tbuckley/cabot-search huggingface dataset:
Abstract 5261: PKC alpha is implicated in epithelial to mesenchymal transition and erlotinib resistance in non-small cell lung carcinoma cells.
Authors: Mahlet Abera, Raffaella Sordella, Marcelo Kazanietz
Journal: Cancer Research (2013)

Abstract Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) play important roles in the pathogenesis of non-small-cell lung cancer (NSCLC). For patients with EGFR activating mutations, EGFR tyrosine kinase inhibitors (TKIs) are given as a primary therapy. However, the majority of these patients eventually develop resistance to TKIs. To address a potential role of PKC isozymes in the resistance to TKIs, we used an isogenic model: the NSCLC H1650 cell line and its erlotinib-resistance derivative H1650-M3. H1650-M3 cells display a mesenchymal-like morphology driven by TGF-β signaling (PNAS 107:15535-15540, 2010). Comparison of the expression of PKC isozymes by Western blot between parental and erlotinib-resistant H1650 cells revealed that the M3 derivative displays remarkably high levels of PKCα and reduced levels of PKCδ. qPCR analysis established that PKCα mRNA levels in H1650-M3 cells are ∼ 40-fold higher than in parental cells. In order to investigate a potential involvement of PKCα in TKI resistance we used RNAi. Upon PKCα depletion H1650-M3 cells display a morphology that is consistent with the epithelial phenotype. Moreover, depletion of PKCα from H1650-M3 cells led to significant changes in the expression of EMT markers. Indeed, mRNA levels of vimentin, Zeb2, SNAIL and TWIST were reduced by more than 50 % in erlotinib-resistant cells when PKCα expression was silenced. Analysis of cell viability in response to erlotinib treatment showed that pretreatment with either the pan-PKC inhibitor GF 109203X or the cPKC inhibitor Gö6976 sensitized H1650-M3 to erlotinib. Furthermore, PKCα RNAi depletion markedly sensitized H1650 cells to the TKI. Therefore, PKCα up-regulation in erlotinib-resistant cells may play an important role in driving the resistance to the drug. Our results also highlight a potential role for PKCα in EMT in lung cancer cells. Citation Format: Mahlet Abera, Raffaella Sordella, Marcelo Kazanietz. PKC alpha is implicated in epithelial to mesenchymal transition and erlotinib resistance in non-small cell lung carcinoma cells. [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 5261. doi:10.1158/1538-7445.AM2013-5261
THE CALL FOR EXPLORATORY OPERATION IN THE GALL-BLADDER REGION.
Authors: F. A. DUNSMOOR
Journal: JAMA (1903)

The surgical age is on, and it is to the credit of the profession that this is true. It were trite to cite cures where drugs have been used to worse than waste precious time, followed by an operation which has brought relief, comfort and usefulness to patients who were a burden to themselves and friends. It is not our intention to criticise former practice of the internalists or surgeons. It is not ages ago that each was barbarous in both senses of the word. It is an old tale to this body to be told of the safety of abdominal incisions when absolute cleanliness and skill attend the operation. Hence this word as advocating such procedure as a simple means of diagnosis and a long step toward the best method of cure. The diagnostician has continually in his mind's eye a map of the surface of the
Impact of the Metabolic Syndrome on Mortality From Coronary Heart Disease, Cardiovascular Disease, and All Causes in United States Adults
Authors: Shaista Malik, Nathan D. Wong, Stanley S. Franklin, Tripthi V. Kamath, Gilbert J. L’Italien, Jose R. Pio, G. Rhys Williams
Journal: Circulation (2004)

Mortality resulting from coronary heart disease (CHD), cardiovascular disease (CVD), and all causes in persons with diabetes and pre-existing CVD is high; however, these risks compared with those with metabolic syndrome (MetS) are unclear. We examined the impact of MetS on CHD, CVD, and overall mortality among US adults.In a prospective cohort study, 6255 subjects 30 to 75 years of age (54% female) (representative of 64 million adults in the United States) from the Second National Health and Nutrition Examination Survey were followed for a mean+/-SD of 13.3+/-3.8 years. MetS was defined by modified National Cholesterol Education Program criteria. From sample-weighted multivariable Cox proportional-hazards regression, compared with those with neither MetS nor prior CVD, age-, gender-, and risk factor-adjusted hazard ratios (HRs) for CHD mortality were 2.02 (95% CI, 1.42 to 2.89) for those with MetS and 4.19 (95% CI, 3.04 to 5.79) for those with pre-existing CVD. For CVD mortality, HRs were 1.82 (95% CI, 1.40 to 2.37) and 3.14 (95% CI, 2.49 to 3.96), respectively; for overall mortality, HRs were 1.40 (95% CI, 1.19 to 1.66) and 1.87 (95% CI, 1.60 to 2.17), respectively. In persons with MetS but without diabetes, risks of CHD and CVD mortality remained elevated. Diabetes predicted all mortality end points. Those with even 1 to 2 MetS risk factors were at increased risk for mortality from CHD and CVD. Moreover, MetS more strongly predicts CHD, CVD, and total mortality than its individual components.CHD, CVD, and total mortality are significantly higher in US adults with than in those without MetS.
Glass particles found in generic atorvastatin
Authors: E. Davies
Journal: BMJ (2012)

Ranbaxy Pharmaceuticals has stopped production and issued a recall of its generic version of the cholesterol lowering drug atorvastatin.

The recall applies to certain lots of the company’s 10 mg, 20 mg, and 40 mg tablets. The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, are being …
Problem based learning, litigation, and EWTD contribute to too much medicine
Authors: S. Samadian, A. Farhat
Journal: BMJ (2013)

Glasziou and colleagues suggest that investigation should be selective and targeted,1 yet a scattergun approach is increasingly being used across all disciplines. Overdiagnosis thus becomes a direct consequence of over-investigation. From serial measurements of C reactive protein and myeloma screening through to full body scans, a doctor’s approach to the patient is increasingly weighted towards, if not reliant on, investigation, while the value of a …
Practical Handbook of Human Biologic Age Determination
Authors: Robert L. Kane
Journal: JAMA (1995)

The challenge that researchers interested in biomarkers face is to identify measures that can reflect aging better than simply knowing an individual's chronologic age. Ideally, one might follow a cohort of people and use various parameters to estimate the risk of dying, but such a study at best takes a long time. Instead, investigators have tried to model factors that seem to be associated with estimated age. Even using mortality can present problems. Risk factors for mortality are often risk factors for disease. We know that aging is associated with an increased prevalence of chronic diseases. There is an ongoing debate about the appropriateness of including disease states in studies of aging. Some hold out for a model of pure aging, independent of disease, and prefer to study only those persons or organs that are free of apparent disease. Others argue that disease is a concomitant of aging and to
Clinical outcome in patients treated with endoscopic submucosal dissection for superficial Barrett’s neoplasia
Authors: Jean Chevaux, Hubert Piessevaux, Anne Jouret-Mourin, Ralph Yeung, Etienne Danse, Pierre Deprez
Journal: Endoscopy (2014)

<b>Background and study aims:</b> The role of endoscopic submucosal dissection (ESD) in Barrett's neoplasia is ill-defined, although it might provide a higher curative resection rate and better histologic assessment than endoscopic mucosal resection (EMR). We aimed to assess efficacy, safety, and long-term results of ESD. <b>Patients and methods:</b> A retrospective analysis was done of 75 consecutive patients with Barrett's esophagus who underwent ESD between January 2007 and February 2014. ESD was performed for visible lesions that were multiple, larger than 15 mm, or poorly lifting, or suspected of submucosal infiltration. The primary end point was the rate of curative resection of carcinoma. <b>Results:</b> Median patient age was 68 years (interquartile range [IQR] 61 – 76), median follow-up was 20 months (IQR 8.5 – 37.5), and median maximum specimen diameter was 52.5 mm (IQR 43 – 71). En bloc resection rate was 90 % (66 /73), and rates of curative resection of carcinoma and high grade dysplasia/carcinoma were 85 % (47 /55) and 64 % (42 /66), respectively. G3 differentiation and invasion to greater than pT1m2 were observed in 25 % (14 /55) and 67 % (37 /55) of patients with adenocarcinoma, respectively. There were 5 early ( < 48 hours) adverse events (2 delayed hemorrhages and 3 perforations), all treated endoscopically. No ESD-specific death occurred. Esophageal strictures developed in 60 % of patients, all treated endoscopically. Additional treatment (median sessions 2 [IQR 2 – 3]) for residual Barrett's esophagus were recommended to 62 % (42 /68). At latest follow-up, complete remission of neoplasia and intestinal metaplasia was found in 92 % (54 /59) and 73 % (43 /59) of patients, respectively. <b>Conclusion:</b> ESD appears to be safe and effective, with a high rate of curative resection of carcinoma. ESD should be considered for patients with Barrett's neoplasia at risk of incomplete resection or poor pathologic assessment with conventional EMR.
On the Treatment of Eczema by Bantingism
Authors: Balmanno Squire
Journal: BMJ (1882)

Surgeon to the British Hospital for Diseases of the Skin.IT is familiar to every practitioner that eczema is specially common amongst infants, and particularly amongst lymphatic infants, that is to say, fat and pasty-looking infants.I do not refer only to those instances in which the very fatness of the infant is the mechanical cause of the complaint; that is to say, where " a fold " of skin in the fat infant be.comes raw and discharging (intertrigo) ; but I refer to the well known fact that infants of this constitution are more liable than others to eczema (of the scalp and other parts), not coming under the head of " intertrigo," and that their eczema is more profuse in its discharge,
Expression, Localization, and Phosphorylation of Akt1 in Benign and Malignant Thyroid Lesions
Authors: Anna Krześlak, Lech Pomorski, Anna Lipińska
Journal: Endocrine Pathology (2011)

The serine/threonine protein kinase Akt is a key molecule in the phosphatidyl inositol 3-kinase pathway that is often overactivated in human cancers. Three Akt isoforms (Akt1, Akt2, Akt3) have been identified in human cells and they show different distribution and have non-redundant functions. The aim of this study was to determine whether the expression, phosphorylation, and localization of Akt1 isoform in human thyroid malignant lesions are different from those in benign lesions. Nuclear and cytoplasmic fractions were isolated from tissue samples and Western blot method was used to detect Akt1 presence in both cellular fractions. Akt1 expression was also assessed by ELISA method. To estimate Akt1 phosphorylation, kinase was immunoprecipitated from cell lysates and tested with anti-phospho-Akt antibodies. The Akt1 expression in majority of thyroid cancer samples was significantly higher than in benign lesions (p < 0.05). Akt1 both in differentiated cancers (follicular and papillary) and benign lesions was localized mainly in cytoplasmic fraction. In two of three anaplastic cancer samples Akt1 was predominantly localized in nucleus. The ratio of phosphorylated Akt1 to total Akt1 was lower in cancers than in non-neoplastic lesions and adenomas. Thus, although Akt1 seems to be overexpressed in thyroid neoplasms, its high phosphorylation is not characteristic for thyroid cancers.
Appraisal of Vitamin Nutritional Status-Reply
Authors: William N. Pearson
Journal: JAMA (1962)

<h3>To the Editor:—</h3> I am grateful to Dr. Crandon for calling attention to an obvious error in the text of my article. It is quite true that a person with normal ascorbic acid reserves can subsist on an ascorbic acid-free diet for about 5 months before clinical scurvy becomes apparent. This is clear from Figure 2 in my publication. The second point is also well taken. It is obviously necessary to determine if a patient has had recent access to vitamin supplements before a diagnostic result can be interpreted properly. This is particularly true in the case of ascorbic acid, since its use as a food preservative may result in its introduction into the diet from unsuspected sources. For example, the writer has knowledge of an ascorbic acid depletion study that was unwittingly sabotaged by the eating of frankfurters containing a large quantity of ascorbic acid. One does not normally
A Case of Neuritis of Posterior Roots: Pre-Ataxic Stage of Tabes Dorsalis?
Authors: W. B. Ransom
Journal: BMJ (1900)

THE following case is of interest from its unusual group of symptoms and its diagnostic difficulties: P. K, a man, aged 44, was first seen by me in consultation with Dr. Tresidder, on March ioth, I898, on account of attacks of intense darting pain in the left hypochondrium.History.-The patient, a fitter by trade, said to be an unusually intelli- gent workman, had been healthy until the present illness, which began about a year previously.For the last tbree years he had been practically teetotal, though some years ago he had drank freely of beer.He denied venereal disease, but his wife had had five miscarriages and two live children.His father had died of a stroke, his mother of cancer.
Acknowledging the Psychiatric Cost of War
Authors: Matthew J. Friedman
Journal: New England Journal of Medicine (2004)

The data presented by Hoge and associates in this issue of the Journal 1 about members of the Army and the Marine Corps returning from Operation Iraqi Freedom or Operation Enduring Freedom in Afghanistan force us to acknowledge the psychiatric cost of sending young men and women to war. It is possible that these early findings underestimate the eventual magnitude of this clinical problem. The report is unprecedented in several respects. First, this is the first time there has been such an early assessment of the prevalence of war-related psychiatric disorders, reported while the fighting continues. Second, there are predeployment data, . . .
THE DISTRIBUTION OF SOLUTIONS IN CARDIECTOMIZED FROGS
Authors: S. J. Meltzer
Journal: The Journal of Experimental Medicine (1911)

Strychnin and adrenalin when injected into cardiectomized frogs are efficiently distributed all over the animal body and when administered in sufficient quantities produce the usual reactions of these alkaloids. The experiments with strychnin prove positively that the paralysing effect of this poison is due to its direct action upon the nerve cells of the cord, and not, as Verworn assumes, to a paralysing action upon the heart. When morphin is injected into cardiectomized frogs the effects are much greater and incomparably more rapid than when administered to a normal frog. The normal circulation probably contains substances derived from some organs capable of modifying and retarding the specific effects of morphin. The distribution of solutions in animals deprived of their circulatory apparatus takes place through the tissue spaces, which present a more or less well connected system of communications throughout the entire animal body, especially through its peripheral parts. This mode of distribution is designated as the peripheral mechanism. In contrast to the centralizing cardiovascular apparatus, the peripheral mechanism permits a greater autonomous action of organs and a more localising effect of injections. The peripheral mechanism found to be active in animals deprived of their circulation is probably identical with the mechanism which serves for distribution of the mesolymph in living animals not yet possessing a circulatory apparatus. The existence of the peripheral mechanism in animals with a cardiovascular apparatus possesses probably a phylogenetic significance. It is assumed that the activity of the peripheral mechanism is probably not completely suppressed even in the presence of a normally acting circulatory apparatus; that it exerts a greater physiological influence in parts in which the circulation is normally some-what difficult; and that it unfolds an activity in pathological conditions in which the circulation has been eliminated or reduced in some parts of the body, or in which the energy of the entire circulation has been reduced.
Dic(9;20)(p13;q11) in childhood acute lymphoblastic leukaemia is related to low cellular resistance to asparaginase, cytarabine and corticosteroids
Authors: G Lönnerholm, A Nordgren, B-M Frost, O G Jonsson, J Kanerva, R Nygaard, K Schmiegelow, R Larsson, E Forestier
Journal: Leukemia (2008)
Leptin induces phagocytosis of apoptotic bodies by hepatic stellate cells via a Rho guanosine triphosphatase-dependent mechanism
Authors: Joy X. Jiang, Kenichiro Mikami, Vijay H. Shah, Natalie J. Torok
Journal: Hepatology (2008)

Leptin, a profibrogenic cytokine, plays an important role in the development of non-alcoholic steatohepatitis. Leptin also regulates immune responses, including macrophage phagocytic activity. Stellate cells are key elements in liver fibrogenesis, and previously we have demonstrated that phagocytosis of apoptotic bodies by stellate cells is profibrogenic. To study the effects of leptin on the phagocytic activity of hepatic stellate cells, we exposed both LX-2 cells and primary stellate cells to leptin, and we have observed increased phagocytic activity. In stellate cells isolated from Zucker (fa/fa) rats, the rate of phagocytosis was significantly decreased. To investigate the mechanism by which leptin induces phagocytosis, we focused on the role of Rho-guanosine triphosphate (GTP)-ases. We found that leptin induced the PI3K-dependent activation of Rac1, and that nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase activation was also implicated in this process. Leptin also induced RhoA activation and translocation to the phagosomes. Expression of the constitutive active Rac1 and RhoA both increased the phagocytic rate, whereas inhibition of the Rho-dependent kinase decreased the phagocytic activity.We describe a novel role of leptin in the fibrogenic process, the induction of phagocytosis of apoptotic bodies by hepatic stellate cells. The data provide strong evidence of a Rho-GTPase-mediated regulation of the cytoskeleton during stellate cell phagocytosis. Leptin-mediated phagocytic activity of stellate cells therefore could be an important mechanism responsible for progression of fibrosis in non-alcoholic steatohepatitis.
Developmental changes in the beta-adrenergic modulation of calcium currents in rabbit ventricular cells.
Authors: T Osaka, R W Joyner
Journal: Circulation Research (1992)

We studied the developmental changes in the beta-adrenergic modulation of L-type calcium current (ICa) in enzymatically isolated adult (AD) and newborn (NB, 1-4-day-old) rabbit ventricular cells using the whole-cell patch-clamp method. ICa was measured as the peak inward current at a test potential of +15 mV by applying a 180-450-msec pulse from a holding potential of -40 mV with Cs(+)-rich pipettes and a K(+)-free bath solution at room temperature. In control, ICa density (obtained by normalizing ICa to the cell capacitance) was significantly higher in AD cells (5.5 +/- 0.2 [mean +/- SEM] pA/pF, n = 65) than in NB cells (2.6 +/- 0.1 pA/pF, n = 60). Isoproterenol (ISO, 1 nM-30 microM) increased ICa in a dose-dependent manner for both groups. The maximal effect (Emax) of ISO, expressed as percent increase in ICa over control levels, and the concentration for one half of the maximal effect (EC50) were 203% and 51 nM, respectively, for AD cells and 111% and 81 nM, respectively, for NB cells. The effect of ISO (1 microM) on ICa was decreased as the test potential was increased from -10 to +40 mV. However, the ratio of the percent increase in ICa for AD versus NB cells was almost constant (2.09-2.45) at each test potential. Dose-response curves of forskolin (FOR, 0.3-50 microM) gave Emax and EC50 of 268% and 0.74 microM, respectively, for AD cells and 380% and 1.15 microM, respectively, for NB cells. After stimulating ICa by 10 microM ISO, the addition of 10 microM FOR produced a further increase in ICa of only 12 +/- 2% in AD cells (n = 4) but a further increase of 140 +/- 41% in NB cells (n = 6). FOR (10 microM) did not produce any increase in ICa for AD and NB cells after stimulating ICa by intracellular application of 200 microM cAMP. ICa density stimulated by 10 microM ISO (17.8 +/- 1.1 pA/pF, n = 7), 10 microM FOR (21.0 +/- 1.3 pA/pF, n = 8), or 200 microM cAMP (18.0 +/- 1.3 pA/pF, n = 5) was equivalent in AD cells, whereas ICa density stimulated by 10 microM ISO (5.8 +/- 0.6 pA/pF, n = 9) was significantly lower than that stimulated by either 10 microM FOR (13.8 +/- 1.5 pA/pF, n = 7) or 200 microM cAMP (13.4 +/- 0.7 pA/pF, n = 7) in NB cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Wales is set 20 health targets
Authors: R. Dobson
Journal: BMJ (1997)

Twenty health targets for Wales, including halving the number of deaths from lung cancer within 12 years, have been announced by the new Welsh secretary, Ron Davies.

Even if partly met, the targets may help the principality to move away from its traditional image of being a land with high rates of ill health. In comparison with England life expectancy in Wales is lower, rates of long term illness are up to 30% higher, …
Linda Hazel Hignett
Authors: T. Lester
Journal: BMJ (2002)

Medical examiner the Benefits Agency (b Southport, Lancashire, 1948; q Dundee 1972; DCH), d 18 September 2002.

Linda originally trained as a general practitioner before our children were born. She intended to resume her career when the children were older but this became too difficult when she developed insulin dependent diabetes. She maintained her medical interest by doing domiciliary medicals for the Benefits Agency. Her spare time was devoted to our home and to supporting our children in their activities. We organised fundraising garden parties for Diabetes UK and our social life centred around our tennis tournaments for our friends.
Primary oat cell carcinoma of the oesophagus.
Authors: S Sabanathan, G P Graham, F D Salama
Journal: Thorax (1986)

Three cases of oat cell carcinoma of the oesophagus are presented and published reports reviewed. This is mainly a disease of older age with a 3:2 predominance of men. Of all published cases, 43 (47.3%) occurred in the middle third, 41 (45.1%) in the lower third, and four (4.4%) in the upper third. In one case it was multifocal and in two the location was not stated. Dysphagia was the most common symptom and was found in 82.5% of cases. Overall survival was 4.7 months. The longest survival in a patient treated by resection was 24 months and in a patient treated by chemotherapy 11 months. All but one of the patients had widely disseminated metastatic disease at death. It is concluded that surgery, possibly with adjuvant chemotherapy, holds out the best prospect for such patients.
On Keeping One's Eye on the Ball: Analysis of Biologic Specimens for Copper
Authors: I. Herbert Scheinberg
Journal: New England Journal of Medicine (1969)

In 1887 the state of the art and the science was such that Osler wrote that there were two groups of pneumonia patients "... the alcoholic and the temperate; the majority of the former die in spite of all treatment; the majority of the latter get well with any, or with no, treatment."1 It frequently made little difference to the patient if the diagnosis of his illness was correct, in obvious contrast to the patient today with pneumonia or with one of many other illnesses. Consider, as one of the latter, Wilson's disease.Wilson, over 50 years ago, defined the . . .