. Analog D had the lowest IC50 of 460nM in MDA-MB-231, Analog C had an IC50 of 100nM in MCF-7TN-R, and Analog A had an IC50 of 1.48uM in the MCF-7 breast cancer cell line. All of the IC50s for proliferation assays were at least an order of magnitude more potent than the control drug C8 (IC50 of 5uM). Due to the potency of these drugs, these results exemplify the potential of novel ceramide-targeted therapies in chemo-resistant and endocrine-resistant breast cancer cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1031.
Richard Cedric Horwitz
Authors: Carolyn Charlesworth, Anthony Bradlow, Andrew Kirk
Journal: BMJ (2007)

Richard Horwitz undertook his initial medical training in Cape Town. After emigrating to England in 1978 he completed training in radiology at Oxford before becoming a consultant radiologist for Wycombe and Amersham Hospitals in 1984. Richard was an excellent general radiologist and acquired new skills as the specialty developed, mastering all …
The Supreme Court, Preemption, and Malpractice Liability
Authors: Aaron S. Kesselheim, David M. Studdert
Journal: New England Journal of Medicine (2009)

The U.S. Supreme Court is currently considering the case of Wyeth v. Levine, whose central question is whether approval of a pharmaceutical product's label by the Food and Drug Administration (FDA) should protect the manufacturer from litigation by patients alleging that they were inadequately warned about potential adverse effects. The FDA has suggested that if such protection (or “preemption”) were granted, it might extend to health care practitioners, thereby insulating them, as well, from tort claims “related to dissemination of risk information to patients beyond what is included in the labeling.”1 The more likely scenario, however, is that preemption of . . .
Therapeutic strategies for a functional cure of chronic hepatitis B virus infection
Authors: Jinhong Chang, Fang Guo, Xuesen Zhao, Ju-Tao Guo
Journal: Acta Pharmaceutica Sinica B (2014)

Treatment of chronic hepatitis B virus (HBV) infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc) DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus–host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection.