tbuckley/cabot-search huggingface dataset:
Enhanced Intracellular Dissociation of Major Histocompatibility Complex Class I–associated Peptides: A Mechanism for Optimizing the Spectrum of Cell Surface–Presented Cytotoxic T Lymphocyte Epitopes
Authors: Alice J.A.M. Sijts, Eric G. Pamer
Journal: The Journal of Experimental Medicine (1997)

Association of antigenic peptides with newly synthesized major histocompatibility complex (MHC) class I molecules occurs in the endoplasmic reticulum and is a critical early step for the initiation of cytotoxic T lymphocyte (CTL)-mediated immune defenses. Pathogen-derived peptides compete with a plethora of endogenous peptides for MHC class I grooves. We find that two H2-Kd–restricted peptides, which derive from the Listeria monocytogenes p60 antigen, accumulate in infected cells with different kinetics. Although competition assays suggest that both epitopes are bound with equivalent affinity, they dissociate from MHC class I molecules at markedly different rates. p60 217-225 forms complexes with H2-Kd with a half-life &amp;gt;6 h, while p60 449-457 dissociates from H2-Kd with a half-life of ∼1 h. We find that p60 449-457–H2-Kd complexes retained intracellularly with brefeldin A have a half-life of 30 min, and thus are less stable than surface complexes. While peptide dissociation from retained MHC class I molecules is enhanced, retained H2-Kd molecules maintain a remarkable capacity to bind new T cell epitopes. We find that intracellular H2-Kd molecules can bind new CTL epitopes for up to 3 h after their synthesis. Our studies provide a glimpse of peptide interaction with MHC class I molecules in the endoplasmic reticulum/proximal Golgi complex of intact, infected cells. We propose that the increased intracellular lability of peptide–MHC class I complexes may function to optimize the spectrum of peptides presented to T lymphocytes during cellular infection.
Extended Adjuvant Therapy With Anastrozole Among Postmenopausal Breast Cancer Patients: Results From the Randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a
Authors: R. Jakesz, R. Greil, M. Gnant, M. Schmid, W. Kwasny, E. Kubista, B. Mlineritsch, C. Tausch, M. Stierer, F. Hofbauer, K. Renner, C. Dadak, E. Rucklinger, H. Samonigg
Journal: JNCI Journal of the National Cancer Institute (2007)

Clinical trial data have shown that among breast cancer patients who were disease free after 5 years of adjuvant treatment with tamoxifen, further extended treatment with the nonsteroidal aromatase inhibitor letrozole reduces breast cancer recurrence. We examined the efficacy and tolerability of extended adjuvant therapy with another aromatase inhibitor, anastrozole, for 3 years among women who had completed 5 years of adjuvant therapy. Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a is an extension of ABCSG Trial 6, in which hormone receptor–positive postmenopausal patients received 5 years of adjuvant tamoxifen, with or without the aromatase inhibitor aminoglutethimide, for the first 2 years of therapy. For ABCSG Trial 6a, patients who were disease free at the end of Trial 6 were randomly assigned to receive either 3 years of anastrozole or no further treatment. Efficacy data were analyzed with the use of a Cox proportional hazards regression model with two-sided P values and Kaplan–Meier curves, and tolerability data were estimated using logistic regression analysis with odds ratios and 95% confidence intervals (CIs). ABCSG Trial 6a included 856 patients. At a median follow-up of 62.3 months, women who received anastrozole (n = 387) had a statistically significantly reduced risk of recurrence (locoregional recurrence, contralateral breast cancer, or distant metastasis) compared with women who received no further treatment (n = 469; hazard ratio = 0.62; 95% CI = 0.40 to 0.96, P = .031). Anastrozole was well tolerated, and no unexpected adverse events were reported. These data confirm the benefit of extending adjuvant tamoxifen therapy beyond 5 years with anastrozole compared with no further treatment. Further research is required to define the optimum length of extended adjuvant therapy and to investigate the possibility of tailoring this period to suit different disease types.
β-Cell Function in Mild Type 2 Diabetic Patients
Authors: Andrea Mari, Amalia Gastaldelli, James E. Foley, Richard E. Pratley, Ele Ferrannini
Journal: Diabetes Care (2005)

OBJECTIVE—We studied the effects of the oral insulin secretagogue nateglinide on insulin secretion using a modeling approach to obtain β-cell function parameters from a meal test and examined the impact of the β-cell improvement on glucose tolerance. RESEARCH DESIGN AND METHODS—Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0–8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks. β-Cell function parameters were derived by modeling (based on C-peptide deconvolution) from a standardized meal test at baseline and after 24 weeks of treatment. RESULTS—The baseline demographic and metabolic characteristics of the four groups were similar. Nateglinide treatment resulted in dose-dependent reductions in the mean postprandial glucose response and at the 120-mg dose in fasting glucose. Fasting or total insulin secretion during the meal were not different. In contrast, we found differences in the model parameters. Rate sensitivity (expressing early insulin secretion when glucose is rising) was significantly enhanced at 24 weeks with the lowest nateglinide dose, with no further stimulation at higher doses. Early potentiation (expressing an initial insulin secretion enhancement), glucose sensitivity (the slope of the glucose–insulin secretion relationship), and insulin secretion at a fixed- reference 7-mmol/l glucose concentration all showed a trend toward increasing, with increasing nateglinide dose, and were significantly greater than placebo at the 120-mg dose. In multiple regression analyses, changes in rate sensitivity, glucose sensitivity, and potentiation all contributed to the observed glucose changes. CONCLUSIONS—The model-derived parameters are sensitive measures of β-cell function, showing improvements after nateglinide treatment and predicting changes in glucose tolerance.
Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts
Authors: Kan Cao, Cecilia D. Blair, Dina A. Faddah, Julia E. Kieckhaefer, Michelle Olive, Michael R. Erdos, Elizabeth G. Nabel, Francis S. Collins
Journal: Journal of Clinical Investigation (2011)

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.
Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial
Authors: C Antoni, G G Krueger, K de Vlam, C Birbara, A Beutler, C Guzzo, B Zhou, L T Dooley, A Kavanaugh
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objectives:</b> To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. <b>Methods:</b> 200 patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. <b>Results:</b> At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p&lt;0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p&lt;0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% <i>v</i> 30%; p = 0.025) and week 24 (12% <i>v</i> 34%; p&lt;0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. <b>Conclusions:</b> Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.
Ex vivo pediatric brain tumors express Fas (CD95) and FasL (CD95L) and are resistant to apoptosis induction
Authors: Christopher D. Riffkin, Amy Z. Gray, Christine J. Hawkins, C.W. Chow, David M. Ashley
Journal: Neuro-Oncology (2001)

Neuro-Oncology n O C T O B E R 2 0 0 1 229 Fas (APO-1/CD95/TNFRSF6) is a member of the tumor necrosis/nerve growth factor receptor family that signals apoptotic cell death in sensitive cells.Expression of Fas and its agonistic ligand (FasL/TNFSF6) was investigated in ex vivo pediatric brain tumor specimens of various histologic types.Fas expression was identi ed in all of the 18 tumors analyzed by ow cytometry and immunohistochemistry. FasL expression was identi ed in most of the 13 tumors analyzed by both Western analysis and immunohistochemistry. Nine of these tumor specimens were treated with either the agonistic anti-Fas antibody (APO-1) in combination with protein A or FasL in shortterm cytotoxicity assays.Sensitivity to apoptosis induced by the topoisomerase II inhibitor, etoposide, was also assessed.Despite the presence of Fas, all the specimens analyzed demonstrated a high degree of resistance to Fasmediated apoptosis.These 9 specimens also showed a high degree of resistance to etoposide.Only 2 of the 9 specimens were susceptible to etoposide-induced cell death, whereas only 3 were sensitive to Fas-mediated apoptosis.One brain tumor was sensitive to both Fas ligation and etoposide treatment.This contrasted with the high degree of susceptibility to both etoposide-and Fas-induced apoptosis observed in the reference Jurkat cell line.The results suggest that Fas expression may be a general feature of tumors of the CNS and that a signi cant degree of resistance to Fas-mediated apoptosis may exist in ex vivo pediatric brain tumor specimens.
VEGF Expression in Hypoxia and Hyperglycemia
Authors: Byung-Soo Kim, Jun Chen, Talia Weinstein, Eisei Noiri, Michael S. Goligorsky
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Vascular endothelial growth factor (VEGF), an angiogenic factor for endothelial cells, is produced by glomerular and tubular epithelia. Using immunoelectron microscopy, VEGF expression by podocytes (GEC) and the proximal tubular epithelium of rat kidney was confirmed. To elucidate the mechanisms of VEGF production and its physiologic consequences, studies were performed in cultured GEC and proximal tubular epithelial cells (RPTEC). Both GEC and RPTEC expressed VEGF-120 and 164 mRNA, as detected by quantitative RT-PCR. Hypoxia resulted in an increase in mRNA abundance, more robust in RPTEC than in GEC, and an increase in VEGF expression by 1.9- and 1.6-fold, respectively. 30 mM D-glucose, but not 30 mM L-glucose, resulted in the elevation of VEGF mRNA in RPTEC, but not in GEC, although both cell types showed a comparable modest increase in VEGF expression. Combined treatment (hypoxia and 30 mM D-glucose) resulted in an increase of VEGF mRNA only in RPTEC; however, an enhanced protein expression was detectable in both cell types. To investigate the role of VEGF in branching angiogenesis, "sandwich" co-cultures were applied with endothelial cells and capillary tube formation was compared under the above conditions. Both RPTEC and GEC induced VEGF-dependent capillary tube formation by co-cultured endothelial cells and in both cell types hypoxia further augmented angiogenesis. In contrast, 30 mM D-glucose suppressed angiogenesis in co-cultures with both cell types despite increased mRNA for VEGF receptors 1 and 2. This study shows (1) that VEGF produced by GEC and RPTEC is necessary for branching angiogenesis and (2) that hypoxic environment stimulates VEGF production by both epithelial cell types and augments branching angiogenesis, whereas (3) hyperglycemic microenvironment, although also stimulatory for VEGF production, fails to augment angiogenesis.
Smooth and skeletal muscle actin are mechanically indistinguishable in the in vitro motility assay.
Authors: D E Harris, D M Warshaw
Journal: Circulation Research (1993)

Smooth muscle produces as much stress as skeletal muscle with less myosin. To determine if the actin isoforms specific to smooth muscle contribute to the enhanced force generation, the motility of actin filaments from smooth and skeletal muscle were compared in an in vitro assay in which single fluorescently labeled actin filaments slide over a myosin-coated coverslip. No difference was observed between the velocity of smooth versus skeletal muscle actin filaments over either smooth or skeletal muscle myosin over a large range of assay conditions (changes in pH, ionic strength, and [ATP]). Similarly, no difference was observed between the two actins when the filaments moved under load over mixtures of phosphorylated smooth and skeletal muscle myosin. Thus, it appears that the actin isoforms of smooth and skeletal muscle are mechanically indistinguishable in the motility assay and that smooth muscle's enhanced force generation may originate within the myosin molecule specific to smooth muscle.
SECRETION OF PLASMINOGEN ACTIVATOR BY STIMULATED MACROPHAGES
Authors: Jay C. Unkeless, Saimon Gordon, E. Reich
Journal: The Journal of Experimental Medicine (1974)

Cultured thioglycollate-stimulated peritoneal macrophages synthesize, accumulate, and continuously release high levels of plasminogen activators for at least 4 days whereas cultures of unstimulated macrophages do not; the higher specific catalytic activity of released vs. cell-associated enzyme suggests that the plasminogen activators are actively secreted. The major macrophage plasminogen activator is a serine protease of mol wt 48,000, and thus resembles the comparable enzyme released by virally transformed fibroblasts. Macrophages release a second plasminogen activator of mol wt 28,000 that is also a serine enzyme. The secretion products released by stimulated and unstimulated macrophages have been compared by SDS-polyacrylamide gel electrophoresis after chemical labeling with (3)H-DFP or biosynthetic labeling with (14)C-amino acids. These procedures show that some proteins are formed in both cultures, whereas others are uniquely secreted by each type of macrophage. The serine enzymes released by the two kinds of macrophages differ in specificity and electrophoretic mobility.
Recreating a Functional Ancestral Archosaur Visual Pigment
Authors: Belinda S. W. Chang, Karolina Jönsson, Manija A. Kazmi, Michael J. Donoghue, Thomas P. Sakmar
Journal: Molecular Biology and Evolution (2002)

The ancestors of the archosaurs, a major branch of the diapsid reptiles, originated more than 240 MYA near the dawn of the Triassic Period. We used maximum likelihood phylogenetic ancestral reconstruction methods and explored different models of evolution for inferring the amino acid sequence of a putative ancestral archosaur visual pigment. Three different types of maximum likelihood models were used: nucleotide-based, amino acid–based, and codon-based models. Where possible, within each type of model, likelihood ratio tests were used to determine which model best fit the data. Ancestral reconstructions of the ancestral archosaur node using the best-fitting models of each type were found to be in agreement, except for three amino acid residues at which one reconstruction differed from the other two. To determine if these ancestral pigments would be functionally active, the corresponding genes were chemically synthesized and then expressed in a mammalian cell line in tissue culture. The expressed artificial genes were all found to bind to 11-cis-retinal to yield stable photoactive pigments with λmax values of about 508 nm, which is slightly redshifted relative to that of extant vertebrate pigments. The ancestral archosaur pigments also activated the retinal G protein transducin, as measured in a fluorescence assay. Our results show that ancestral genes from ancient organisms can be reconstructed de novo and tested for function using a combination of phylogenetic and biochemical methods.
Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and cyclophosphamide in advanced cancer: dose escalation possible with granulocyte colony-stimulating factor, but not with prophylactic antibiotics
Authors: D. Rischin, S.P. Ackland, J. Smith, M.B. Garg, S. Clarke, M.J. Millward, G.C. Toner, J. Zalcberg
Journal: Annals of Oncology (2002)
MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS
Authors: Yoon Berm Kim, Dennis W. Watson
Journal: The Journal of Experimental Medicine (1965)

Serum from rabbits rendered tolerant or immune to 100 MPD-3/kg of endotoxin when passively transferred to normal rabbits gave partial tolerance to the standard dose of endotoxin. The same serum was fractionated by DEAE chromatography into 4 major fractions. Immunoelectrophoretic analysis indicated that the 7S gamma(2)-and the 19S gamma(1)-immunoglobulins were separated into two distinct fractions. Of the four fractions tested, only fraction IV containing 19S gamma(1)-immunoglobulm conferred complete pyrogenic tolerance to 100 MPD-3/kg of endotoxin. Additional fractionation of DEAE fraction IV by exclusion chromatography on sephadex G-200 gave 3 fractions. Of these only the first, containing 19S gamma(1)-immunoglobulin conferred complete pyrogenic and lethal tolerance to normal rabbits. There was no correlation between the quantity of O-specific antibodies and the ability to transfer tolerance. It is concluded that endotoxin tolerance involves a classical immune mechanism which includes both 19S gamma(1)-immunoglobulin specific for toxophore groups common to many endotoxins and a normally functioning RES. To avoid confusion with immunologic tolerance, it is suggested that the term endotoxin immunity be substituted for endotoxin tolerance.
Magnetic Resonance Angiography Visualization of Abnormal Tumor Vasculature in Genetically Engineered Mice
Authors: Lauren M. Brubaker, Elizabeth Bullitt, Chaoying Yin, Terry Van Dyke, Weili Lin
Journal: Cancer Research (2005)

Abstract Previous research on the vasculature of tumor-bearing animals has focused upon the microvasculature. Magnetic resonance angiography (MRA) offers a noninvasive, complementary approach that provides information about larger vessels. Quantitative analysis of MRA images of spontaneous preclinical tumor models has not been previously reported. Eleven TgT121;p53+/− mice, which invariably develop choroid plexus carcinoma (CPC), and nine age-matched healthy controls were imaged using T1, T2, and a high-resolution three-dimensional time-of-flight MRA sequences at 3 T. Tumors and vessels were segmented to determine tumor volume and vascular attributes, including number of terminal branches, vessel count, and the average vessel radii of MRA-visible vessels within the tumor. Differences in the vasculature between tumor-bearing animals and healthy controls were analyzed statistically. Although the spatial resolution of MRA prohibits visualization of capillaries, a high density of intratumor blood vessels was visualized in CPC mice. A significant increase in terminal branch count and vessel count, but not average vessel radius, was observed in CPCs when compared with normal controls. Both terminal branch count and vessel count were highly correlated with tumor volume. This study represents the first MRA analysis of a spontaneous preclinical brain tumor model. Although the spatial resolution of MRA is less than histologic analysis, MRA-obtained vascular attributes provide useful information with full brain coverage. We show that consistent tumor vasculature properties can be determined by MRA. Such methods are critical for developing preclinical therapeutic testing and will help guide the development of human brain tumor analyses.
Endocrinological derangements in COPD
Authors: F. Laghi, N. Adiguzel, M. J. Tobin
Journal: European Respiratory Journal (2009)

Chronic obstructive pulmonary disease (COPD) is no longer considered to affect only the lungs and airways but also the rest of the body. The systemic manifestations of COPD include a number of endocrine disorders, such as those involving the pituitary, the thyroid, the gonads, the adrenals and the pancreas. The mechanisms by which COPD alters endocrine function are incompletely understood but likely involve hypoxaemia, hypercapnia, systemic inflammation and glucocorticoid administration. Altered endocrine function can worsen the clinical manifestations of COPD through several mechanisms, including decreased protein anabolism, increased protein catabolism, nonenzymatic glycosylation and activation of the rennin–angiotensin–aldosterone system. Systemic effects of endocrine disorders include abnormalities in control of breathing, decreases in respiratory and limb-muscle mass and function, worsening of respiratory mechanics, impairment of cardiac function and disorders of fluid balance. Research on endocrine manifestations of COPD embraces techniques of molecular biology, integrative physiology and controlled clinical trials. A sound understanding of the various disorders of endocrine function associated with COPD is prudent for every physician who practices pulmonary medicine.