tbuckley/cabot-search huggingface dataset:
Abstract LB-49: ABC transporters in the blood-brain barrier limit the brain penetration of the PARP inhibitor ABT-888
Authors: Lin Fan, Mark C. de Gooijer, Jan H. Beumer, Susan M. Christner, Jos H. Beijnen, Olaf van Tellingen
Journal: Cancer Research (2010)

Abstract Introduction: ABT-888 is a potent poly(ADP-ribose) polymerase (PARP) inhibitor and is currently in phase 2 clinical trials. PARP inhibitors enhance the activity of DNA damaging therapies, due to the critical function of PARP-1 and PARP-2 in base excision repair. The combination of ABT-888 with chemo-radiation therapies for the treatment of glioma patients is receiving considerable interest because this combination has shown promise in preclinical models. High-grade glioma patients have a very poor prognosis, in particular due to the inability to achieve complete surgical resection. Importantly, the residual tumor cells that have infiltrated surrounding normal brain tissue are using pre-existing brain vasculature and are thus protected by the blood-brain barrier (BBB). Consequently, the ability of potential chemotherapeutics to cross the BBB, including the role of ABC transporters in brain penetration, needs to be characterized. Goal: To establish the impact of the BBB and the role of the ABC transporters ABCB1 and ABCG2 in the brain disposition of ABT-888. Methods: We performed in vitro transwell assays using polarized epithelial monolayers of parental vs ABC-transporter transduced cell lines. In vivo pharmacokinetic studies were conducted with wildtype (WT), single and compound ABC transporter knockout mice. Drug concentrations were determined by HPLC-UV and LC-MS. Results: Transwell assays demonstrated basolateral-to-apical translocation in both Abcb1 expressing LLC-Mdr1a vs LLC-PK1 cells as in Abcg2 expressing MDCK-Bcrp1 vs MDCK-parent cells, which could be inhibited by zosuquidar and elacridar, respectively. The plasma levels of ABT-888 in WT vs single Abcb1−/−, single Abcg2−/−, or compound Abcb1−/−;Abcg2−/− mice 1 h after i.v. administration of 10 mg/kg were not different. However, the brain-to-plasma ratios for WT, Abcb1−/−, Abcg2−/−, and Abcb1−/−;Abcg2−/−mice were 0.98, 4.46 ((p&amp;lt;0.006*), 1.45 (p=NS*) and 7.47 (p&amp;lt;0.001*, p=0.022**), respectively. Significance was assessed by ANOVA with Bonferroni post-hoc test (*relative to WT; **relative to Abcb1−/−). Conclusions and Relevance: The brain penetration of ABT-888 is more than 7-fold reduced by the action of Abcb1 and Abcg2, with Abcb1 being the most important limiting factor. This information will aid in the interpretation of clinical trials in glioma. Disappointing efficacy of ABT-888 based therapy in glioma may merely reflect inadequate drug exposure, and could be improved by using inhibitors of selected ABC-transporters or by the development of PARP inhibitors with lesser affinities for ABC-transporters. 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 LB-49.
Competition Between Physicians
Authors: Edward J. Connell
Journal: JAMA (1983)

To the Editor.—  In Competition or Regulation: A Critical Choice for Organized Medicine, in the April 8 issue, Mr Pollard 1 indicates that the assumption of a credentialing role by professional associations or information dissemination by consumer groups will lead to more competition among physicians. This conclusion, on the surface at least, satisfies the elements of logic. Greater knowledge of physicians' abilities produces more informed physician selection, and more informed physician selection produces greater competition among physicians for the available pool of consumers.  Closer examination of the argument shows it to be fallacious because the premises themselves are false.  This first premise assumes that physicians' abilities and qualifications can be quantified and communicated to the consumer. It is unrealistic to assume that consumers can differentiate between a Harvard or USC medical school graduate or between a physician trained in Texas or New York. Scholars involved in medical education and physician training
TCT-498 Chronic Myocardial Tissue Effects of Intracoronary Supersaturated Oxygen in a Porcine Model of Anterior Myocardial Infarction
Authors: Greg Kaluza, Jeffrey Creech, Maxwell Afari, Armando Tellez, Krzysztof Milewski, Geng-Hua Yi, Yanping Cheng, Gerard Conditt, Jenn McGregor, Donald Blum, Serge Rousselle, Juan Granada
Journal: Journal of the American College of Cardiology (2012)
TEMPORAL DEVELOPMENT OF RESISTANCE TO PULMONARY TUBERCULOSIS IN SWISS ALBINO MICE
Authors: Takateru Izumi, Richard Costello
Journal: The Journal of Experimental Medicine (1971)

The course of pulmonary tuberculosis was followed in control and BCG-vaccinated mice. Resistance was evaluated by determining the numbers of virulent mycobacteria recovered from the organs at various intervals after airborn infection. A limited but significant retardation of growth of challenge bacilli was observed in both pulmonary and splenic tissues of successfully vaccinated animals. This retardation was manifested chiefly during the early stages of the infection. However, the numbers of virulent organisms recovered from the organs of either vaccinated or control animals were much the same at later stages of the infection. The appearance of pulmonary immunity was related to the stage of development in vivo of the vaccinal population. Only after large numbers of vaccinal bacilli could be recovered from the tissues was heightened resistance observed.
Reduced peak aerobic capacity in asymptomatic left ventricular systolic dysfunction. A substudy of the studies of left ventricular dysfunction (SOLVD). SOLVD Investigator. Studies of Left Ventricular Dysfunction.
Authors: T H LeJemtel, C S Liang, D K Stewart, P C Kirlin, K M McIntyre, T H Robertson, A Moore, L Cahill, M Galvao, K L Wellington
Journal: Circulation (1994)

Peak oxygen consumption is reduced in patients with symptomatic congestive heart failure, but functional capacity of patients with asymptomatic left ventricular systolic dysfunction has not been assessed by measurement of peak oxygen consumption attained during graded exercise testing.Peak oxygen consumption, that is, aerobic capacity (VO2, mL/kg per minute), was determined during graded treadmill exercise using the modified Naughton protocol in 40 patients with left ventricular systolic dysfunction (mean ejection fraction ranging from 14% to 35%; mean, 29%) who, while not receiving any cardiac medications, were totally asymptomatic, and in 41 age-matched normal subjects. Peak exercise duration and VO2 were significantly lower in patients with asymptomatic left ventricular systolic dysfunction than in normal subjects (948 +/- 273 versus 1239 +/- 372 seconds, P < .001, and 22.1 +/- 5.9 versus 29.8 +/- 7.7 mL/kg per minute, respectively, P < .001), while asymptomatic patients and normal subjects reached similar respiratory equivalents (1.14 +/- 0.11 versus 1.11 +/- 0.11 [NS]) and level of perceived exertion, using the modified Borg scale (7.4 +/- 2.6 versus 8.1 +/- 1.5 [NS]). Heart rate, systemic blood pressure, and oxygen pulse response to peak exercise were significantly lower in asymptomatic patients than in normal subjects.Although patients with left ventricular systolic dysfunction can be totally asymptomatic in their daily activities, they have experienced a substantial reduction in peak aerobic capacity when compared with normal subjects of similar age.
Targeting of neuronal subsets mediated by their sequentially expressed carbohydrate markers
Authors: Jonathan Song, Birgit Zipser
Journal: Neuron (1995)

The targeting of sensory afferent neurons in the leech CNS occurs in two discrete steps that are mediated via different carbohydrate recognitions, as shown by molecular perturbations of cultured embryos. A constitutive carbohydrate marker that is generic to all of these neurons mediates their initial defasciculation and arborization across the entire target region via mannose-specific recognition. Subsequently, two subsets of these same neurons can be differentiated by their expression of other markers that are located on hybrid or complex type carbohydrate chains. These developmentally regulated carbohydrate markers then mediate the target assembly of their respective neuronal subsets into discrete subregions. Thus, by performing opposing functions in a temporal sequence, constitutive and developmentally regulated carbohydrate markers collaborate in the targeting of neuronal subsets in the CNS.
Review of prescribed treatment for children with asthma in 1990
Authors: J O Warner
Journal: BMJ (1995)

<h3>Abstract</h3> <b>Objective</b>: To review treatment prescribed to asthmatic children in Great Britain during the 12 months after publication of the first guidelines and to assess effectiveness of prophylactic treatment. <b>Design</b>: Review of prescribing information from January 1990 to June 1991 in a representative sample of general practices in Great Britain with a Compufile/AAH Meditel computer. <b>Subjects</b>: 17846 children with asthma aged 4-17 years. <b>Main outcome measures</b>: Numbers of children prescribed different asthma treatments; estimated use of inhaled β agonists in those receiving prophylactic treatment. <b>Results</b>: From January to December 1990, 9362 (52.5%) children were prescribed preventive treatments. 16211 (90.8%) children were prescribed bronchodilators of some kind. 3055 (17.1%) were prescribed sodium cromoglycate, and the proportion decreased significantly during the study (from 19.5% (95% confidence interval 18.6% to 20.4%) to 17.2% (16.4% to 18.1%), P&lt;0.001, in children aged 4-11 years and from 14.9% (14.0% to 15.9%) to 11.3% (10.4% to 12.2%), P&lt;0.001, in those aged 12-17 during January-July 1991). 6952 (39. 0%) were prescribed inhaledsteroids, and the proportion increased during the study (from 35.1% (34.0% to 36.2%) to 44.1% (43.0% to 45.2%), P&lt;0.001, in children aged 4-11 years and from 38.7% (37.4% to 40.0%) to 44.1% (42.7% to 45.5%), P&lt;0.001, in those aged 12-17 during January-July 1991). Only 1358 of the 9362 children (14.5%) received sufficient repeat prescriptions to suggest that they might be taking the prophylactic treatment regularly. Among these children short acting inhaled β agonists were being used on average four to eight times a day. <b>Conclusions</b>: These results are useful baseline data for audit of the impact of published clinical guidelines, particularly in terms of reducing the need for short acting inhaled β agonists with prophylactic treatment.
Molecular Changes Associated with Acquired Resistance to Crizotinib in <i>ROS1</i>-Rearranged Non–Small Cell Lung Cancer
Authors: Ahnah Song, Tae Min Kim, Dong-Wan Kim, Soyeon Kim, Bhumsuk Keam, Se-Hoon Lee, Dae Seog Heo
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Although ROS1-rearranged non–small cell lung cancer (NSCLC) is sensitive to crizotinib, development of resistance is inevitable. Here, we identified molecular alterations in crizotinib-resistant tumors from two NSCLC patients with the CD74–ROS1 rearrangement, and in HCC78 cells harboring SLC34A2–ROS1 that showed resistance to crizotinib (HCC78CR cells). Experimental Design: ROS1 kinase domain mutations were examined in fresh tumor tissues from two NSCLC patients and HCC78CR1-3 cells by direct sequencing. Ba/F3 cells expressing ROS1 secondary mutations were constructed to evaluate resistance to crizotinib. An upregulated pathway was identified using phospho-receptor tyrosine kinase array, EGFR signaling antibody array, and RNA sequencing (RNA-seq). Cell proliferation and ROS1 downstream signaling pathways were compared between HCC78 and HCC78CR1-3 cells. Results: The ROS1 G2032R mutation was identified in crizotinib-resistant tumors from one patient. Furthermore, HCC78CR1 and CR2 cells harbored a novel ROS1 L2155S mutation (73.3% and 76.2%, respectively). ROS1 G2032R and L2155S mutations conferred resistance to crizotinib in Ba/F3 cells. Evidence of epithelial-to-mesenchymal transition with downregulated E-cadherin and upregulated vimentin was observed in HCC78CR1-2 cells and in the other patient. RNA-seq and EGFR signaling antibody array revealed that the EGFR pathway was significantly upregulated in HCC78CR3 versus HCC78 cells. Cells with the ROS1 mutation and upregulated EGFR were sensitive to foretinib, an inhibitor of c-MET, VEGFR2, and ROS1 and irreversible EGFR tyrosine kinase inhibitors plus crizotinib, respectively. Conclusions: Molecular changes associated with acquired crizotinib resistance in ROS1-rearranged NSCLC are heterogeneous, including ROS1 tyrosine kinase mutations, EGFR activation, and epithelial-to-mesenchymal transition. Clin Cancer Res; 21(10); 2379–87. ©2015 AACR.
Captopril and Pericarditis-Reply
Authors: Jacob Zatuchni
Journal: JAMA (1984)

<h3>In Reply.—</h3> The issues that Dr Garbitelli raises are important and relevant and were fully addressed in an original manuscript, which was reduced to a brief letter at the request of the editor. The serum urea nitrogen level was 103 mg/dL, and the creatinine level was 8.3 mg/dL. Uremic pericarditis was a definite possibility and could not be excluded with certainty but was considered unlikely for the reasons cited in the letter. Second, pericardial effusion was not responsible for refractory heart failure, for it was absent initially and, later, not large but small, as revealed by echocardiography. Third, the elevated ESR was thought to be part of a drug-induced immune dysregulatory phenomenon. Finally, to be sure, the evidence of a causal relationship is circumstantial but favored by findings and sequence of events.
Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells.
Authors: C T Wagner, W Durante, N Christodoulides, J D Hellums, A I Schafer
Journal: Journal of Clinical Investigation (1997)

Both nitric oxide (NO) and carbon monoxide (CO) are vessel wall-derived messenger molecules that cause platelet inhibition and vasodilation by activating guanylyl cyclase in target cells. Since vascular smooth muscle cells (SMCs) are exposed to shear and tensile stresses, this study examined the effects of these hemodynamic forces on the enzymes that generate NO and CO in SMCs. Monolayers of cultured rat aortic SMCs were subjected to shear stress using a modified cone and plate viscometer, or cyclic elongational stretch using a compliant silastic culture membrane. Shear stress stimulated time-dependent increases in mRNA and protein for inducible heme oxygenase-1 (HO-1), the enzyme which forms CO as a byproduct of heme degradation. The threshold level of shear necessary to induce HO-1 expression was between 5 and 10 dynes/cm2. In contrast, shear stress did not stimulate inducible NO synthase (iNOS) expression. Cyclic stretch also induced the expression of HO-1 but not of iNOS mRNA. Exposure of vascular SMCs to shear stress stimulated the production and release of CO as demonstrated by the CO-dependent increase in intracellular cGMP levels in coincubated platelets. In addition, ADP-stimulated aggregation was inhibited in platelets exposed to sheared SMCs but not in platelets exposed to untreated control SMCs. Treatment of sheared SMCs with the HO-1 inhibitor, tin protoporphyrin-IX, blocked the antiaggregatory effect of the cells, whereas the iNOS inhibitor, methyl--arginine, had no effect. These results indicate that hemodynamic forces induce HO-1 gene expression and CO production in vascular SMCs, and that SMC-derived CO inhibits platelet aggregation. Thus, CO is a novel endogenous vessel wall-derived messenger molecule that may be selectively induced by hemodynamic forces to inhibit platelet reactivity and preserve blood fluidity at sites of vascular injury.
Hypotension is more risky than hypertension in very old people
Authors: F. M. Engelaer, D. van Bodegom, R. G. J. Westendorp
Journal: BMJ (2012)

The open label treatment extension of the original HYVET study received enthusiastic applause as further evidence for direct and long term benefits of treating hypertension in very old people (≥80 years).1 However, we should be cautious in extrapolating these findings to clinical practice.

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The role of radical prostatectomy in the treatment of prostate cancer
Authors: C. B. Brendler, P. C. Walsh
Journal: CA A Cancer Journal for Clinicians (1992)

Recent advances in our understanding of the surgical anatomy of the prostate have led to an improved operative technique for radical prostatectomy. This technique achieves excellent results in terms of urinary continence and preservation of sexual function without compromising cancer control. It is therefore reasonable to offer radical prostatectomy for the cure of localized prostate cancer to patients who are otherwise well and have a life expectancy of more than 10 years.
Cardiac Arrest Following Fluorescein Angiography-Reply
Authors: Venkataraman Balu
Journal: JAMA (1980)

<h3>In Reply.—</h3> Our patient did receive drops of phenylephrine hydrochloride 10% to dilate the pupils 20 minutes before the onset of the fatal event. Acute systemic hypertension after conjunctional instillation of phenylephrine has been reported.<sup>1,2</sup>The other important systemic effect seems to be the increased frequency of cardiac extrasystoles.<sup>3</sup>The transient systemic effect of phenylephrine has been incriminated as a cause of increased oxygen demand on the heart, possibly leading to cardiac arrest.<sup>4</sup>The time of occurrence of these effects after local instillation is not known, and one would expect it to occur in a matter of a few minutes. In our patient, phenylephrine causing the event appears unlikely, although it cannot be excluded, since our patient did not show any arrhythmias on the earliest possible monitored ECG but showed electromechanical dissociation. In our institution, one routinely uses phenylephrine 10% or tropicamide 1% for dilation of pupils
X-ray Appearances in Chronic Rheumatism
Authors: G. D. Steven
Journal: Annals of the Rheumatic Diseases (1947)

Radiography provides us with a means of studying the structure and architec- ture of bones and joints.The normal bone shadowing presents definite and recognizable features.The fundamental processes which maintain the normal bone appearance throughout life are few in number, and disturbance of any of these processes is a feature of more than one disease.It is fortunate, for the purpose of differential diagnosis, that the diseases have certain individual character- istics in the combination of changes they produce when disturbing these funda- mental processes.One type of change may be specially pronounced, but in that case others must be looked for before the evidence can be considered of more than presumptive diagnostic value.As one might expect in diseases of chronic type, changes at various stages of activity or quiescence may be found in one and the same patient.It is the active processes which produce the characteristic features, whereas reconstructive and degenerative changes may obscure the nature of the quiescent lesions.Gross abnormality, therefore, is often a hindrance rather than a help even to the skilled observer.It may be just as necessary to search assiduously with a magnifying lens over bones which are grossly osteoporosed or honeycombed with punched-out areas as it is for minimal changes of early disease.The clinician and the pathologist are no doubt faced with somewhat similar difficulties in the complex phases of these diseases, and no one form of examination should be considered a short cut to the diagnosis of chronic rheuma- tism.The experienced radiologist usually correlates his findings with the clinical and pathological features, as these must have some bearing on the interpretation of changes which appear on a radiograph.By this means he may be able to give a presumptive report-when certain signs are present, instead of an indeterminate one which would be of no informative value.To conform with this team work, the radiologist usually refers in his report to changes being of a certain disease type.This leaves the clinician to decide if further investigation is required before the diagnostic label is applied to the case.In the following brief survey the principal diseases and disorders which will be considered are the familiar triad, rheumatoid arthritis, osteo-arthritis, and gout.Where terms such as " early", "established ", "late ", "active ", or " quiescent " are used, they will refer to local lesions unless otherwise stated, since all forms may be found-in one and the same patient, whether the disease is early or advanced.I
THE PREVENTION OF INFANT MORTALITY FROM AN EDUCATIONAL STANDPOINT
Authors: L. T. ROYSTER
Journal: JAMA (1910)

In no line of research has scientific investigation achieved more striking results than in medicine. Nor has the broad-mindedness of the physician been content with the mere alleviation of human suffering, however praiseworthy this may be, but that altruism which has always characterized the profession is impelling it to strive with ever-widening success for the complete eradication of preventable disease and suffering and the developing of a race noted for health, vigor and strength. Preeminent among such efforts stand the investigations of the pediatrists, who hold an undisputed position among the pioneers in the study of prevention, and I may safely say that enough is known to-day to reduce materially the present fearful rate of infant mortality if the knowledge were properly applied, and yet with all that has been discovered and the knowledge which has been acquired, the actual number of deaths during infancy has not been materially decreased,
A Hospital's Precautions during Air Raids
Authors: R. P. Osborne
Journal: BMJ (1940)

<h3>Objective.</h3> To compare outcomes over the first 8 years in patients with early rheumatoid arthritis (RA) recruited in the 1990s and the 2000s, with a special focus on functional disability and its possible predictors. <h3>Methods.</h3> Data were acquired from 1938 patients with early RA (American College of Rheumatology 1987 criteria) included in the BARFOT study, who had completed the 8-year followup. The patients were divided into 2 cohorts: cohort 1 (n = 928, 68% women) included from 1992 to 1999 and cohort 2 (n = 1010, 70% women) included from 2000 to 2006. Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28), visual analog scale pain, and radiographs of hands and feet scored by the van der Heijde modified Sharp method were assessed during the 8 years. Longitudinal data analyses were performed using a generalized linear model. <h3>Results.</h3> Despite more active medical treatment during the 2000s, the courses of HAQ and pain showed no difference between the cohorts during followup, in either women or in men, with significantly higher levels in women compared with men. However, as expected, disease activity decreased more over time in cohort 2 compared with cohort 1, for both sexes, and women in cohort 2 had less radiographic progression compared with cohort 1. HAQ was associated with DAS28, pain, radiological scores, and sex in both cohorts, and in cohort 2 also with age and smoking. <h3>Conclusion.</h3> Patients included in the 2000s had lower disease activity, but not less activity limitation and pain over 8 years of followup despite more active treatment. Pain, aging, and smoking might explain why patients included in the 2000s still had the same disability levels as those included in the 1990s.