tbuckley/cabot-search huggingface dataset:
Abstract 4408: A functional genomics approach for identification of sirolimus sensitizer genes regulated by HDAC inhibitors.
Authors: Benjamin J. Gamache, John Simmons, Jyoti Patel, Lihui Ou, Aleksandra Michalowski, Patrick Sullivan, Bih-Rong Wei, R. Mark Simpson, Shuling Zhang, Ke Zhang, W. Michael Kuehl, Ola Landgren, Natasha Caplen, Beverly Mock
Journal: Cancer Research (2013)

Abstract The molecular pathogenesis of many cancer types, including multiple myeloma (MM), involves alterations in the PI3K/Akt/mTOR and cyclin/CDK/CDKI/Rb (Rb) pathways. We have shown the combination of a Class I-specific HDAC inhibitor (entinostat, MS-275) with the mTOR inhibitor sirolimus to be synergistic in a large panel of B cell tumor cell lines including multiple myeloma, mantle cell and Burkitt's lymphoma. While tumor outgrowth occurred in both single agent arms, the combination effectively controlled in vivo tumor growth in long-term preclinical studies. The combination was also highly effective in a tumor-cell specific bioluminescence assay where myeloma cells are co-cultured with bone marrow stromal cells to mimic the protective effects of the tumor microenvironment. We found the combination antagonized the oncogenic activation of the AKT pathway associated with single-agent rapamycin treatment, inhibited the ERK/MAPK pathway, decreased pro-survival signaling, and increased growth inhibitory signals to a much greater extent than either single agent alone. To further understand the molecular mechanisms contributing to the synergy of this combination, a functional genomics approach utilizing high-throughput RNAi screening and gene expression profiling was taken. Several cell cycle-specific kinases were identified that upon inhibition enhance the activity of sirolimus and are significantly down-regulated by entinostat. Thus far, we have confirmed by western blot that PLK1 and AURKB are decreased in a dose-dependent manner by entinostat. Specific inhibition of these targets synergizes with sirolimus. Additionally, we found very low (&amp;lt;EC20) entinostat/sirolimus combination doses to hyper-sensitize tumor cells to a number of cell cycle inhibitors. These findings are further supported by increased cell cycle arrest seen in the combination treatment compared to either drug alone, as well as marked reduction in the cell cycle progression marker phospho-Histone H3. Taken together, our findings indicate the anti-tumor synergy of combined HDAC/mTOR inhibition is the result of multiple cooperative effects. Citation Format: Benjamin J. Gamache, John Simmons, Jyoti Patel, Lihui Ou, Aleksandra Michalowski, Patrick Sullivan, Bih-Rong Wei, R. Mark Simpson, Shuling Zhang, Ke Zhang, W. Michael Kuehl, Ola Landgren, Natasha Caplen, Beverly Mock. A functional genomics approach for identification of sirolimus sensitizer genes regulated by HDAC inhibitors. [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 4408. doi:10.1158/1538-7445.AM2013-4408
Effect of serum subfractions from peritoneal dialysis patients on Hep-G2 cell apolipoprotein A-I and B metabolism
Authors: Gaurang M. Shah, Zuo-Lun Lin, Vaijinath S. Kamanna, Rama Pai, Babu Bassa, Fu-You Jin, Daeyoung Dave Roh, Moti L. Kashyap, Michael A. Kirschenbaum
Journal: Kidney International (1996)
Prediction of Outcome of Patients With Life-Threatening Ventricular Arrhythmias Treated With Automatic Implantable Cardioverter-Defibrillators Using SPECT Perfusion Imaging
Authors: Giuseppe Gioia, Bruce Bagheri, Charles D. Gottlieb, David S. Schwartzman, David J. Callans, Frank E. Marchlinski, Jaekyeong Heo, Ami E. Iskandrian
Journal: Circulation (1997)

In the present study, we examined the predictors of outcome of 103 patients with coronary artery disease and left ventricular dysfunction who had life-threatening ventricular arrhythmias and were treated with implantable cardioverter-defibrillators with the use of single-photon emission computed tomography (SPECT).During a mean follow-up of 29 months, there were 29 cardiac deaths. In comparison with patients who died, survivors had less diabetes mellitus (45% versus 19%, P < .007), higher left ventricular ejection fraction (23 +/- 9% versus 27 +/- 11%, P = .04), and fewer perfusion defects as determined with stress SPECT (15 +/- 5 versus 12 +/- 5, P < .004). Most of the perfusion defects were fixed, indicative of scarring; the extent of reversible defects did not differ (2 +/- 3 in survivors and 3 +/- 4 in nonsurvivors). Multivariate Cox survival analysis identified the number of fixed defects as the only independent predictor of death (chi 2 = 10, P = .002). There were six deaths among 42 patients (14%) with < 8 fixed defects compared with 23 deaths among 61 patients (38%) with > or = 8 defects (P = .005). The 4-year survival was better in patients with < 8 segmental fixed defects than in those with > or = 8 fixed defects (80% versus 36%) (chi 2 = 8, P = .005).The myocardial perfusion pattern is an important determinant of outcome in patients with life-threatening ventricular arrhythmias who are treated with a implantable cardioverter-defibrillator. The extent of scarring separates patients into high- and low-risk groups with a 2.7-fold difference in death rate.
The Venous and Arterial Pulse
Authors: Bernard L. Segal
Journal: JAMA (1963)

THE EXAMINATION, at the bedside, of the venous and arterial pulse is often the first clue suggesting the presence of heart disease. The pulse has been examined from earliest times, although in recent years it has become a neglected art in physical diagnosis.  In China, 1 many centuries ago, the Chinese pursued a vague mystical study of the pulse. There are also ill-understood references concerning the phenomenon of pulsation in some of the Egyptian papyri. There is no evidence that Hippocrates ever paid attention to the pulse, but by the end of the second century, Galen recognized the quick wave of aortic reflux and the slow wave of aortic stenosis. He appreciated the force and weakness of the pulse, the state of the wall of the artery, and the apparent fullness of the vessel. It was not until 1707, with the publication of the essay The Physician's Pulse-Watch , by Sir
UCL's response
Authors: J. Tooke, D. Price
Journal: BMJ (2011)

UCL takes any allegation of research misconduct seriously, and we will certainly investigate those raised in the BMJ .1 However, we have not seen all the related articles yet so can give only a general institutional response to the issues raised so far.

The Royal Free Medical School was not part of UCL when the relevant research was conducted. It is over a decade since this research …
Abstract 1082: BI 811283, a potent inhibitor of the mitotic kinase Aurora B, shows dose- and schedule-dependent efficacy in human cancer xenograft models
Authors: Ulrich Gürtler, Ulrike Tontsch-Grunt, Stephan K. Zahn, Jens Quant, Guenther R. Adolf, Flavio Solca
Journal: Cancer Research (2010)

Abstract Background. The serine/threonine kinase Aurora B is involved in the regulation of several mitotic processes, including chromosome condensation, congression and segregation as well as cytokinesis. The essential functions of Aurora B and its overexpression in many cancer types render this protein kinase an attractive target for therapeutic intervention. BI 811283, a potent inhibitor of this key mitotic regulator, inhibits proliferation of a wide range of cultured human cancer cells at low nanomolar concentrations by inducing polyploidy, senescence and apoptosis. Methods. BomTac:NMRI-Foxn1nu mice were grafted subcutaneously with NCI-H460 non-small cell lung carcinoma (mutant KRAS, wild-type p53), HCT 116 colon carcinoma (mutant KRAS, wild-type p53) or BxPC-3 pancreas adenocarcinoma cells (wild-type KRAS, mutant p53). Treatment was initiated when the tumors had reached a volume of ∼50 mm3. BI 811283 was injected intravenously once or twice weekly as a single bolus or b.i.d. Alternatively, the compound was administered once-weekly by a continuous 24 h infusion via subcutaneously implanted osmotic mini-pumps. Multiple dose levels and dosing schedules were evaluated. Results. In models of human non-small cell lung cancer, colon carcinoma and pancreas carcinoma, multiple cycles of treatment with BI 811283 at total weekly doses of 20 to 75 mg/kg resulted in dose-dependent inhibition of tumor growth or tumor regression. Continuous s.c. infusion at 20 mg/kg over 24 h once-weekly was clearly superior to all bolus injection schedules delivering weekly doses up to 75 mg/kg. Furthermore, regression of large tumors (350 mm3) was induced in the HCT 116 colon carcinoma model. Biomarker analyses of HCT 116 tumors revealed that therapeutic doses of BI 811283 inhibited phosphorylation of histone H3, a direct substrate of Aurora B. Histological examination showed an accumulation of enlarged, multinucleated cells in accordance with the expected mechanism of action. Conclusions. BI 811283 has demonstrated potent antitumor activity in multiple cancer models at well-tolerated doses; treated tumors show hallmarks of Aurora B inhibition. Continuous infusion over 24 h provides a superior therapeutic index compared with bolus administration. The compound is currently under investigation in Phase I clinical trials. 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 1082.
Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis
Authors: Annalisa Berzigotti, Guadalupe Garcia-Tsao, Jaime Bosch, Norman D. Grace, Andrew K. Burroughs, Rosa Morillas, Angels Escorsell, Juan Carlos Garcia-Pagan, David Patch, Daniel S. Matloff, Roberto J. Groszmann
Journal: Hepatology (2011)

Obesity is associated with an aggressive course in chronic viral hepatitis; however, its impact in the development of clinical decompensation (CD) in patients with established cirrhosis is uncertain. We evaluated the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis. The study population, a subset of patients included in a randomized trial of beta-blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis. Laboratory tests and portal pressure (assessed by the hepatic venous pressure gradient or HVPG) were assessed on inclusion. Patients were followed until CD (ascites, hepatic encephalopathy, or variceal hemorrhage), or until September 2002. Altogether, 29% had a normal BMI, 40% were overweight, and 30% were obese. In a median follow-up of 59 months, CD occurred in 48/161 (30%) patients with an increasingly higher rate according to BMI group (15% in those with normal BMI; 31% in overweight; 43% in obese patients, P=0.011). The actuarial probability of developing CD was significantly higher in the abnormal BMI groups (P=0.022). In a multivariate model that included parameters previously identified as being predictive of CD (HVPG, albumin, Mayo endstage liver disease score), etiology, and treatment group, BMI (hazard ration 1.06; 95% confidence interval 1.01-1.12), P=0.02] was an independent predictor of decompensation, together with HVPG and albumin.Obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population.
Asymptomatic Urinary Tract Infection in Gynaecological Outpatients
Authors: J. D. Williams, J. L. Thomlinson, J. G. L. Cole, E. Cope
Journal: BMJ (1969)

In this study mid-stream specimens of urine were collected from all new patients attending a gynaecological outpatient department and tested for significant bacteriuria. Those having an asymptomatic infection were folloWed up, treated, and investigated adiologically.Of 1,506 women screened for bacteriuria 82 (5.4%) were found to have a persistent infection. The predominant organism was Escherichia coli, present in 83% of infections. Treatment with sulphonamides produced a good cure rate, which was improved by ampicillin given to failures. Some patients, however, had infections that persisted or recurred despite several antibiotics. The radiological investigations showed that a high proportion of women with asymptomatic urinary infection had severe renal disease which was quite symptomless. This was more pronounced in those with persistent or recurrent infections.
A SYSTEMATIC APPROACH TO THE TREATMENT OF HOMOSEXUALITY BY CONDITIONED AVERSION: PRELIMINARY REPORT
Authors: M. P. FELDMAN, M. J. MACCULLOCH
Journal: American Journal of Psychiatry (1964)

A detailed outline is given of the clinical application of anticipatory avoidance learning to the treatment of homosexuality. Clinical data on the first patient of a series currently under treatment are also given, together with a report on his progress, after 9 months follow-up. Further clinical and experimental reports are planned.
Curative percutaneous catheter ablation using radiofrequency energy for accessory pathways in all locations: Results in 100 consecutive patients
Authors: Michael D. Lesh, George F. Van Hare, David J. Schamp, Walter Chien, Michael A. Lee, Jerry C. Griffin, Jonathan J. Langberg, Todd J. Cohen, Keith G. Lurie, Melvin M. Scheinman
Journal: Journal of the American College of Cardiology (1992)
Noninvasive Glucose Monitoring
Authors: Janet A. Tamada, Satish Garg, Lois Jovanovic, Kenneth R. Pitzer, Steve Fermi, Russell O. Potts, None and the Cygnus Research Team
Journal: JAMA (1999)

ContextIntensive diabetes management using frequent blood glucose measurements to guide therapy has been shown to significantly improve short- and long-term outcomes. Development of a device that makes possible frequent, automatic, painless, and accurate measurements of glucose would facilitate intensive management.ObjectiveTo determine the accuracy of the GlucoWatch automatic glucose biographer (Cygnus Inc) compared with that of serial blood glucose measurements.DesignMulticenter comparative study of the GlucoWatch biographer and the HemoCue blood glucose analyzer (Aktiebolaget Leo) performed between August 29 and October 17, 1998. Participants wore up to 2 biographers during the 15-hour study session and performed 2 fingersticks per hour for comparative blood glucose measurements. The biographers were calibrated with a single HemoCue measurement after a 3-hour warm-up period. Diet and insulin were manipulated to produce a broad glycemic range during the study.SettingControlled clinical environment at 2 diabetes centers and 3 contract research organizations in the United States.ParticipantsA total of 92 subjects (mean [SD] age, 42.1 [15.1] years; 59.8% women) with type 1 or 2 diabetes requiring treatment with insulin.Main Outcome MeasuresMean error, mean absolute error, correlation, slope, and intercept using Deming regression, and clinical significance of differences between biographer readings and blood glucose measurements using the Clarke error grid.ResultsResults showed close tracking of blood glucose over a range of 2.2 to 22.2 mmol/L (40-400 mg/dL) for up to 12 hours using a single point calibration. The biographer readings lagged behind serial blood glucose values by a mean of 18 minutes. An analysis of 2167 data pairs shows a linear relationship (r = 0.88; slope = 1.03; intercept = −0.33 mmol/L [−6 mg/dL]) between biographer readings and serial glucose measurements. The mean absolute error between the 2 measurements was 15.6% (mean error [SD], −0.07 [1.82] mmol/L [−1 {33} mg/dL]), and 96.8% of the data fell in the therapeutically relevant regions of the error grid analysis.ConclusionThese results demonstrate close agreement between GlucoWatch biographer readings and blood glucose measurements using repeated fingerstick blood samples. The automatic, frequent, and noninvasive measurements obtained with the biographer provides more information about glucose levels than the current standard of care.
Chronic idiopathic urticaria: Comparison of the clinical features of patients with and without anti-FcϵRI or anti-IgE autoantibodies
Authors: R.A. Sabroe, P.T. Seed, D.M. Francis, R.M. Barr, A.Kobza Black, M.W. Greaves
Journal: Journal of the American Academy of Dermatology (1999)
Personalized Medicine in Advanced Non–Small-Cell Lung Cancer: Reality or Wishful Thinking?
Authors: Filip Janku, Brian Bird
Journal: Journal of Clinical Oncology (2008)

Scagliotti et al 1 reporting results of a noninferiority study comparing cisplatin plus gemcitabine to cisplatin and pemetrexed in advanced stage non-small-cell lung cancer (NSCLC).The authors are to be congratulated for completing the largest ever reported randomized trial in advanced NSCLC with more than twice as many patients assigned to treatment arms compared with other pivotal phase III trials.We have some reservations in relation to the conclusion recommending cisplatin plus pemetrexed as a reference regimen for future studies in nonsquamous NSCLC testing molecular-targeted therapies.While the prespecified analysis demonstrated the superiority of cisplatin plus pemetrexed over cisplatin and gemcitabine in terms of response rate, progression-free survival (PFS) and overall survival in nonsquamous histology, this trial was neither designed nor powered to answer this question.Rather, it should be considered hypothesis generating.The preclinical rationale derives from a study showing high expression of thymidylate synthase (therapeutic target of pemetrexed) in squamous carcinoma, indicating resistance to pemetrexed. 2 However, the clinical evidence currently available is not overwhelming.The majority of published studies of chemotherapy in NSCLC have not shown any significant difference with respect to histology.Recently Pang et al 3 reported a combined analysis of two phase II trials.Patients with adenocarcinoma had better response rates to pemetrexed-based first-line chemotherapy but this did not transform to any significant differences in PFS and overall survival.It appears that response rates were not independently reviewed.A retrospective analysis of a phase III study of second-line therapy comparing docetaxel with pemetrexed suggested worse survival in pemetrexed arm with squamous histology and, conversely, a benefit in nonsquamous histology. 4 Another study comparing standard-and low-dose of pemetrexed in second and third line showed on retro-spective analysis that patients with nonsquamous histology did remarkably better. 5Finally Ciuleanu et al 6 presented better PFS with pemetrexed maintenance after first-line therapy in comparison to placebo in nonsquamous histology.This data could be interpreted in various ways.It may mean that pemetrexed is less effective in squamous histology with similar efficacy in nonsquamous in comparison with other platinum doublets.Therefore, we believe the definite answer can only be provided by a specifically designed prospective randomized trial.
A novel translabial platform utilizing bioexcipients from Litchi chinesis for the delivery of rosiglitazone maleate
Authors: N.V. Satheesh Madhav, Abhay Pratap Yadav
Journal: Acta Pharmaceutica Sinica B (2013)

The aim of this study was to formulate drug-loaded bio-lipstrips using novel bioexcipients isolated from the fruit pulp of Litchi chinesis (biomaterial L) and to explore the potentiality of lip skin as a novel translabial drug delivery system. The biomaterial, prepared by a simplified economical process and purified by hot dialysis, was subjected to various physicochemical evaluations along with spectral analysis including UV, FT-IR, Mass and 1H NMR. The lipstrip formulated with the novel bioexcipients was screened for its functional properties, including filmability using a film-casting method, and bio/muco-adhesitivity using a shear-stress method, the Park and Robinson method and a rotating cylinder method. Rosiglitazone-loaded bio-lipstrips were formulated by using biomaterial L as a strip former and dextrose as a flexicizer. The formulated strips were subjected to various evaluations, including thickness, folding endurance, in-vitro release and in-vivo release. The release of rosiglitazone maleate was maintained over 24 h, which was confirmed in in-vitro and in-vivo release experiments. Our results reveal that this biopolymer possesses promising stripability as well as bio-adhesitivity. The formulated bio-lipstrips are feasible for delivering rosiglitazone maleate by translabial administration.
Lethal Radiation in Animals
Authors: Jacob Fine
Journal: JAMA (1967)

<h3>To the Editor:—</h3> The editorial on accidental radiation injury in man describes three lethal dose-dependent clinical states, the mildest of which, hematopoietic failure, is considered reversible if given good care (<b>200</b>:885, 1967). Since certain parallels exist between man and rat in their responses to radiation exposure, we would like to call attention to some relevant experimental data. The mortality of rats exposed to whole-body radiation in the midlethal range ( 550 rads), which is nearly 100%, can be reduced to near zero if the intestinal coliform flora is suppressed by an orally administered nonabsorbable antibiotic (<i>J Exp Med</i><b>48</b>:935, 1967). The protection is maximal if it is started shortly before radiation or immediately afterward. For full recovery from the injury, the antibiotic is needed up to 21 days after exposure. This protection is lost if bacterial endotoxin is fed to such animals. Therefore, the conclusion is warranted that bacteria
Delirium Associated With Sulindac
Authors: Thomas L. Thornton
Journal: JAMA (1980)

<h3>To the Editor.—</h3> This letter is to alert fellow physicians of a potentially dangerous adverse reaction after the use of sulindac (Clinoril Tablets). At this time I am unsure whether the adverse reaction experienced by my patient was idiosyncratic, primarily relatable to the chemical structure of sulindac, or to a drug interaction between sulindac and the antidepressant doxepin hydrochloride (Sinequan), which my patient was also taking. It is known that indomethacin (Indocin), which is similar in structure to sulindac, has been reported to precipitate a toxic delirium—a delirium of variable characteristics but often characterized by a rage reaction or a tendency toward anger outbursts at minimal frustration stimuli. <h3>Report of a Case.—</h3> My patient is a 53-year-old man whom I had followed up since Dec 4, 1978, for a biologic depression and have treated with doxepin. His response to the tricyclics has been substantial, with resolution of his insomnia, poor
Intravenous Injection of Milk
Authors: A. Meldon
Journal: BMJ (1881)

only in chronic cases that will not yield to ordinary treatment ; 4. To use it only with the consent of the patient's friends; the nature of the treatment, and the effect of the croton-oil on the skin, being first fully explained.If the last rule be not carried out, parents are apt to think that their children are being over-treated.MENINGITIS IN TYPHOID FEVER.
PRE–PROCEDURAL SIX–MINUTE WALK TEST AS A PREDICTOR OF MORTALITY IN PATIENTS UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION
Authors: Michael Mok, Luis Nombela–Franco, Marina Urena, Eric Dumont, Robert DeLarochelliere, Daniel Doyle, Henrique Barbosa Ribeiro, Melanie Cote, Philippe Pibarot, Hugo DeLarochelliere, Louis Laflamme, Paul Poirier, Josep Rodes–Cabau
Journal: Journal of the American College of Cardiology (2013)