tbuckley/cabot-search huggingface dataset:
Nigel Crisp steps down from NHS amid financial pressures
Authors: Rebecca Coombes
Journal: BMJ (2006)

The chief executive of the NHS and permanent secretary at the Department of Health, Nigel Crisp, is to step down at the end of this month after acknowledging accountability for the health service's financial problems.

Sir Nigel said his decision to enter early retirement at the age of 54 was taken with “sadness.”

Despite overseeing huge increases in spending and waiting list reductions he admitted in a frank statement that “not everything had gone well.”

“I am particularly saddened by the difficulties we have had over the last few months and the financial problems we are …
Cytokines and Soluble Cytokine Receptors in Pleural Effusions from Septic and Nonseptic Patients
Authors: CHRISTELLE MARIE, MARIE-REINE LOSSER, CATHERINE FITTING, NATHALIE KERMARREC, DIDIER PAYEN, JEAN-MARC CAVAILLON
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The balance between proinflammatory cytokines and their inhibitors has rarely been investigated in pleural effusions of nonmalignant or noninfectious origin. To evaluate the impact of a lung and/or intrathoracic infection in such a circumstance, we compared the levels of proinflammatory cytokines (interleukin-8 [IL-8]); tumor necrosis factor- α (TNF- α ); the cytokine antagonists and inhibitors (IL-1 receptor antagonist [IL-1ra] ) and soluble TNF receptors Types I and II (sTNFRI, sTNFRII); and antiinflammatory cytokines (transforming growth factor- β [TGF- β ]) in pleural effusion and plasma from septic (n = 15) and nonseptic (n = 9) patients. In addition, we analyzed the levels of IL-6 and its soluble receptor (sIL-6R). Bronchoalveolar lavage fluids (BALFs) were also studied in a few septic patients. High and nonsignificantly different levels of cytokines and inhibitors were detected in both groups of patients. The levels of IL-6 and sTNFRI and sTNFRII in pleural effusion were higher than in plasma, whereas the levels of IL-1ra and sIL-6R were higher in plasma. The levels of sIL-6R influenced the bioactivity of IL-6. There was no correlation between the levels of cytokines in plasma and in pleural effusion. In contrast, a significant correlation was observed for the soluble receptors sIL-6R (r = 0.67, p < 0.001), sTNFRI (r = 0.76, p < 0.001) and sTNFRII (r = 0.66, p = 0.001). Furthermore, a high correlation was found between the levels of both forms of sTNFRs in plasma (r = 0.95, p < 0.001) and in pleural effusion (r = 0.79, p < 0.001). In addition, a correlation was observed between the levels of TGF- β in pleural effusion and in BALF. The highest levels of some markers in plasma and of others in pleura argue in favor of both a systemic and a compartmentalized response, independently of the presence of infection. Because cytokines can be trapped by the surrounding cells in their environment, measurable levels of cytokines in biologic fluids represent the ”tip of the iceberg,” which is not the case for soluble receptors. The correlations of these latter markers between plasma and pleura strongly suggest that exchanges between both compartments can occur in both directions.
Quantifying the ventilatory control contribution to sleep apnoea using polysomnography
Authors: Philip I. Terrill, Bradley A. Edwards, Shamim Nemati, James P. Butler, Robert L. Owens, Danny J. Eckert, David P. White, Atul Malhotra, Andrew Wellman, Scott A. Sands
Journal: European Respiratory Journal (2014)

Elevated loop gain, consequent to hypersensitive ventilatory control, is a primary nonanatomical cause of obstructive sleep apnoea (OSA) but it is not possible to quantify this in the clinic. Here we provide a novel method to estimate loop gain in OSA patients using routine clinical polysomnography alone. We use the concept that spontaneous ventilatory fluctuations due to apnoeas/hypopnoeas (disturbance) result in opposing changes in ventilatory drive (response) as determined by loop gain (response/disturbance). Fitting a simple ventilatory control model (including chemical and arousal contributions to ventilatory drive) to the ventilatory pattern of OSA reveals the underlying loop gain. Following mathematical-model validation, we critically tested our method in patients with OSA by comparison with a standard (continuous positive airway pressure (CPAP) drop method), and by assessing its ability to detect the known reduction in loop gain with oxygen and acetazolamide. Our method quantified loop gain from baseline polysomnography (correlation versus CPAP-estimated loop gain: n=28; r=0.63, p&lt;0.001), detected the known reduction in loop gain with oxygen (n=11; mean± sem change in loop gain (ΔLG) −0.23±0.08, p=0.02) and acetazolamide (n=11; ΔLG −0.20±0.06, p=0.005), and predicted the OSA response to loop gain-lowering therapy. We validated a means to quantify the ventilatory control contribution to OSA pathogenesis using clinical polysomnography, enabling identification of likely responders to therapies targeting ventilatory control.
Diet and Exercise in the Treatment of NIDDM: The need for early emphasis
Authors: R James Barnard, Tiffany Jung, Stephen B Inkeles
Journal: Diabetes Care (1994)

OBJECTIVE To investigate the effectiveness of an intensive diet and exercise program for controlling non-insulin-dependent diabetes mellitus (NIDDM) and reducing risk factors associated with macrovascular complications. RESEARCH DESIGN AND METHODS Medical charts obtained from 4,587 participants in a lifestyle modification program were screened for patients with NIDDM. A total of 652 patients was identified, and their responses to the 3-week program were analyzed. RESULTS Fasting glucose level was reduced from 10.0 to 8.45 mmol/l, and 71% of 197 subjects taking oral hypoglycemic agents and 39% of 212 taking insulin were able to discontinue their medication. Of the 243 not taking medication, 76% reduced their fasting glucose levels to ≤ 7.84 mmol/l. Blood pressure was significantly reduced, and of the 319 initially taking antihypertension drugs, 34% had their medication discontinued. Serum total and low-density lipoprotein cholesterol were reduced by 22% and triglycerides by 33%. The ratio of total to high-density lipoprotein cholesterol was reduced by 13%. CONCLUSIONS Lifestyle modification consisting of diet combined with aerobic exercise can be effective for controlling NIDDM and reducing risk factors associated with macrovascular complications in both men and women. The program was far more effective in controlling the disease in patients taking no medication or oral agents compared with patients taking insulin. These results stress the need for early emphasis on lifestyle modification in the treatment of NIDDM.
BENCE JONES PROTEINS AND LIGHT CHAINS OF IMMUNOGLOBULINS
Authors: Alan Solomon, Carla L. McLaughlin
Journal: The Journal of Experimental Medicine (1969)

Three distinct classes of kappa light polypeptide chains have been detected immunochemically by an antiserum (R185) prepared against a kappa Bence Jones protein with a glutamyl amino terminal residue. This antiserum had specificity for kappa light chains with glutamyl amino terminal residues and differentiated kappa-chains with aspartyl amino terminal residues into two classes: the three kappa-chain classes have been designated as kappa(glu), kappa(aspII), and kappa(aspI). The ability of antiserum R185 to detect these antigenic differences on the intact immunoglobulin molecule, as well as on the isolated light chain or Bence Jones protein, made feasible the direct classification of type K myeloma proteins and M-macroglobulins (Waldenström). The multispecificity of the antiserum permitted the quantitation of type kappa(glu) light chains in normal, hypergammaglobulinemic, and hypogammaglobulinemic sera. Whereas the distribution of myeloma proteins and Bence Jones proteins in the kappa(glu) class correlated with the distribution of kappa(glu) chains in normal and hypergammaglobulinemic sera, the M-macroglobulins in the kappa(glu) class represented 90% of the total M-macroglobulins tested and revealed a marked divergence from the range of 24-31% of kappa(glu) immunoglobulins in normal sera. A preponderance of kappa(glu) chains was detected in the sera from patients with non-sex-linked hypogammaglobulinemia and represented 60-77% of the total type K light chain content. The controlled cleavage of a Bence Jones protein representative of each kappa-chain class into its variant half and constant half made possible the localization on the light polypeptide chain, the reactive sites for which antiserum R185 had specificity. The correlations between immunochemical and structural classification of kappa light chains are discussed.
Host gastric Lewis expression determines the bacterial density of Helicobacter pylori in babA2 genopositive infection
Authors: B-S Sheu
Journal: Gut (2003)

<b>Background and aims:</b> We tested if host gastric Lewis antigens and the <i>babA2</i> genotype of <i>Helicobacter pylori</i> correlated with clinicohistological outcome. <b>Methods:</b> We enrolled 188 dyspeptic patients (45 with duodenal ulcer, 45 with gastric ulcer, and 98 with chronic gastritis) with <i>H pylori</i> infection, proved by culture and gastric histology, reviewed by the updated Sydney system. Gastric expression of Lewis (Le) antigens Le<sup>a</sup>, Le<sup>b</sup>, Le<sup>x</sup>, and Le<sup>y</sup> was determined immunochemically to determine intensity (range 0–3). The corresponding 188 <i>H pylori</i> isolates were screened for <i>babA2</i> genotype by polymerase chain reaction. <b>Results:</b> All <i>H pylori</i> isolates had a positive <i>babA2</i> genotype. We identified Le<sup>a</sup> in 33.5%, Le<sup>b</sup> in 72.9%, Le<sup>x</sup> in 86.2%, and Le<sup>y</sup> in 97.4% of biopsies from these 188 patients. Patients who expressed Le<sup>b</sup> had a higher <i>H pylori</i> density than those who did not express Le<sup>b</sup> (p&lt;0.001). Among 139 patients who expressed Le<sup>b</sup>, <i>H pylori</i> density increased with a higher Le<sup>b</sup> intensity (p&lt;0.05). Gastric atrophy decreased with Le<sup>b</sup> intensity and thus resulted in lower <i>H pylori</i> density in the antrum (p&lt;0.05). For the 49 patients without gastric Le<sup>b</sup> expression, <i>H pylori</i> density was positively related with Le<sup>x</sup> and Le<sup>a</sup> expression (p&lt;0.05). <b>Conclusions:</b> Taiwanese <i>H pylori</i> isolates are 100% <i>babA2</i> genopositive. Gastric Le<sup>b</sup> as well as Le<sup>x</sup> intensity may be major determinants of <i>H pylori</i> density. While lacking gastric Le<sup>b</sup> expression, Le<sup>x</sup> and Le<sup>a</sup> were closely related to <i>H pylori</i> colonisation.
Formation of a Highly Peptide-Receptive State of Class II MHC
Authors: Joshua D. Rabinowitz, Marija Vrljic, Peter M. Kasson, Michael N. Liang, Robert Busch, J.Jay Boniface, Mark M. Davis, Harden M. McConnell
Journal: Immunity (1998)

Peptide binding to class II MHC proteins occurs in acidic endosomal compartments following dissociation of class II–associated invariant chain peptide (CLIP). Based on peptide binding both to empty class II MHC and to molecules preloaded with peptides including CLIP, we find evidence for two isomeric forms of empty MHC. One (inactive) does not bind peptide. The other (active) binds peptide rapidly, with kon 1000-fold faster than previous estimates. The active isomer can be formed either by slow isomerization of the inactive molecule or by dissociation of a preformed peptide/MHC complex. In the absence of peptide, the active isomer is unstable, rapidly converting to the inactive isomer. These results demonstrate that fast peptide binding is an inherent property of one isomer of empty class II MHC. Dissociation of peptides such as CLIP yields this transient, peptide-receptive isomer.
Metabolic Imaging Predicts Response, Survival, and Recurrence in Adenocarcinomas of the Esophagogastric Junction
Authors: Katja Ott, Wolfgang A. Weber, Florian Lordick, Karen Becker, Raymonde Busch, Ken Herrmann, Hinrich Wieder, Ulrich Fink, Markus Schwaiger, Jörg-Rüdiger Siewert
Journal: Journal of Clinical Oncology (2006)

A previous study suggested that measurement of therapy-induced changes in tumor glucose metabolism by positron emission tomography (PET) with the glucose analog [18F]fluorodeoxyglucose (FDG) allows to select patients most likely to benefit from preoperative chemotherapy in adenocarcinomas of the esophagogastric junction (AEG). The aim of this study was to prospectively validate these findings by using an a priori definition of metabolic response.Sixty-five patients with locally advanced AEGs were included. Tumor glucose utilization was quantitatively assessed by FDG-PET before chemotherapy and 14 days after initiation of therapy. Patients were classified as metabolic responders when the metabolic activity of the primary tumor had decreased by more than 35% at the time of the second PET.Metabolic responders showed a high histopathologic response rate (44%) with a 3-year survival rate of 70%. In contrast, prognosis was poor for metabolic nonresponders with a histopathologic response rate of 5% (P = .001) and a 3-year survival rate of 35% (P = .01). A multivariate analysis (covariates: ypT-, ypN-category, histopathologic response) demonstrated that metabolic response was the only factor predicting recurrence (P = .018) in the subgroup of completely resected (R0) patients.This study prospectively demonstrates that changes in tumor metabolic activity during chemotherapy predict response, prognosis, and recurrence. These data provide the basis for clinical trials in which preoperative treatment is changed for patients without a metabolic response early in the course of therapy. PET-guided induction therapy may even be applicable to earlier tumor stages because surgery is only minimally delayed in nonresponding patients.
O1.06 * NOVEL MARKERS OF MENINGIOMA AGGRESSIVENESS - A STUDY OF MENINGIOMA VERSUS PERITUMORAL NERVOUS TISSUE
Authors: S. Mazzetti, C. Calatozzolo, M. Patane, M. Farinotti, R. Nunziata, S. Lodrini, P. Bianca
Journal: Neuro-Oncology (2014)

Meningiomas constitute approximately one-third of primary CNS tumors and classified by WHO in meningioma (grade I), with many histologic variants, atypical meningioma (grade II) and anaplastic meningioma (grade III). Most of them have a long survival, 1-3% are anaplastic with poor outcome and high recurrence rate and 15-20% of meningiomas are atypical with an intermediate and variable behavior. At present, only histologic grading is a reliable prognostic factor and we lack markers to identify among atypical meningiomas the most aggressive ones. For the first time in meningiomas, we propose to evaluate Lycopersicon esculentum lectin (LEA, specific for N-acetyl-D-glucosamine and N-acetyl-polylactosamine oligomers) and Aquaporin-4 (AQP4) as new factors involved in tumor invasion. LEA was chosen because it was localized in endothelial cell glycocalix in blood brain barrier (BBB) and it has been demonstrated that altered glycosilation of neoplastic cells induce vascular infiltration of cancer cells through endothelium. AQP4 is the most abundant water channel localized in the glial endfoots of the CNS and has been correlated with peritumoral oedema, that in meningioma can result as a marker of tumor invasion. The present study was performed in 20 grade I, 10 atypical and 5 anaplastic meningiomas in which a part of nervous tissue adjacent the meningioma was present on the surgical specimen. We observed a huge increase of AQP4 expression in the peritumoral nervous tissue in meningioma compared to normal nervous tissue. A thin staining in the leptomeninge and the muscolaris mucosae of the biggest vessels in tumor periphery was noticed, while tumor cells were always negative. Also in atypical meningioma AQP4 clearly define tumor boundaries. So, a minimum infiltration of nervous tissue, poorly identifiable with HE staining, could be simply visible using AQP4 staining. As for the anaplastic meningioma, which shows infiltration of nervous tissue, AQP4 has been localized also in astrocytes trapped into the tumor. In this aggressive meningioma, we found a strong LEA staining in tumor cells membrane, while grade I meningioma showed a less intense positivity. LEA expression was localized in meningothelial tumor cells and tumor vessels, as in the nervous tissue only in the endothelial cells. These observations show a role of AQP4 in peritumoral oedema and point to AQP4 as a useful marker to identify nervous tissue infiltration extension and thus meningioma aggressiveness. Moreover, LEA staining localized both in meningioma cell membranes and in the endothelial cells of the tumor vessels indicates that LEA-affinity oligomers could be implicated in adhesion and invasiveness of tumor cells. Both the glycosidic residues stained by LEA and AQP4 could be potential therapeutic targets.
Estrogen Regulation of Growth Hormone Action
Authors: Kin-Chuen Leung, Gudmundur Johannsson, Gary M. Leong, Ken K. Y. Ho
Journal: Endocrine Reviews (2004)

GH plays a pivotal role in regulating body growth and development, which is modulated by sex steroids. A close interplay between estrogen and GH leads to attainment of gender-specific body composition during puberty. The physiological basis of the interaction is not well understood. Most previous studies have focused on the effects of estrogen on GH secretion. There is also strong evidence that estrogen modulates GH action independent of secretion. Oral but not transdermal administration of estrogen impairs the metabolic action of GH in the liver, causing a fall in IGF-I production and fat oxidation. This results in a loss of lean tissue and a gain of body fat in postmenopausal women and an impairment of GH effect in hypopituitary women on GH replacement. The negative metabolic sequelae are potentially important because of the widespread use of oral estrogen and estrogen-related compounds. Estrogen affects GH action at the level of receptor expression and signaling. More recently, estrogen has been shown to inhibit Janus kinase/signal transducer and activator of transcription signaling by GH via the induction of suppressor of cytokine signaling-2, a protein inhibitor for cytokine signaling. This represents a novel paradigm of steroid regulation of cytokine receptors and is likely to have significance for a diverse range of cytokine function.
Probability of Carrying a Mutation of Breast-Ovarian Cancer Gene BRCA1 Based on Family History
Authors: D. A. Berry, G. Parmigiani, J. Sanchez, J. Schildkraut, E. Winer
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Heritable mutations of the breast cancer gene BRCA1 are rare, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovarian cancers. Nevertheless, the presence of such mutations is highly predictive of the development of these cancers. Purpose: We developed and applied a mathematic model for calculating the probability that a woman with a family history of breast and/or ovarian cancer carries a mutation of BRCA1. Methods and Results: As a basis for the model, we use Mendelian genetics and apply Bayes' theorem to information on the family history of these diseases. Of importance are the exact relationships of all family members, including both affected and unaffected members, and ages at diagnosis of the affected members and current ages of the unaffected members. We used available estimates of BRCA1 mutation frequencies in the general population and age-specific incidence rates of breast and ovarian cancers in carriers and noncarriers of mutations to estimate the probability that a particular member of the family carries a mutation. This probability is based on cancer statuses of all first- and second-degree relatives. We first describe the model by considering single individuals: a woman diagnosed with breast and/or ovarian cancer and also a woman free of cancer. We next considered two artificial and two actual family histories and addressed the sensitivity of our calculations to various assumptions. Particular relationships of family members with and without cancer can have a substantial impact on the probability of carrying a susceptibility gene. Ages at diagnosis of affected family members and their types of cancer are also important. A woman with two primary cancers can have a probability of carrying a mutation in excess of 80%, even with no other information about family history. The number and relationships of unaffected members, along with their current ages or ages at death, are critical determinants of one's carrier probability. An affected woman with several cancers in her family can have a probability of carrying a mutation that ranges from close to 100% to less than 5%. Conclusion: Our model gives informative and specific probabilities that a particular woman carries a mutation. Implications: This model focuses on mutations in BRCA1 and assumes that all other breast cancer is sporadic. With the cloning of BRCA2, we now know that this assumption is incorrect. We have adjusted the model to include BRCA2, but the use of this version must await publication of penetrance data for BRCA2, including those for male breast cancer that are apparently associated with BRCA2 but not with BRCA1. The current model is, nevertheless, appropriate and useful. Of principal importance is its potential and that of improved versions for aiding women and their health care providers in assessing the need for genetic testing.
Targeting Cancer Metabolism
Authors: Beverly A. Teicher, W. Marston Linehan, Lee J. Helman
Journal: Clinical Cancer Research (2012)

Abstract The understanding that oncogenes can have profound effects on cellular metabolism and the discovery of mutations and alterations in several metabolism-related enzymes—isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2)—has renewed interest in cancer metabolism and renewed hope of taking therapeutic advantage of cancer metabolism. Otto Warburg observed that aerobic glycolysis was a characteristic of cancer cells. More than 50 years later, we understand that aerobic glycolysis and uptake of glutamine and glycine allow cancer cells to produce energy (ATP) and the nucleotides, amino acids, and lipids required for proliferation. Expression of the MYC oncogene drives the increase in cellular biomass facilitating proliferation. PKM2 expression in cancer cells stimulates aerobic glycolysis. Among intermediary metabolism enzymes, mutations in SDH occur in gastointestinal stromal tumors and result in a pseudohypoxic metabolic milieu. FH mutations lead to a characteristic renal cell carcinoma. Isocitrate dehydrogenase (IDH1/2) mutations have been found in leukemias, gliomas, prostate cancer, colon cancer, thyroid cancer, and sarcomas. These recently recognized oncogenic metabolic lesions may be selective targets for new anticancer therapeutics. Clin Cancer Res; 18(20); 5537–45. ©2012 AACR.