tbuckley/cabot-search huggingface dataset:
Abstract 2163: RSK signaling in HER2-positive breast cancer cells
Authors: Marc Y. Fink, Shawn Singh, Yohan Cho, Daksha Mestry
Journal: Cancer Research (2012)

Abstract Heregulin (HRG) is a soluble growth factor involved in the control of proliferation, survival, invasion, and differentiation of normal and malignant mammary epithelial cells. HRG binds its receptor, HER3, leading to activation of the HER2-HER3 heterodimer, which acts as an oncogenic factor in breast cancers. Pharmacological inhibitors to HER2 are currently being used in the clinic to treat HER2-positive breast cancer, however, they are associated with resistance after one year of therapy. A more comprehensive understanding of the signaling network downstream of HRG, in HER2-positive breast cancer cells, will be crucial for further development of inhibitors that do not elicit resistance. This study assessed HRG signaling in the HER2-positive breast cancer cell lines BT474 and SKBR3. The RSK (p90 ribosomal S6 Kinase) pathway was activated in an ERK-dependent manner. HRG stimulation increased phosphorylation of RSK at S380, T359, and S363. HRG stimulated the phosphorylation of CREB (cAMP Response-Element Binding Protein), an established substrate of RSK, at S133 and this was blocked by pharmacological inhibition of RSK. HRG induced the expression of c-FOS in an RSK-dependent manner. These data demonstrate that RSK has an important role in transducing HRG signaling to the gene expression program and suggest that inhibitors of RSK may be useful in the treatment of HER2-positive breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2163. doi:1538-7445.AM2012-2163
M43 The Accuracy Of Clinical Tb Diagnoses In Culture Negative Patients
Authors: L. M. Smith, N. Jayasekera, V. Macavei, T. O'Shaughnessy
Journal: Thorax (2014)

<h3>Background</h3> NICE guidelines for TB diagnosis recommend that sputum is obtained for culture for all suspected cases of pulmonary TB, and biopsies for all cases extrapulmonary TB. As results can take 6 weeks, treatment initiation decisions are frequently made without microbiological confirmation. <h3>Aim</h3> This study set out to examine the accuracy of clinical diagnoses in a high incidence area, and the basis for these decisions. <h3>Methods</h3> The data entered onto the national TB database was used to obtain a list of patients for whom no culture results had been recorded. Clinic letters, laboratory records and imaging were examined to determine whether samples had been sent for culture, how diagnoses were made in the event of negative results, and if alternative diagnoses were concluded. <h3>Results</h3> Of 323 patients on the database, 7% had no samples sent for culture. There were 109 culture negative patients, of whom 13 (4% all cases) had alternative diagnoses. A combination of relevant history and imaging was the most commonly used method of diagnosis when culture was negative (47%). Histology was used in 17% patients and Mantoux or IGRA testing supported initiating treatment in 39% cases. The database was missing positive culture results for 102 patients, of which four were MDR TB. <h3>Conclusions</h3> In this study, we found accurate initial clinical diagnoses, with only 4% patients subsequently obtaining alternative diagnoses. Most diagnoses were made on the basis of relevant history and imaging. Of concern are the 7% patients for whom tissue was never sent for culture. This is likely to be an underestimate when including all patients initially suspected of TB, raising the possibility of missed diagnoses. The utility of Mantoux and IGRA testing in active disease is now disputed. It is hoped with inter-specialty education regarding the importance of culture and futility of immunological based assays, the proportion of patients with suspected TB who have sputum or tissue sent for culture increases. Accurate recording of MDR-TB on the national TB database needs to be improved, to enable efficient monitoring of intervention programmes.
Feasibility of GRACE and TIMI Scores in Predicting the Extension of Coronary Artery Disease in Patients with Non ST Elevation Myocardial Infarction
Authors: Hale Unal Aksu, Şevket Gorgulu, Ender Oner, Mehmet Erturk, Omer Celik, Huseyin Aksu
Journal: Journal of the American College of Cardiology (2013)
Initiation of autoimmunity by a reactive metabolite of a lupus-inducing drug in the thymus.
Authors: R L Rubin, A Kretz-Rommel
Journal: Environmental Health Perspectives (1999)

Drug-induced lupus is a side effect of deliberate ingestion of various medications, but its etiology, underlying mechanisms, and pathogenesis are puzzling. In vivo metabolic transformation of lupus-inducing drugs to reactive products explains how a heterogeneous set of drugs can mediate the same disease syndrome. Evidence has accumulated that drugs are transformed by extracellular oxidation from reactive oxygen species and myeloperoxidase produced when neutrophils are activated, maximizing the in situ accumulation of reactive drug metabolites within lymphoid compartments. The metabolite of procainamide, procainamide hydroxylamine, displays diverse biologic properties, but no apparent autoimmune effect has been observed. However, when procainamide hydroxylamine was introduced into the thymus of young adult normal mice, a delayed but robust autoimmune response developed. Disruption of central T-cell tolerance by intrathymic procainamide hydroxylamine resulted in the production of chromatin-reactive T cells that apparently drove the autoantibody response in the periphery. Drug-induced autoantibodies in this mouse model were remarkably similar to those in patients with procainamide-induced lupus. Therefore, this system has considerable promise to provide insight into the initiating events in drug-induced lupus and may provide a paradigm for how other xenobiotics might induce systemic autoimmunity.
The 2005 International Symposium on Advances in Targeted Therapies: What have we learned in the 2000s and where are we going?
Authors: R N Maini
Journal: Annals of the Rheumatic Diseases (2005)

This essay summarises a personal perspective on where we have got to in the five years since the turn of the last century. The focus is on advances in knowledge of antitumour necrosis factor (anti-TNF) therapy of rheumatoid arthritis and other chronic immune-inflammatory rheumatic diseases. The accumulating knowledge is clarifying the scope and limitations of efficacy, safety, and durability of these agents. It is defining the unmet needs of patients and communities worldwide for the future. The call is for progress in providing more cost-effective advances in therapeutics that not only interrupt the disease process long term but also reverse the anatomical and functional consequences of disease and the impairment in quality of life.
Chronic Plumbism in Children
Authors: Louis Kopito
Journal: JAMA (1969)

The determination of lead in scalp hair is a valuable diagnostic aid in chronic or mild lead intoxication particulary when the other clinical or laboratory evidence is of questionable diagnostic quality. This continuously growing tissue accumulates and stores lead for long periods and may be used for estimating the time and duration of the exposure. Hair is easy to obtain, store, transport, and analyze and may provide a practical means for finding little children who may have been exposed to lead.
Cardiac Work Demands and Left Ventricular Function in End-Stage Renal Disease
Authors: JOHN P. CAPELLI
Journal: Annals of Internal Medicine (1977)

Cardiac hemodynamics were assessed by right and left heart catheterizations in nine patients on hemodialysis. Results showed increased stroke work index and left ventricular work indices. Left ventricular end-diastolic pressure was elevated in all patients (markedly so in five) and did not fall with occlusion of arteriovenous communications. Cardiac output was significantly elevated, but fell to normal postocclusion. Myocardial oxygen consumption, indirectly assessed by tension time and pressure rate indices, appeared increased. Six patients died: four from complications attributed to myocardial failure without infarction, one from transplant-related complications, and one from bacterial meningitis. Five had increased cardiac weights at autopsy, but none showed infarction. This study suggests that increased cardiac work is present in chronic renal failure. Myocardial mass increases result in increased myocardial oxygen demand; however, the increased oxygen requirements may not be met because of reduced erythrocyte mass. Persistance of pressure-volume overload and severe anemia are conducive to myocardial failure.
Modeling Chronic Glycemic Exposure Variables as Correlates and Predictors of Microvascular Complications of Diabetes
Authors: Peter J. Dyck, Jenny L. Davies, Vicki M. Clark, William J. Litchy, P. James B. Dyck, Christopher J. Klein, Robert A. Rizza, John M. Pach, Ronald Klein, Timothy S. Larson, L. Joseph Melton, Peter C. O’Brien
Journal: Diabetes Care (2007)

We are pleased to respond to the letter by Orchard et al. (1), especially since they first raised the following question: Do composite measures of chronic glycemia correlate or predict complications better than individual components? Orchard et al. reported evidence against the hypothesis, while we (2) reported evidence for the hypothesis. Having considered their suggestions, we offer an explanation for why their conclusions differed from ours.

Orchard et al. (3) compared the fit from two models, one consisting …
Indicators of psychiatric disorder among women admitted to prison.
Authors: T H Turner, D S Tofler
Journal: BMJ (1986)

A random sample of 708 women prisoners recently admitted to Holloway Prison was screened for evidence of psychiatric disorder. Of the 708 women, 195 had a history of self harm, 44 of whom had a history of cutting themselves, 125 had a history of psychiatric illness, 99 were dependent on opiates, and 89 took psychotropic drugs regularly. These findings suggest that there is a need for psychiatric units in women9s prisons such as Holloway Prison, and that initiatives to alter policies of admission to psychiatric hospitals should be pursued.
Oxygen free radicals in acute pancreatitis of the rat.
Authors: M H Schoenberg, M Buchler, M Gaspar, A Stinner, M Younes, I Melzner, B Bultmann, H G Beger
Journal: Gut (1990)

This study aimed to assess the role of oxygen free radicals in acute pancreatitis. Acute pancreatitis was induced in rats by infusion of the CCK-analogue cerulein (5 micrograms/kg per hour) for 30 minutes, 3.5 hours, and 12 hours. After the infusion, serum enzymes and conjugated tissue dienes and malondialdehyde were measured and tissue samples were subjected to electron and light microscopy. Electron microscopy after 30 minutes showed moderate intracellular alterations. After 3.5 hours of cerulein infusion interstitial oedema and intravascular margination of granulocytes in the pancreatic gland were seen. After 12 hours histological evaluation showed pronounced zymogen degranulation, extensive tissue necrosis, and migration of granulocytes into the tissue. Amylase and lipase activities increased 15 and 35-fold respectively during this time. After 30 minutes of cerulein infusion conjugated dienes and malondialdehyde increased, they reached their peak after 3.5 hours and decreased to normal values after 12 hours. Treatment with superoxide dismutase (100,000 U/kg/hour) and catalase (400,000 U/kg/hour) either before or after the start of the cerulein infusion prevented lipid peroxidation and reduced zymogen degranulation and tissue necrosis. Tissue oedema and inflammatory response, however, were not affected in any of the treated rats. Oxygen free radicals are instrumental in the development of acute pancreatitis. Even after its onset, scavenger treatment reduced the tissue damage normally observed.
Mechanism of exaggerated natriuresis in hypertensive man: impaired sodium transport in the loop of henle
Authors: Vardaman M. Buckalew, Jules B. Puschett, James E. Kintzel, Martin Goldberg
Journal: Journal of Clinical Investigation (1969)

To evaluate the effects of saline loading on distal sodium reabsorption in hypertensive man, studies were performed during both water deprivation and water diuresis in eight hypertensive subjects, and the results were compared to data obtained from similar studies in normal subjects. All hypertensive patients exhibited an enhanced excretion of filtered sodium (C(Na)/C(In)) at any level of distal delivery of sodium compared to normal controls. Free water reabsorption (T(c) (H2O)) during hypertonic saline loading was quantitatively abnormal in the hypertensives at high levels of osmolar clearance (C(Osm)), and also the curve of T(c) (H2O) vs. C(Osm) leveled off above a C(Osm) of 18 ml/min per 1.73 m(2) in the hypertensive group in contrast to the normal controls in whom T(c) (H2O) showed no evidence of achieving an upper limit. Sodium depletion exaggerated the abnormality in T(c) (H2O) in hypertensives, and resulted in a positive free water clearance (C(H2O)) during hydropenia. During hypotonic saline loading in water diuresis, changes in free water clearance per 100 ml of glomerular filtrate (C(H2O)/C(In)) were less at any given increment in urine flow per 100 ml of glomerular filtrate (V/C(In)) in the hypertensives compared to normal controls (P < 0.001). This abnormality in C(H2O)/C(In) in the hypertensives in conjunction with the defect in T(c) (H2O) observed during hydropenia indicates that sodium reabsorption in the loop of Henle was abnormal at any given rate of distal delivery of sodium in hypertension. Furthermore, these abnormalities in T(c) (H2O) and C(H2O) coincided temporally with the development of the exaggerated natriuresis. Although the distal defect in sodium transport, in large part, accounted for the augmented natriuresis in hypertension, evidence was present also for enhanced rejection of sodium in the proximal tubule during saline loading in the hypertensives. Additional studies utilizing acetazolamide which increases distal delivery of sodium without extracellular fluid volume expansion showed only minimal abnormalities in C(H2O) in the hypertensive group, indicating that the defect in sodium transport in the loop of Henle in hypertensives is mainly an abnormal response to extracellular fluid expansion rather than an intrinsic defect in the loop to handle increased tubular loads of sodium. It is possible that the abnormality in sodium reabsorption in the loop of Henle is due to the transmission of the abnormally elevated blood pressure of the hypertensives to the medullary vasa recta during saline loading.
Antenatal screening for Down's syndrome. Counselling may not help vulnerable women.
Authors: C M Anderson
Journal: BMJ (1993)

This matter is of sufficient importance that we encourage others to perform the analysis and report their findings.We believe that it is unsatisfactory to compare selected peer reviewed publications of prospective trials with unpublished or not peer reviewed summary data.Spencer and his colleagues cited only two of the three published studies using triple markers in women of all ages.The study not cited reported a detection rate of 91% (20/22) when amniocentesis was offered to 6% of the study population5 (this latter rate is identified as the false positive rate in the letter by Spencer and his colleagues).When evaluating prospective trials, it is essential to give details of the methods used to ensure complete ascertainment of all cases of Down's syndrome.Equally important is a comparison of the number of cases of Down's syndrome expected to be found in the second trimester (on the basis of the maternal age distribution of the screened population) with the actual number identified.The overall prevalence of Down's syndrome in the four studies using free ,B is lower than the prevalence in the two studies using triple markers, suggesting that incomplete identification of Down's syndrome pregnancies missed by the screening test may have led to an exaggerated detection rate.This possibility can be explored only if complete information is available.
THE SURGICAL TREATMENT OF INTESTINAL TUBERCULOSIS.
Authors: N. SENN
Journal: JAMA (1898)

The title of this paper will probably appear somewhat strange and out of place to the general practitioner and the surgeons who have not kept fully abreast with the great advancements that have been made during the last decade in the diagnosis and surgical treatment of localized lesions of the intestinal tract. Our increased knowledge of the location, nature and clinical tendencies of accessible tubercular affections has opened a wide and fertile field for successful surgical intervention. There is hardly an organ in the body which when the seat of a localized tubercular process has not been exposed and subjected to direct treatment with a fair expectation of removing or limiting the further extension of the disease. The medical treatment of tuberculosis in its various forms at the present time is not much in advance of that of fifty years ago. The numerous specifics invented and vaunted in different
The relationship between the free pool of proline and collagen content in human liver cirrhosis
Authors: David Kershenobich, Francisco J. Fierro, Marcos Rojkind
Journal: Journal of Clinical Investigation (1970)

The free proline, free glutamic acid, and total collagen contents of the livers of cirrhotic and noncirrhotic patients were determined. The amounts of free proline in the sera of the patients were also determined. The results indicated that certain metabolic changes occurred in cirrhotic livers of humans that were similar to the metabolic changes observed previously in CCl(4)-induced cirrhosis in the rat. The amount of free proline was coordinate with the increase in total collagen, and both were inversely related to the amount of free glutamic acid. The average proline concentration in sera of cirrhotic patients was not higher than that of non cirrhotic patients, suggesting that the metabolic alteration noted above is a local event in the liver related to fibrogenesis. These and other results suggest that the pool size of free proline may play a prime role in regulation of collagen biosynthesis in liver cirrhosis.
S95 Exploiting the immunoregulatory role of Siglec-E via sialic acid-functionalised nanoparticles as a novel approach for the treatment of acute lung injury
Authors: MK Greene, S Spence, F Fay, D Small, D Schmid, J Jaworski, JF Burrows, CM O'Kane, A Kissenpfennig, DF McAuley, CJ Scott
Journal: Thorax (2013)

<h3></h3> Acute Lung Injury (ALI) is a life-threatening disorder underpinned by dysregulated inflammatory cascades, with resultant injury to lung architecture. Currently, provision of supportive care represents the mainstay of treatment for ALI and novel anti-inflammatory therapeutic strategies are urgently required. We have developed a polymeric nanoconstruct surface-functionalised with sialic acid targeting moieties (SNP), exploiting the anti-inflammatory effects arising from the targeted engagement of Siglec-E receptors on activated macrophages, with potential therapeutic utility in ALI. Polylactic-co-glycolic acid (PLGA) nanoparticles of uniform size distribution (approximately 150nm in diameter) were synthesised in accordance with a salting-out formulation. Intratracheal instillation of 20μg lipopolysaccharide (LPS) was utilised as a model of ALI in C57BL/6 mice, co-administered with 1μg SNP or non-functionalised nanoparticles (NP). Bronchoalveolar lavage (BALF) samples were collected 24 hours after treatment for analysis by enzyme-linked immunosorbent assay (ELISA). As exemplified in Figure 1., intratracheal instillation of SNP significantly attenuated BALF levels of pro-inflammatory TNFα and IL-6 cytokines, in addition to the neutrophil chemoattractant KC. Moreover, BALF differential cell counts revealed a decrease in neutrophil numbers upon treatment with SNP under LPS-induced pro-inflammatory conditions. Further analyses addressing the therapeutic utility of SNP have been undertaken, including lung wet/dry ratios, histology and toxicological evaluation, with promising outcomes. This research clearly demonstrates the ability of SNP to diminish the inflammatory response in a murine model of LPS-induced ALI. Considering that chemoattractants and cytokines are key mediators in the pathogenesis of ALI, these results substantiate the credibility of this nanoscaffold as a therapy for ALI. Ultimately, we aim to progress this modality to a human setting, specifically analysing its effects on alveolar macrophages isolated from human volunteers, before advancing to a human <i><i>ex vivo</i></i>lung perfusion model.
Abstract 5437: Dual targeting of ErbB-2 and ErbB-3: A new potential strategy for the treatment of pancreatic cancer
Authors: Gianluca Sala, Reza Ghasemi, Emily Capone, Ilario Giovanni Rapposelli, Sara Traini, Cosmo Rossi, Pier Giorgio Natali, Stefano Iacobelli
Journal: Cancer Research (2014)

Abstract Background: Pancreatic cancer (PC) is one of the most lethal cancers and there is an urgent need to find out new therapeutic approaches. Deregulated signaling through ErbB-1 and ErbB-2, members of the epidermal growth factor receptor family, frequently occurs in PC. However, attempts aiming at inhibiting ErbB-1 and ErbB-2 have revealed only a modest impact on disease outcome. A growing body of evidence suggests that ErbB-3 and its ligand NRG-1β are key players in driving oncogenic signaling and resistance to targeted therapy in PC. We have recently developed a novel humanized ErbB-3 antibody, named EV20, which displayed a potent antitumor activity by promoting receptor downregulation in vitro and in vivo. Here we hypothesized that targeting of ErbB-3 with EV20 would enhance the therapeutic effect of ErbB-2 inhibitors in PC. Materials and Methods: Three different PC cell lines (BxPC-3, HPAF II and SW1990) were chosen based on their metastatic origin, genetic background (KRAS status) and responsiveness to erlotinib. The expression of ErbB-1, ErbB-2 and ErbB-3 was analyzed by FACS and WB. The effects of trastuzumab, cetuximab, EV20 and their combinations on NRG-1β-induced activation of the ErbB3/PI3K/Akt axis, cell proliferation, and in vivo tumor growth were evaluated by standard procedures. Results: ErbB-1 was overexpressed by all the cell lines, whereas the expression levels of ErbB-2 and ErbB-3 were moderate in HPAFII cells and low in BxPC-3 and SW1990 cells. NRG-1β was more effective than EGF (an ErbB-1 ligand) in activating ErbB-3 downstream signaling, which was not inhibited by cetuximab, despite a high ErbB-1 expression in the cells. Conversely, inhibition of ErbB-2 and/or ErbB-3 resulted in a marked suppression of NRG-1β-driven Akt activation. Finally, EV20 in combination with trastuzumab exerted a superior antitumor activity compared to single agent alone in terms of cell proliferation and growth of PC xenografts in nude mice. Conclusions: Dual targeting of ErbB-2 and ErbB-3 could represent a newer therapeutic approach in PC. Note: This abstract was not presented at the meeting. Citation Format: Gianluca Sala, Reza Ghasemi, Emily Capone, Ilario Giovanni Rapposelli, Sara Traini, Cosmo Rossi, Pier Giorgio Natali, Stefano Iacobelli. Dual targeting of ErbB-2 and ErbB-3: A new potential strategy for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5437. doi:10.1158/1538-7445.AM2014-5437