tbuckley/cabot-search huggingface dataset:
Glucocorticoids suppress bone formation via the osteoclast
Authors: Hyun Ju Kim, Haibo Zhao, Hideki Kitaura, Sandip Bhattacharyya, Judson A. Brewer, Louis J. Muglia, F. Patrick Ross, Steven L. Teitelbaum
Journal: Journal of Clinical Investigation (2006)

The pathogenesis of glucocorticoid-induced (GC-induced) bone loss is unclear. For example, osteoblast apoptosis is enhanced by GCs in vivo, but they stimulate bone formation in vitro. This conundrum suggests that an intermediary cell transmits a component of the bone-suppressive effects of GCs to osteoblasts in the intact animal. Bone remodeling is characterized by tethering of the activities of osteoclasts and osteoblasts. Hence, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To define the direct impact of GCs on bone-resorptive cells, we compared the effects of dexamethasone (DEX) on WT osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells (GRoc–/– mice). While the steroid prolonged longevity of osteoclasts, their bone-degrading capacity was suppressed. The inhibitory effect of DEX on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF. DEX specifically arrested M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances GRoc–/– mice were spared the impact of DEX on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of DEX, GRoc–/– mice are protected from the steroid’s inhibition of bone formation.
Dmp1 Physically Interacts with p53 and Positively Regulates p53′s Stability, Nuclear Localization, and Function
Authors: Donna P. Frazier, Robert D. Kendig, Fumitake Kai, Dejan Maglic, Takayuki Sugiyama, Rachel L. Morgan, Elizabeth A. Fry, Sarah J. Lagedrost, Guangchao Sui, Kazushi Inoue
Journal: Cancer Research (2012)

Abstract The transcription factor Dmp1 is a Ras/HER2-activated haplo-insufficient tumor suppressor that activates the Arf/p53 pathway of cell-cycle arrest. Recent evidence suggests that Dmp1 may activate p53 independently of Arf in certain cell types. Here, we report findings supporting this concept with the definition of an Arf-independent function for Dmp1 in tumor suppression. We found that Dmp1 and p53 can interact directly in mammalian cells via the carboxyl-terminus of p53 and the DNA-binding domain of Dmp1. Expression of Dmp1 antagonized ubiquitination of p53 by Mdm2 and promoted nuclear localization of p53. Dmp1–p53 binding significantly increased the level of p53, independent of the DNA-binding activity of Dmp1. Mechanistically, p53 target genes were activated synergistically by the coexpression of Dmp1 and p53 in p53−/−;Arf−/− cells, and genotoxic responses of these genes were hampered more dramatically in Dmp1−/− and p53−/− cells than in Arf−/− cells. Together, our findings identify a robust new mechanism of p53 activation mediated by direct physical interaction between Dmp1 and p53. Cancer Res; 72(7); 1740–50. ©2012 AACR.
Classifying Human Brain Tumors by Lipid Imaging with Mass Spectrometry
Authors: Livia S. Eberlin, Isaiah Norton, Allison L. Dill, Alexandra J. Golby, Keith L. Ligon, Sandro Santagata, R. Graham Cooks, Nathalie Y.R. Agar
Journal: Cancer Research (2011)

Brain tissue biopsies are required to histologically diagnose brain tumors, but current approaches are limited by tissue characterization at the time of surgery. Emerging technologies such as mass spectrometry imaging can enable a rapid direct analysis of cancerous tissue based on molecular composition. Here, we illustrate how gliomas can be rapidly classified by desorption electrospray ionization-mass spectrometry (DESI-MS) imaging, multivariate statistical analysis, and machine learning. DESI-MS imaging was carried out on 36 human glioma samples, including oligodendroglioma, astrocytoma, and oligoastrocytoma, all of different histologic grades and varied tumor cell concentration. Gray and white matter from glial tumors were readily discriminated and detailed diagnostic information could be provided. Classifiers for subtype, grade, and concentration features generated with lipidomic data showed high recognition capability with more than 97% cross-validation. Specimen classification in an independent validation set agreed with expert histopathology diagnosis for 79% of tested features. Together, our findings offer proof of concept that intraoperative examination and classification of brain tissue by mass spectrometry can provide surgeons, pathologists, and oncologists with critical and previously unavailable information to rapidly guide surgical resections that can improve management of patients with malignant brain tumors.
Histamine induces K+, Ca2+, and Cl- currents in human vascular endothelial cells. Role of ionic currents in stimulation of nitric oxide biosynthesis.
Authors: K Groschner, W F Graier, W R Kukovetz
Journal: Circulation Research (1994)

The nature of the membrane currents mediating agonist-induced Ca2+ entry and enhanced nitric oxide (NO) production in endothelial cells is still unclear. Using both perforated-patch and conventional whole-cell clamp technique, we have studied the membrane response associated with histamine stimulation of human vascular endothelial cells. In perforated-patch experiments, the initial histamine (10 mumol/L)-induced current reversed close to the K+ equilibrium potential and was blocked by tetrabutylammonium ions (TBA, 10 mmol/L). In addition, a TBA-insensitive current that developed slowly in the presence of histamine was recorded. This delayed histamine-induced current reversed close to neutral potential and was inhibited by SK&amp;F 96365 (25 mumol/L), a putative blocker of receptor-operated Ca2+ channels. Similar histamine effects were observed in conventional whole-cell experiments using pipette solutions with low Ca(2+)-buffering capacity. Strong buffering of intracellular free Ca2+ suppressed the initial, but not the delayed, current response. The delayed component of histamine-induced current was substantially inhibited by the Cl- channel blocker N-phenylanthranilic acid (NPA, 100 mumol/L), and an eightfold change in the Cl- gradient shifted the reversal potential of this current by 30 mV. In Cl(-)-free solutions, histamine induced an SK&amp;F 96365-sensitive NPA-resistant current, which, according to reversal potential measurements in 20 mmol/L extracellular Ca2+, corresponded to a cation conductance with 13- to 25-fold selectivity for Ca2+ over K+. Both SK&amp;F 96365 and TBA strongly suppressed histamine-induced rises in intracellular free Ca2+ and cellular cGMP levels, whereas NPA did not. Our results provide the first demonstration that three distinct ionic conductances contribute to the histamine-induced membrane response of endothelial cells. It is suggested that histamine induces a Cl- conductance that is apparently not involved in Ca2+ homeostasis and regulation of NO biosynthesis, while, in parallel, joint activation of a rapidly induced K+ permeability and a slowly developing cation permeability mediate Ca2+ entry and stimulation of endothelial NO production.
Oral Mucositis Complicating Chemotherapy and/or Radiotherapy: Options for Prevention and Treatment
Authors: W. J. Kostler, M. Hejna, C. Wenzel, C. C. Zielinski
Journal: CA A Cancer Journal for Clinicians (2001)

Chemotherapy- and radiotherapy-induced oral mucositis represents a therapeutic challenge frequently encountered in cancer patients. This side effect causes significant morbidity and may delay the treatment plan, as well as increase therapeutic expenses. The pathogenesis of this debilitating side effect can be attributed to the direct mucosal toxicity of cytotoxic agents and ionizing radiation and to indirect mucosal damage caused by a concomitant inflammatory reaction exacerbated in the presence of neutropenia, and the emergence of bacterial, mycotic, and viral infections. The prophylactic and therapeutic armamentarium for the treatment of oral mucositis consists of locally and systemically applied nonpharmacological measures and pharmacotherapeutics.
MPs raise alarm over underfunded mental health services for children
Authors: A. O'Dowd
Journal: BMJ (2014)

Commissioning and provision of mental health services for children and adolescents in England was a cause for serious concern, MPs have said in a highly critical report.

Lack of funding, failures in early intervention, poor access to services, out of date information, growing waiting times for help, and a lack of scrutiny over services were all highlighted as serious problems by MPs on the parliamentary health select committee.

The Health Committee published a report on 5 November after its inquiry into children’s and adolescents’ mental health services, saying that overall there were “serious and deeply ingrained problems” in this area.1

MPs received 237 written submissions to their inquiry, the highest number it had received for any inquiry it has held during this parliament, from many organisations, clinicians, and individual service users and their parents.

The report said, “The prevailing picture was of CAMHS …
How is Xpert MTB/RIF being implemented in 22 high tuberculosis burden countries?
Authors: Zhi Zhen Qin, Madhukar Pai, Wayne Van Gemert, Suvanand Sahu, Marzieh Ghiasi, Jacob Creswell
Journal: European Respiratory Journal (2014)

Accurate and rapid diagnosis is crucial for tuberculosis control by ensuring a timely start to treatment and reducing transmission. In 2012, almost one third of tuberculosis cases were not diagnosed and/or reported to national tuberculosis programmes (NTPs), and <25% of estimated incident multidrug-resistant (MDR) cases were diagnosed [1]. Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), a nucleic acid amplification test, was recommended in 2010 by the World Health Organization (WHO) for detection of HIV-associated pulmonary tuberculosis and rifampicin resistance [2]. In 2013, the test was recommended for detection of paediatric tuberculosis and some forms of extrapulmonary tuberculosis (EPTB), as well as an initial test to replace smear microscopy [3]. Xpert MTB/RIF implementation is mainly donor-funded, focused on DST and is not widely used outside South Africa <http://ow.ly/CK4NS> We are grateful to all NTP staff and respondents who completed the surveys and answered our follow-up questions. We are also grateful to Claudia Denkinger (Foundation for Innovative New Diagnostics, Geneva, Switzerland), Sandra Kik (KNCV Tuberculosis Foundation, The Hague, The Netherlands) and Pamela Chedore (independent laboratory consultant, Toronto, Canada) for useful input on the survey design.
Dilution of Respiratory Solutes in Exhaled Condensates
Authors: RICHARD M. EFFROS, KELLY W. HOAGLAND, MARK BOSBOUS, DANIEL CASTILLO, BRADLEY FOSS, MARSHALL DUNNING, MEIR GARE, WEN LIN, FENG SUN
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Most exhaled water is produced as gaseous water vapor, which can be collected in cooled condensers. The presence of nonvolatile solutes in these condensates suggests that droplets of respiratory fluid (RF) have also been collected. However, calculation of RF solute concentrations from condensates requires estimation of the dilution of RF droplets by water vapor. We used condensate electrolyte concentrations to calculate the dilution of RF droplets in condensates from 20 normal subjects. The total ionic concentration (conductivity) was 497 ± 68 (mean ± SEM) μ M. Of this, 229 ± 43 μ M was NH4 +, but little NH4 + was collected from subjects with tracheostomies, indicating oral formation. The Na+ concentration in condensate ([Na+]cond) averaged 242 ± 43 μ M. Large variations in [Na+]cond correlated well with variations of K+ in condensate ([K+]cond) and Cl− in condensate ([Cl−]cond), and were attributed to differences in respiratory droplet dilution. Dividing condensate values of ([Na+] + [K+] ) by those of plasma indicated that RF represented between 0.01% and 2.00% of condensate volumes. Calculated values for Na+, K+, Cl−, lactate, and protein in RF were [Na+]RF = 91 ± 8 mM, [K+]RF = 60 ± 11 mM, [Cl−]RF = 102 ± 17 mM, [lactate]RF = 44 ± 17 mM, and [protein]RF = 7.63 ± 1.82 g/dl, respectively.
Altered peptidase and viral-specific T cell response in LMP2 mutant mice
Authors: Luc Van Kaert, Philip G. Ashton-Rickardt, Maryna Eichelberger, Maria Gaczynska, Kumiko Nagashima, Kenneth L. Rock, Alfred L. Goldberg, Peter C. Doherty, Susumu Tonegawa
Journal: Immunity (1994)
Type 1 Diabetes Through the Life Span: A Position Statement of the American Diabetes Association
Authors: Jane L. Chiang, M. Sue Kirkman, Lori M.B. Laffel, Anne L. Peters
Journal: Diabetes Care (2014)

Type 1 diabetes is characterized by an immune-mediated depletion of b-cells that results in lifelong dependence on exogenous insulin.While both type 1 and type 2 diabetes result in hyperglycemia, the pathophysiology and etiology of the diseases are distinct and require us to consider each type of diabetes independently.As such, this position statement summarizes available data specific to the comprehensive care of individuals with type 1 diabetes.The goal is to enhance our ability to recognize and manage type 1 diabetes, to prevent its associated complications, and to eventually cure and prevent this disease.
Inflammatory Response in Airway Epithelial Cells Isolated from Patients with Cystic Fibrosis
Authors: Nada Aldallal, Erin E. McNaughton, Lori J. Manzel, Autumn M. Richards, Joseph Zabner, Thomas W. Ferkol, Dwight C. Look
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

The concept that inflammatory gene expression is dysregulated in airway epithelial cells from patients with cystic fibrosis (CF) is controversial. To examine this possibility systematically, responses to inflammatory stimuli were compared in CF airway epithelial cell lines without versus with wild-type CF transmembrane conductance regulator (CFTR) complementation and in tracheobronchial epithelial cells from patients with versus without CF. Epithelial cell expression of the leukocyte adhesion glycoprotein intercellular adhesion molecule-1 (ICAM-1) and release of the neutrophil chemoattractant interleukin (IL)-8 were determined under basal conditions or after exposure to stimuli important in CF airway inflammatory responses. We found that uncorrected CF airway epithelial cell lines inconsistently expressed higher ICAM-1 and IL-8 levels. Human CF tracheobronchial epithelial cells in primary culture released moderately increased IL-8 only after exposure to Pseudomonas aeruginosa. In CF cells with higher IL-8 release, transient expression of wild-type CFTR using an adenoviral vector did not specifically affect cytokine levels. The results indicate that there is considerable variability in airway epithelial cell responses to inflammatory stimuli among different individuals and cell models systems. Although increased ICAM-1 and IL-8 expression are observed in some CF airway epithelial cell models, many CF cells do not exhibit significant dysregulation of these important inflammatory genes.
Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008
Authors: Paul Okunieff, Lisa A. Kachnic, Louis S. Constine, Clifton D. Fuller, Laurie E. Gaspar, Daniel F. Hayes, Jean Hooks, Clifton Ling, Frank L. Meyskens, Philip A. Philip, David Raben, Stephen R. Smalley, Gregory P. Swanson, Beverly A. Teicher, Charles R. Thomas, Bhadrasain Vikram, Michael J. Zelefsky, Laurence H. Baker
Journal: Clinical Cancer Research (2009)

Abstract Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High-priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational end points that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans. (Clin Cancer Res 2009;15(18):5663–70)
Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor
Authors: Denise A. Yardley, Roohi R. Ismail-Khan, Bohuslav Melichar, Mikhail Lichinitser, Pamela N. Munster, Pamela M. Klein, Scott Cruickshank, Kathy D. Miller, Min J. Lee, Jane B Trepel
Journal: Journal of Clinical Oncology (2013)

Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone.Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity.One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS.Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.
Lung Metastasis Fails in MMTV-PyMT Oncomice Lacking S100A4 Due to a T-Cell Deficiency in Primary Tumors
Authors: Birgitte Grum-Schwensen, Jörg Klingelhöfer, Mariam Grigorian, Kasper Almholt, Boye Schnack Nielsen, Eugene Lukanidin, Noona Ambartsumian
Journal: Cancer Research (2010)

Interactions between tumor and stroma cells are essential for the progression of cancer from its initial growth at a primary site to its metastasis to distant organs. The metastasis-stimulating protein S100A4 exerts its function as a stroma cell-derived factor. Genetic depletion of S100A4 significantly reduced the metastatic burden in lungs of PyMT-induced mammary tumors. In S100A4(+/+) PyMT mice, massive leukocyte infiltration at the site of the growing tumor at the stage of malignant transition was associated with increased concentration of extracellular S100A4 in the tumor microenvironment. In contrast, in S100A4(-/-) PyMT tumors, a significant suppression of T-cell infiltration was documented at the transition period. In vitro, the S100A4 protein mediated the attraction of T cells. Moreover, S100A4(+/+), but not S100A4(-/-), fibroblasts stimulated the invasion of T lymphocytes into fibroblast monolayers. In vivo, the presence of S100A4(+/+), but not S100A4(-/-), fibroblasts significantly stimulated the attraction of T lymphocytes to the site of the growing tumor. Increased levels of T cells were also observed in the premetastatic lungs of tumor-bearing mice primed to metastasize by S100A4(+/+) fibroblasts. Treatment of T cells with the S100A4 protein stimulated production of cytokines, particularly granulocyte colony-stimulating factor and eotaxin-2. The same cytokines were detected in the fluid of S100A4(+/+) PyMT tumors at the transition period. We suggest that release of S100A4 in the primary tumor stimulates infiltration of T cells and activates secretion of cytokines, thus triggering sequential events that fuel tumor cells to metastasize. Similar processes could occur in the premetastatic lungs, facilitating generation of inflammatory milieu favorable for metastasis formation.
Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity
Authors: M. Margarida Bernardo, Alexander Kaplun, Sijana H. Dzinic, Xiaohua Li, Jonathan Irish, Adelina Mujagic, Benjamin Jakupovic, Jessica B. Back, Eric Van Buren, Xiang Han, Ivory Dean, Yong Q. Chen, Elisabeth Heath, Wael Sakr, Shijie Sheng
Journal: Cancer Research (2015)

Abstract Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of two-dimensional (2D), three-dimensional (3D), and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro, and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro, and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, docetaxel, MS275, and salinomycin were all cytotoxic. In suspension, while MS275 and salinomycin were toxic, docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension and to salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity and enhances tumor sensitivity to salinomycin, which may hold promise in overcoming tumor cell heterogeneity and plasticity. Cancer Res; 75(18); 3970–9. ©2015 AACR.
Hemineglect, extinction, and the importance of conscious processing
Authors: Eric Siéroff
Journal: Behavioral and Brain Sciences (2002)

Neuropsychological studies on hemineglect and extinction show that “neglected” or “extinguished” stimuli can access a semantic level. However, processing of these stimuli is usually not accomplished at the same level as non-neglected stimuli. These data are compatible with Perruchet &amp; Vinter's hypothesis of the importance of consciousness in the construction of representations and knowledge.