tbuckley/cabot-search huggingface dataset:
Abstract 5752: Molecular mechanisms driving oncogenesis in KRAS mutant non-small cell lung cancer
Authors: Matthew Holderfield, Frank McCormick, Tobi Nagel
Journal: Cancer Research (2010)

Abstract The poor prognosis associated with Non Small Cell Lung Cancers (NSCLC) harboring KRAS mutations (∼20-30% frequency) has highlighted the need for RAS targeted therapeutics in oncology for decades. However, attempts to target RAS directly using small molecule inhibitors have historically proven unsuccessful. Additionally, pre-clinical data repeatedly demonstrates that KRAS mutated cancer cells show variable responses to inhibition of downstream effectors, RAF, MEK and PI3K, suggesting that proliferation and survival may be driven through additional pathways and that the molecular mechanisms through which KRAS drives oncogenesis have yet to be fully elucidated. Moreover, parallel pathways activated in human lung cancer that might cooperate with RAS to maintain a transformed state, likewise remain poorly defined. By screening a panel of KRAS mutant NSCLCs for functional dependence on KRAS by shRNA knockdown, we have identified cell lines that require KRAS for proliferation and suppression of apoptosis. In an effort to identify the signaling pathways that promote cellular proliferation and survival in KRAS-mutant lung cancers we have conducted an unbiased cellular screen to identify shRNAs that mitigate dependence on the KRAS oncoprotein. Using this method we have identified molecular pathways that appear to cooperate with the KRAS oncogene to promote tumorogenesis and contribute to the distinct proliferative and apoptotic phenotypes of KRAS dependent NSCLC 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 5752.
Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.
Authors: T A Slotkin, C B Nemeroff, G Bissette, F J Seidler
Journal: Journal of Clinical Investigation (1994)

Cholinergic deficits in Alzheimer's disease are typically as- sessed by choline acetyltransferase, the enzyme that synthe- sizes acetylcholine.However, the determining step in acetyl- choline formation is choline uptake via a high affinity transporter in nerve terminal membranes.Evaluating uptake is difficult because regulatory changes in transporter function decay rapidly postmortem.To overcome this problem, brain regions from patients with or without Alzheimer's disease were frozen within 4 h of death and examined for both choline acetyltransferase activity and for binding of [1H]hemicholinium-3 to the choline transporter.Consistent with the loss of cholinergic projections, cerebral cortical areas exhibited marked decreases in enzyme activity whereas the putamen, a region not involved in Alzheimer's disease, was unaffected.However, [3H]hemicholinium-3 binding was sig- nificantly enhanced in the cortical regions.In the frontal cortex, the increase in [3H]hemicholinium-3 binding far ex- ceeded the loss of choline acetyltransferase, indicating trans- porter overexpression beyond that necessary to offset loss of synaptic terminals.These results suggest that, in Alzhei- mer's disease, the loss of cholinergic function is not dictated simply by destruction of nerve terminals, but rather involves additional alterations in choline utilization; interventions aimed at increasing the activity of cholinergic neurons may thus accelerate neurodegeneration. (J.Clin.Invest.
Hamstrings are most susceptible to injury during the early stance phase of sprinting: Table 1
Authors: John W Orchard
Journal: British Journal of Sports Medicine (2011)

The first publications which considered the time of onset in the gait cycle for hamstring strains concluded that early stance was the highest risk period.1,2 The rationale proposed was that external joint moments were much higher in stance phases than swing (table 1) because of the presence of high hip and knee joint reaction forces secondary to the ground reaction force (GRF).3,–,6 Ralph Mann's original argument has been rejected by many subsequent authors, perhaps because of the dogma that muscles probably strain during eccentric contractions (table 1). This is a widely held belief despite experimental muscle strains being able to be produced during concentric (shortening) contractions.7

View this table:

Table 1 
Comparison of hamstring and opposing forces in late swing and early stance



Table 1 shows that the high knee flexion moment (sum of angular forces) in late swing occurs because the hamstrings are highly active and angular forces in the opposite direction (ie, due to quadriceps activity and external forces) are minimal. The hamstring does work hard in late swing to reverse the inertia of the shank angular movement in the opposite direction, but inertia …
Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome
Authors: M G Danieli
Journal: Annals of the Rheumatic Diseases (2004)

To study the long term effectiveness of intravenous immunoglobulin and plasmapheresis associated with prednisone and cyclophosphamide in Churg-Strauss syndrome.and methods: We studied 18 subjects with new onset Churg-Strauss syndrome. All received the "standard" treatment based on prednisone (1 mg/kg/day for 1 month and then slowly tapered) and cyclophosphamide (2 mg/kg/day for 6 months in severe cases). In nine patients, synchronised cycles with plasmapheresis and intravenous immunoglobulin (2 g/kg) were repeated monthly for 6 months and every other month for a further three cycles. Clinical (disease activity monitored by Birmingham vasculitis activity score (BVAS) and damage index (modified Rankin score)) and functional (C reactive protein, blood eosinophil count, and electromyogram-electoneurogram) parameters were collected during treatment and the 3 year follow up period.After 12 months, all patients in the treatment group and four (44%) in the control group were in remission. At the end of the 3 year follow up period, we documented significant differences in BVAS (p<0.01), global damage (p<0.02), modified Rankin score (p<0.04), and the daily maintenance prednisone dose (p<0.002) between the two groups. We found a tendency towards lower frequency of relapse and incidence of osteoporosis in the treatment group.Complete clinical and functional recovery with a long term stable remission and a low incidence of side effects can be achieved by intravenous immunoglobulin associated with plasmapheresis in patients with Churg-Strauss syndrome.
Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes
Authors: Bingye Han, Pau Serra, Jun Yamanouchi, Abdelaziz Amrani, John F. Elliott, Peter Dickie, Teresa P. DiLorenzo, Pere Santamaria
Journal: Journal of Clinical Investigation (2005)

The progression of immune responses is generally associated with an increase in the overall avidity of antigen-specific T cell populations for peptide-MHC. This is thought to result from preferential expansion of high-avidity clonotypes at the expense of their low-avidity counterparts. Since T cell antigen-receptor genes do not mutate, it is puzzling that high-avidity clonotypes do not predominate from the outset. Here we provide a developmental basis for this phenomenon in the context of autoimmunity. We have carried out comprehensive studies of the diabetogenic CD8 T cell population that targets residues 206-214 of the beta cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP(206-214)) and undergoes avidity maturation as disease progresses. We find that the succession of IGRP(206-214)-specific clonotypes with increasing avidities during the progression of islet inflammation to overt diabetes in nonobese diabetic mice is fueled by autoimmune inflammation but opposed by systemic tolerance. As expected, naive high-avidity IGRP(206-214)-specific T cells respond more efficiently to antigen and are significantly more diabetogenic than their intermediate- or low-avidity counterparts. However, central and peripheral tolerance selectively limit the contribution of these high-avidity T cells to the earliest stages of disease without abrogating their ability to progressively accumulate in inflamed islets and kill beta cells. These results illustrate the way in which incomplete deletion of autoreactive T cell populations of relatively high avidity can contribute to the development of pathogenic autoimmunity in the periphery.
Why Are Ethnic Minorities Under-Represented in US Research Studies?
Authors: Aziz Sheikh
Journal: PLoS Medicine (2005)

Most economically developed nations are now multiethnic,and, given current demographic trends, there is reason to believe that societies will continue to become more ethnically and culturally diverse. For example, the 1991 and 2001 UK censuses, which both included a mandatory question on ethnic identity, revealed that the proportion of the UK population classifying themselves as belonging to a non-white minority ethnic group increased by 53% over this 10-year period, from 3 million to 4.6 million (or 7.9% of the UK population)[1]. We have more than two decades of research highlighting ethnic inequalities for a range of long-term disorders [2], such as asthma (Table 1), but despite the policy imperative to improve health outcomes for marginalised populations, there has, unfortunately, been little progress toward this end [3,4]. Perversely, data indicate that for some conditions these health inequalities may actually be increasing.
TREATMENT OF NEUROPSYCHIATRIC DISORDERS WITH VITAMINS
Authors: NORMAN JOLLIFFE
Journal: JAMA (1941)

During the past decade vitamin deficiency has been looked for and often found in many neuropsychiatric disorders. It must be emphasized, however, that merely finding a vitamin deficiency concurrent with a disease does not indicate that this deficiency is the cause of the original disease. Secondary or "conditioned" vitamin deficiencies should be clearly distinguished from the original or primary disease, else utter confusion will result. Almost every vitamin has also been credited with playing a role in the maintenance of a normal nervous system. The more important of the vitamins thus accredited are thiamine hydrochloride, nicotinic acid, riboflavin, pyridoxine and alpha-tocopherol. Only thiamine hydrochloride and nicotinic acid, however, have been related clinically in a definite causal role to neuropsychiatric syndromes in man. The sequence of events in a vitamin deficiency disease begins with an inadequate vitamin supply, due to failure to ingest, absorb or utilize, followed in succession by tissue
The Measurement of Moral Judgment
Authors: Michael Thackrey
Journal: JAMA (1988)

This two-volume set is a result of more than 30 years of pioneering work by the late Lawrence Kohlberg, professor of human development at the Graduate School of Education, Harvard University. With collaborator Anne Colby, director of the Henry A. Murray Research Center at Radcliffe College, Kohlberg presents the "Standard Issue Moral Judgment Interview and Scoring System," its theoretical assumptions, and supporting empirical data. This scoring system is an attempt to use clear and concrete criteria to assess an individual's state of moral development objectively and reliably. Essentially, a subject is presented with a set of hypothetical moral dilemmas (eg, "Should Heinz steal a drug to save his dying wife when the only druggist with the drug asks a price that Heinz cannot pay?"); then the subject explains what course of action should be taken and why. Through the use of intensive probing, the examiner attempts to elicit the most
Methods of anaesthesia used for reduction of Colles' fractures.
Authors: J. B. Hunter, M. J. Scott, S. A. Harries
Journal: BMJ (1989)

rates of diabetes mellitus (ICD code 250) in non-uisers and current and former users of oral contraceptives influence the use of oral contraceptives in our study population.'Intravenous pethidine with antiemetic 1 (2) *Two were treated as inpatients.
Vitamin D-Dependent Calcium Binding Proteins: Chemistry, Distribution, Functional Considerations, and Molecular Biology*
Authors: SYLVIA CHRISTAKOS, CHRISTINE GABRIELIDES, WILLIAM B. RHOTEN
Journal: Endocrine Reviews (1989)

One of the most important contributions to the vitamin D field has been the discovery by Wasserman and Taylor in 1966 (1) of vitamin D-dependent calcium binding protein [calbindin-D (2)]. Early studies using competitive ion exchange methods as well as equilibrium dialysis indicated that administration of vitamin D to rachitic chicks resulted in an increase in the calcium binding activity of crude extracts of intestinal mucosa (1). Further investigations showed that the calcium binding activity was associated with a protein of about 28,000 mol wt (3, 4). Soon after the discovery of avian intestinal calbindin (1), a vitamin D-responsive calcium binding protein was also shown to be present in rat intestine (5, 6). Since the initial discoveries of the avian and rat intestinal calbindins, calbindins have been reported in a variety of species (7–19) and in many other tissues including kidney (20–25), bone (26), and tissues which are not regulators of serum calcium such as pancreas (27–32), placenta (33, 34), and brain (35–40). Several of these proteins have been isolated and biochemically characterized. In addition, antisera against a few of these proteins have been developed, which provide a tool for their assay and a means of determining their localization. Hypotheses concerning the functional significance of the calbindins, based on immunocytochemical localization studies, have been presented. Although the exact physiological function of calbindin is unknown at this time, regulation of its biosynthesis has provided an important model for studying the molecular mechanisms of action of the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 1,25-(OH)2D3 is concentrated in target cells by stereospecific binding to a high affinity receptor protein in the target cell nucleus, resulting in the expression of genetic information coding for calbindin (41, 42).
Oil Embolism, Self Induced
Authors: Gerald Marschke
Journal: JAMA (1973)

To the Editor.—  The results of intravascular lipid injection in man are rarely seen, although there is a body of literature on the pulmonary complications of lymphangiography and hysterosalpingography. We recently observed a man who injected intravenously into himself an oily substance thought to be    Report of a Case.—  A 24-year-old male orderly with a history of drug abuse locked himself in his bathroom. When there was no response to parental entreaties, his father broke in to find that he had injected something from a container labeled mineral oil. Unfortunately the father destroyed the container, but the patient subsequently admitted he injected 10 to 30 ml of the oil because he had been told it contained cocaine. Shortly after injection he experienced breathlessness, agitation, and general aching. Two days later, marked diaphoresis was present, and four days after injection he was brought to the hospital, cyanotic, with temperature
Recovery from infectious mononucleosis after altitude training in an elite middle distance runner.
Authors: D M Bailey, B Davies, R Budgett, G Gandy
Journal: British Journal of Sports Medicine (1997)

This investigation was designed to monitor altitude acclimatisation in an elite cohort of distance runners and follow the subsequent recovery from infectious mononucleosis which developed in one of these athletes.Twenty six national standard distance runners performed treadmill tests 24 days before they travelled to an altitude camp (1500 to 2000 m). One of these athletes was diagnosed as suffering from infectious mononucleosis 14 days after return to sea level. A physician prescribed an individualised training programme which was designed to maximise recovery from the condition, which was monitored on days 16 and 147 after altitude training.The data suggest that the athlete was in a state of over-reaching during the altitude sojourn. After return to sea level, the early stages of infectious mononucleosis resulted in a marked impairment in physiological response to endurance exercise, which improved over time. Longitudinal physiological monitoring in conjunction with a carefully prescribed training programme made recovery from this condition possible.
After Harm: Medical Error and the Ethics of Forgiveness
Authors: Farr A Curlin
Journal: BMJ (2005)

The title of the US Institute of Medicine's 1999 report, “To Err is Human,” truncates a well known aphorism, “To err is human; to forgive, divine.” In After Harm, Medical Error and the Ethics of Forgiveness Nancy Berlinger notes that the omission of the second clause symbolises the way modern health care has, in its preoccupation with preventing medical error, neglected the moral obligations that follow from the errors that human agents inevitably commit. In a laudable effort to address the imbalance, Berlinger applies a “religious studies perspective” to describe the words and actions that make forgiveness possible after medical harm.

Before harms can be addressed they must first be disclosed. In a turn that initially seems paradoxical, Berlinger commends the norm of disclosure by appropriating the German pastor Dietrich Bonhoeffer's theological justification for lying to his Nazi interrogators in the period before his eventual execution. Bonhoeffer was repulsed by Immanuel Kant's notion that lying, on principle, is not justifiable even to defend the innocent from evil. Against Kant, Bonhoeffer argued that our moral obligations can never be reduced to anything less …
THE APPOINTMENT OF STATE BOARDS OF MEDICAL AND DENTAL EXAMINERS.
Authors: William Carr
Journal: JAMA (1901)

Not many years ago it seemed to the majority, as it now seems to some of those interested in the advancement of medical and dental education, that diplomas from chartered colleges or schools gave sufficient assurance that their possessors were qualified to practice in the general or special fields of medicine in which degrees had been conferred upon them, and that the diplomas granted served as an adequate standard for license. This view assumed that instruction in such schools was faithfully given, by competent teachers, during a period of sufficient length to qualify students for the commencement of their careers, and also assumed that diplomas were conferred only upon those who, at the completion of such a period of study, had demonstrated, upon examination, their qualifications. It also assumed that charters would not be recklessly granted to professional schools, and that such charters would be revoked upon proof of their
Electronic Alerts Versus On-Demand Decision Support to Improve Dyslipidemia Treatment
Authors: Jacobus T. van Wyk, Marc A.M. van Wijk, Miriam C.J.M. Sturkenboom, Mees Mosseveld, Peter W. Moorman, Johan van der Lei
Journal: Circulation (2008)

Indirect evidence shows that alerting users with clinical decision support systems seems to change behavior more than requiring users to actively initiate the system. However, randomized trials comparing these methods in a clinical setting are lacking. We studied the effect of both alerting and on-demand decision support with respect to screening and treatment of dyslipidemia based on the guidelines of the Dutch College of General Practitioners.In a clustered randomized trial design, 38 Dutch general practices (77 physicians) and 87,886 of their patients (39,433 men 18 to 70 years of age and 48,453 women 18 to 75 years of age) who used the ELIAS electronic health record participated. Each practice was assigned to receive alerts, on-demand support, or no intervention. We measured the percentage of patients screened and treated after 12 months of follow-up. In the alerting group, 65% of the patients requiring screening were screened (relative risk versus control=1.76; 95% confidence interval, 1.41 to 2.20) compared with 35% of patients in the on-demand group (relative risk versus control=1.28; 95% confidence interval, 0.98 to 1.68) and 25% of patients in the control group. In the alerting group, 66% of patients requiring treatment were treated (relative risk versus control=1.40; 95% confidence interval, 1.15 to 1.70) compared with 40% of patients (relative risk versus control=1.19; 95% confidence interval, 0.94 to 1.50) in the on-demand group and 36% of patients in the control group.The alerting version of the clinical decision support systems significantly improved screening and treatment performance for dyslipidemia by general practitioners.
Apical Na+/H+ antiporter and glycolysis-dependent H+-ATPase regulate intracellular pH in the rabbit S3 proximal tubule.
Authors: I Kurtz
Journal: Journal of Clinical Investigation (1987)

The apical transport processes responsible for proton secretion were studied in the isolated perfused rabbit S3 proximal tubule. Intracellular pH (pHi) was measured with the pH dye, 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein. Steady state pHi in S3 tubules in nominally HCO3(-)-free solutions was 7.08 +/- 0.03. Removal of Na+ (lumen) caused a decrease in pHi of 0.34 +/- 0.06 pH/min. The decrease in pHi was inhibited 62% by 1 mM amiloride (lumen) and was unaffected by 50 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (lumen) and Cl- removal (lumen, bath). After a brief exposure to 20 mM NH4Cl, pHi fell by approximately 0.7 and recovered at a rate of 0.89 +/- 0.15 pH/min in the nominal absence of Na+, HCO3-, organic anions, and SO4(2-) (lumen, bath). 1 mM N,N'-dicyclohexylcarbodiimide (lumen), 1 mM N-ethylmaleimide (lumen), 0.5 mM colchicine (bath), and 0.5 mM iodoacetic acid (lumen, bath) inhibited the Na+-independent pHi recovery rate by 73%, 55%, 77%, and 86%, respectively, whereas 1 mM KCN (lumen, bath) did not inhibit pHi recovery. Reduction of intracellular, but not extracellular chloride, also decreased the Na+-independent pHi recovery rate. In conclusion, the S3 proximal tubule has an apical Na+/H+ antiporter with a Michaelis constant for Na+ of 29 mM and a maximum velocity of 0.47 pH/min. S3 tubules also possess a plasma membrane H+-ATPase that can regulate pHi, has a requirement for intracellular chloride, and utilizes ATP derived primarily from glycolysis.
Long-Term Treatment of Refractory Hypertensive Patients With Minoxidil
Authors: Helen C. Mitchell
Journal: JAMA (1978)

Twenty-nine hypertensive patients refractory to conventional medications were treated continuously with minoxidil, sympathetic suppressants, and diuretics for six months to five years (mean, 30 months). All had evidence of hypertensive end-organ damage before minoxidil therapy. Good blood pressure control was obtained in 21 (72%) of 29 patients when minoxidil was given in dosages up to 40 mg/day. No tolerance was found. In the remaining eight, good control was obtained in three when phenoxybenzamine therapy was added, and in one when clonidine therapy was added. Renal failure requiring hemodialysis developed in five of 29, one had temporary hemiparesis, and one had fatal cerebral hemorrhage. In the remainder, myocardial infarctions and strokes were effectively prevented. Patients receiving minoxidil and propranolol hydrochloride had elevated plasma norepinephrine levels while those receiving clonidine had normal plasma norepinephrine levels.