tbuckley/cabot-search huggingface dataset:
Novel Facts About FAK: New Connections to Drug Resistance?
Authors: C. M. Annunziata, E. C. Kohn
Journal: JNCI Journal of the National Cancer Institute (2013)

Resistance to taxane chemotherapy presents a major hurdle in the treatment of recurrent ovarian cancer. The majority of epithelial ovarian cancers are sensitive to paclitaxel or docetaxel with initial treatment, but resistance ultimately develops in the majority of women. Development of a successful method to maintain susceptibility to taxane and platinum chemotherapy is an unmet clinical need. The article by Kang and colleagues in the current issue of the Journal describes a novel mechanism of taxane resistance, through FAK-dependent upregulation of YB-1, a transcription factor that in turn upregulates CD44 (1). Intriguing findings in their work include the importance of nuclear-activated p397Tyr-FAK for this resistance process, and the demonstration that nuclear colocalization of activated FAK and p102Ser-YB1 dichotomized overall survival of patients with ovarian cancer. How might this relate to taxane resistance in ovarian cancer? The mechanism of anticancer activity of taxanes relies on their ability to bind and stabilize polymerized tubulin. Stabilization of tubulin filaments prevents spindle disassembly during mitosis, leading to catastrophic cell death. Lack of tubulin depolymerization also prevents transport of proteins within nondividing cells, a likely cause for neuropathy associated with taxane therapy. Additionally, the decrease in free tubulin leads to mitochondrial hyperpolarization and release of cytochrome c, triggering proapoptotic cascades (2,3). Classically, resistance to taxanes has been attributed to alterations in tubulin structure preventing the binding of taxane to its target. Other potential mechanisms include imbalance in the cellular apoptotic machinery (4), increased expression of the multidrug-resistance drug efflux pumps (5,6), and increased activation of MAPK (7,8). Class III s-tubulin overexpression in clear cell carcinoma of the ovary was shown to discriminate poor prognosis; in the same study, p-glycoprotein did not correlate with clinical outcome (9). However, s-tubulin changes have not been borne out as common mechanisms of taxane resistance in ovarian cancer; nor has MDR-1 been demonstrated as a major mechanism of chemotherapy resistance in ovar
Systemic lupus erythematosus presenting as pneumococcal septicaemia and septic arthritis.
Authors: J Webster, B D Williams, A P Smith, M Hall, J D Jessop
Journal: Annals of the Rheumatic Diseases (1990)

A 50 year old woman presented with pneumococcal septicaemia, septic arthritis, and a lobar pneumonia and was subsequently diagnosed as having systemic lupus erythematosus. The blood film and splenic 99mTc sulphur colloid uptake were normal, although selective functional hyposplenism was shown by the impaired clearance of immunoglobulin coated erythrocytes. Systemic lupus erythematosus presenting with fulminating pneumococcal sepsis in the presence of selective defects in spleen function is previously unreported.
MRI to X-ray mammography registration using a volume-preserving affine transformation
Authors: Thomy Mertzanidou, John Hipwell, M. Jorge Cardoso, Xiying Zhang, Christine Tanner, Sebastien Ourselin, Ulrich Bick, Henkjan Huisman, Nico Karssemeijer, David Hawkes
Journal: Medical Image Analysis (2012)
Reactive Oxygen Species Originating From Mitochondria Regulate the Cardiac Sodium Channel
Authors: Man Liu, Hong Liu, Samuel C. Dudley
Journal: Circulation Research (2010)

Pyridine nucleotides regulate the cardiac Na(+) current (I(Na)) through generation of reactive oxygen species (ROS).We investigated the source of ROS induced by elevated NADH.In human embryonic kidney (HEK) cells stably expressing the cardiac Na(+) channel, the decrease of I(Na) (52±9%; P<0.01) induced by cytosolic NADH application (100 μmol/L) was reversed by mitoTEMPO, rotenone, malonate, DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid), PK11195, and 4'-chlorodiazepam, a specific scavenger of mitochondrial superoxide and inhibitors of the mitochondrial complex I, complex II, voltage-dependent anion channels, and benzodiazepine receptor, respectively. Anti-mycin A (20 μmol/L), a complex III inhibitor known to generate ROS, decreased I(Na) (51±4%, P<0.01). This effect was blocked by NAD(+), forskolin, or rotenone. Inhibitors of complex IV, nitric oxide synthase, the NAD(P)H oxidases, xanthine oxidases, the mitochondrial permeability transition pore, and the mitochondrial ATP-sensitive K(+) channel did not change the NADH effect on I(Na). Analogous results were observed in cardiomyocytes. Rotenone, mitoTEMPO, and 4'-chlorodiazepam also blocked the mutant A280V GPD1-L (glycerol-3-phosphate dehydrogenase 1-like) effect on reducing I(Na), indicating a role for mitochondria in the Brugada syndrome caused by this mutation. Fluorescent microscopy confirmed mitochondrial ROS generation with elevated NADH and ROS inhibition by NAD(+).Altering the oxidized to reduced NAD(H) balance can activate mitochondrial ROS production, leading to reduced I(Na). This signaling cascade may help explain the link between altered metabolism, conduction block, and arrhythmic risk.
IL-9–mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation
Authors: Jan-Eric Turner, Peter J. Morrison, Christoph Wilhelm, Mark Wilson, Helena Ahlfors, Jean-Christophe Renauld, Ulf Panzer, Helena Helmby, Brigitta Stockinger
Journal: The Journal of Experimental Medicine (2013)

IL-9 fate reporter mice established type 2 innate lymphoid cells (ILC2s) as major producers of this cytokine in vivo. Here we focus on the role of IL-9 and ILC2s during the lung stage of infection with Nippostrongylus brasiliensis, which results in substantial tissue damage. IL-9 receptor (IL-9R)–deficient mice displayed reduced numbers of ILC2s in the lung after infection, resulting in impaired IL-5, IL-13, and amphiregulin levels, despite undiminished numbers of Th2 cells. As a consequence, the restoration of tissue integrity and lung function was strongly impaired in the absence of IL-9 signaling. ILC2s, in contrast to Th2 cells, expressed high levels of the IL-9R, and IL-9 signaling was crucial for the survival of activated ILC2s in vitro. Furthermore, ILC2s in the lungs of infected mice required the IL-9R to up-regulate the antiapoptotic protein BCL-3 in vivo. This highlights a unique role for IL-9 as an autocrine amplifier of ILC2 function, promoting tissue repair in the recovery phase after helminth-induced lung inflammation.
Studies on the Cardiomegaly of the Spontaneously Hypertensive Rat
Authors: BARBARA B. FARMER, ROBERT A. HARRIS, WALTER W. JOLLY, WILLIAM J. VAIL
Journal: Circulation Research (1974)

Changes in size, morphology, and certain relevant biochemical components of hearts from spontaneously hypertensive and normal Wistar rats were studied comparatively. Groups of rats were killed at stages which represented developing and stable cardiac hypertrophy and approaching cardiac failure. Mitochondrial content was determined by comparing cytochrome oxidase activity per milligram of heart homogenate protein with cytochrome oxidase activity per milligram of heart mitochondrial protein. Based on the relationship of heart weight and body weight found in normotensive rats (hearts weight [mg] = 1.85 x body weight [g] + 287), left ventricular dimensions, and micrographs of left ventricular muscle fibers, hypertrophy of the hearts from the spontaneously hypertensive rats was conclusively demonstrated. Approximately 25% of the total heart protein was mitochondrial in both control and hypertensive rats; the percent increased during the period of rapid growth but subsequently decreased with age. The amount of heart mitochondrial protein was greater for spontaneously hypertensive rats relative to body weight but was not greater relative to heart weight. The maximum increase in heart mitochondria relative to body weight was observed in 6-month-old spontaneously hypertensive rats, whereas the maximum increase in heart weight occurred at 12 months of age. A decrease in heart weight occurred in 17-month-old spontaneously hypertensive rats. No preferential retention of mitochondria was apparent during atrophy induced by starvation in either control or hypertensive rats.
Diversion colitis and involution of the defunctioned anorectum.
Authors: A M Roe, B F Warren, A J Brodribb, C Brown
Journal: Gut (1993)

To measure the effects of defunction in the anorectum, 12 patients (seven men and five women aged 59 (44-81) years) were studied after the Hartmann operation. The operation was for septic complications of diverticular disease in nine and sigmoid carcinoma in three patients. Physiology studies were undertaken 1 and 3 months after surgery, and diversion colitis was assessed endoscopically and by mucosal biopsy at 3 months. There was no change in anal sphincter function by three months. Proctometrogram studies, however, showed an appreciable decrease in rectal volume in all cases, by a mean of 35% of the 1 month volume. The maximum tolerable volume at 1 month was 157 (111-210) ml and at 3 months 87 (71-145) ml; p &lt; 0.01. There was no change in rectal sensation or compliance. Erythema and granularity without gross erosions or ulceration were found at endoscopy. Histology showed abnormalities in all cases by 3 months. The characteristic features were of a chronic inflammatory cell infiltrate with surface exudate, microscopic erosions, and lymphoid follicular hyperplasia. Crypt abscesses were not a feature at this stage and there was no distortion of crypt architecture. After defunction the previously normal rectum is affected by diversion colitis which, at 3 months, is mild but has characteristics that distinguish the changes from those of inflammatory bowel disease. It is associated with progressive rectal stump involution.
Duodenal ulcers: early and late onset.
Authors: S K Lam, G B Ong
Journal: Gut (1976)

A hospital series of 1042 duodenal ulcer patients was examined to determine the relationship of the age of onset of ulcer dyspepsia with the blood group and with the family history of ulcer dyspepsia. It was found that those patients whose symptoms begin in the first two decades of life (early onset patients) contain a significantly larger proportion of group A, B, and AB subjects and a significantly stronger family history of dyspepsia than those whose symptoms begin from the fourth decade of life onwards (late onset patients), in whom blood group O prevails. The group O status is shown to be associated with a significant proneness to duodenal ulceration and a significant proneness to bleed, and in the late onset patients a significant proneness to bleed recurrently and severely. Bleeding is the predominent complication in the early onset patients. There is a significantly increased tendency for the late onset ulcers to perforate, to become stenosed, to have severe pain, and to be virulent--that is, to be multiple, post-bulbar, or giant. While these features do not appear to be related to the effect of ageing, the occurrence of associated gastric ulceration and the mortality rate was shown to be related.
The Duration of Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Signaling during Cell Cycle Reentry Distinguishes Proliferation from Apoptosis in Response to Asbestos
Authors: Ziqiang Yuan, Douglas J. Taatjes, Brooke T. Mossman, Nicholas H. Heintz
Journal: Cancer Research (2004)

Abstract Asbestos exposure causes activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in lung epithelial cells, the targets of asbestos-associated lung carcinomas. The functional significance of ERK1/2 activation in pulmonary epithelial and mesothelial cells is unclear. Using serum-stimulated mouse alveolar type II epithelial cells as a model for cell cycle reentry, we show that the duration of phospho-ERK1/2 in the nucleus determines cell fate in response to crocidolite asbestos. In response to 10% serum, a proliferative stimulus, phosphorylated ERK1/2 initially accumulated in the nucleus, and reduction of nuclear phospho-ERK1/2 after 2 to 4 hours was followed by expression of cyclin D1 and S-phase entry. Low levels of asbestos (&amp;lt;0.5 μg/cm2) promoted S-phase entry in low (2%) serum through an epidermal growth factor receptor-dependent pathway but did not promote cell cycle progression or induce apoptosis in the presence of high (10%) serum-containing medium. Higher levels of asbestos (1.0 to 5.0 μg/cm2) prolonged the localization of phospho-ERK1/2 in the nucleus in the presence of high serum, impeded S-phase entry, and induced apoptosis in a dose-dependent manner. Immunofluorescence microscopy indicated that the duration of signaling by phospho-ERK1/2 in the nucleus was predictive of cell fate at any concentration of asbestos. After 8 hours of exposure, cells with nuclear phospho-ERK1/2 also were positive for nuclear localization of apoptosis-inducing factor (AIF), an early event in apoptosis. In contrast, asbestos-exposed cells that displayed cytoplasmic phospho-ERK1/2 at 8 hours expressed cyclin D1 and proceeded to S phase. Our studies show that prolonged localization of phospho-ERK1/2 in the nucleus is incompatible with expression of cyclin D1 and is predictive of asbestos-associated cell death by AIF, thereby providing an approach for determining cell fate in asbestos-induced tumorigenesis.
Patient-centred care after Shipman
Authors: R. Baker
Journal: Journal of the Royal Society of Medicine (2004)

The inquiry chaired by Dame Janet Smith has determined that Harold Shipman unlawfully killed 215 patients, and in a further 45 there were reasons for being concerned about the true cause of death.1 A statistical analysis gives a figure of 236.2 The first definite killing was in March 1975; the last was in June 1998. On average, there were around 10 killings a year, but the number was highly variable. Between 1990 and 1993 he killed only 3 people, but in 1996 he killed at least 30, and in 1997 at least 37, a rate of one killing every ten days.

Yet even then, no concerns were raised officially until a courageous doctor from a neighbouring practice, together with her partners, began to think the unthinkable. In March 1998, by which time he had already killed well over 200 people, a police investigation was begun—but quickly abandoned. It was not until Shipman decided to forge the will of one of his victims in June 1998 that a thorough investigation took place, leading to his arrest three months later.

Since beginning to investigate Shipman in 2000, I have been trying to understand how it was that he could kill so many patients without detection. There were, of course, some system failures, but it has been impossible to avoid the question as to why the system weaknesses were tolerated to the extent that Shipman was able to murder not merely one or two patients, but over 200. The conclusion I have come to is that all doctors, and not general practitioners alone, share responsibility for creating the circumstances that enabled Shipman to be so successful a killer. We must accept that responsibility, and embark on a process of professional renewal in which the principle of patient-centredness is given greater force by the addition of the idea of the patient as the source of control.
The Cell Biology of Acute Myocardial Ischemia
Authors: R B Jennings, K A Reimer
Journal: Annual Review of Medicine (1991)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
Hemodynamic and neurohormonal effects of clonidine in patients with preganglionic and postganglionic sympathetic lesions. Evidence for a central sympatholytic action.
Authors: J S Kooner, R Birch, H L Frankel, W S Peart, C J Mathias
Journal: Circulation (1991)

BACKGROUND Clonidine, a partial presynaptic and postsynaptic alpha-adrenoceptor agonist, has been shown to lower blood pressure in normal subjects but not in tetraplegics; however, the mechanisms of this action have not been elucidated. METHODS AND RESULTS The hemodynamic and hormonal basis of the hypotensive action of clonidine was investigated in tetraplegics with complete cervical spinal cord transection and preganglionic sympathetic denervation, in patients with unilateral brachial plexus injury and postganglionic sympathetic denervation, and in normal subjects. In normal subjects, the fall in blood pressure after clonidine infusion was accompanied by a reduction in cardiac output that was predominantly due to a fall in stroke volume and in heart rate. The lack of fall in blood pressure, cardiac output, and stroke volume in tetraplegics indicates that these effects are exerted at a supraspinal level and require intact descending sympathetic pathways. After clonidine infusion, digital skin vasodilatation occurred in normal subjects, in the innervated but not the denervated limb of patients with unilateral brachial plexus injury, and in tetraplegics, indicating that this response is due to the central sympatholytic effect of clonidine. Plasma norepinephrine was much lower in tetraplegics compared with normal subjects, and after clonidine infusion, it fell substantially in normal subjects alone. Plasma renin activity did not change. Bladder stimulation in tetraplegics resulted in a rise in blood pressure and vasoconstriction in digital skin vessels. The inability of clonidine to significantly reduce or abolish the pressor and digital vasoconstrictor responses after bladder stimulation in tetraplegics indicates that clonidine does not exert a major effect on spinal preganglionic neurons or peripheral presynaptic alpha 2-adrenoceptors. CONCLUSIONS Therefore, clonidine is a suitable drug for use in analyzing the central supraspinal levels of control in varying circulatory disorders, such as hypertension and postural hypotension.
Renal Vascular Responses to Angiotensin and Norepinephrine in Normal Man: EFFECT OF SODIUM INTAKE
Authors: NORMAN K. HOLLENBERG, HAROLD S. SOLOMON, DOUGLASS F. ADAMS, Herbert L. ABRAMS, John P. MERRILL
Journal: Circulation Research (1972)

The effect of sodium intake on renal vascular responses to angiotensin and norepinephrine infused intra-arterially was assessed in normal man by xenon washout. In subjects on an unrestricted diet, the dose of angiotensin inducing a 50% reduction in mean blood flow (ED 50 ) was 38.2 ± 12.6 ng/min, a hundredfold lower dose than that for norepinephrine. Sodium restriction reduced the sensitivity to angiotensin tenfold: the ED 50 rose to 378 ± 12 ng/min. This diet, conversely, potentiated responses to norepinephrine: the threshold dose fell from 37 ± 10 to 3.6 ± 1.9 ng/min. Thus, the reduction in sensitivity to angiotensin induced by sodium restriction was not a nonspecific effect on the vascular smooth muscle. Sodium restriction also reduced the variability in the vascular response to angiotensin, and a close correlation was found between urine sodium content and angiotensin responsiveness. The blood vessels of the normal human kidney are remarkably sensitive to angiotensin: the threshold dose is approximately 1 ng/min for intra-arterial infusion. Circulating angiotensin may be a mediator of renal vascular tone, but circulating catecholamines probably play a minimal role.
The Relationship Between Diabetes and Infectious Hospitalizations in Renal Transplant Recipients
Authors: M. Cecilia Lansang, Linan Ma, Jesse D. Schold, Herwig-Ulf Meier-Kriesche, Bruce Kaplan
Journal: Diabetes Care (2006)

The implications of diabetes developing after kidney transplantation (PostTDM group) need further study. Worse graft survival is seen in PostTDM compared with nondiabetic (NonDM group) patients (1,2). Yet, there is paucity of data on the risk of infection, an issue that becomes even more important since posttransplant patients are already immunocompromised. Thus, we aim to compare the risk of infection in the posttransplant period in PostTDM patients and in patients who were diagnosed with diabetes before transplant (PreTDM group) with those without diabetes.

Data were obtained from the U.S. Renal Data System (3). The study population was limited to adult renal transplant patients whose primary payer was Medicare to enable analysis of hospital outcomes. Primary (i.e., first time) kidney transplant recipients from the years 1995 to 2000 were included. Pancreas recipients were excluded.

The diagnosis of diabetes was obtained from Medicare claims using a previously validated method and from U.S. Renal Data System transplant files (2,4). Patients were classified as PreTDM if diabetes was detected before, or at the time of, hospitalization for transplantation. The remaining diabetic patients were classified as PostTDM.

The outcome of interest was infection requiring hospitalization (HI) and occurring in the posttransplant period. The survival time until development of HI was analyzed using Cox multivariate proportional hazard …
Action of Ryanodine on Mammalian Cardiac Muscle
Authors: STEPHEN HAJDU, EDWARD LEONARD
Journal: Circulation Research (1961)

The relationship between stimulation frequency and twitch tension was determined for isolated strips of rat right ventricle. Prolonged perfusion of the tissue in physiological saline solution results in diminished twitch tension at low rates of stimulation without alteration of contractility at high stimulation frequency. These changes, which develop over a period of several hours of perfusion, can be induced within 15 minutes by the addition of ryanodine. The addition of strophanthidin restores the twitch tension-frequency relationship of the long-perfused rat ventricle to normal. However strophanthidin has no effect on the impaired contractility of ryanodine treated ventricle ; and, conversely, the addition of ryanodine to digitalized ventricle abolishes the action of the glycoside. The effects of ryanodine can be reversed by perfusing the muscle in a solution which is deficient in either sodium or potassium. Because of the opposing actions of ryano-dine and the cardiac glycosides, the effect of ryanodine was studied in anesthetized animals with digitoxin-induced cardiac arrhythmias. The intravenous infusion of ryanodine rapidly abolishes the ventricular arrhythmias characteristic of digitalis toxicity. However, the presence of both digitoxin and ryanodine is frequently associated with depression of sinus node activity, and the cardiac cycle is initiated by another focus, probably nodal. The effect on the sinus node may be mediated by the vagus, through a synergistic action of the two drugs, since normal sinus rhythm can be restored by the administration of atropine.