tbuckley/cabot-search huggingface dataset:
Abstract 1523: Caffeine antagonizes multidrug resistance by down-regulating ABCG2
Authors: Rui Ding, Jia Shi, Kathleen W. Scotto
Journal: Cancer Research (2010)

Abstract ABCG2/BCRP (Breast Cancer Resistance Protein) is an ATP-binding-cassette (ABC) transporter that has been shown to confer multidrug resistance (MDR) in cancer cells, ultimately resulting in the failure of cancer chemotherapy. Accordingly, the downregulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. Caffeine and its analogs are a category of natural/synthetic and cell-permeable compounds that are used therapeutically in the treatment of occurring migraines and asthma, radiosensitization and obesity. In this study, we found that caffeine, at pharmacologically relevant concentrations, can dramatically decrease ABCG2 protein in cells that have either moderate (BeWo, a placental choriocarcimoma cell line) or high (MCF7/MX100 cells, a breast cancer drug resistant cell subline) levels of ABCG2 expression. This downregulation is time-dependent, dose-dependent, and reversible. Immunofluorescence studies revealed that caffeine treatment decreases membrane-localized ABCG2 protein and significantly increases the retentions of an established ABCG2 substrate in MCF7/MX100, but not in the parental cells, demonstrating that the caffeine-mediated downregulation of ABCG2 directly decreases drug efflux. Importantly, we found that caffeine can sensitize cells to the chemotherapeutic agent mitoxantrone (MX), where combination treatment with MX and caffeine decreased the IC50 of MX ∼10-fold and induced a greater degree of apoptotic cell death compared to MX treatment alone. Additionally, several caffeine analogs were tested and exhibited a similar ability to down-regulate ABCG2; theophylline (a metabolite of caffeine, also naturally found in tea) appeared to be the most potent. Taken together, these findings suggest that caffeine or caffeine analogs could be developed as combination therapy to improve the efficacy of drugs that are ABCG2 substrates. 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 1523.
Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and “narrow” QRS
Authors: Augusto Achilli, Massimo Sassara, Sabina Ficili, Daniele Pontillo, Paola Achilli, Claudio Alessi, Stefano De Spirito, Roberto Guerra, Nicolino Patruno, Francesco Serra
Journal: Journal of the American College of Cardiology (2003)
Tacrine for Alzheimer's disease
Authors: A. Wolferman
Journal: JAMA (1994)

To the Editor.  —The reading of the two articles on tacrine in Alzheimer's disease 1,2 left me with a bitter aftertaste.  To me, it demonstrated a decline of the ethical standards of the American Medical Association, or at least of JAMA . The principal authors of the articles are employees of the pharmaceutical establishment producing tacrine, and it is quite obvious that the article is a promotion of their product, the value of which is far from being established.  I am not a neurologist, a psychiatrist, or a biochemist, and I do not pretend to have any qualifications to evaluate the articles scientifically. However, I have cared for a wife with Alzheimer's disease for many years, and I have experienced personally the horror of this dreadful disease. I have associated with many other desperate persons who cared for a beloved spouse or parent with Alzheimer's disease through support groups. Therefore, I
GMC urges national support service for doctors' health concerns
Authors: A. Rimmer
Journal: BMJ (2014)

The General Medical Council (GMC) has called for a national support service for doctors. The recommendation comes as part of the regulator’s report on doctors who die by suicide while under GMC fitness to practise investigations. 

The report, which was published on 19 December, found that 28 doctors had died by suicide or by suspected suicide while being investigated.1

The GMC said that wider factors that often contributed to a doctor being referred for a fitness to practise investigation, such as the breakdown of a marriage, financial hardship, or bereavement, needed to be tackled. The …
Minimal-change glomerulonephritis associated with circulating anticoagulant to factor XII.
Authors: D Bateman, R Gokal, R Prescott, P J Hamilton, D N Kerr
Journal: BMJ (1980)

particularly difficult cases in whom standard treatment had failed.In three of them mexiletine alone controlled the arrhythmia, but only at the cost of intolerable adverse effects.Combined treatment with mexiletine and propranolol, which have different actions and different adverse effects, enables arrhythmia to be suppressed through co-operative antiarrhythmic action.Since adverse effects have been a major limitation to widespread use of mexiletine 3 4combined therapy with propranolol may broaden its usefulness as an antiarrhythmic drug by two means-by decreasing its adverse effects and by more effective arrhythmia suppression through co-operative drug action.
The Macrophage as an Effector Cell
Authors: Carl F. Nathan, Henry W. Murray, Zanvil A. Cohn
Journal: New England Journal of Medicine (1980)

IT has only been a decade since the "mononuclear phagocyte system" was defined, linking monoblasts, promonocytes, monocytes, and the structurally heterogeneous tissue macrophages. Cells of this lineage develop over several days in the marrow, emigrate from the blood within hours to days, and survive for months in the tissues, where they are involved in important homeostatic mechanisms as well as diverse pathologic events. For 70 years, investigators followed the lead of Metchnikoff, focusing on phagocytosis and the intracellular digestion of particles by macrophages. In the past few years, it has emerged that the macrophage is also a secretory cell. Through . . .
Epileptogenic Side Effects of Psychotropic Drugs
Authors: Turan M. Itil
Journal: JAMA (1980)

Patient- and drug-related factors influence the inherent epileptogenic properties of psychotropic drugs. This article suggests measures to deal with these properties prophylactically and therapeutically in epileptic and nonepileptic psychiatric patients. The appropriate use of psychotropic drugs is emphasized in light of their epileptogenic potential. (<i>JAMA</i>244:1460-1463, 1980)
Castor Oil Catharsis in Acute Glutethimide Intoxication
Authors: Joseph M. Baron
Journal: JAMA (1970)

<h3>To the Editor.—</h3> The failure of standard hemodialysis to shorten the duration of coma, lessen complications, or improve survival in acute severe glutethimide intoxication as recently reported by Chazan and Cohen<sup>1</sup>serves to emphasize the importance of removing this drug from the gastrointestinal tract before it can be absorbed. We were recently impressed by the possible value of catharsis in this regard when a 29-year-old housewife who had been deeply comatose for 48 hours, after ingestion of 13 gm of glutethimide, was given 30 ml of castor oil per nasogastric tube. During the next nine hours, there was a marked cathartic effect, and the patient awoke. We wish to suggest from this experience that, in addition to initial gastric lavage,<sup>2</sup>induction of catharsis, even many hours after ingestion of glutethimide, may be useful in reducing the absorbed dose of this lipid-soluble drug which has been found to persist
Torsion of the testis: why is the prognosis so poor?
Authors: S Bennett, M S Nicholson, T M Little
Journal: BMJ (1987)

The cases of 83 boys who were admitted to hospital with acute testicular pain or swelling were studied. Twenty seven had torsion of the testis, and 15 (55%) of these lost a testis. The main reason for the poor results was delay by the patient or his parents in seeking medical attention.
Store doping samples for 10 years to stop sports cheats, say anti-doping bodies
Authors: Z. Kmietowicz
Journal: BMJ (2014)

Blood and urine samples taken from athletes to check for doping should be stored for 10 years to enable technology to catch up with substances that currently evade detection, international anti-doping experts have said.

The recommendation is one of a raft of measures agreed by 24 international bodies to “help protect the integrity of sport and all those athletes who do not dope.”

The consensus statement was published in a special issue of the British Journal of Sports Medicine 1 and focused on how to implement the World Anti-Doping Code 2015.2

The other recommendations in the statement included a …
Heparin‐induced thrombocytopenia and recurrent thromboembolism in siblings
Authors: Rodney E. Kosfeld, Allan M. Lansing, Zahi Masri, Yong K. Liu
Journal: American Journal of Hematology (1985)

Abstract Two brothers with heparin‐induced thrombocytopenia and multiple arterial and venous thromboembolism affecting peripheral vessels are described. Heparin‐dependent antiplatelet antibody was detected using platelet aggregometry in both patients. Although these observations may be coincidental, the possibility of familial occurrence of this adverse reaction to heparin cannot be excluded with certainty.
Successful Renal Transplantation in Progressive Systemic Sclerosis
Authors: WILLIAM F. KEANE
Journal: Annals of Internal Medicine (1976)

Hemodialysis and renal transplantation were done in a patient with progressive systemic sclerosis and renal failure. The patient's clinical course following transplantation was uncomplicated, and a biopsy of the renal allograft done 14 months after transplantation did not show recurrence of the original disease. These observations favor the consideration of early renal transplantation in patients with scleroderma and renal failure.
Abstract 1659: Exhaustion of autophagy-mediated cell survival underlies the pre-clinical and clinical activity of chemotherapy combined with the AKT inhibitor MK-2206 in BRAF wild-type melanoma.
Authors: Vito W. Rebecca, Renato R. Massaro, Silvya S. Maria-Engler, Jane L. Messina, Geoffrey T. Gibney, Vernon K. Sondak, Ragini Kudchadkar, Keiran S. Smalley
Journal: Cancer Research (2013)

Abstract Although targeted therapy strategies are currently lacking for patients whose melanomas are BRAF wild-type, some therapeutic efficacy was noted in a phase I clinical trial of the AKT inhibitor MK-2206 in combination with Carboplatin (C) and Paclitaxel (P). In the present study we addressed the mechanism underlying the responses to MK-2206 + CP in BRAF wild-type melanoma. As single agents, MK-2206, carboplatin and paclitaxel had only limited cytotoxic activity in both 2D and 3D cell culture and induced very little apoptosis. Prolonged treatment (&amp;gt;9 days) with the AKT inhibitor in combination with C+P led to significant levels of cell death in 4 3D spheroid culture models of BRAF-wild type melanoma. In contrast, treatment with single agent MK-2206 or C+P alone induced little cell death. To investigate the mechanism of interaction between these three compounds we focused upon autophagy induction. It was noted that significant levels of autophagy, as demonstrated by increased LC3-II staining, p62 expression and increased acridine orange staining, were induced following up to 6 days of treatment with the combination. In this context autophagy was protective, with levels of cell death induced by the combination significantly enhanced following treatment with the autophagy inhibitor chloroquine. The protective autophagy induced by MK-2206 + CP was only transient, with diminished levels of autophagy being observed by 9 days. The observed reduction in autophagic flux was associated with marked increases in cell death. In summary it appears that chronic insult with MK-2206 and CP pushes autophagy to its limit, relinquishing its protective role and enhancing sensitivity of the cells to therapy-induced apoptosis. These studies form the basis for a phase II trial evaluating MK-2206 in combination with chemotherapy, as well as autophagy inhibitors, in patients whose melanomas are BRAF-wild type. Citation Format: Vito W. Rebecca, Renato R. Massaro, Silvya S. Maria-Engler, Jane L. Messina, Geoffrey T. Gibney, Vernon K. Sondak, Ragini Kudchadkar, Keiran S. Smalley. Exhaustion of autophagy-mediated cell survival underlies the pre-clinical and clinical activity of chemotherapy combined with the AKT inhibitor MK-2206 in BRAF wild-type melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1659. doi:10.1158/1538-7445.AM2013-1659
P230 Symptomatic benefit of olodaterol QD delivered via Respimat<sup>®</sup>vs placebo and formoterol BID in patients with COPD: combined analysis from two 48-week studies: Abstract P230 Table 1.
Authors: A Koch, P Paggiaro, A Hamilton, L Hart, L Korducki, Mc De Salvo, E Pizzichini
Journal: Thorax (2013)

<h3>Background</h3> The novel LABA olodaterol has 24-h bronchodilator activity. <h3>Objective</h3> To evaluate the symptomatic benefit of olodaterol QD in patients with GOLD 2–4 COPD. <h3>Methods</h3> In replicate, randomised, double-blind, placebo-controlled, parallel-group studies, patients with post-bronchodilator FEV<sub>1</sub> &lt;80% predicted normal and FEV<sub>1</sub>/FVC &lt;70% received olodaterol (5 or 10 µg) QD via Respimat<sup>®</sup>, formoterol (12 μg) BID via Aerolizer<sup>®</sup> or placebo for 48 weeks (Study A: NCT00793624; Study B: NCT00796653). Patients continued to receive usual care background COPD maintenance therapy, including SAMA, LAMA, ICS and xanthines. In addition to FEV<sub>1</sub>-based primary end points, TDI and SGRQ after 24 weeks were identified as co-primary and key secondary symptomatic end points, respectively. <h3>Results</h3> 904 (Study A) and 934 (Study B) patients were treated. In the primary analysis using a mixed model for repeated measures (MMRM; combined dataset), there was no significant difference in TDI focal score after 24 weeks for olodaterol or formoterol vs placebo. A post hoc analysis using pattern mixture modelling (PMM) to account for discontinued patients demonstrated statistical significance for olodaterol vs placebo. There were significant improvements in SGRQ total score with olodaterol, but not formoterol, vs placebo after 24 weeks using MMRM and PMM. <h3>Conclusions</h3> Lung function improvements with olodaterol QD translated into symptomatic benefit in COPD patients receiving usual care background therapy.
Roles for Endoplasmic Reticulum–Associated Degradation and the Novel Endoplasmic Reticulum Stress Response Gene Derlin-3 in the Ischemic Heart
Authors: Peter J. Belmont, Wenqiong J. Chen, Matthew N. San Pedro, Donna J. Thuerauf, Nicole Gellings Lowe, Natalie Gude, Brett Hilton, Roland Wolkowicz, Mark A. Sussman, Christopher C. Glembotski
Journal: Circulation Research (2009)

Stresses, such as ischemia, impair folding of nascent proteins in the rough endoplasmic reticulum (ER), activating the unfolded protein response, which restores efficient ER protein folding, thus leading to protection from stress. In part, the unfolded protein response alleviates ER stress and cell death by increasing the degradation of terminally misfolded ER proteins via ER-associated degradation (ERAD). ERAD is increased by the ER stress modulator, activating transcription factor (ATF)6, which can induce genes that encode components of the ERAD machinery.Recently, it was shown that the mouse heart is protected from ischemic damage by ATF6; however, ERAD has not been studied in the cardiac context. A recent microarray study showed that the Derlin-3 (Derl3) gene, which encodes an important component of the ERAD machinery, is robustly induced by ATF6 in the mouse heart.In the present study, activated ATF6 induced Derl3 in cultured cardiomyocytes, and in the heart, in vivo. Simulated ischemia (sI), which activates ER stress, induced Derl3 in cultured myocytes, and in an in vivo mouse model of myocardial infarction, Derl3 was also induced. Derl3 overexpression enhanced ERAD and protected cardiomyocytes from simulated ischemia-induced cell death, whereas dominant-negative Derl3 decreased ERAD and increased simulated ischemia-induced cardiomyocyte death.This study describes a potentially protective role for Derl3 in the heart, and is the first to investigate the functional consequences of enhancing ERAD in the cardiac context.
Comparison of the antiemetics metoclopramide and promethazine in labour.
Authors: L Vella, D Francis, P Houlton, F Reynolds
Journal: BMJ (1985)

A double blind trial was conducted in 477 mothers in labour to compare the antiemetics metoclopramide 10 mg and promethazine 25 mg and placebo when added to the first dose of pethidine. Metoclopramide and promethazine were equally effective, and both better than placebo, in reducing the incidence of nausea and vomiting after the administration of pethidine. Seventy seven per cent of mothers were drowsy, and 8% slept in the hour after the pethidine injection, with no difference between the groups. The sedative effect was more persistent in the promethazine group, 66% of whom were still drowsy after delivery. One third of the mothers in each group needed further analgesia, with 77% of these ultimately requesting an epidural. The reduction in pain half an hour and one hour after pethidine, assessed by a visual analogue scale, were, respectively, 22% and 22% for placebo; 26% and 23% for metoclopramide; 13% and 9% for promethazine. Analgesia after metoclopramide was significantly better than that after promethazine in terms of pain score, duration of first injection, and need for Entonox. Metoclopramide is therefore to be preferred to promethazine as an antiemetic in labour.
Cathepsin B in osteoarthritis: cytochemical and histochemical analysis of human femoral head cartilage.
Authors: A Baici, A Lang, D Horler, R Kissling, C Merlin
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To localise the cysteine endopeptidase cathepsin B in chondrocytes and cartilage from normal and osteoarthritic (OA) human femoral heads in order to provide qualitative information on its cellular expression and distribution at possible sites of action. METHODS--OA articular cartilage was obtained at surgery for total hip replacement; control cartilage was obtained at postmortem. Chondrocytes were isolated by sequential enzymatic digestion and cathepsin B analysed by immunocytochemistry and activity staining with a fluorogenic substrate. Lysosomes were visualised by fluorescence microscopy after staining of living cells with acridine orange. Using a histochemical reaction, enzyme activity was measured in cryosections of full thickness cartilage. RESULTS--Chondrocytes from normal cartilage contained very few lysosomes and only a minor cell population was cathepsin B positive. A high proportion of chondrocytes from active OA cartilage contained a large number of lysosomes and an excess of cathepsin B in intracellular organelles; the enzyme was stored in an active form. In this respect, OA chondrocytes closely resembled normal cells that had been phenotypically modulated by serial subcultures. No cathepsin B activity could be detected by histochemistry in either chondrocytes or matrix of normal cartilage. While apparently intact and severely degraded OA cartilage was also cathepsin B negative, tissue at sites of active destruction and, particularly, at repair sites was highly positive. CONCLUSION--The presence and the particular distribution of active cathepsin B in OA cartilage at 9more involved9 sites suggest a pathological role for this enzyme in sustaining and perpetuating cartilage degradation. While other stimuli may also be responsible for cathepsin B expression in OA chondrocytes, the similarity with artificially modulated cells indicates fibroblastic metaplasia as a plausible mechanism.
Use of 5-Fluorocytosine in Patients with Impaired Renal Function
Authors: J. K. Dawborn, M. D. Page, D. J. Schiavone
Journal: BMJ (1973)

The plasma level and elimination of 5-fluorocytosine (5-FC) was measured in normal subjects and patients with impaired renal function. Prolongation of the half-life of the drug in renal failure has been confirmed. Renal clearance of 5-FC was about 75% of the creatinine clearance and a corresponding modification of drug dosage should be made in patients with renal insufficiency.
ARGYRIA FROM HAIR DYES
Authors: E. W. Abramowitz
Journal: JAMA (1928)

<h3>To the Editor:</h3> —The development of argyria from the use of hair dyes containing silver salts has been suggested as a possibility and therefore such compounds have not met with the approval of those who have investigated the harmful effects of cosmetic preparations. Cole (The Dermatoses Due to Cosmetics,The Journal, Jan. 14, 1924, p. 1904; Investigation of Injuries from Hair Dyes, Dyed Furs and Cosmetics, ibid., Feb. 5, 1927, p. 397) and McCafferty (Hair Dyes and Their Toxic Effects,<i>Arch. Dermat. &amp; Syph.</i><b>14</b>:136 [Aug.] 1926) are of the opinion that argyria may develop, but no definite instances are reported. This of course is known to those who market such dyes and may be used as an excuse to exclude them from any possible legislation against those proved to be harmful by actual case reports. In the recent flurry for expert opinion (Expert Opinion on Hair Dyes—Take It
TINCTURE OF STROPHANTHUS.
Authors: R. A. HATCHER
Journal: JAMA (1907)

Strophanthus has not rivaled digitalis in the extent of its use, except, perhaps, for a short time after the former was brought into prominence by Fraser. This is somewhat remarkable in view of the fact that numerous investigators have found that the action of strophanthus presents certain advantages over that of digitalis; thus, strophanthus, and to a greater extent its active principle, strophanthin, act much more promptly than digitalis or digitoxin. Fraenkel found that the action of a single effective dose of digitoxin was delayed for many hours beyond that of a corresponding dose of strophanthin, and while he was unable to induce slowing of the cat's heart from a single non-toxic dose of digitoxin, a single non-toxic dose of strophanthin promptly proved effective. Strophanthus produces much less vasoconstriction in the splanchnic area than digitoxin does, and while this is a disadvantage in shock, it is often desirable in producing