tbuckley/cabot-search huggingface dataset:
Improved quality of life after lung volume reduction surgery
Authors: J. Hamacher, S. Büchi, C.L. Georgescu, U. Stammberger, R. Thurnheer, K.E. Bloch, W. Weder, E.W. Russi
Journal: European Respiratory Journal (2002)

Lung volume reduction surgery (LVRS) improves dyspnoea, pulmonary function, and physical performance in patients with severe pulmonary emphysema. This study investigated the impact of LVRS on health-related quality of life (HRQL) over a 2-yr period following surgery. Thirty-nine consecutive patients were prospectively assessed before LVRS, and followed over 24 months postoperatively. The assessments included pulmonary function, dyspnoea (Medical Research Council (MRC) dyspnoea score), 6-min walking distance (6MWD) and HRQL using the Short Form 36-item questionnaire (SF-36) . Several domains of SF-36 improved considerably over 2 yrs after surgery: Physical Functioning: 39±4 (mean±sem) <i>versus</i> 16±2 (p&lt;0.01); Vitality: 51±3 <i>versus</i> 32±3 (p&lt;0.01); Social Functioning: 72±4 <i>versus</i> 51±5 (p&lt;0.01). Also, improvements in pulmonary function (forced expiratory volume in one second (FEV<sub>1</sub>): 27±1% predicted, residual volume (RV)/total lung capacity (TLC): 0.65±0.01), 6 MWD (274±16 m) and dyspnoea (MRC: 3.9±01) were sustained for up to 2 yrs after LVRS (FEV<sub>1</sub> 36±2% pred, RV/TLC: 0.58±0.02; 6 MWD: 342±19 m; MRC: 2.0±0.2; p&lt;0.05). In patients with severe emphysema, lung volume reduction surgery had positive effects on health-related quality of life and pulmonary function over 2 yrs.
Dexamethasone Downregulates Calcification-Inhibitor Molecules and Accelerates Osteogenic Differentiation of Vascular Pericytes
Authors: John Paul Kirton, Fiona L. Wilkinson, Ann E. Canfield, M. Yvonne Alexander
Journal: Circulation Research (2006)

Vascular calcification is present in many pathological conditions and is recognized as a strong predictor of future cardiovascular events. Current evidence suggests that it is a regulated process involving inducing and inhibitory molecules. Glucocorticoids have great clinical importance as antiinflammatory drugs and can act as potent inducers of osteogenic differentiation in vitro. The effect of glucocorticoids on vascular cells in vivo remains obscure. Pericytes are pluripotent cells that can differentiate into osteoblasts, and recent evidence suggests that they could participate in vascular calcification. We hypothesized that the synthetic glucocorticoid dexamethasone would enhance the rate of pericyte differentiation and mineralization in vitro with a concomitant suppression of calcification-inhibitory molecules. Three weeks of dexamethasone treatment induced a 2-fold increase in (1) alkaline phosphatase activity, (2) calcium deposition, and (3) the number of nodules formed in vitro; and a reduction in the expression of matrix Gla protein (MGP), osteopontin (OPN), and vascular calcification-associated factor (VCAF) mRNAs. The glucocorticoid receptor antagonist Org 34116 abolished dexamethasone-accelerated pericyte differentiation, nodule formation, and mineralization. Data obtained using Org 34116, the transcription inhibitor actinomycin D, and the protein synthesis inhibitor cyclohexamide suggest that MGP, OPN, and VCAF mRNA abundance are controlled at different and multiple levels by dexamethasone. This is the first report showing that dexamethasone enhances the osteogenic differentiation of pericytes and downregulates genes associated with inhibition of mineralization. Our study highlights the need for further investigation into the long-term consequences of prolonged glucocorticoid therapy on vascular calcification.
Human upper epidermal cytoplasmic antibodies are directed against keratin intermediate filament proteins.
Authors: H Hintner, P M Steinert, T J Lawley
Journal: Journal of Clinical Investigation (1983)

Upper cytoplasmic (U-Cyt) antibodies are directed against cytoplasmic antigens found in keratinocytes in the upper layers of the epidermis. Until now, they have been defined by indirect immunofluorescence and are known to occur in the sera of patients with cutaneous diseases such as bullous dermatoses, basal cell carcinomas, and melanomas. An increased incidence of U-Cyt antibodies has also been reported in the sera of patients with noncutaneous diseases, such as pulmonary neoplasms. They have been found in addition in the sera of some normal individuals. In this study we have identified keratin intermediate filaments (KIF) as antigens U-Cyt antibodies are directed against. KIF proteins were prepared, separated by polyacrylamide gel electrophoresis, transblotted to nitro-cellulose strips, and used as substrates for antibody binding. Sera containing U-Cyt antibodies by indirect immunofluorescence also had antibodies that were directed against high molecular weight (65,000, 63,000, 61,500) KIF proteins. When KIF proteins were separated according to their charge and their molecular weight by two-dimensional gel electrophoresis and transblotted, the anti-KIF protein antibodies bound to virtually all charge isomers of the KIF proteins at the respective molecular weight. The antibody titers measured using the transblotting technique were 10 to 160 times higher than those found by indirect immunofluorescence. To determine whether U-Cyt antibodies were directed against KIF, a series of absorption and elution experiments were performed. Absorption of test sera with purified KIF removed both U-Cyt antibodies and anti-KIF protein antibodies. Absorption with another type of intermediate filament derived from fibroblasts, vimentin, did not remove U-Cyt or anti-KIF protein antibodies. Absorbed U-Cyt and anti-KIF protein antibodies were both eluted from the same KIF preparation and shown to bind to U-Cyt antigens by indirect immunofluorescence and KIF proteins by transblotting. Absorption of a serum containing U-Cyt antibodies, anti-nuclear antibodies, and anti-basement membrane zone antibodies with purified KIF resulted in the removal of the U-Cyt antibodies but not the other types of antibody. In addition, all test sera, even those that lacked U-Cyt antibodies, were found to have low-titer antibodies against KIF proteins by the transblotting technique. These data indicate that KIF proteins bear antigens to which U-Cyt antibodies are directed and that low titer antibodies against KIF proteins may be much more common than previously appreciated.
Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: a phase II study
Authors: D. Pectasides, M. Pectasides, D. Farmakis, N. Bountouroglou, M. Nikolaou, M. Koumpou, N. Mylonakis, C. Kosmas
Journal: Annals of Oncology (2003)
[585] DECREASED RISK OF LIVER GVHD AND GVHD RELATED MORTALITY FOLLOWING ALLO BMT IN CHILDREN RECEIVING PREEMPTIVE ANTIVIRAL THERAPY FOR HBV OR HCV
Authors: M.H. El-Saved, A. El-Haddad, I. Ahmed, H. ElMahalawy, X. Chen
Journal: Journal of Hepatology (2007)
The specificity of energy utilisation by trained and untrained adolescent boys.
Authors: N. Armstrong, B. Davies, M. Heal
Journal: British Journal of Sports Medicine (1983)

This study examined the relationship between estimates of alactacid anaerobic power, lactacid anaerobic power and aerobic power in a sample of trained swimmers (age 14.4 yr., n = 8) and a sample of untrained boys (age 13.7 yr., n = 13). The anaerobic power outputs were estimated using a modification of the Wingate Anaerobic Test and aerobic power was estimated using a continuous, incremental cycle ergometer test. In addition to leg power outputs the swimmers' arm power using each energy system was estimated and compared with the corresponding leg value. There was no relationship between the estimates of the power of the three energy systems with either the trained or untrained boys. Furthermore with the trained boys there was no relationship between estimates of the power of the same energy system utilised by different limbs. The data support a specificity hypothesis of energy utilisation during exercise with both trained and untrained adolescent boys.
Phase 0 Trials: An Industry Perspective
Authors: Helen Eliopoulos, Vincent Giranda, Robert Carr, Rita Tiehen, Terri Leahy, Gary Gordon
Journal: Clinical Cancer Research (2008)

Worldwide, cancer is a leading cause of morbidity and mortality. An increased understanding of the disease and its process has resulted in a multitude of new targeted therapies. The costs as well as time from drug discovery to market, however, remain staggeringly high and protracted, with the majority of compounds never reaching phase III. The concept of an exploratory or phase 0 trial was introduced as a mechanism to enhance and accelerate the overall process of new oncologic drug development. Performance of a phase 0 study allows researchers to better understand the pharmacokinetic and pharmacodynamic properties of compounds in human subjects before initiation of phase I trials. Data gleaned from a phase 0 trial are beneficial not only in prioritizing promising compounds but also in allowing the modification of phase I study design before initiation. To date, few researchers have taken advantage of the potential benefits of phase 0 trials. This review focuses on the purpose as well as the potential merits of phase 0 trials from the perspective of a pharmaceutical company. The review summarizes the experience of a team of researchers with ABT-888, a novel poly (ADP-ribose) polymerase agent that inhibits an enzyme critical for repairing damage to DNA, which is one of the first compounds to be investigated using the phase 0 clinical trial design.
Sampling the Conformational Energy Landscape of a Hyperthermophilic Protein by Engineering Key Substitutions
Authors: J.-P. Colletier, A. Aleksandrov, N. Coquelle, S. Mraihi, E. Mendoza-Barbera, M. Field, D. Madern
Journal: Molecular Biology and Evolution (2012)

Proteins exist as a dynamic ensemble of interconverting substates, which defines their conformational energy landscapes. Recent work has indicated that mutations that shift the balance between conformational substates (CSs) are one of the main mechanisms by which proteins evolve new functions. In the present study, we probe this assertion by examining phenotypic protein adaptation to extreme conditions, using the allosteric tetrameric lactate dehydrogenase (LDH) from the hyperthermophilic bacterium Thermus thermophilus (Tt) as a model enzyme. In the presence of fructose 1, 6 bis-phosphate (FBP), allosteric LDHs catalyze the conversion of pyruvate to lactate with concomitant oxidation of nicotinamide adenine dinucleotide, reduced form (NADH). The catalysis involves a structural transition between a low-affinity inactive "T-state" and a high-affinity active "R-state" with bound FBP. During this structural transition, two important residues undergo changes in their side chain conformations. These are R171 and H188, which are involved in substrate and FBP binding, respectively. We designed two mutants of Tt-LDH with one ("1-Mut") and five ("5-Mut") mutations distant from the active site and characterized their catalytic, dynamical, and structural properties. In 1-Mut Tt-LDH, without FBP, the K(m)(Pyr) is reduced compared with that of the wild type, which is consistent with a complete shifting of the CS equilibrium of H188 to that observed in the R-state. By contrast, the CS populations of R171, k(cat) and protein stability are little changed. In 5-Mut Tt-LDH, without FBP, K(m)(Pyr) approaches the values it has with FBP and becomes almost temperature independent, k(cat) increases substantially, and the CS populations of R171 shift toward those of the R-state. These changes are accompanied by a decrease in protein stability at higher temperature, which is consistent with an increased flexibility at lower temperature. Together, these results show that the thermal properties of an enzyme can be strongly modified by only a few or even a single mutation, which serve to alter the equilibrium and, hence, the relative populations of functionally important native-state CSs, without changing the nature of the CSs themselves. They also provide insights into the types of mutational pathways by which protein adaptation to temperature is achieved.
Abnormal Glomerular Permeability Characteristics in Diabetic Nephropathy
Authors: Edmund J. Lewis, Xiulong Xu
Journal: Diabetes Care (2008)

The physicochemical characteristics of the glomerular capillary filtration membrane restrict the passage of macromolecules on the basis of molecular weight, charge, and shape. The proposed ionic charge permselectivity characteristics of the glomerular basement membrane (GBM) are determined by its chemical composition, primarily the highly sulfated glycosaminoglycan heparan. In diabetic nephropathy, the heparan sulfate content of the GBM is diminished. It has been proposed that decreased GBM heparan sulfate content causes decreased permselectivity to negatively charged macromolecules such as albumin, allowing this protein to leak into the urinary space. One possible explanation for decreased GBM heparan sulfate content in diabetic nephropathy is the observation that heparanase, an enzyme capable of degrading heparan sulfate, is upregulated in the glomerular epithelial cell (GEC) in response to increased glucose. Increased GEC heparanase activity has been demonstrated in glomeruli in diabetic kidneys, and increased urine heparanase has been observed in diabetic nephropathy. In vitro studies have shown that GEC heparanase activity depends on the glucose concentration of the culture medium. GEC heparanase activity can be inhibited by heparin compounds. Sulodexide, an orally active low-molecular weight heparin, has been shown to lower urine albumin excretion. The working hypothesis that has emerged is that sulodexide may be an in vivo heparanase inhibitor that reaches the glomerular capillary wall and prevents heparan sulfate degradation, thus allowing reconstruction of heparan sulfate content and restoration of GBM ionic permselectivity. Two clinical trials are currently being carried out to determine whether sulodexide is renoprotective in diabetic nephropathy.
Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial
Authors: Helen Ayles, Monde Muyoyeta, Elizabeth Du Toit, Ab Schaap, Sian Floyd, Musonda Simwinga, Kwame Shanaube, Nathaniel Chishinga, Virginia Bond, Rory Dunbar, Petra De Haas, Anelet James, Nico C Gey van Pittius, Mareli Claassens, Katherine Fielding, Justin Fenty, Charalampos Sismanidis, Richard J Hayes, Nulda Beyers, Peter Godfrey-Faussett
Journal: The Lancet (2013)
Downregulation of HuR as a new mechanism of doxorubicin resistance in breast cancer cells
Authors: Elisa Latorre, Toma Tebaldi, Gabriella Viero, Antonino Maria Spartà, Alessandro Quattrone, Alessandro Provenzani
Journal: Molecular Cancer (2012)

Abstract Background HuR, an RNA binding protein involved in the post-transcriptional regulation of a wide spectrum of mRNAs, has been demonstrated to be a determinant of carcinogenesis and tumor aggressiveness in several cancer types. In this study, we investigated the role of HuR in the apoptosis and in the chemoresistance induced by the widely used anticancer drug doxorubicin in human breast cancer cells (MCF-7). Results We showed that HuR acts in the early phase of cell response to doxorubicin, being induced to translocate into the cytoplasm upon phosphorylation. Reducing HuR levels diminished the apoptotic response to doxorubicin. Doxorubicin-induced apoptosis was also correlated with the presence of HuR in the cytoplasm. Rottlerin, which was able to block HuR nuclear export, had correspondingly antagonistic effects with doxorubicin on cell toxicity. The proapoptotic activity of HuR was not due to cleavage to an active form, as was previously reported. In in vitro selected doxorubicin resistant MCF-7 cells (MCF-7/doxoR) overexpressing the multidrug resistance (MDR) related ABCG2 transporter, we observed a significant HuR downregulation that was paralleled by a corresponding downregulation of HuR targets and by loss of rottlerin toxicity. Restoration of HuR expression in these cells resensitized MCF-7/doxoR cells to doxorubicin, reactivating the apoptotic response. Conclusions The present study shows that HuR is necessary to elicit the apoptotic cell response to doxorubicin and that restoration of HuR expression in resistant cells resensitizes them to the action of this drug, thereby identifying HuR as a key protein in doxorubicin pharmacology.
A Phase 1 Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 7 Days Every 21 Days in Pediatric Patients with Solid Tumors
Authors: Elizabeth Fox, John M. Maris, Brigitte C. Widemann, Kysa Meek, Anne Goodwin, Wendy Goodspeed, Marie Kromplewski, Molly E. Fouts, Diane Medina, Steve Y. Cho, Susan L. Cohn, Andrew Krivoshik, Anne E. Hagey, Peter C. Adamson, Frank M. Balis
Journal: Clinical Cancer Research (2006)

To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days.Patients who were </=18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m(2)/d (n = 3) and was escalated to 130 mg/m(2)/d (n = 6), 165 mg/m(2)/d (n = 6), 200 mg/m(2)/d (n = 6), and 250 mg/m(2)/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle.Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m(2)/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m(2)/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed.ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m(2)/d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.
Targeting the Limitless Replicative Potential of Cancer: The Telomerase/Telomere Pathway
Authors: Lloyd Kelland
Journal: Clinical Cancer Research (2007)

Abstract The maintenance of telomeric DNA underlies the ability of tumors to possess unlimited replicative potential, one of the hallmarks of cancer. Telomere length and structure are maintained by the reverse transcriptase telomerase and a multiprotein telomere complex termed shelterin. Telomerase activity is elevated in the vast majority of tumors, and telomeres are critically shortened in tumors versus normal tissues, thus providing a compelling rationale to target the telomerase/telomere pathway for broad-spectrum cancer therapy. This strategy is supported by a variety of genetic-based target validation studies. Both telomerase inhibitors and telomere interactive molecules have shown stand-alone antitumor activity at nontoxic doses against a variety of human tumor xenografts in mice. These translational advances have resulted in the first antitelomerase agent, the oligonucleotide-based GRN163L targeting the telomerase RNA template, entering clinical evaluation. Additional translational approaches, such as targeting telomeres using G-quadruplex ligands, should result in antitelomere agents, such as RHPS4, entering the clinic in the near future. These prototype trials will be extremely informative in determining the role of the telomerase/telomere pathway in clinical oncology and, moreover, whether drugs targeting the unlimited replicative potential of cancer will find a place in cancer chemotherapy.
Four US drug companies pay $124m for defrauding Medicaid
Authors: J. Hopkins Tanne
Journal: BMJ (2009)

Four US drug companies have made settlements with the US Department of Justice and agreed to pay $124m (£75m; €84m) to resolve false claims that they submitted to the US Medicaid programme after a whistleblower complained.

The companies were Mylan Pharmaceuticals and UDL Laboratories, which paid $118m; Astra Zeneca, which paid $2.6m; and Ortho McNeil, which paid $3.4m.

The amount recovered by the US government will be shared between the federal government, the states, the Public Health Service’s drug pricing programme, and the whistleblower.

“The [US federal] False Claims Act allows a citizen [a whistleblower] to bring fraud to the attention of the government. …
Bleomycin-induced interstitial pneumonia in dogs
Authors: R. W. Fleischman, J. R. Baker, G. R. Thompson, U. H. Schaeppi, V. R. Illievski, D. A. Cooney, R. D. Davis
Journal: Thorax (1971)

The intravenous administration of Bleomycin to 10 dogs at different dosages resulted in varying degrees of interstitial pneumonia in all cases and a lower incidence of nephrosis, foot pad excoriation and ulceration, onychoptosis, and alopecia. Pulmonary changes did not occur as a simple dose-related phenomenon. The lesions required at least 38 days to become apparent and appeared to increase in severity with time. Even at the lowest dose used (0·625 mg/kg body weight) very severe changes were seen 128 days after cessation of therapy. Morphological features of interstitial pneumonia were subpleural localization, focal mesothelial hyperplasia, marked hyperplasia and metaplasia of type II pneumocytes, fetalization of alveoli, and a pleomorphic inflammatory infiltrate. In cross-sections of lung lobes selected for histology approximately 1 to 22% of the parenchyma contained lesions. Involved areas showed marked elastosis, excess of reticular fibres, fibrosis, and increased acid mucopolysaccharides. The administration of Bleomycin produced pulmonary changes similar in many respects to those reported in busulphan-treated patients and desquamative interstitial pneumonia. The finding of interstitial pneumonia and pulmonary fibrosis in dogs treated with low doses over prolonged periods points the need to monitor pulmonary function in humans treated with Bleomycin.
EphB6 crosslinking results in costimulation of T cells
Authors: Hongyu Luo, Guang Yu, Yulian Wu, Jiangping Wu
Journal: Journal of Clinical Investigation (2002)

Erythropoietin-producing hepatocyte (Eph) kinases represent the largest receptor tyrosine kinase family. Some of them are expressed in the T cell compartment, but their function in T cells is unknown. In peripheral blood, EphB6 was predominantly expressed on T cells, and was upregulated after culture. EphB6 crosslinking by anti-EphB6 mAb or ephrinB2 in the presence of suboptimal T cell receptor (TCR) stimulation led to drastic T cell proliferation, suggesting that EphB6 can co-stimulate T cells. The proliferation was accompanied by enhanced production of several lymphokines, such as IFN-γ, IL-6, IL-10, TGF-β, TNF-α, and GM-CSF, but not IL-2 and IL-4. Sorted EphB6+ T cells had significantly stronger response to anti-CD3 and anti-CD28 stimulation than EphB6– T cells had. Taken together, these data suggest an important role of EphB6 in normal T cell activation. Within two minutes of anti-CD3 and anti-CD28 stimulation, EphB6 aggregated and colocalized with TCR, and this provides a morphological basis for EphB6 to enhance TCR signaling. The capping was followed by p38 MAPK activation, showing that EphB6 is capable of signaling, in spite of its lack of intrinsic kinase activity. This study demonstrates that interaction between EphB6 and its ligands facilitates T cell responses to antigen.