tbuckley/cabot-search huggingface dataset:
Central Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese Adolescents
Authors: Ebe D'Adamo, Anna M.G. Cali, Ram Weiss, Nicola Santoro, Bridget Pierpont, Veronika Northrup, Sonia Caprio
Journal: Diabetes Care (2010)

We evaluated the role of fatty liver in the alteration of insulin sensitivity and beta-cell function in two groups of obese adolescents, differing in hepatic fat content (hepatic fat fraction [HFF]) but with similar intrabdominal intramyocellular lipid content (IMCL) and overall degree of obesity.We studied 23 obese adolescents with high HFF (HFF >5.5%) and 20 obese adolescents with low HFF (HFF <5.5%), matched for age, Tanner stage, BMI z score, and percentages of body fat, visceral fat, and IMCL. All subjects underwent an oral glucose tolerance test and a two-step hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and (1)H nuclear magnetic resonance to assess abdominal fat distribution, HFF, and IMCL, respectively.The high HFF group showed significantly lower whole-body insulin sensitivity index (P = 0.001) and estimates of insulin secretion (P = 0.03). The baseline hepatic glucose production (EGP) rate was not different between the two groups. Suppression of EGP was significantly lower (P = 0.04) in the high HFF group during low-dose insulin; no differences were observed during the second step. Baseline fatty acids, glycerol concentrations, and clamp suppression of glycerol turnover did not differ between the groups. During the second step, the glucose disposal rate was significantly lower (P = 0.01) in the high HFF group.Fatty liver, independent of visceral fat and IMCL, plays a central role in the insulin-resistant state in obese adolescents.
Erythromycin in renal failure.
Authors: M S Wheeley
Journal: BMJ (1977)

ceptives, usually condoms and spermicides, are provided with these free of charge.If we could avoid the need to use two forms of contraception at the same time this would result in a considerable saving of money to the NHS, but above all it would relieve couples from the nuisance and inconvenience of having to use mechanical contraceptives, which so many of them dislike.
Inhaled antibiotics in cystic fibrosis: what's new?
Authors: Simon Langton Hewer
Journal: Journal of the Royal Society of Medicine (2012)

Cystic Fibrosis is an autosomal recessive inheritable condition principally involving the lungs, pancreas, liver and intestines. Pulmonary involvement is characterized by airway inflammation and infection starting at an early age1,2 and is the primary cause of premature death.3 This paper will review the current situation in terms of prevalence of bacterial pathogens causing pulmonary infections and the strategies currently employed to treat these infections, focusing primarily on inhaled antibiotic therapy. This will be followed by a review of newly introduced inhaled antibiotics and of those in development.
Assessment of airway neutrophils by sputum colour: correlation with airways inflammation
Authors: R A Stockley
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Airway inflammation, with recruitment of neutrophils to the airway lumen, results in purulent secretions and a variety of potential adverse consequences for patients with chronic bronchitis and bronchiectasis. We hypothesised that gradations of sputum colour would correlate directly with the myeloperoxidase content of sputum and with various other indicators of the activity and consequences of bronchial diseases. <h3>METHODS</h3> To test this hypothesis, we quantified sputum colour by reference to a sensitive nine point colour chart and correlated this assessment with indices of a number of inflammatory mediators in sputum. <h3>RESULTS</h3> The results indicate that standardised visual measurements of sputum colour correlated strongly with myeloperoxidase, interleukin 8, leucocyte elastase (both activity and total quantity), sputum volume, protein leak, and secretory leucocyte proteinase inhibitor (p&lt;0.001 for all). In addition, there was a strong direct correlation between leucocyte elastase and both myeloperoxidase (p&lt;0.003) and sputum volume (p&lt;0.001), but a strong negative correlation with secretory leucocyte proteinase inhibitor (p&lt;0.001). <h3>CONCLUSIONS</h3> These results indicate that sputum colour graded visually relates to the activity of the underlying markers of bronchial inflammation. The results of this simple visual analysis of sputum provides guidance concerning underlying inflammation and its damaging potential. It also provides a useful scientific tool for improving the monitoring of chronic airways diseases and response to treatment.
Solitary congenital self-healing reticulohistiocytosis
Authors: E.F. BERNSTEIN, K.S. RESNIK, J.H. LOOSE, C. HALCIN, Y.C. KAUH
Journal: British Journal of Dermatology (1993)

Congenital self-healing reticulohistiocytosis (CSHR) was first described in 1973 by Hashimoto and Pritzker. Since then, both multiple and solitary forms have been described. We report a further case of solitary congenital self-healing reticulohistiocytosis. CSHR is a rare disorder which frequently presents a diagnostic dilemma in the newborn. Nodular forms of systemic Langerhans cell histiocytosis may present in a manner similar to CSHR. Because their differentiation on histopathological grounds is impossible, physical examination, laboratory investigations, and follow-up are necessary to ensure a lack of systemic involvement. Although previously thought to represent a rare variant of CSHR, solitary lesions of CSHR account for almost 25% of reported cases. A review of the literature relating to solitary CSHR, and a consideration of the differential diagnosis of a solitary congenital nodule, are also presented.
Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer
Authors: F. Maindrault-Gæbel, A. de Gramont, C. Louvet, T. André, E. Carola, V. Gilles, J.-P. Lotz, C. Tournigand, M. Mabro, J.-L. Molitor, P. Artru, V. Izrael, M. Krulik
Journal: Annals of Oncology (2000)
Evaluation for Surrogacy of End Points by Using Data from Observational Studies: Tumor Downstaging for Evaluating Neoadjuvant Chemotherapy in Invasive Bladder Cancer
Authors: Satoshi Teramukai, Hiroyuki Nishiyama, Yoshiyuki Matsui, Osamu Ogawa, Masanori Fukushima
Journal: Clinical Cancer Research (2006)

Abstract Purpose: In clinical cancer trials for evaluating neoadjuvant chemotherapy, tumor downstaging is frequently used as a surrogate end point for overall survival. We evaluated the surrogacy of tumor downstaging using data from a follow-up observational study in bladder cancer. Experimental Design: A total of 586 patients (from 32 Japanese hospitals) who underwent radical cystectomy for invasive bladder cancer (clinical T2 to T4) between 1990 and 2000 were analyzed. We considered changes over time in clinical stage at diagnosis and pathologic stage at cystectomy as a surrogate end point, and survival time after cystectomy as a true end point. First, we developed a new criterion for tumor downstaging. Second, we statistically evaluated surrogacy for the criterion using Prentice's criteria. Results: To develop the criterion of end points based on tumor downstaging, we selected the best classification among all possible classifications in an attempt to separate prognosis for patients. The hazard ratios after adjustment for prognostic factors in the intermediate effect patients and the poor effect patients were 1.9 (95% confidence interval, 1.0-3.7) and 5.0 (95% confidence interval, 2.6-9.8), respectively, compared with that in the good effect patients. The conditions for correlation and conditional independency of Prentice's criteria were satisfied approximately. Neoadjuvant chemotherapy has a statistically significant tumor downstaging effect, whereas there was no difference on survival between treatment groups. Conclusions: The tumor downstaging effect could be an appropriate intermediate end point for screening novel neoadjuvant chemotherapy for invasive bladder cancer. The dataset from follow-up studies were useful for evaluating the surrogacy of end points.
Association between MRI-detected knee joint regional effusion-synovitis and structural changes in older adults: a cohort study
Authors: Xia Wang, Leigh Blizzard, Andrew Halliday, Weiyu Han, Xingzhong Jin, Flavia Cicuttini, Graeme Jones, Changhai Ding
Journal: Annals of the Rheumatic Diseases (2014)

Objective To describe the cross-sectional and longitudinal associations between knee regional effusion-synovitis and structural changes in older adults. Methods A total of 977 subjects were randomly selected from the local community (mean 62 years, 50% female) at baseline and 404 were followed up 2.6 years later. T2-weighted MRI was used to assess knee effusion-synovitis in four subregions: suprapatellar pouch, central portion, posterior femoral recess and subpopliteal recess. Knee cartilage defects, cartilage volume and bone marrow lesions (BMLs) were measured using MRI at baseline and follow-up. Results Cross-sectionally, effusion-synovitis in most subregions was significantly associated with a higher risk of cartilage defects, BMLs and reduced cartilage volume. Longitudinally, suprapatellar pouch effusion-synovitis at baseline predicted an increase in cartilage defects (p&lt;0.01), loss of cartilage volume (p=0.04) and an increase in BMLs (p=0.02) in multivariable analyses. The significant associations of effusion-synovitis with cartilage volume and BMLs disappeared after adjustment for cartilage defects. Effusion-synovitis in whole knee joint (p&lt;0.01) and subpopliteal recess (p&lt;0.05) was consistently associated with longitudinal changes in cartilage defects but not in cartilage volume and BMLs. Conclusions There are independent associations between knee joint effusion-synovitis and knee cartilage defects in both cross-sectional and longitudinal analyses, suggesting a potential causal relationship. The associations of effusion-synovitis with BMLs and cartilage volume were largely dependent on cartilage defects, suggesting potential causal pathways.
Antibodies against CD14 protect primates from endotoxin-induced shock.
Authors: D J Leturcq, A M Moriarty, G Talbott, R K Winn, T R Martin, R J Ulevitch
Journal: Journal of Clinical Investigation (1996)

Lipopolysaccharide (LPS), residing in the outer membrane of all gram-negative bacteria, is considered a major initiating factor of the gram-negative septic shock syndrome in humans. LPS forms a complex with the LPS binding protein (LBP) in plasma, and LPS-LBP complexes engage a specific receptor, CD14, on the surface of myeloid cells, leading to the production of potent proinflammatory cytokines. The major goal of this study was to test the importance of the CD14 pathway in vivo in a primate model that is similar to human septic shock. Primates were pretreated with one of two different inhibitory anti-CD14 mAbs, then challenged with intravenous endotoxin (375 microg/kg/h) for 8 h. The anti-CD14 treatment regimens were successful in preventing profound hypotension, reducing plasma cytokine levels (TNF-alpha, IL-1beta, IL-6, and IL-8), and inhibiting the alteration in lung epithelial permeability that occurred in animals treated with LPS and an isotype-matched control antibody. These results demonstrate for the first time the importance of the CD14 pathway in a primate model that is similar to human septic shock. Inhibition of the CD14 pathway represents a novel therapeutic approach to treating this life-threatening condition.
Targeted and regulable expression of transgenes in hepatic stellate cells and myofibroblasts in culture and in vivo using an adenoviral Cre/loxP system to antagonise hepatic fibrosis
Authors: K. Kinoshita, Y. Iimuro, J. Fujimoto, Y. Inagaki, K. Namikawa, H. Kiyama, Y. Nakajima, K. Otogawa, N. Kawada, S. L Friedman, K. Ikeda
Journal: Gut (2006)

<b>Background:</b> Activated hepatic stellate cells (HSCs) are an attractive target for antifibrotic therapy based on their key role in extracellular matrix accumulation during liver injury. <b>Aim:</b> : To develop a system for regulable and cell-specific gene expression in HSCs to enable targeted delivery of therapeutic genes. <b>Method:</b> Two types of recombinant adenoviral vectors were constructed, one expressing the Cre gene under the surveillance of specific promoters and the other containing a potent expression unit that was activated by Cre recombinase-mediated recombination to remove an upstream lox-flanked "stuffer" sequence, thereby amplifying the expression of downstream transgene of interest while maintaining specificity. <b>Results:</b> When the promoter of the collagen 1A2 gene drove Cre recombinase expression in primary quiescent rat HSC, modest green fluorescence protein (GFP) expression was observed. However, in activated HSC, the collagen promoter effectively drove Cre recombinase activity, as assessed by the increased expression of GFP. In contrast, GFP expression was barely observed when the collagen promoter was expressed in hepatocytes. HSC-specific expression of Smad7 considerably reduced the expression of type I collagen in culture and decreased fibrosis in two liver fibrosis models. Finally, to achieve targeted clearance of activated HSC in culture and in vivo, thymidine kinase was selectively expressed under the control of the collagen promoter, which conferred cell-specific killing by ganciclovir leading to reduced fibrosis. <b>Conclusion:</b> Our results show the potential utility of transcriptionally controlled gene therapy using a Cre/loxP system to ameliorate hepatic fibrosis in vivo.
Endpoints for the Evaluation of Breast Cancer Treatments
Authors: J. Cuzick
Journal: JNCI Journal of the National Cancer Institute (2014)

In this issue of the Journal, Moossdorff et al. ( 1), report on a systematic approach for reaching a consensus about the definition of endpoints for breast cancer patients.The goals were very focussed and limited, but still this is an important contribution to the standardization of reporting of study outcomes.It was based on a multiround process, consisting of two rounds of questionnaires followed by a face-to-face meeting involving 24 experts in the field.Being based on opinion rather than data, there is no certainty that the correct answers were obtained.However, this is less important for this question, where standardization is the key outcome, than for treatment or biomarker questions, which must be evidence-and not opinion-based.The focus was primarily on reproducible objective categories rather than biologic entities.Thus, the categories considered for classification of a recurrence were local, regional, contralateral, and distant.One of the most interesting areas was in the classification of local recurrence.No attempt was made to separate true recurrence from a new ipsilateral primary cancer, and recurrent ductal carcinoma in situ (DCIS) was not treated separately from recurrent invasive disease.While the simplicity and reproducibility of this approach is commendable, there are situations in which it is probably not adequate.One of these is the management of DCIS, where 'recurrent' DCIS alone is often considered to reflect incomplete excision of the primary tumor, whereas recurrent invasive disease is a strong indicator of a progressive lesion.This distinction seems important to retain in this situation, as the biology is quite different.Additionally, one recent trial of intraoperative radiotherapy (2) attempted to distinguish within quadrant recurrence as a treatment failure and a local recurrence in other quadrants as new disease.For such localized treatments, including surgical ones, this may be valuable to distinguish, but it may be very hard to standardize more generally.Another interesting consensus was that a contralateral within breast tumor should be considered as a new tumor, but disease found only in the contralateral lymph nodes should be considered a metastasis.If disease was found in both the contralateral breast and lymph nodes, this was still considered a new tumor.The paper was silent about the case when disease is found in the contralateral breast and a distant site, although the common current practice (3) is to only consider isolated disease in the contralateral breast (and lymph nodes) without other affected sites as a new primary tumor.This is particularly important for assessing the potential value of an adjuvant treatment as a preventive agent, as with tamoxifen and the aromatase inhibitors where the first evidence that these drugs might have a preventive role came from the analysis of contralateral tumors in adjuvant trials (3,4).
Combined Vemurafenib and Cobimetinib in <i>BRAF</i>-Mutated Melanoma
Authors: James Larkin, Paolo A Ascierto, Brigitte Dréno, Victoria Atkinson, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stroyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Caroline Dutriaux, Claus Garbe, Mika A Sovak, Ilsung Chang, Nicholas Choong, Stephen P Hack, Grant A McArthur, Antoni Ribas
Journal: New England Journal of Medicine (2014)

The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).
Re: Designing a Randomized Clinical Trial to Evaluate Personalized Medicine: A New Approach Based on Risk Prediction
Authors: R. M. Simon, B. Freidlin
Journal: JNCI Journal of the National Cancer Institute (2011)

Baker and Sargent (1) proposed using data from patients in the control arm of a randomized clinical trial (RCT) to develop a prognostic score using patient outcome and covariate information and then to compare the new treatment to control arms in subgroups of patients defined by ranges of that score. We believe that the proposed design and analysis plan are generally not valid. Baker and Sargent (1) stated that “It may appear as though the control arm is used for both model fitting and treatment evalua tion, a procedure that could lead to bias. However, this is not the case because the control arm provides no information on the effect of treatment.” Unfortunately, this is incorrect. For example, selecting a subgroup with the highest observed risk will tend to identify a subset of the control arm patients with poor observed outcome at least in part because of random outcome
A Matter of Life or Death (or Both): Understanding Autophagy in Cancer
Authors: William N. Hait, Shengkan Jin, Jin-Ming Yang
Journal: Clinical Cancer Research (2006)

### Definition

Autophagy is a conserved response to nutrient deprivation found in yeast, plants, worms, flies, mice, and man ([1][1]). In yeast, nutrient deprivation activates a genetic program that results in ( a ) self-digestion of cytoplasm and organelles and the recycling of amino acids and
Sequential maturation stages of monoclonal B lineage cells from blood, spleen, lymph node, and bone marrow from a terminal myeloma patient
Authors: Gitte S. Jensen, Michael J. Mant, Linda M. Pilarski
Journal: American Journal of Hematology (1992)

Abstract In order to fully understand the complexity of the monoclonal B lineage cells in multiple myeloma, it is necessary to evaluate the extent to which these cells are resident in solid lymphoid tissues and the phenotypic differences and similarities as compared to the circulating or bone marrow derived B lineage cells. Peripheral blood mononuclear cells from a patient with multiple myeloma were obtained 8 and 3 days prior to death, and mononuclear cells from lymph nodes, spleen, and bone marrow were obtained at autopsy. Rapid changes in the stage of differentiation of blood late‐stage B lineage cells towards mature end‐stage plasma cells were observed during the last week prior to death. Lymphoid cells within the blood comprised very few T cells, sub‐normal numbers of monocytes, and 80% of B lineage cells which were at a late stage of differentiation. Shortly before death, plasma cells were found in the peripheral blood, indicating progression to plasma cell leukemia. At autopsy, the monoclonal B lineage cells in lymph node, spleen, and bone marrow represented different stages of terminal B cell differentiation. In each tissue, the B lineage cells were at an earlier differentiation stage, as defined phenotypically, than the circulating B lineage cells found in blood 3 days prior to death. Analysis of B cell markers and CD45 was used to define the differentiation stage of the relevant B cell populations, revealing a series of differentiation stages. The least mature B lineage cells (CD45 hi ) were found in lymph node. However, the CD45 isoform expressed was CD45R0, unlike most normal lymph node B cells. More differentiated B lineage cells (CD45 mod ) were found in the bone marrow, and three sequential stages of pre‐plasma cells were found in the spleen (CD45 bright , CD45 moderate and CD45 low‐neg ), all of which were CD45R0 + . The B cells in normal spleen and bone marrow are CD45RA. The presence of monoclonal B lineage cells in spleen was confirmed by Southern blotting. The B lineage cells from peripheral blood 3 days prior to death were approaching an end‐stage plasma cell stage (CD45 low/ ). On B lineage cells from the various myeloma tissues, a concomitant loss of CD11b and increasing density of CD29 were observed as a function of progression to terminally differentiated stages. © 1992 Wiley‐Liss, Inc.