tbuckley/cabot-search huggingface dataset:
NHS reforms could destroy partnerships between primary and secondary care
Authors: A. O'Dowd
Journal: BMJ (2011)

Progress on close clinical working between primary and secondary care clinicians could be halted as a consequence of the NHS reforms, MPs have been told.

MPs on the parliamentary health select committee heard from several witnesses involved in GP commissioning on 8 March as part of their inquiry into commissioning.

The committee’s MPs asked how the current NHS world compared and contrasted with how the NHS would be under the NHS reforms as set out in the Health and Social Care Bill .

Deborah Colvin, GP at the Lawson Practice Hackney, London, giving evidence, said: “We have been engaging quite closely with secondary care and we have been able to make some …
Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531
Authors: Alan S. Gamis, Todd A. Alonzo, Soheil Meshinchi, Lillian Sung, Robert B. Gerbing, Susana C. Raimondi, Betsy A. Hirsch, Samir B. Kahwash, Amy Heerema-McKenney, Laura Winter, Kathleen Glick, Stella M. Davies, Patti Byron, Franklin O. Smith, Richard Aplenc
Journal: Journal of Clinical Oncology (2014)

Purpose To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. Patients and Methods Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m 2 /dose) administered once in induction course 1 and once in intensification course 2 (two of three). Results There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P = .04) but not OS (3 years: 69.4% v 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07). Conclusion GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.
Autophagy Inhibition Augments the Anticancer Effects of Epirubicin Treatment in Anthracycline-Sensitive and -Resistant Triple-Negative Breast Cancer
Authors: Suganthi Chittaranjan, Svetlana Bortnik, Wieslawa H. Dragowska, Jing Xu, Namal Abeysundara, Amy Leung, Nancy E. Go, Lindsay DeVorkin, Sherry A. Weppler, Karen Gelmon, Donald T. Yapp, Marcel B. Bally, Sharon M. Gorski
Journal: Clinical Cancer Research (2014)

Triple-negative breast cancers (TNBC) are defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2). Although initially responsive to chemotherapy, most recurrent TNBCs develop resistance, resulting in disease progression. Autophagy is a lysosome-mediated degradation and recycling process that can function as an adaptive survival response during chemotherapy and contribute to chemoresistance. Our goal was to determine whether autophagy inhibition improves treatment efficacy in TNBC cells in tumors either sensitive or refractory to anthracyclines.We used in vitro and in vivo models of TNBC using cell lines sensitive to epirubicin and other anthracyclines, as well as derivative lines, resistant to the same drugs. We assessed basal autophagy levels and the effects of chemotherapy on autophagy in parental and resistant cells. Applying various approaches to inhibit autophagy alone and in combination with chemotherapy, we assessed the effects on cell viability in vitro and tumor growth rates in vivo.We demonstrated that epirubicin induced autophagic flux in TNBC cells. Epirubicin-resistant lines exhibited at least 1.5-fold increased basal autophagy levels and, when treated with autophagy inhibitors, showed a significant loss in viability, indicating dependence of resistant cells on autophagy for survival. Combination of epirubicin with the autophagy inhibitor hydroxychloroquine resulted in a significant reduction in tumor growth compared with monotherapy with epirubicin.Autophagy inhibition enhances therapeutic response in both anthracycline-sensitive and -resistant TNBC and may be an effective new treatment strategy for this disease.
<b> <i>In vitro</i> </b> and <b> <i>In vivo</i> </b> Models Analyzing von Hippel-Lindau Disease-Specific Mutations
Authors: W. Kimryn Rathmell, Michele M. Hickey, Natalie A. Bezman, Christie A. Chmielecki, Natalie C. Carraway, M. Celeste Simon
Journal: Cancer Research (2004)

Abstract Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene cause tissue-specific tumors, with a striking genotype-phenotype correlation. Loss of VHL expression predisposes to hemangioblastoma and clear cell renal cell carcinoma, whereas specific point mutations predispose to pheochromocytoma, polycythemia, or combinations of hemangioblastoma, renal cell carcinoma, and/or pheochromocytoma. The VHL protein (pVHL) has been implicated in many cellular activities including the hypoxia response, cell cycle arrest, apoptosis, and extracellular matrix remodeling. We have expressed missense pVHL mutations in Vhl−/− murine embryonic stem cells to test genotype-phenotype correlations in euploid cells. We first examined the ability of mutant pVHL to direct degradation of the hypoxia inducible factor (HIF) subunits HIF1α and HIF2α. All mutant pVHL proteins restored proper hypoxic regulation of HIF1α, although one VHL mutation (VHLR167Q) displayed impaired binding to Elongin C. This mutation also failed to restore HIF2α regulation. In separate assays, these embryonic stem cells were used to generate teratomas in immunocompromised mice, allowing independent assessment of the effects of specific VHL mutations on tumor growth. Surprisingly, teratomas expressing the VHLY112H mutant protein displayed a growth disadvantage, despite restoring HIFα regulation. Finally, we observed increased microvessel density in teratomas derived from Vhl−/− as well as VHLY112H, VHLR167Q, and VHLR200W embryonic stem cells. Together, these observations support the hypothesis that pVHL plays multiple roles in the cell, and that these activities can be separated via discrete VHL point mutations. The ability to dissect specific VHL functions with missense mutations in a euploid model offers a novel opportunity to elucidate the activities of VHL as a tumor suppressor.
Changes in pulmonary microvascular permeability accompanying re-expansion oedema: evidence from dual isotope scintigraphy.
Authors: P D Wilkinson, J Keegan, S W Davies, J Bailey, R M Rudd
Journal: Thorax (1990)

The pathophysiological mechanism of pulmonary oedema following rapid re-expansion of a collapsed lung is poorly understood. It has been suggested that the period of collapse or subsequent reinflation produces an increase in pulmonary microvascular permeability. To investigate this, the pulmonary accumulation of the plasma protein transferrin was measured by radiolabelling it in vivo with indium-113m. Plasma protein accumulation was calculated after correcting the accumulation of transferrin for changes in intrathoracic blood distribution by simultaneously monitoring technetium-99m labelled red blood cells. Functional images of plasma protein accumulation were constructed for the lung fields on a pixel by pixel basis. Investigations were performed on 14 subjects after drainage of a pleural effusion (n = 9) or evacuation of a pneumothorax (n = 5), and on 11 control subjects. Plasma protein accumulation was greater over the regions of lung re-expansion (-0.1-9.6, mean 2.9 x 10(-3)/min) than over the corresponding region of the contralateral lung (-1.2-0.8, mean 0.01 x 10(-3)/min; p less than 0.001). Patients who had undergone re-expansion procedures also had significantly greater plasma protein accumulation than normal controls. Nine of the 14 patients in the re-expansion group had clearly identifiable areas of increased plasma protein accumulation that corresponded to the part of the lung that had been re-expanded; no regional abnormalities were recorded in the control group. These results suggest that the reinflated lung displays abnormal microvascular permeability.
Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial
Authors: Hans-Joachim Schmoll, Josep Tabernero, Jean Maroun, Filippo de Braud, Timothy Price, Eric Van Cutsem, Mark Hill, Silke Hoersch, Karen Rittweger, Daniel G. Haller
Journal: Journal of Clinical Oncology (2015)

Purpose To report the final efficacy findings and biomarker analysis from the NO16968 trial comparing bolus fluorouracil/folinic acid (FU/FA) with capecitabine plus oxaliplatin (XELOX) in resected stage III colon cancer. Patients and Methods After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m 2 on day 1 and capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 every 3 weeks, or bolus FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS). Results The intention-to-treat population comprised 1,886 patients (XELOX, n = 944; FU/FA, n = 942). Seven-year DFS rates were 63% and 56% in the XELOX and FU/FA groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.69 to 0.93; P = .004). Seven-year OS rates were 73% and 67% in the XELOX and FU/FA groups, respectively (HR, 0.83; 95% CI, 0.70 to 0.99; P = .04). A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease. Four hundred ninety-eight patients consented to the biomarker analysis: 242 in the XELOX group and 256 in the FU/FA group. Low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy; in the XELOX group, for high versus low dihydropyrimidine dehydrogenase expression levels, DFS HR was 2.45 (95% CI, 1.55 to 3.86; P &lt; .001), and OS HR was 2.75 (95% CI, 1.65 to 4.59; P &lt; .001). In the FU/FA group, no statistically significant associations were observed between any tumor biomarker and outcomes. Conclusion XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years. XELOX should be considered a standard adjuvant treatment option in patients with stage III disease. Tumoral dihydropyrimidine dehydrogenase expression is a promising predictive, and potentially, highly clinically relevant, biomarker for XELOX efficacy requiring further prospective evaluation.
Differential regulation of membrane and secretory mu chain synthesis in human beta cell lines. Regulation of membrane mu or secreted mu.
Authors: L Hendershot, D Levitt
Journal: The Journal of Experimental Medicine (1982)

Regulation of membrane and secretory mu synthesis was examined in human lymphoblastoid cell lines representing various stages of differentiation. Immunoglobulin phenotype was determined by surface and cytoplasmic staining with fluorochrome-conjugated antibodies and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of anti-mu precipitable cellular products. The thymidine analogue, 5-bromo-2'-deoxyuridine (BUdR), which inhibits differentiation-specific proteins in a variety of systems, was used to examine regulation of immunoglobulin synthesis. We found that BUdR had a differential effect on membrane (mum) and secretory (mus) type mu heavy chains. Ig production in pre-B and plasma cell-like lines, which make mus, was unaffected by BUdR. However, surface expression of IgM (mum) in B cell lines was drastically inhibited at similar doses of BUdR without diminishing total Ig or protein synthesis. Examination of labeled mu chains from control and BUdR-treated B cell lines by SDS-PAGE revealed the production of two sizes of mu (mum and mus) in control cells and only the smaller size (mus) in BUdR-treated cells. This size difference could not be attributed to alterations in glycosylation of the molecules. These data show that BUdR inhibits the production of membrane mu chains without diminishing secretory mu chain synthesis in the same cell. Our findings suggest that thymidine-rich regions of the genome are involved in the regulation of mum vs. mus during B cell differentiation.
Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer
Authors: M.J. Sotelo, J. Sastre, M.L. Maestro, S. Veganzones, J.M. Viéitez, V. Alonso, C. Grávalos, P. Escudero, R. Vera, E. Aranda, P. García-Alfonso, J. Gallego-Plazas, C. Lopez, C. Pericay, A. Arrivi, P. Vicente, P. Ballesteros, E. Elez, A. López-Ladrón, E. Díaz-Rubio
Journal: Annals of Oncology (2014)
Maternal Personal Exposure to Airborne Benzene and Intrauterine Growth
Authors: Rémy Slama, Olivier Thiebaugeorges, Valérie Goua, Lucette Aussel, Paolo Sacco, Aline Bohet, Anne Forhan, Béatrice Ducot, Isabella Annesi-Maesano, Joachim Heinrich, Guillaume Magnin, Michel Schweitzer, Monique Kaminski, Marie-Aline Charles
Journal: Environmental Health Perspectives (2009)

Studies relying on outdoor pollutants measures have reported associations between air pollutants and birth weight.Our aim was to assess the relation between maternal personal exposure to airborne benzene during pregnancy and fetal growth.We recruited pregnant women in two French maternity hospitals in 2005-2006 as part of the EDEN mother-child cohort. A subsample of 271 nonsmoking women carried a diffusive air sampler for a week during the 27th gestational week, allowing assessment of benzene exposure. We estimated head circumference of the offspring by ultrasound measurements during the second and third trimesters of pregnancy and at birth.Median benzene exposure was 1.8 microg/m(3) (5th, 95th percentiles, 0.5, 7.5 microg/m(3)). Log-transformed benzene exposure was associated with a gestational age-adjusted decrease of 68 g in mean birth weight [95% confidence interval (CI), -135 to -1 g] and of 1.9 mm in mean head circumference at birth (95% CI, -3.8 to 0.0 mm). It was associated with an adjusted decrease of 1.9 mm in head circumference assessed during the third trimester (95% CI, -4.0 to 0.3 mm) and of 1.5 mm in head circumference assessed at the end of the second trimester of pregnancy (95% CI, -3.1 to 0 mm).Our prospective study among pregnant women is one of the first to rely on personal monitoring of exposure; a limitation is that exposure was assessed during 1 week only. Maternal benzene exposure was associated with decreases in birth weight and head circumference during pregnancy and at birth. This association could be attributable to benzene and a mixture of associated traffic-related air pollutants.
Transcription factor Fra-1 induces cholangitis and liver fibrosis
Authors: Trayana Kireva, Annette Erhardt, Gisa Tiegs, Herbert Tilg, Helmut Denk, Johannes Haybaeck, Elmar Aigner, Alexander Moschen, Jörg H. Distler, Georg Schett, Jochen Zwerina
Journal: Hepatology (2011)

Chronic diseases of the biliary system are common and may cause fibrosis and eventually progression to liver cirrhosis. The aim was to define a new mouse model of a cholangiopathy leading to liver fibrosis in fra-1tg mice. Liver pathology of fra-1tg mice was analyzed in detail by histology and flow cytometry. Transcript levels of fibrosis-related genes and matrix metalloproteinase (MMP) activities were quantified and immunohistochemical analysis additionally applied. The role of the immune system in this model was analyzed by crossing fra-1tg mice with rag2 -/- mice. Furthermore, expression of Fra-1 in corresponding human liver diseases was investigated on transcription level and histologically. Fra-1tg mice spontaneously develop biliary fibrosis preceded by ductular proliferation and infiltration of inflammatory cells. Fra-1 protein is present in cholangiocytes and inflammatory cells within the liver. These findings were replicated in human biopsies of patients with advanced liver fibrosis. The inflammatory infiltrate showed a strong increase in activated T cells and decreased natural killer (NK), natural killer T cells (NKT), and B cells in fra-1tg mice as compared to wildtype mice. Moreover, fra-1tg mice develop biliary fibrosis with a time-dependent increase in hepatic collagen content and increase in relative messenger RNA (mRNA) expression of profibrotic genes. Attenuation but not complete prevention of collagen accumulation in liver was observed in the fra-1tg × rag2-/- mice. However, transplantation of fra-1tg bone marrow cells into wildtype mice could not induce disease. Conclusion: Fra-1tg mice spontaneously develop a progressive biliary disease. These mice are an attractive model for the investigation of cholangiopathies and their interaction with the immune system. (HEPATOLOGY 2011;)
Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD
Authors: D. M. Mannino, D. Thorn, A. Swensen, F. Holguin
Journal: European Respiratory Journal (2008)

Chronic obstructive pulmonary disease (COPD) is associated with important chronic comorbid diseases, including cardiovascular disease, diabetes and hypertension. The present study analysed data from 20,296 subjects aged ≥45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS). The sample was stratified based on baseline lung function data, according to modified Global Initiative for Obstructive Lung Disease (GOLD) criteria. Comorbid disease at baseline and death and hospitalisations over a 5-yr follow-up were then searched for. Lung function impairment was found to be associated with more comorbid disease. In logistic regression models adjusting for age, sex, race, smoking, body mass index and education, subjects with GOLD stage 3 or 4 COPD had a higher prevalence of diabetes (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.1–1.9), hypertension (OR 1.6, 95% CI 1.3–1.9) and cardiovascular disease (OR 2.4, 95% CI 1.9–3.0). Comorbid disease was associated with a higher risk of hospitalisation and mortality that was worse in people with impaired lung function. Lung function impairment is associated with a higher risk of comorbid disease, which contributes to a higher risk of adverse outcomes of mortality and hospitalisations.
Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy.
Authors: M Tanaka, H Fujiwara, T Onodera, D J Wu, M Matsuda, Y Hamashima, C Kawai
Journal: Circulation (1987)

To clarify the pathophysiologic role of intramyocardial small artery (IMSA) diseases in hypertrophied hearts, narrowings of the IMSA were quantitatively evaluated in 39 autopsied hearts, 10 from patients with typical hypertrophic cardiomyopathy (HCM), four from patients with HCM showing features mimicking dilated cardiomyopathy (DCM-like HCM), 10 from patients with hypertension, and 15 from normal adults. The relations of narrowings of the IMSA to myocytic hypertrophy, myocardial fiber disarray, and fibrosis were also examined. The external caliber and the ratio of the luminal area to the total vascular area (percent luminal area, % lumen) were calculated by an image analyzer in 85 to 203 IMSAs from each patient. The external calibers of the IMSAs were similar among groups of hearts with HCM, hypertensive hearts, and normal hearts but were greater in those with DCM-like HCM. The mean % lumen of the IMSAs was similarly reduced in the hearts with HCM (29 +/- 5% in the ventricular septum and 31 +/- 5% in the left ventricular free wall) and in hypertensive hearts (30 +/- 8% and 31 +/- 7%) compared with that in normal hearts (40 +/- 5% and 38 +/- 5%) and was the lowest in the ventricular septum of hearts with DCM-like HCM (17 +/- 3%). The mean % lumen of the IMSA was inversely correlated with heart weight (r = -.59), the mean size of myocytes (r = -.66 in the ventricular septum, r = -.63 in the free wall), and percent fibrotic area in the septum (r = -.68). The mean % lumen values of the IMSAs in the tissues with and without disarray in the hearts with HCM were similar. Thus IMSA disease is of pathophysiologic importance in patients with HCM, DCM-like HCM in particular, or with hypertension.
Molecular Phenotypes of Acute Rejection Predict Kidney Graft Prognosis
Authors: Ondrej Viklicky, Petra Hribova, Hans-Dieter Volk, Janka Slatinska, Jan Petrasek, Stepan Bandur, Eva Honsova, Petra Reinke
Journal: Journal of the American Society of Nephrology (2009)

Earlier detection of antibody-mediated rejection of kidney allografts may improve graft outcomes. Profiling of gene expression holds promise for the diagnosis and prognosis of antibody-mediated rejection. Here, we identified 730 patients who received kidney transplants during 2002–2005, including 21 patients (2.9%) who experienced early acute antibody-mediated rejection. We also identified a matched group of 43 patients with early acute T cell-mediated rejection to serve as controls. Compared with patients with T cell-mediated rejection, those with antibody-mediated rejection had significantly higher intrarenal mRNA expression of the cytoprotective heme oxygenase-1 but had lower expression of the regulatory T cell marker forkhead box P3 (FoxP3), the B cell marker CD20, and the chemokine regulated upon activation, normal T cell expressed and secreted (RANTES). T cell infiltration was similar in both groups of patients. Compared with grafts that had a favorable course, those that failed as a result of antibody-mediated rejection had expression profiles suggesting a lack of regulation (less FoxP3, TGF-β1, RANTES, and CD20). Grafts that failed as a result of T cell-mediated rejection only revealed lower expression of CD20 mRNA. In summary, these data suggest that severe antibody-mediated rejection and T cell-mediated rejection result in graft loss by distinct mechanisms. Molecular phenotypes of early acute rejection might help to identify grafts with poor prognosis, allowing earlier application of additional therapies.