tbuckley/cabot-search huggingface dataset:
Receptor-mediated binding and internalization of leukocyte elastase by alveolar macrophages in vitro.
Authors: E J Campbell, R R White, R M Senior, R J Rodriguez, C Kuhn
Journal: Journal of Clinical Investigation (1979)

Radioiodinated leukocyte elastase was found to bind rapidly and specifically to alveolar macrophages in vitro. In contrast to the binding of pancreatic and bacterial proteases, leukocyte elastase binding did not require the presence of alpha 2 macroglobulin. The binding was inhibited by an excess of unlabeled enzyme and was saturable by increasing elastase concentrations. Leukocyte elastase binding thus met criteria for receptor-mediated binding, with and estimated association constant of 4.97 x 10(5) M-1 and an estimated total of 640 x 10(6) binding sites/cell. It differed from the previously described binding of lysosomal glycosidases to macrophages in that it was insensitive to trypsin pretreatment, did not require calcium ions, and was not inhibited by yeast mannan. High-resolution autoradiography indicated that the cell-associated radiolabeled leukocyte elastase was rapidly incorporated into phagolysosomes. Macrophage binding may have a role in clearance of leukocyte elastase from tissue sites where alpha 2 macroglobulin is absent or present in low concentration. Thus, enzyme uptake by alveolar macrophages may be an important factor in the amelioration of lung tissue injury by extracellular leukocyte elastase.
Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 
Authors: Z. Cai, H. Zhong, M. Bosch-Marce, K. Fox-Talbot, L. Wang, C. Wei, M. A. Trush, G. L. Semenza
Journal: Cardiovascular Research (2007)

We investigated whether hypoxia-inducible factor 1 alpha (HIF-1 alpha) plays a role in the acute phase of ischaemic preconditioning (IPC).Hearts from wild-type (WT) mice and mice heterozygous for a null allele at the locus encoding HIF-1 alpha (HET) were subjected to IPC (10-min ischaemia/5 min reperfusion, or two cycles of 5 min ischaemia/5 min reperfusion), followed by 30 min ischaemia and reperfusion. Left ventricular-developed pressure, heart rate, and coronary flow rate were measured continuously. Apoptosis and infarct size were assessed by TUNEL assay, cleaved caspase 3 immunohistochemistry, and triphenyltetrazolium chloride staining. Production of reactive oxygen species (ROS) in isolated cardiac mitochondria was measured by a chemiluminescence assay. The phosphatase and tensin homologue (PTEN) and AKT (protein kinase B) were analysed by immunoblot assay. IPC improved functional recovery and limited infarct size and apoptosis after prolonged ischaemia-reperfusion in WT hearts, but not in HET hearts. Mitochondrial ROS production, PTEN oxidation, and AKT phosphorylation were impaired in HET hearts. WT and HET hearts were protected by adenosine, which acts via an ROS-independent mechanism.HIF-1 alpha is required for IPC-induced mitochondrial ROS production and myocardial protection against ischaemia-reperfusion injury.
PGC-1α Rescues Huntington’s Disease Proteotoxicity by Preventing Oxidative Stress and Promoting TFEB Function
Authors: Taiji Tsunemi, Travis D. Ashe, Bradley E. Morrison, Kathryn R. Soriano, Jonathan Au, Ruben A. Vázquez Roque, Eduardo R. Lazarowski, Vincent A. Damian, Eliezer Masliah, Albert R. La Spada
Journal: Science Translational Medicine (2012)

Huntington's disease (HD) is caused by CAG repeat expansions in the huntingtin (htt) gene, yielding proteins containing polyglutamine repeats that become misfolded and resist degradation. Previous studies demonstrated that mutant htt interferes with transcriptional programs coordinated by the peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a regulator of mitochondrial biogenesis and oxidative stress. We tested whether restoration of PGC-1α could ameliorate the symptoms of HD in a mouse model. We found that PGC-1α induction virtually eliminated htt protein aggregation and ameliorated HD neurodegeneration in part by attenuating oxidative stress. PGC-1α promoted htt turnover and the elimination of protein aggregates by activating transcription factor EB (TFEB), a master regulator of the autophagy-lysosome pathway. TFEB alone was capable of reducing htt aggregation and neurotoxicity, placing PGC-1α upstream of TFEB and identifying these two molecules as important therapeutic targets in HD and potentially other neurodegenerative disorders caused by protein misfolding.
Gleason Score 6 Adenocarcinoma: Should It Be Labeled As Cancer?
Authors: H. Ballentine Carter, Alan W. Partin, Patrick C. Walsh, Bruce J. Trock, Robert W. Veltri, William G. Nelson, Donald S. Coffey, Eric A. Singer, Jonathan I. Epstein
Journal: Journal of Clinical Oncology (2012)

Overtreatment of low-grade prostate cancer (Gleason score 6) is a recognized problem today, with systematic prostate gland sampling triggered by prostate-specific antigen (PSA) measurements. The extent to which overtreatment is caused by fear of death resulting from cancer, fear of litigation from undertreatment, and misaligned incentives that reimburse more for treating rather than monitoring when appropriate is not known. Nevertheless, fear of death resulting from cancer likely plays some role, and removing the label “cancer” could reduce unnecessary treatment of low-grade disease. On the other hand, undertreatment of prostate cancer and a missed opportunity for cure in those who could benefit is a real risk of relabeling a cancer as noncancer. We have decided on an alternative modification of the Gleason scoring system and herein present the arguments for and against removing the label of cancer from Gleason 6 tumors. We believe that our alternative approach may help: one, ensure that patients receive the proper counseling/treatment; two, reduce the risk of overtreatment and its associated harms; and three, improve shared decision making.
Induction of Tumor Antigen-Specific Immunity In Vivo by a Novel Vaccinia Vector Encoding Safety-Modified Simian Virus 40 T Antigen
Authors: Y C Xie, C Hwang, W Overwijk, Z Zeng, M H Eng, J J Mulé, M J Imperiale, N P Restifo, M G Sanda
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Evidence that simian virus 40 (SV40) is associated with human mesotheliomas, osteosarcomas, and brain tumors suggests that a recombinant vaccine directed against lethal cancers expressing SV40 T antigen (Tag) could have clinical utility. To address this potential need, we designed a novel vaccinia virus construct that encodes an SV40 Tag in which oncogenic domains were excluded and immunogenic domains were preserved. We named this recombinant construct vaccinia-encoding safety-modified SV40 Tag (vac-mTag). METHODS: Purified vac-mTag was characterized by DNA sequencing, reverse transcription-coupled polymerase chain reaction, western blot analysis, and immunocytochemical techniques. Induction of Tag-specific immunity was examined by cytolytic T-cell assays, and the efficacy of vac-mTag in protecting animals against Tag-expressing tumors and in treating pre-established microscopic tumors was evaluated in vac-mTag-immunized BALB/c mice. RESULTS: The immune response elicited by vac-mTag in C57BL/6 and BALB/c mice included an SV40 Tag-specific cytolytic T-lymphocyte activity against syngeneic (identical genetic background) SV40 Tag-expressing tumor targets. Immunization of mice with a single dose of vac-mTag resulted in potent protection against subsequent challenge with a lethal mouse cancer expressing SV40 Tag. In addition, single-dose vac-mTag immunization coadministered with interleukin 2 produced a possible therapeutic effect against a preadministered microscopic (but lethal) burden of Tag-expressing tumor cells in vivo . CONCLUSION: vac-mTag induces an effective immune response in mice that is specific for a tumor-associated antigen. This response protects against a lethal tumor challenge and results in a possible therapeutic effect against Tag-expressing tumors in vivo . Thus, vac-mTag provides a new avenue for the development of therapies for human cancers thought to be associated with SV40.
Short and long term variability of the interrupter technique under field and standardised conditions in 3-6 year old children
Authors: R M J Beelen
Journal: Thorax (2003)

<b>Background:</b> The short and long term variability of the interrupter technique was assessed to determine whether interrupter resistance is a stable individual characteristic over time. The effect of field and standardised measurement conditions on the within-subject variability of the interrupter technique was also examined. <b>Methods:</b> The interrupter technique was studied under field and standardised conditions in children aged 3–6 years. Under field conditions, five investigators performed the measurements using two different measurement devices in random sequence. Both short term (20–30 minutes) and long term variability (median 38 days) were assessed in 32 children. Under standardised conditions, a single investigator conducted all measurements using a single device; the repeated measurements were conducted at the same time of day in a familiar quiet classroom. Long term variability (median 11 days) was estimated in 15 children. Within-subject standard deviations were estimated by analysis of variance with adjustment for the effects of different investigators and measurement devices on within-subject variability under field conditions. <b>Results:</b> Under field conditions within-subject standard deviations for short and long term variability were 0.10 kPa/l/s (adjusted 0.10 kPa/l/s) and 0.13 kPa/l/s (adjusted 0.14 kPa/l/s), respectively. Under standardised conditions the within-subject standard deviation for long term variability was 0.10 kPa/l/s. <b>Conclusions:</b> Measurement of interrupter resistance under field conditions only slightly increased the within-subject variability compared with standardised conditions. The results indicate that interrupter resistance is a stable individual characteristic over a period of some weeks.
Working memory in youth following sports-related concussion: is it still working? an fMRI study
Authors: Michelle L Keightley, Rajeet Singh Saluja, Jen-Kai Chen, Alain Ptito, Isabelle Gagnon
Journal: British Journal of Sports Medicine (2013)

Objective To compare working memory performance and related brain activity using fMRI in concussed youth and healthy age-matched control subjects. Design Standard T 1 and T 2 * weighted echo planar images for blood oxygenation level dependent (BOLD) were collected on a 3Tesla System with a 32 channel head coil while subjects performed verbal and nonverbal working memory tasks. fMRIstat was used to analyse the data. Setting Participants were purposively recruited between 2007 and 2010 from The Montreal Children's Hospital Trauma Programs. Subjects 15 concussed youth (8 females, 7 males, mean age=14.47±2.29 years) and 15 age-matched control subjects (7 females, 8 males, mean age=14±2.3 years). Intervention None. Outcome Measures Post-Concussion Scale—Revised, accuracy and reaction time (RT) on a verbal and nonverbal working memory task. Results Post-concussion symptoms were higher for concussed versus control participants. The concussed group demonstrated significantly poorer accuracy but equivalent RT on the working memory task. Greater percent BOLD signal change from baseline to task was observed for control versus concussed participants in the left and right dorsolateral prefrontal cortex, left premotor cortex, dorsal anterior cingulate cortex, supplementary motor area, left superior parietal lobule, left thalamus and left caudate nucleus. Activity in the left and right dorsolateral prefrontal cortices positively correlated with task accuracy. Conclusions Compared to adults, concussed youth may be unable to engage to the same extent compensatory strategies to maintain cognitive performance following neuronal injury. Greater caution in clinical management is therefore recommended. Acknowledgements Canadian Institute of Health Research (CIHR) and Ontario Neurotrauma Foundation (ONF). Competing interests None.
Human β-Defensin-1, a Potential Chromosome 8p Tumor Suppressor: Control of Transcription and Induction of Apoptosis in Renal Cell Carcinoma
Authors: Carrie Q. Sun, Rebecca Arnold, Carina Fernandez-Golarz, Amanda B. Parrish, Tara Almekinder, Ju He, Shuk-mei Ho, Pavel Svoboda, Jan Pohl, Fray F. Marshall, John A. Petros
Journal: Cancer Research (2006)

Human beta-defensin-1 (hBD-1) is a candidate tumor suppressor gene located on chromosome 8p23. Previously, we showed that cancer-specific loss of hBD-1 was found in 90% of renal clear cell carcinomas and in 82% of prostate cancers. To investigate the possible mechanisms of decreased gene expression and determine the function of hBD-1 protein in urological cancers, we sequenced hBD-1 gene coding regions in prostatic and renal cancer samples. We then analyzed the frequency distribution of promoter polymorphisms and determined the effect of these base changes on transcriptional activity of the hBD-1 promoter. A polymorphism at -688 bases upstream of the ATG start codon affects hBD-1 promoter activity, leading to a rate of reporter gene transcription that is 40% to 50% lower than the wild-type sequence when tested in either DU145 or TSU-Pr1 cell lines. In addition, a polymorphism at -44 bases was shown to enhance transcription up to 2.3 times more than the wild-type sequence in the same cell lines. In addition, three novel hBD-1 promoter mutations were found in renal and prostate cancer clinical samples. An iso-5-aza-2'-deoxycytidine treatment was effective in transcription up-regulation in DU145, suggesting a possible upstream methylation-dependent effect. Synthetic hBD-1 peptide inhibited bladder cancer cell TSU-Pr1 proliferation. Overexpression of the hBD-1 gene in renal cancer cells SW156 resulted in caspase-3-mediated apoptosis. These data support the hypothesis that hBD-1 is a potential tumor suppressor gene for urological cancers. Promoter point mutations may be responsible for cancer-specific loss of hDB-1 expression.
DNA Methyltransferase Inhibitors and the Development of Epigenetic Cancer Therapies
Authors: Frank Lyko, Robert Brown
Journal: JNCI Journal of the National Cancer Institute (2005)

Epimutations, such as the hypermethylation and epigenetic silencing of tumor suppressor genes, play a role in the etiology of human cancers. In contrast to DNA mutations, which are passively inherited through DNA replication, epimutations must be actively maintained because they are reversible. In fact, the reversibility of epimutations by small-molecule inhibitors provides the foundation for the use of such inhibitors in novel cancer therapy strategies. Among the compounds that inhibit epigenetic processes, the most extensively studied are DNA methyltransferase inhibitors. In this review, we examine the literature on DNA methyltransferase inhibitors and discuss the efficacy of such compounds as antitumor agents, as evaluated in phase I-III clinical trials. We also discuss future areas of research, including the development of nonnucleoside inhibitors, the application of novel bioanalytical tools for DNA methylation analysis (which will be important for the clinical application of these compounds by allowing rational approaches to trial design), the need to optimize treatment schedules for maximal biologic effectiveness, and the need to define molecular endpoints so that changes induced by demethylating drugs in patients can be monitored during treatment. Assays for genome-wide and tumor-specific DNA methylation also need to be further developed to establish the pharmacodynamic parameters of DNA methyltransferase inhibitors in patients and to provide rational approaches to maximizing the therapeutic efficacy of these compounds.
601 PEG-INTERFERON-ALPHA PLUS RIBAVIRIN TREATMENT INDUCES A CENTRAL MEMORY SPECIFIC CD8+ T CELL RESERVOIR IN CHRONIC HEPATITIS C PATIENTS WITH SUSTAINED VIROLOGIC RESPONSE
Authors: S. Benito, J.R. Larrubia, E. Sanz-de-Villalobos, M. Calvino, M.L. Garcia-Buey, S. Garcia-Garzon, F. Gonzalez-Mateos, A. Gonzalez-Praetorius, J. Miquel, A. Bienvenido, T. Parra
Journal: Journal of Hepatology (2008)
Calcification of Vascular Smooth Muscle Cell Cultures
Authors: Takeo Wada, Marc D. McKee, Susie Steitz, Cecilia M. Giachelli
Journal: Circulation Research (1999)

Abstract —Calcification of vascular tissue is a common complication in aging, atherosclerosis, diabetes, renal failure, aortic stenosis, and prosthetic valve replacement. Osteopontin is a noncollagenous adhesive protein routinely found at sites of dystrophic calcification and synthesized at high levels by macrophages in calcified aortic valves and atherosclerotic plaques. In the present study, we have characterized the calcification of bovine aortic smooth muscle cell (BASMC) cultures in vitro and have studied the effects of exogenous osteopontin on mineral deposition. Induction of calcification in BASMC cultures was alkaline phosphatase–dependent and was characterized by a multilayer cell morphology. Mineral deposition occurred in the basal matrix of multilayered areas as indicated by von Kossa staining, and transmission electron microscopy and electron diffraction identified the mineral as apatite. Ultrastructural analysis of the cultures showed the presence of extracellular matrix vesicles, calcifying collagen fibrils, and nodular-type calcifications similar to those found in calcified heart valves and atherosclerotic plaques. Purified osteopontin (0.05 to 5 μg/mL) dose dependently inhibited calcification of BASMC cultures, whereas vitronectin and fibronectin had no effect. In contrast to the inhibitory mechanism of levamisole on mineral deposition, osteopontin did not inhibit alkaline phosphatase activity or reduce phosphorus levels in the culture medium. Addition of calcium to the cultures overcame the inhibitory effect of osteopontin on BASMC culture calcification and resulted in decreased levels of calcium in the culture medium and increased levels in the cell layer. Moreover, using high-resolution, colloidal-gold immunocytochemistry, osteopontin was found intimately associated with growing apatite crystals. These data indicate that the effect of osteopontin, although calcium-dependent, was not mediated by simple calcium chelation but most likely by direct interaction of osteopontin with crystal surfaces. These studies suggest that BASMCs can be used to model vascular calcification in vitro and that soluble osteopontin released near sites of vascular calcification may represent an adaptive mechanism aimed at preventing vascular calcification.
The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice.
Authors: M B Baker, N H Altman, E R Podack, R B Levy
Journal: The Journal of Experimental Medicine (1996)

The role of cell-mediated cytotoxicity in the complex pathophysiology of graft-versus-host disease (GVHD) has remained poorly defined for several decades. We transplanted T cells from Fas-ligand (FasL)-defective and perforin-deficient mutant donor mice into lethally irradiated MHC-matched allogeneic recipient mice to characterize the role of cell-mediated cytotoxicity in GVHD. Although recipients of allogeneic FasL-defective donor T cells underwent severe GVHD-associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perforin-deficient allogeneic donor T cells developed signs of acute GVHD, but the time of onset was significantly delayed. These findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage.
Effect of Diesel on Chemokines and Chemokine Receptors Involved in Helper T Cell Type 1/Type 2 Recruitment in Patients with Asthma
Authors: Stéphanie Sénéchal, Patricia de Nadai, Natacha Ralainirina, Arnaud Scherpereel, Han Vorng, Philippe Lassalle, André-Bernard Tonnel, Anne Tsicopoulos, Benoît Wallaert
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The objective of this study was to evaluate if diesel exhausts could favor helper T cell type (Th) 2-associated allergic reactions either through an increased production of Th2-associated chemokines and of their associated receptors or through a decrease of Th1-attracting chemokines and chemokine receptors. Diesel but not allergen exposure of peripheral blood mononuclear cells from subjects with allergy induced a release of I-309, whereas both diesel and Der p 1 induced an early but transient release of monokine induced by IFN-gamma and a late release of pulmonary and activation-regulated chemokine. Although both Th1- and Th2-attracting chemokines were induced, the resulting effect was an increased chemotactic activity on Th2 but not Th1 cells. Surprisingly, diesel induced a late increase in the expression of the Th1-associated CXC receptor 3 and CC receptor 5. T cell CXC receptor 3 upregulation was not associated with an increased migration to its ligands. These two antagonistic effects have been previously reported as a scavenger mechanism to clear chemokines. Altogether, these results suggest that diesel, even without allergen, may amplify a type 2 immune response but that it can also increase late Th1-associated chemokine receptor expression, perhaps as a scavenger mechanism to clear pro-Th1 chemokines and promote the Th2 pathway.
Interleukin 6 is essential for in vivo development of B lineage neoplasms.
Authors: D M Hilbert, M Kopf, B A Mock, G Köhler, S Rudikoff
Journal: The Journal of Experimental Medicine (1995)

Interleukin (IL) 6 has been suggested to be the major cytokine responsible for proliferation of neoplastic plasma cells in both human myeloma and mouse plasmacytoma. Much of the evidence supporting this suggestion is derived from in vitro studies in which the survival or proliferation of some plasma cell tumors has been found to be IL-6 dependent. However, it remains unclear whether this dependency is the consequence of in vivo or in vitro selective pressures that preferentially expand IL-6-responsive tumor cells, or whether it reflects a critical in vivo role for IL-6 in plasma cell neoplasia. To address this question, we have attempted to induce plasma cell tumors in normal mice and in IL-6-deficient mice generated by introduction of a germline-encoded null mutation in the IL-6 gene. The results demonstrate that mice homozygous (+/+) or heterozygous (+/-) for the wild-type IL-6 allele yield the expected incidences of plasma cell tumors. In contrast, mice homozygous for the IL-6-null allele (-/-) are completely resistant to plasma cell tumor development. These studies define the essential role of IL-6 in the development of B lineage tumors in vivo and provide experimental support for continued efforts to modulate this cytokine in the treatment of appropriate human B cell malignancies.