tbuckley/cabot-search huggingface dataset:
Protein Kinase C ζ Is Required for Epidermal Growth Factor–Induced Chemotaxis of Human Breast Cancer Cells
Authors: Ronghua Sun, Ping Gao, Lin Chen, Dalong Ma, Jiming Wang, Joost J. Oppenheim, Ning Zhang
Journal: Cancer Research (2005)

Chemotaxis plays an important role in cancer cell metastasis. In this study, we showed that epidermal growth factor (EGF) was a more potent chemoattractant than chemokine SDF-1alpha/CXCL12 for human breast cancer cell MDA-MB-231. Different inhibitors were used to evaluate the involvement of 12 protein kinase C (PKC) isotypes in the chemotactic signaling pathway. Chelerythrine chloride, an inhibitor of all PKC isotypes, blocked chemotaxis, whereas inhibitors of classic and novel PKC, such as Gö6976, Gö6850, or calphostin C, only impaired EGF-induced chemotaxis to a minor extent by not greater-than32% inhibition. These data suggested that atypical PKC were involved. The ligand-induced actin polymerization and cell adhesion were also similarly dependent on atypical PKC. Immunofluorescent staining showed an EGF-induced, LY294002-sensitive translocation of PKCzeta from the cytosol to the plasma membrane, indicating that EGF was capable of activating PKCzeta, probably via phosphoinositide 3 kinases. A myristoylated PKCzeta pseudosubstrate blocked the chemotaxis with an IC(50) of 20 mumol/L. To expand our investigation, we further showed that in MCF-7 and T47D, two additional human breast cancer cell lines, EGF-activated PKCzeta and the PKCzeta pseudosubstrate, inhibited chemotaxis. Taken together, our data suggest that PKCzeta is an essential component of the EGF-stimulated chemotactic signaling pathway in human breast cancer cells.
A Randomized Placebo-Controlled Trial of Saccharomyces boulardii in Combination With Standard Antibiotics for Clostridium difficile Disease
Authors: L V McFarland, C M Surawicz, R N Greenberg, R Fekety, G W Elmer, K A Moyer, S A Melcher, K E Bowen, J L Cox, Z Noorani
Journal: JAMA (1994)

<h3>Objective.</h3> —To determine the safety and efficacy of a new combination treatment for patients with<i>Clostridium difficile</i>—associated disease (CDD). The treatment combines the yeast<i>Saccharomyces boulardii</i>with an antibiotic (vancomycin hydrochloride or metronidazole). <h3>Design.</h3> —A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and<i>S boulardii</i>or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. <h3>Setting.</h3> —National referral study of ambulatory or hospitalized patients from three main study coordinating centers. <h3>Patients.</h3> —A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. <h3>Intervention.</h3> —Treatment with oral<i>S boulardii</i>(1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. <h3>Main Outcome Measure.</h3> —Recurrence of active CDD. <h3>Results.</h3> —A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with<i>S boulardii</i>and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of<i>S boulardii</i>was significant (recurrence rate 34.6%, compared with 64.7% on placebo;<i>P</i>=.04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo;<i>P</i>=.86). There were no serious adverse reactions associated with<i>S boulardii</i>. <h3>Conclusions.</h3> —The combination of standard antibiotics and<i>S boulardii</i>was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of<i>S boulardii</i>was demonstrated for those with an initial episode of CDD. (<i>JAMA</i>. 1994;271:1913-1918)
Cell-to-Cell Connection of Endothelial Progenitor Cells With Cardiac Myocytes by Nanotubes
Authors: Masamichi Koyanagi, Ralf P. Brandes, Judith Haendeler, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2005)

The regeneration of new myocardium by stem or progenitor cells is an important therapeutic option. Cellular or nuclear fusion is considered as an alternative to cell reprogramming by transdifferentiation. However, the generation of hybrid cells may also be a consequence of a transient transmembrane exchange of proteins and organelles between cells. Therefore, we investigated the formation of intercellular connections, which may allow the transport of macromolecular structures between labeled adult human endothelial progenitor cells (EPC) and GFP-expressing neonatal rat cardiomyocytes (CM) in a coculture system. FACS analysis revealed that, 6 days after initiation of coculture, 2.1±0.4% of the cells stained positive for GFP and Dil-ac-LDL. 6 hours after initiation of the coculture, ultrafine intercellular structures between Dil-ac-LDL-labeled EPC and GFP-expressing CM were observed. The number of EPC, which established nanotubular connections with CM increased from 0.5±0.2% after 6 hours to 2.6±0.3% after 24 hours of coculture. The intercellular connections had a diameter from 50 to 800 nm, a length of 5 to 120 μm, and were only transiently established. To determine whether the nanotubular structures allowed the transport of organelles, we labeled CM with a mitochondrial live tracker (MitoTracker). Using time-lapse video microscopy, we observed the transport of stained complexes between CM and EPC resulting in up-take of MitoTracker-positive structures in EPC. Thus, the present study shows a novel type of cell-to-cell communication between progenitor cells and CM in vitro, which may contribute to the acquisition of a cardiomyogenic phenotype independent of permanent cellular or nuclear fusion.
Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation
Authors: David Y. Chiang, Na Li, Qiongling Wang, Katherina M. Alsina, Ann P. Quick, Julia O. Reynolds, Guoliang Wang, Darlene Skapura, Niels Voigt, Dobromir Dobrev, Xander H.T. Wehrens
Journal: Cardiovascular Research (2014)

Altered Ca2+ handling in atrial fibrillation (AF) has been associated with dysregulated protein phosphatase 1 (PP1) and subcellular heterogeneities in protein phosphorylation, but the underlying mechanisms remain unclear. This is due to a lack of investigation into the local, rather than global, regulation of PP1 on different subcellular targets such as ryanodine receptor type 2 (RyR2), especially in AF. We tested the hypothesis that impaired local regulation of PP1 causes RyR2 hyperphosphorylation thereby promoting AF susceptibility. To specifically disrupt PP1's local regulation of RyR2, we used the spinophilin knockout (Sp−/−) mice (Mus musculus) since PP1 is targeted to RyR2 via spinophilin. Without spinophilin, the interaction between PP1 and RyR2 was reduced by 64%, while RyR2 phosphorylation was increased by 43% at serine (S)2814 but unchanged at S2808. Lipid bilayer experiments revealed that single RyR2 channels isolated from Sp−/− hearts had an increased open probability. Likewise, Ca2+ spark frequency normalized to sarcoplasmic reticulum Ca2+ content was also enhanced in Sp−/− atrial myocytes, but normalized by Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitors KN-93 and AIP and also by genetic inhibition of RyR2 S2814 phosphorylation. Finally, Sp−/− mice exhibited increased atrial ectopy and susceptibility to pacing-induced AF, both of which were also prevented by the RyR2 S2814A mutation. PP1 regulates RyR2 locally by counteracting CaMKII phosphorylation of RyR2. Decreased local PP1 regulation of RyR2 contributes to RyR2 hyperactivity and promotes AF susceptibility. This represents a novel mechanism for subcellular modulation of calcium channels and may represent a potential drug target of AF.
S100A1 Deficiency Impairs Postischemic Angiogenesis Via Compromised Proangiogenic Endothelial Cell Function and Nitric Oxide Synthase Regulation
Authors: Patrick Most, Carolin Lerchenmüller, Giuseppe Rengo, Adrian Mahlmann, Julia Ritterhoff, David Rohde, Chelain Goodman, Cornelius J. Busch, Felix Laube, Julian Heissenberg, Sven T. Pleger, Norbert Weiss, Hugo A. Katus, Walter J. Koch, Karsten Peppel
Journal: Circulation Research (2012)

Mice lacking the EF-hand Ca2+ sensor S100A1 display endothelial dysfunction because of distorted Ca2+ -activated nitric oxide (NO) generation.To determine the pathophysiological role of S100A1 in endothelial cell (EC) function in experimental ischemic revascularization.Patients with chronic critical limb ischemia showed almost complete loss of S100A1 expression in hypoxic tissue. Ensuing studies in S100A1 knockout (SKO) mice subjected to femoral artery resection unveiled insufficient perfusion recovery and high rates of autoamputation. Defective in vivo angiogenesis prompted cellular studies in SKO ECs and human ECs, with small interfering RNA-mediated S100A1 knockdown demonstrating impaired in vitro and in vivo proangiogenic properties (proliferation, migration, tube formation) and attenuated vascular endothelial growth factor (VEGF)-stimulated and hypoxia-stimulated endothelial NO synthase (eNOS) activity. Mechanistically, S100A1 deficiency compromised eNOS activity in ECs by interrupted stimulatory S100A1/eNOS interaction and protein kinase C hyperactivation that resulted in inhibitory eNOS phosphorylation and enhanced VEGF receptor-2 degradation with attenuated VEGF signaling. Ischemic SKO tissue recapitulated the same molecular abnormalities with insufficient in vivo NO generation. Unresolved ischemia entailed excessive VEGF accumulation in SKO mice with aggravated VEGF receptor-2 degradation and blunted in vivo signaling through the proangiogenic phosphoinositide-3-kinase/Akt/eNOS cascade. The NO supplementation strategies rescued defective angiogenesis and salvaged limbs in SKO mice after femoral artery resection.Our study shows for the first time downregulation of S100A1 expression in patients with critical limb ischemia and identifies S100A1 as critical for EC function in postnatal ischemic angiogenesis. These findings link its pathological plasticity in critical limb ischemia to impaired neovascularization, prompting further studies to probe the microvascular therapeutic potential of S100A1.
Identification of Independent Primary Tumors and Intrapulmonary Metastases Using DNA Rearrangements in Non–Small-Cell Lung Cancer
Authors: Stephen J. Murphy, Marie-Christine Aubry, Faye R. Harris, Geoffrey C. Halling, Sarah H. Johnson, Simone Terra, Travis M. Drucker, Michael K. Asiedu, Benjamin R. Kipp, Eunhee S. Yi, Tobias Peikert, Ping Yang, George Vasmatzis, Dennis A. Wigle
Journal: Journal of Clinical Oncology (2014)

Distinguishing independent primary tumors from intrapulmonary metastases in non-small-cell carcinoma remains a clinical dilemma with significant clinical implications. Using next-generation DNA sequencing, we developed a chromosomal rearrangement-based approach to differentiate multiple primary tumors from metastasis.Tumor specimens from patients with known independent primary tumors and metastatic lesions were used for lineage test development, which was then applied to multifocal tumors. Laser capture microdissection was performed separately for each tumor. Genomic DNA was isolated using direct in situ whole-genome amplification methodology, and next-generation sequencing was performed using an Illumina mate-pair library protocol. Sequence reads were mapped to the human genome, and primers spanning the fusion junctions were used for validation polymerase chain reaction.A total of 41 tumor samples were sequenced (33 adenocarcinomas [ADs] and eight squamous cell carcinomas [SQCCs]), with a range of three to 276 breakpoints per tumor identified. Lung tumors predicted to be independent primary tumors based on different histologic subtype did not share any genomic rearrangements. In patients with lung primary tumors and paired distant metastases, shared rearrangements were identified in all tumor pairs, emphasizing the patient specificity of identified breakpoints. Multifocal AD and SQCC samples were reviewed independently by two pulmonary pathologists. Concordance between histology and genomic data occurred in the majority of samples. Discrepant tumor samples were resolved by genome sequencing.A diagnostic lineage test based on genomic rearrangements from mate-pair sequencing demonstrates promise for distinguishing independent primary from metastatic disease in lung cancer.
Regional Neural Dysfunctions in Chronic Schizophrenia Studied With Positron Emission Tomography
Authors: Jae-Jin Kim, Somaia Mohamed, Nancy C. Andreasen, Daniel S. O’Leary, G. Leonard Watkins, Laura L. Boles Ponto, Richard D. Hichwa
Journal: American Journal of Psychiatry (2000)

Whether chronicity of illness produces progressive neural abnormality is an important question in current schizophrenia research. Positron emission tomography (PET) offers an opportunity to visualize and measure blood flow in vivo to address this issue. The authors previously compared healthy volunteers with neuroleptic-naive patients experiencing their first episode of schizophrenia and reported that abnormalities in blood flow, including lower flow in prefrontal regions and higher flow in the thalamus and cerebellum, are present at the early stage of schizophrenic illness. The goal of the present study was to measure blood flow with PET in patients with chronic schizophrenia.PET was used to examine regional cerebral blood flow (rCBF) in 30 patients with chronic schizophrenia and 30 normal comparison subjects. To determine if the patterns of flow abnormality in the patients with chronic schizophrenia were similar to those of patients experiencing their first episode of schizophrenia, the same cognitive condition was examined as in the earlier study. The patients with chronic schizophrenia in the current study had been neuroleptic-free for at least 3 weeks.As in the authors' previous study, the chronically ill patients showed lower flow in prefrontal areas and higher flow in thalamic and cerebellar regions than normal comparison subjects, suggesting that a similar neural dysfunction occurs in both first-episode and chronic schizophrenia.rCBF abnormalities in patients with chronic schizophrenia are not due to chronicity of illness or the effects of medication. These results provide evidence that the primary neural abnormalities in schizophrenia may occur in cortical, cerebellar, and thalamic regions and that the dysfunction in these regions may explain the "loosening of associations" that Bleuler considered to be the fundamental cognitive phenotype of schizophrenia. These abnormalities can be reconceptualized as "cognitive dysmetria."
Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas
Authors: E Dejean, M H Renalier, M Foisseau, X Agirre, N Joseph, G R de Paiva, T Al Saati, J Soulier, C Desjobert, L Lamant, F Prósper, D W Felsher, J Cavaillé, H Prats, G Delsol, S Giuriato, F Meggetto
Journal: Leukemia (2011)
Discovery of DNA Repair Inhibitors by Combinatorial Library Profiling
Authors: Benjamin J. Moeller, Richard L. Sidman, Renata Pasqualini, Wadih Arap
Journal: Cancer Research (2011)

Small molecule inhibitors of DNA repair are emerging as potent and selective anticancer therapies, but the sheer magnitude of the protein networks involved in DNA repair processes poses obstacles to discovery of effective candidate drugs. To address this challenge, we used a subtractive combinatorial selection approach to identify a panel of peptide ligands that bind DNA repair complexes. Supporting the concept that these ligands have therapeutic potential, we show that one selected peptide specifically binds and noncompetitively inactivates DNA-PKcs, a protein kinase critical in double-strand DNA break repair. In doing so, this ligand sensitizes BRCA-deficient tumor cells to genotoxic therapy. Our findings establish a platform for large-scale parallel screening for ligand-directed DNA repair inhibitors, with immediate applicability to cancer therapy.
Advances in High-Field Magnetic Resonance Imaging
Authors: Xiaoping Hu, David G. Norris
Journal: Annual Review of Biomedical Engineering (2004)

Among advances in magnetic resonance imaging (MRI), the increase of the magnetic field strength is perhaps one of the most significant. The use of high magnetic fields for in vivo magnetic resonance is motivated by a number of considerations. Advantages are increases in signal-to-noise ratio, blood-oxygenation level-dependent contrast, and spectral resolution, while disadvantages include potential reduction of contrast in anatomic imaging owing to lengthening of T1 and effects of susceptibility of high fields. To address these challenges, technical advances have been made in various aspects of MRI, allowing high-field MRI to provide exquisite morphological and functional details in clinical and research settings. This review provides an overview of technical issues and applications of high-field MRI.
Osteopontin as an airway epithelial tumor promoter
Authors: I. Psallidas, A.D. Giannou, S. Magkouta, C. Moschos, I. Giopanou, T. Agalioti, K. Katsikani, D.C.M. Simoes, C. Roussos, I. Kalomenidis, G.T. Stathopoulos
Journal: European Respiratory Journal (2013)

Osteopontin (secreted phosphoprotein 1; SPP1) expression has been identified in human lung cancer and has been linked with enhanced tumor progression. To examine its functional role, we induced lung tumors by repetitive urethane or MCA/BHT lung carcinogens in C57BL/6 mice lacking both (Spp1-/-), one (Spp1+/-), or no (Spp1+/+) copy of the endogenous Spp1 gene. Primary end-points were lung tumor number and size; secondary end-points were SPP1 expression, epithelial cell survival, carcinogen-induced inflammation, and angiogenesis. Data are presented as mean±SD. Compared with Spp1+/+ mice (n=22), Spp1-/- mice (n=25) developed dramatically fewer and significantly smaller lung tumors in response to urethane, while Spp1+/- mice (n=12) behaved similar to Spp1-/- mice (number/diameter of lung tumors in Spp1+/+, Spp1+/-, and Spp1-/- mice, respectively: 16.1±12.7/1.2±0.3 mm, 2.4±2.3/0.9±0.2 mm, and 1.3±1.6/0.7±0.2 mm; P  These studies were supported by a European Research Council Starting Independent Investigator Grant (#260524).
Obesity in children and adolescents
Authors: L. Hudson, R. M. Viner
Journal: BMJ (2012)

New data help to shed light on scale of future disease burden

As the epidemic of childhood obesity in high income countries has developed over the past 20 years, questions have emerged about the implications of adiposity in children and adolescents for current and future health. In a linked systematic review (doi:10.1136/bmj.e4759), Friedemann and colleagues report that obese children and adolescents aged 5-15 years have raised serum lipids, blood pressure, glucose, and insulin as well as increased left ventricular mass compared with children with a healthy weight.1 This is worrying, but what exactly does it mean?

The long term outcomes for the current generation’s obese children and adolescents remain to be seen. However, the current study will help build a more accurate picture of the cardiometabolic risk that these young people are likely to face. Most worrying is that these findings indicate that end organ effects in the form of increased left ventricular mass are already present in obese children. Despite high heterogeneity in many of the meta-analyses, the current review provides a stark illustration of the probable threat that childhood obesity poses to disease …
Osler on acupuncture
Authors: M. H. Lipkovitz
Journal: JAMA (1973)

To the Editor.—  The following description of  by Sir William Osler 1 may be of interest.  For lumbago acupuncture is, in acute cases, the most efficient treatment. Needles from three to four inches in length (ordinary bonnetneedles, sterilized, will do) are thrust into the lumbar muscles at the seat of pain, and withdrawn after five or ten minutes. In many instances the relief is immediate, and I can corroborate fully the statements of Ringer, who taught me this practice, as to its extraordinary and prompt efficacy in many instances.  Apparently the principle utilized was that of local counter-irritation, which would leave only a semantic connection between Osler's practice and that of inserting needles at distant sites—the technique advocated by current acupuncturists.
The National Physical Activity Plan: A Call to Action From the American Heart Association
Authors: William E. Kraus, Vera Bittner, Lawrence Appel, Steven N. Blair, Timothy Church, Jean-Pierre Després, Barry A. Franklin, Todd D. Miller, Russell R. Pate, Ruth E. Taylor-Piliae, Dorothea K. Vafiadis, Laurie Whitsel
Journal: Circulation (2015)
The Pathogenesis of Pituitary Tumors
Authors: Sylvia L. Asa, Shereen Ezzat
Journal: Annual Review of Pathology Mechanisms of Disease (2009)

Recently there has been significant progress in our understanding of pituitary development, physiology, and pathology. New information has helped to clarify the classification of pituitary tumors. Epidemiologic analyses have identified a much higher incidence of pituitary tumors than previously thought. We review the pathogenetic factors that have been implicated in pituitary tumorigenesis and the application of novel targeted therapies that underscore the increasingly important role of the pathologist in determining accurate diagnoses and facilitating appropriate treatment of patients with these disorders.
Successful outcome of severe aplastic anemia following epstein‐barr virus infection
Authors: Judy E. Grishaber, Kenneth L. McClain, Donald H. Mahoney, Donald J. Fernbach
Journal: American Journal of Hematology (1988)

Abstract Severe aplastic anemia has been reported in children following Epstein‐Barr virus (EBV) infection. The pathophysiology of disease is not known, but an immunologic mechanism is suspected because of the rapid response to steroids. A patient with severe aplastic anemia following EBV infection experienced bone marrow recovery after treatment with high‐dose prednisone. After reviewing the literature it is concluded that steroid therapy is indicated in this select group of patients.