tbuckley/cabot-search huggingface dataset:
Phase III Study of Immediate Compared With Delayed Docetaxel After Front-Line Therapy With Gemcitabine Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer
Authors: Panos M. Fidias, Shaker R. Dakhil, Alan P. Lyss, David M. Loesch, David M. Waterhouse, Jane L. Bromund, Ruqin Chen, Maria Hristova-Kazmierski, Joseph Treat, Coleman K. Obasaju, Martin Marciniak, John Gill, Joan H. Schiller
Journal: Journal of Clinical Oncology (2008)

Purpose Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non–small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression. Patients and Methods The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m 2 ) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m 2 on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL). Results Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups. Conclusion We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.
Adoptive Immunotherapy Following Allogeneic Bone Marrow Transplantation
Authors: Francesco Dazzi, John M. Goldman
Journal: Annual Review of Medicine (1998)

Some of the recent advances in our knowledge of immune recognition have provided new tools to circumvent or reverse some of the major disadvantages of allogeneic bone marrow transplantation (BMT). The pretransplant conditioning regimen produces a major defect in the immune system that greatly favors the occurrence of life-threatening infections, caused particularly by Epstein-Barr virus and cytomegalovirus. However, adoptive transfer of virus-specific cytotoxic T lymphocytes can reconstitute specific immunity and/or cure viral disease in immunocompromised post-BMT patients. The other major drawback of allogeneic BMT is graft-versus-host disease (GVHD). Although potentially detrimental, it is closely associated with an antileukemia reaction (graft-versus- leukemia, GVL). The most direct evidence of the GVL effect has been provided by the efficacy of donor leukocyte infusions (DLI). DLI can induce long-lasting remissions, especially in patients with chronic myeloid leukemia who relapse post-BMT. Although allogeneic cell therapy should still be considered a “naive” form of immunotherapy, work in progress on the identification of leukemia-specific antigens will improve the outcome and enlarge its applications.
PMO-223 Tattooing of suspicious colonic lesions at colonoscopy: is adherence to local protocol better if identified through the Bowel Cancer Screening Programme?
Authors: H Travers, T Shirazi, S Mansfield
Journal: Gut (2012)

<h3>Introduction</h3> The Joint Advisory Group on gastrointestinal endoscopy and the National Bowel Cancer Screening Programme (BCSP) have published guidelines on the tattooing of malignant and suspicious lesions at colonoscopy. Our endoscopy department has a local protocol for the tattooing of these lesions based on these guidelines. The BCSP has led to an increase in the number of colonoscopies performed and the number of lesions identified. <h3>Aim</h3> To assess adherence to a local protocol in a single endoscopy unit and identify if lesions identified through the BCSP are more likely to be tattooed than lesions identified for other reasons. <h3>Methods</h3> A retrospective review of a prospectively maintained database was performed. All colonoscopies performed between 1 April 2010 and 31 March 2011 were reviewed and screening cases identified. <h3>Results</h3> 4023 colonoscopies were performed, 307 (8%) as part of the BCSP. Malignancy or polyps were identified in 192 (63%) of BSCP colonoscopies compared to 26% (958/3716) of non-BCSP colonoscopies. Significantly more polyps and malignancies were identified during BCSP colonoscopies than non-BCSP colonoscopies (p&lt;0.0001 χ<sup>2</sup> test). Our local protocol states that any malignant/suspicious/&gt;1 cm lesion distal to the right colon should be marked by placing three tattoos just distal to the lesion. 94 (49%) lesions were identified during BCSP colonoscopies that met these criteria. Of these 54 (57%) were tattooed, and 20 (21 %) were tattooed by the method advised. This compared to 262 non-BCSP lesions identified that should have been tattooed of which 77 (29%) were tattooed and 20 (8%) were tattooed by the method advised. Tattooing rate was significantly higher in BCSP detected lesions (54/94 compared with 77/262, p≤0.0001, χ<sup>2</sup> test). <h3>Conclusion</h3> Tattooing practice in our endoscopy unit is poor despite the presence of a local protocol. However, tattooing practice is significantly better in lesions identified through the BCSP. Reasons for this may include the higher yield of lesions in screening colonoscopies or lack of awareness of the protocol. We aim to improve adherence by increasing awareness among all endoscopy staff to ensure optimum management of malignant and suspicious lesions. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Chilton A,</b> Rutter M, <i>et al.</i> Quality assurance guidelines for colonoscopy. <i>NHS BCSP Publication 6</i>. 2010. 2. <b>BSG Quality and Safety indicators for Endoscopy, Joint Advisory Group on GI Endoscopy</b>. 2007. http://www.thejag.org.uk/downloads%5CUnit%20Resources%5CBSG%20Quality%20and%20Safety%20Indicators.pdf
Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
Authors: Haiyan Xu, Glenn T. Barnes, Qing Yang, Guo Tan, Daseng Yang, Chieh J. Chou, Jason Sole, Andrew Nichols, Jeffrey S. Ross, Louis A. Tartaglia, Hong Chen
Journal: Journal of Clinical Investigation (2003)

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.
Increased production of the TrkB protein tyrosine kinase receptor after brain insults
Authors: Jean-Philippe Merlio, Patrik Ernfors, Zaal Kokaia, David S. Middlemas, Johan Bengzon, Merab Kokaia, Maj-Lis Smith, Bo K. Siesjö, Tony Hunter, Olle Lindvall, Håkan Persson
Journal: Neuron (1993)
Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study
Authors: Judith M. Bliss, Lucy S. Kilburn, Robert E. Coleman, John F. Forbes, Alan S. Coates, Stephen E. Jones, Jacek Jassem, Thierry Delozier, Jørn Andersen, Robert Paridaens, Cornelis J.H. van de Velde, Per E. Lønning, James Morden, Justine Reise, Laura Cisar, Thomas Menschik, R. Charles Coombes
Journal: Journal of Clinical Oncology (2011)

Purpose Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non–breast cancer–related events have been reported. Exploratory analyses describe breast cancer–free survival (BCFS) and explore incidence and patterns of the different competing events. Patients and Methods Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) –positive and 547 with ER-unknown tumors. Results In all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P &lt; .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115). Conclusion The protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.
B cell progenitors have different growth requirements before and after immunoglobulin heavy chain commitment.
Authors: H Sauter, C J Paige
Journal: The Journal of Experimental Medicine (1988)

Using the clonable pre-B cell assay, we have identified B cell progenitors that are not yet committed to the production of a particular H chain allele. These cells represent approximately 10-20% of clonable pre-B cells found in 15-d fetal liver. The clonable pre-B cell assay provides an environment adequate for the expansion and differentiation of these cells into mature, Ig-secreting, cells. Using the same methodology, we have also identified progenitors that are uncommitted to the production of a particular L chain isotype. Moreover, investigating the growth requirements for clonable pre-B cells has led to the discovery of selective growth conditions that distinguish cells before and after commitment to H chain allotype.
MAPK Superfamily Plays an Important Role in Daunomycin-Induced Apoptosis of Cardiac Myocytes
Authors: Weidong Zhu, Yunzeng Zou, Ryuichi Aikawa, Koichiro Harada, Sumiyo Kudoh, Hiroki Uozumi, Doubun Hayashi, Yaping Gu, Tsutomu Yamazaki, Ryozo Nagai, Yoshio Yazaki, Issei Komuro
Journal: Circulation (1999)

Background —Although anthracyclines, such as daunomycin (DM) and adriamycin, are potent chemotherapeutic agents, they have serious adverse effects, including cardiac toxicity. In the present study, we investigated the molecular mechanisms of DM-induced cardiomyocyte impairment. Methods and Results —When cultured cardiac myocytes of neonatal rats were exposed to 1 μmol/L DM for 24 hours, many cells became positive for TUNEL staining, with morphological changes characteristic of apoptosis. Fragmentation of DNA into oligonucleosome-size fragments was recognized by agarose gel electrophoresis in DM-treated myocytes. DM activated 3 members of the mitogen-activated protein kinase (MAPK) family dose-dependently, such as extracellular signal-regulated protein kinases (ERKs), c-Jun NH 2 -terminal kinases, and p38 MAPK in cardiac myocytes. Oxyradical scavengers or Ca 2+ chelators inhibited DM-induced activation of ERKs and p38 MAPK. DM-induced activation of ERKs was also inhibited by overexpression of dominant negative mutants of Ras (D.N.Ras), and the p38 MAPK activation was attenuated by D.N.Rho. The number of DM-induced apoptotic cells was markedly increased when the ERK signaling pathway was selectively blocked by a specific MAPK/ERK kinase inhibitor, PD98059, whereas pretreatment with a specific inhibitor of p38 MAPK, SB203580, significantly reduced the amount of apoptosis. Conclusions —These results suggest that DM activates MAPKs through reactive oxygen species and Ca 2+ and that the MAPK family plays important roles in DM-induced apoptosis in cardiac myocytes. ERKs protect cardiomyocytes from apoptosis, whereas p38 MAPK is involved in the induction of cardiomyocyte apoptosis.
Angiotensin II Induces Neutrophil Accumulation In Vivo Through Generation and Release of CXC Chemokines
Authors: Yafa Naim Abu Nabah, Teresa Mateo, Rossana Estellés, Manuel Mata, John Zagorski, Henry Sarau, Julio Cortijo, Esteban J. Morcillo, Peter J. Jose, Maria-Jesus Sanz
Journal: Circulation (2004)

Angiotensin II (Ang II) is implicated in the development of cardiac ischemic disorders in which prominent neutrophil accumulation occurs. Ang II can be generated intravascularly by the renin-angiotensin system or extravascularly by mast cell chymase. In this study, we characterized the ability of Ang II to induce neutrophil accumulation.Intraperitoneal administration of Ang II (1 nmol/L) induced significant neutrophil recruitment within 4 hours (13.3+/-2.3x10(6) neutrophils per rat versus 0.7+/-0.5x10(6) in control animals), which disappeared by 24 hours. Maximal levels of CXC chemokines were detected 1 hour after Ang II injection (577+/-224 pmol/L cytokine-inducible neutrophil chemoattractant [CINC]/keratinocyte-derived chemokine [KC] versus 5+/-3, and 281+/-120 pmol/L macrophage inflammatory protein [MIP-2] versus 14+/-6). Intravital microscopy within the rat mesenteric microcirculation showed that the short-term (30 to 60 minutes) leukocyte-endothelial cell interactions induced by Ang II were attenuated by an anti-rat CINC/KC antibody and nearly abolished by the CXCR2 antagonist SB-517785-M. In human umbilical vein endothelial cells (HUVECs) or human pulmonary artery media in culture, Ang II induced interleukin (IL)-8 mRNA expression at 1, 4, and 24 hours and the release of IL-8 at 4 hours through interaction with Ang II type 1 receptors. When HUVECs were pretreated with IL-1 for 24 hours to promote IL-8 storage in Weibel-Palade bodies, the Ang II-induced IL-8 release was more rapid and of greater magnitude.Ang II provokes rapid neutrophil recruitment, mediated through the release of CXC chemokines such as CINC/KC and MIP-2 in rats and IL-8 in humans, and may contribute to the infiltration of neutrophils observed in acute myocardial infarction.
Functional and biochemical characterization of a secreted I-J(+) suppressor factor that binds to immunoglobulin.
Authors: M J Daley, M Nakamura, M L Gefter
Journal: The Journal of Experimental Medicine (1986)

A secreted product of a T cell leukemic cell line, LH-8, was examined for its biochemical and biological properties. The factor that we have termed Immunoglobulin-Binding T cell Suppressor Factor (IgB-TsF) was shown to be suppressive for the in vitro and in vivo humoral response to a variety (but not all) antigens tested. The cell surface phenotype of the LH-8.1 subclone was M.Ig(-), Thy-1(+), L3T4(-), Lyt-2(+), FcR(-), MAC-1(-), and H-2b(+). In addition, both the cell surface and secreted factor, IgB-TsF, of LH-8.1 expressed determinants that were recognized by anti-I-Jb mAbs but not by an anti-I-Jd monoclonal. The same factor also retained an affinity for the Fc portion of approximately 30% of randomly selected, purified mAbs. This binding could be abolished if the Fab or F(ab')2 fragments of these mAb were used, but was found to be unrelated to isotype of the respective mAbs. Using subclones that expressed quantitative differences in their ability to exert suppression as sources of biosynthetically labeled IgB-TsF, we have shown the suppressor activity correlated with a single, 28 kD protein. Furthermore, comparisons of these same subclones that differ in their suppressor activity, do not show any direct correlation of this biological activity with the expression of the previously described T cell receptor genes. It also suggests that at least some suppressor cell subsets may use the same or related family of T cell receptor genes for their recognitive stage of activation as helper and cytotoxic T cell subsets, but not for their effector stage of immunologic suppression.
Sex Differences in Developmental Reading Disability
Authors: Michael Rutter, Avshalom Caspi, David Fergusson, L. John Horwood, Robert Goodman, Barbara Maughan, Terrie E. Moffitt, Howard Meltzer, Julia Carroll
Journal: JAMA (2004)

An influential article published in 1990 claimed that the increased rate of reading disability in boys was a consequence of referral bias.To summarize the history of research on sex differences in reading disability and to provide new evidence from 4 independent epidemiological studies about the nature, extent, and significance of sex differences in reading disability.The Dunedin Multidisciplinary Health and Development Study comprised 989 individuals (52.1% male) in a cohort born between April 1972 and March 1973 in Dunedin, New Zealand, and followed up from age 3 years; reading performance and IQ were assessed at ages 7, 9, and 11 years using the Burt Word Reading Test and the Wechsler Intelligence Scale for Children-Revised (WISC-R), respectively. The Christchurch Health and Development Study comprised 895 individuals (50% male) in a prospectively studied cohort born in the Christchurch, New Zealand, region during a 4-month period in 1977; reading performance and IQ were assessed at ages 8 to 10 years using the Burt Word Reading Test and the WISC-R. The Office for National Statistics (ONS) Study comprised a UK nationally representative sample of 5752 children (50.1% male) aged 9 to 15 years in 1999; reading was assessed on the British Ability Scales II and IQ on the British Picture Vocabulary Scales II. The Environmental Risk Longitudinal Twin Study (E-Risk) comprised 2163 twin children from England and Wales (49.1% male) identified at birth in 1994 and 1995 and included administration of the Test of Word Reading Efficiency at age 7 years and the Wechsler Preschool and Primary Scale of Intelligence-Revised as a test of IQ at age 5 years.Reading performance by sex in the lowest 15% of the distribution for all 4 studies, with and without taking IQ into account.In all 4 studies, the rates of reading disability were significantly higher in boys. For non-IQ-referenced reading disability: Dunedin study, 21.6% in boys vs 7.9% in girls (odds ratio [OR], 3.19; 95% confidence interval [CI], 2.15-4.17); Christchurch study, 20.6% in boys vs 9.8% in girls (OR, 2.38; 95% CI, 1.62-3.50); ONS study, 17.6% in boys vs 13.0% in girls (OR, 1.43; 95% CI, 1.23-1.65); and E-Risk, 18.0% in boys vs 13.0% in girls (OR, 1.39; 95% CI, 1.04-1.86). The rates for IQ-referenced reading disabilities were similar.Reading disabilities are clearly more frequent in boys than in girls.
Basolateral Translocation by Vasopressin of the Aldosterone-Induced Pool of Latent Na-K-ATPases Is Accompanied by α1 Subunit Dephosphorylation
Authors: SABRI DJELIDI, AHMED BEGGAH, NATHALIE COURTOIS-COUTRY, MICHEL FAY, FRANCOISE CLUZEAUD, SAY VIENGCHAREUN, JEAN-PIERRE BONVALET, NICOLETTE FARMAN, MARCEL BLOT-CHABAUD
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The regulation of plasma membrane Na+-K+-ATPases (NKA) expression by aldosterone and arginin vasopressin (AVP) in the cortical collecting duct (CCD) has been examined in a new rat CCD cell line, designated as RCCD2. This cell line has maintained many characteristics of the CCD—in particular, the expression of the mineralocorticoid receptor. Mineralocorticoid receptor is expressed at the protein level and binds 3H-aldosterone (approximately 15 to 20 fmol/mg protein). Short-circuit current (Isc) experiments showed approximately a twofold increase in Isc associated with a decrease in transepithelial resistance when cells were treated with aldosterone concentrations as low as 10-9 M. This effect on Isc was significant 2 h after aldosterone addition and was still present after 24 h. It was accompanied by an increase in the amount of mRNA encoding for the α subunit of the epithelial sodium channel (sixfold) and the α1 subunit of NKA (fourfold) after 24 h of hormone treatment. In addition, mRNA expression of the serum- and glucocorticoid-induced kinase (Sgk) was increased by 10-9 M aldosterone treatment as early as 45 min after hormone addition. As had already been documented in native CCD obtained by microdissection, incubation of RCCD2 cells for 24 h with aldosterone resulted in the constitution of a latent pool of NKA that could be rapidly recruited by AVP (15 min). NKA biotinylation experiments and preparation of membrane fractions show that this latent pool of NKA is present in the intracellular compartment of the cells and is recruited by AVP in the basolateral membrane through a translocation process. This mechanism is accompanied by dephosphorylation of the α1 catalytic subunit of NKA.