tbuckley/cabot-search huggingface dataset:
Combined Therapeutic Effects of Vinblastine and Rapamycin on Human Neuroblastoma Growth, Apoptosis, and Angiogenesis
Authors: Danilo Marimpietri, Chiara Brignole, Beatrice Nico, Fabio Pastorino, Annalisa Pezzolo, Federica Piccardi, Michele Cilli, Daniela Di Paolo, Gabriella Pagnan, Luca Longo, Patrizia Perri, Domenico Ribatti, Mirco Ponzoni
Journal: Clinical Cancer Research (2007)

Vinblastine and rapamycin displayed synergistic inhibition of human neuroblastoma-related angiogenesis. Here, we studied the antitumor activity of vinblastine and rapamycin against human neuroblastoma.Cell proliferation, cell cycle progression, and apoptosis were evaluated by measuring (3)H-thymidine incorporation, bromodeoxyuridine uptake, and phosphatidylserine exposure, respectively. The in vivo sensitivity of neuroblastoma cells to vinblastine and rapamycin was determined in orthotopic neuroblastoma-engrafted mice. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay.Each compound alone was able to induce a dose-dependent significant inhibition of cell proliferation, with a dramatically enhanced antiproliferative effect for the drugs used in combination. A marked G(2)-M cell cycle arrest with a nearly complete depletion of S phase was associated. The combined treatment triggered an increased apoptosis compared with either drug tested alone. A significant inhibition of tumor growth and microvessel area was obtained in neuroblastoma-bearing mice when treated with vinblastine or rapamycin alone, and a more dramatic effect with the combined treatment, compared with control mice. The therapeutic effectiveness, expressed as increased life span, was statistically improved by the combined therapy, compared with mice treated with either drug tested separately. Histologic evaluation of primary tumors showed that the combined treatment inhibited proliferation and angiogenesis and induced apoptosis. Combined treatment of neuroblastoma cells and neuroblastoma-bearing mice with vinblastine and rapamycin induced the down-modulation of both vascular endothelial growth factor production and vascular endothelial growth factor receptor 2 expression. In the chorioallantoic membrane assay, angiogenesis induced by human neuroblastoma biopsy specimens was significantly inhibited by vinblastine and rapamycin.These results may be relevant to design new therapeutic strategies against neuroblastoma.
1044-58 Drug-eluting stent utilization and outcomes from the strategic evaluation of new transvascular therapies (STENT) group: A large prospective multicenter “Real-World” registry of percutaneous coronary intervention
Authors: Charles A Simonton, Bruce Brodie, Barry Cheek, Gregory San, Fred Krainin, Patricia Walker, Sherry Laurent
Journal: Journal of the American College of Cardiology (2004)
Avoiding overdiagnosis in lung cancer screening: the volume doubling time strategy
Authors: Marie-Pierre Revel
Journal: European Respiratory Journal (2013)

Volumetry-based management of nodules observed with screening succeeds in omitting indolent, slow-growing cancers http://ow.ly/pkHY7It has been 2 years since the breakthrough publication of the National Lung Cancer Screening Trial (NLST) results, yet there are still unresolved questions about cancer screening.Despite the possibility of reducing lung cancer-related mortality, the risk of detecting indolent lesions that are not life threatening, especially in advanced-age patients, still exists.Another problem is the number of false-positive findings leading to unnecessary diagnostic work-ups.In the NSLT study, for example, 27.2% of computed tomography participants were false positives, leading to follow-up diagnostic procedures in 90% of cases and to surgery in 4.2% [1].Of course, computed tomography protocols and criteria for screening positivity should ensure accurate detection of all potentially malignant lesions, but this goal alone is not sufficient.Ideally, screening protocols should allow us to detect only true lung cancers, leaving out benign lesions, and among the malignant lesions detected, we should only be identifying those that are sufficiently aggressive to be potentially life threatening.This issue of the European Respiratory Journal includes two articles addressing precisely these problems.The paper by INFANTE et al. [2] is a review article dedicated to the slow-growing lung cancer entity, whereas the paper from HOREWEG et al. [3] gives an overview of the NELSON strategy's performance, especially its rate of false positives. Do slow-growing lung cancers exist? INFANTE et al.[2] provide evidence of slow-growing lung cancers by analysing tumour volume doubling times (VDTs) in different lung cancer series.Considering a VDT .400days to define slow-growing lung cancers, they report a highly variable proportion, ranging from 3% in the International Early Lung Cancer Action Program (I-ELCAP) [4] to 45% in some Japanese series [5].The authors emphasise that only a minority of baseline VDTs were assessed in I-ELCAP, but there are other explanations as well.Differences in the screening method (chest radiography or computed tomography) must be taken into account, along with differences regarding the sex and ethnicity of the screened population.Series with a high proportion of slow-growing cancers include not only males but also females or, potentially, more patients with subsolid lesions [6].The term subsolid refers to: 1) pure ground-glass (e.g.nonsolid) nodules (pGGNs), through which normal parenchymal structures can be visualised; and 2) part-solid nodules (or mixed ground-glass opacities (GGO)), combining ground glass and solid components.
SETA: A novel SH3 domain-containing adapter molecule associated with malignancy in astrocytes
Authors: Oliver Bögler, Frank B. Furnari, Andrea Kindler-Roehrborn, Virginia W. Sykes, Richard Yung, H.-J. Su Huang, Webster K. Cavenee
Journal: Neuro-Oncology (2000)

Differential display poymerase chain reaction analysis was used to compare five differentiation states of the O-2A progenitor-like cell line CG4: progenitor cells and cells at 12 h or 4 days after the induction of differentiation into oligodendrocytes or astrocytes. This led to the identification of 52 sequence tags that were expressed differentially with cellular phenotype. One sequence was upregulated during differentiation of CG4 cells and represented a novel gene that we named SETA (SH3 domain-containing gene expressed in tumorigenic astrocytes). This gene encodes an SH3 domain-containing adapter protein with sequence similarity to the CD2AP (CD2 adapter protein) and CMS (Cas ligand with multiple Src homology) genes. SETA mRNA was expressed at high levels in the developing rat brain but was barely detectable in the normal adult rat or human brain. However, SETA mRNA was found in approximately one half of the human gliomas tested, including astrocytomas grades II, III, and IV, as well as oligodendrogliomas, mixed oligoastrocytomas, and human glioma-derived cell lines. A rat glioma generated by treatment with the alkylating carcinogen ethylnitrosourea on postnatal day 1 and a derived cell line also expressed SETA mRNA. Furthermore, in an in vitro model of astrocytoma progression based on p53-/- astrocytes, expression of SETA was restricted to cells that are tumorigenic.
Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function
Authors: Atsushi Nakamura, Risa Ebina-Shibuya, Ari Itoh-Nakadai, Akihiko Muto, Hiroki Shima, Daisuke Saigusa, Junken Aoki, Masahito Ebina, Toshihiro Nukiwa, Kazuhiko Igarashi
Journal: The Journal of Experimental Medicine (2013)

Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony–stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling.
Rethinking Antioxidants in the Intensive Care Unit
Authors: Manu Jain, Navdeep S. Chandel
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Recently there was yet another clinical trial using antioxidants that failed in patients with critical illness. In this perspective, we suggest that antioxidants likely interfere with the normal immune response, thus contributing to the lack of efficacy in patients with critical illness.
<i>In Vitro</i> and <i>In Vivo</i> Antitumor Activity of a Novel Alkylating Agent, Melphalan-Flufenamide, against Multiple Myeloma Cells
Authors: Dharminder Chauhan, Arghya Ray, Kristina Viktorsson, Jack Spira, Claudia Paba-Prada, Nikhil Munshi, Paul Richardson, Rolf Lewensohn, Kenneth C. Anderson
Journal: Clinical Cancer Research (2013)

The alkylating agent melphalan prolongs survival in patients with multiple myeloma; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of melphalan-flufenamide (mel-flufen), a novel dipeptide prodrug of melphalan in multiple myeloma.Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft animal model were used to study the antitumor activity of mel-flufen.Low doses of mel-flufen trigger more rapid and higher intracellular concentrations of melphalan in multiple myeloma cells than are achievable by free melphalan. Cytotoxicity analysis showed significantly lower IC50 of mel-flufen than melphalan in multiple myeloma cells. Importantly, mel-flufen induces apoptosis even in melphalan- and bortezomib-resistant multiple myeloma cells. Mechanistic studies show that siRNA knockdown of aminopeptidase N, a key enzyme mediating intracellular conversion of mel-flufen to melphalan, attenuates anti-multiple myeloma activity of mel-flufen. Furthermore, mel-flufen-induced apoptosis was associated with: (i) activation of caspases and PARP cleavage; (ii) reactive oxygen species generation; (iii) mitochondrial dysfunction and release of cytochrome c; and (iv) induction of DNA damage. Moreover, mel-flufen inhibits multiple myeloma cell migration and tumor-associated angiogenesis. Human multiple myeloma xenograft studies showed a more potent inhibition of tumor growth in mice treated with mel-flufen than mice receiving equimolar doses of melphalan. Finally, combining mel-flufen with lenalidomide, bortezomib, or dexamethasone triggers synergistic anti-multiple myeloma activity.Our preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve multiple myeloma patient outcome.
Changes in Titin Isoform Expression in Pacing-Induced Cardiac Failure Give Rise to Increased Passive Muscle Stiffness
Authors: Yiming Wu, Stephen P. Bell, Karoly Trombitas, Christian C. Witt, Siegfried Labeit, Martin M. LeWinter, Henk Granzier
Journal: Circulation (2002)

Background— Titin contains a molecular spring segment that underlies passive myocardial stiffness. Myocardium coexpresses titin isoforms with molecular spring length variants and, consequently, distinct stiffness characteristics: the stiff N2B isoform (short spring) and more compliant N2BA isoform (long spring). We tested whether changes in titin isoform expression occur in the diastolic dysfunction that accompanies heart failure. Methods and Results— We used the tachycardia-induced dilated cardiomyopathy canine model (4-week pacing) and found that control myocardium coexpresses the N2B and N2BA isoforms at similar levels, whereas in dilated cardiomyopathy the expression ratio had shifted, without affecting the amount of total titin, toward more prominent N2B expression. This shift was accompanied by elevated titin-based passive muscle stiffness. Pacing also resulted in significant upregulation of obscurin, an ≈800-kDa elastic protein with several signaling domains. Conclusions— Coexpression of titin isoforms with distinct mechanical properties allows modulation of passive stiffness via adjustment of the isoform expression ratio. The canine pacing-induced heart failure model uses this mechanism to increase myocardial stiffness. Thus, changes in titin isoform expression may play a role in diastolic dysfunction in heart failure.
Acute Psychiatric Services in the General Hospital: II. Current Status of Emergency Psychiatric Services
Authors: HOWARD T. BLANE, JAMES J. MULLER, MORRIS E. CHAFETZ
Journal: American Journal of Psychiatry (1967)

After reviewing emergency services in general hospitals, the authors conclude that only a few of them have innovative, community-oriented emergency programs; most seem to follow traditional practices. The authors suggest that we recognize that large segments of the population will always turn to the general hospital for emergency care: the potential for early psychiatric casefinding and preventive intervention with this group is substantial.
Telomere Shortening Accompanies Increased Cell Cycle Activity during Serial Transplantation of Hematopoietic Stem Cells
Authors: Richard C. Allsopp, Samuel Cheshier, Irving L. Weissman
Journal: The Journal of Experimental Medicine (2001)

Reactivation of telomerase and maintenance of telomere length can lead to the prevention of replicative senescence in some human somatic cells grown in vitro. To investigate whether telomere shortening might also play a role in the limitation of hematopoietic stem cell (HSC) division capacity in vivo, we analyzed telomere length during serial transplantation of murine HSCs. Southern blot analysis of telomere length in donor bone marrow cells revealed extensive shortening (∼7 kb) after just two rounds of HSC transplantation. The number of cycling HSCs increased after transplantation and remained elevated for at least 4 mo, while the frequency of HSCs in the bone marrow was completely regenerated by 2 mo after transplantation. Direct analysis of telomeres in HSCs by fluorescent in situ hybridization during serial transplantation also revealed a reduction in telomere size. Together, these data show that telomeres shorten during division of HSCs in vivo, and are consistent with the hypothesis that telomere shortening may limit the replicative capacity of HSCs.
Myosin Binding Protein C, a Phosphorylation-Dependent Force Regulator in Muscle That Controls the Attachment of Myosin Heads by Its Interaction With Myosin S2
Authors: Gudrun Kunst, Kai R. Kress, Mathias Gruen, Dietmar Uttenweiler, Mathias Gautel, Rainer H. A. Fink
Journal: Circulation Research (2000)

Myosin binding protein C (MyBP-C) is one of the major sarcomeric proteins involved in the pathophysiology of familial hypertrophic cardiomyopathy (FHC). The cardiac isoform is tris-phosphorylated by cAMP-dependent protein kinase (cAPK) on beta-adrenergic stimulation at a conserved N-terminal domain (MyBP-C motif), suggesting a role in regulating positive inotropy mediated by cAPK. Recent data show that the MyBP-C motif binds to a conserved segment of sarcomeric myosin S2 in a phosphorylation-regulated way. Given that most MyBP-C mutations that cause FHC are predicted to result in N-terminal fragments of the protein, we investigated the specific effects of the MyBP-C motif on contractility and its modulation by cAPK phosphorylation. The diffusion of proteins into skinned fibers allows the investigation of effects of defined molecular regions of MyBP-C, because the endogenous MyBP-C is associated with few myosin heads. Furthermore, the effect of phosphorylation of cardiac MyBP-C can be studied in a defined unphosphorylated background in skeletal muscle fibers only. Triton skinned fibers were tested for maximal isometric force, Ca(2+)/force relation, rigor force, and stiffness in the absence and presence of the recombinant cardiac MyBP-C motif. The presence of unphosphorylated MyBP-C motif resulted in a significant (1) depression of Ca(2+)-activated maximal force with no effect on dynamic stiffness, (2) increase of the Ca(2+) sensitivity of active force (leftward shift of the Ca(2+)/force relation), (3) increase of maximal rigor force, and (4) an acceleration of rigor force and rigor stiffness development. Tris-phosphorylation of the MyBP-C motif by cAPK abolished these effects. This is the first demonstration that the S2 binding domain of MyBP-C is a modulator of contractility. The anchorage of the MyBP-C motif to the myosin filament is not needed for the observed effects, arguing that the mechanism of MyBP-C regulation is at least partly independent of a "tether," in agreement with a modulation of the head-tail mobility. Soluble fragments occurring in FHC, lacking the spatial specificity, might therefore lead to altered contraction regulation without affecting sarcomere structure directly.
Why Time Matters: Codon Evolution and the Temporal Dynamics of dN/dS
Authors: Carina F. Mugal, Jochen B.W. Wolf, Ingemar Kaj
Journal: Molecular Biology and Evolution (2013)

The ratio of divergence at nonsynonymous and synonymous sites, dN/dS, is a widely used measure in evolutionary genetic studies to investigate the extent to which selection modulates gene sequence evolution. Originally tailored to codon sequences of distantly related lineages, dN/dS represents the ratio of fixed nonsynonymous to synonymous differences. The impact of ancestral and lineage-specific polymorphisms on dN/dS, which we here show to be substantial for closely related lineages, is generally neglected in estimation techniques of dN/dS. To address this issue, we formulate a codon model that is firmly anchored in population genetic theory, derive analytical expressions for the dN/dS measure by Poisson random field approximation in a Markovian framework and validate the derivations by simulations. In good agreement, simulations and analytical derivations demonstrate that dN/dS is biased by polymorphisms at short time scales and that it can take substantial time for the expected value to settle at its time limit where only fixed differences are considered. We further show that in any attempt to estimate the dN/dS ratio from empirical data the effect of the intrinsic fluctuations of a ratio of stochastic variables, can even under neutrality yield extreme values of dN/dS at short time scales or in regions of low mutation rate. Taken together, our results have significant implications for the interpretation of dN/dS estimates, the McDonald-Kreitman test and other related statistics, in particular for closely related lineages.
Renal insufficiency and anemia are independent risk factors for death among patients with acute myocardial infarction1,21As published material, the contents of this manuscript may not be cited, quoted, reproduced or published without the consent of the authors.2The analyses upon which this publication is based were performed under Contract Number 500-96-P704, entitled “Operation Utilization and Quality Control Peer Review Organization (PRO) for the State of Georgia” and sponsored by the Centers…
Authors: Robert D. Langston, Rodney Presley, W. Dana Flanders, William M. Mcclellan
Journal: Kidney International (2003)
Polyclonal Development of Mouse Mammary Preneoplastic Nodules
Authors: William C. Kisseberth, Eric P. Sandgren
Journal: Cancer Research (2004)

Abstract Studies of cellular interactions are critical to the understanding of tumorigenesis. Although many studies have demonstrated a monoclonal composition of advanced neoplasms in humans and mice, the clonal composition of smaller, antecedent lesions has been studied less thoroughly. To examine the clonal development of breast cancer, we generated chimeric mammary glands using mouse mammary epithelium with an inherited predisposition for neoplasia. Analysis of whey acidic protein-transforming growth factor-α transgenic mouse mammary glands, chimeric for two different cell lineage markers, revealed that mammary ducts and alveoli are polyclonal, and putative early preneoplastic lesions, hyperplastic alveolar nodules (HANs), frequently are polyclonal. Furthermore, the chimeric patch patterns in individual HANs were similar to the patterns observed in pregnant chimeric mammary glands. Thus, polyclonality in HANs appears to reflect persistence of the polyclonal architecture of ducts and/or alveoli, suggesting that hyperplasia formation can be the result of non-cell autonomous local tissue microenvironmental influences on groups of cells, rather than clonal progression of a single initiated cell.
The PAS Superfamily: Sensors of Environmental and Developmental Signals
Authors: Yi-Zhong Gu, John B. Hogenesch, Christopher A. Bradfield
Journal: The Annual Review of Pharmacology and Toxicology (2000)

Over the past decade, PAS domains have been identified in dozens of signal transduction molecules and various forms have been found in animals, plants, and prokaryotes. In this review, we summarize this rapidly expanding research area by providing a detailed description of three signal transduction pathways that utilize PAS protein heterodimers to drive their transcriptional output. It is hoped that these model pathways can provide a framework for use in understanding the biology of the less well-understood members of this emerging superfamily, as well as of those to be characterized in the days to come. We use this review to develop the idea that most eukaryotic PAS proteins can be classified by functional similarities, as well as by predicted phylogenetic relationships. We focus on the α-class proteins, which often act as sensors of environmental signals, and the β-class proteins, which typically act as broad-spectrum partners that target these heterodimers to their genomic targets.