tbuckley/cabot-search huggingface dataset:
Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
Authors: Francisco G. Pernas, Clint T. Allen, Mary E. Winters, Bin Yan, Jay Friedman, Bhavana Dabir, Kunal Saigal, Gerhard S. Mundinger, Xiaojiang Xu, John C. Morris, Katherine R. Calvo, Carter Van Waes, Zhong Chen
Journal: Clinical Cancer Research (2009)

Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment.The IC(50) of gefitinib for HNSCC cell lines were determined using 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial.In vitro, gefitinib inhibited cell proliferation with differing IC(50), and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappaB. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients.Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKT and p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC.
Notch1 Deficiency Dissociates the Intrathymic Development of Dendritic Cells and T Cells
Authors: Freddy Radtke, Isabel Ferrero, Anne Wilson, Rosemary Lees, Michel Aguet, H. Robson MacDonald
Journal: The Journal of Experimental Medicine (2000)

Thymic dendritic cells (DCs) form a discrete subset of bone marrow (BM)-derived cells, the function of which is to mediate negative selection of autoreactive thymocytes. The developmental origin of thymic DCs remains controversial. Although cell transfer studies support a model in which T cells and thymic DCs develop from the same intrathymic pluripotential precursor, it remains possible that these two types of cells develop from independent intrathymic precursors. Notch proteins are cell surface receptors involved in the regulation of cell fate specification. We have recently reported that T cell development in inducible Notch1-deficient mice is severely impaired at an early stage, before the expression of T cell lineage markers. To investigate whether development of thymic DCs also depends on Notch1, we have constructed mixed BM chimeric mice. We report here that thymic DC development from Notch1−/− BM precursors is absolutely normal (in terms of absolute number and phenotype) in this competitive situation, despite the absence of Notch1−/− T cells. Furthermore, we find that peripheral DCs and Langerhans cells are also not affected by Notch1 deficiency. Our results demonstrate that the development of DCs is totally independent of Notch1 function, and strongly suggest a dissociation between intrathymic T cell and DC precursors.
Temporary Prostatic Stenting and Androgen Suppression: A New Minimally Invasive Approach to Malignant Prostatic Retention
Authors: K M Anson, D G Barnes, T P Briggs, G M Watson, R A Miller
Journal: Journal of the Royal Society of Medicine (1993)

Urinary retention secondary to carcinoma of the prostate is usually treated by 'channel' transurethral resection of the prostate either performed alone or in combination with hormone manipulation. The combination of temporary prostatic stenting and androgen suppression may reduce the morbidity and mortality associated with this treatment. We report on our initial experience using the combination of a temporary prostatic stent with the oral anti-androgen Flutamide in 10 patients with urinary retention or severe bladder outflow obstruction secondary to prostatic carcinoma. Eight of the ten patients successfully voided and maintained normal voiding after stent removal. There were two treatment failures requiring prostatic resection. We believe the cost of stenting and medication is entirely justified by patient preference and clearance of hospital beds.
Transplantable Murine Salivary Gland Carcinoma (Myoepithelioma). I. Biologic Behavior and Ultrastructural Features2
Authors: William E. Delaney
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Transplantable Murine Salivary Gland Carcinoma (Myoepithelioma). I. Biologic Behavior and Ultrastructural Features Get access William E. Delaney, M.D. William E. Delaney, M.D. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 58, Issue 1, January 1977, Pages 61–65, https://doi.org/10.1093/jnci/58.1.61 Published: 01 January 1977 Article history Received: 10 June 1974 Revision received: 04 June 1976 Accepted: 18 June 1976 Published: 01 January 1977
P102 Recovery Of Baseline Lung Function After A Pulmonary Exacerbation In Children With Primary Ciliary Dyskinesia (pcd)
Authors: M. Sunther, S. Carr, C. Hogg, A. Bush
Journal: Thorax (2014)

<h3>Rationale</h3> Spirometry in children with cystic fibrosis (CF) frequently fails to return to baseline after treatment for a pulmonary exacerbation [Am J Respir Crit Care Med 2010; 182: 627–32]. It is unclear however how often lung function returns to previous baseline levels after treatment of a pulmonary exacerbation with intravenous antibiotics in children with PCD. <h3>Objectives</h3> To determine in children with PCD: (1) the proportion treated for a pulmonary exacerbation who recover to baseline FEV<sub>1 </sub>within 3 months and at 12 months and (2) to try to identify factors which are associated with failure to recover spirometry. <h3>Methods</h3> Cohort study using the PCD database for children at the Royal Brompton Hospital from 2003 to 2013. We selected the first clinically diagnosed pulmonary exacerbation treated with intravenous antibiotics. The best FEV<sub>1 </sub>in the 3 months after treatment and at 12 months was compared to the best FEV<sub>1 </sub>in the 12 months before treatment (baseline). Recovery to baseline was defined as any FEV<sub>1</sub> after treatment that was greater than or equal to 90% of the baseline FEV<sub>1</sub>. <h3>Results</h3> Of the 30 children treated for pulmonary exacerbations, 77% recovered to baseline lung function within 3 months and 73% at 12 months. There were no significant differences between the responders and non-responders in terms of age, sex, ethnicity, BMI, baseline FEV<sub>1</sub>, persistent sputum infection or use of antibiotic prophylaxis or mucolytic agent (Table). <h3>Conclusions</h3> Similar to findings in CF, around 25% PCD patients fail to recover to baseline lung function after treatment of a pulmonary exacerbation with intravenous antibiotics. Better treatment strategies are needed, and the results also suggest that prevention of exacerbations would be a useful end-point in clinical trials.
Health‐related quality of life in children with sickle cell anemia: Impact of blood transfusion therapy
Authors: Lauren M. Beverung, John J. Strouse, Monica L. Hulbert, Kathleen Neville, Robert I. Liem, Baba Inusa, Beng Fuh, Allison King, Emily Riehm Meier, James Casella, Michael R. DeBaun, Julie A. Panepinto
Journal: American Journal of Hematology (2014)

The completion of the Multicenter Silent Infarct Transfusion Trial demonstrated that children with pre-existing silent cerebral infarct and sickle cell anemia (SCA) who received regular blood transfusion therapy had a 58% relative risk reduction of infarct recurrence when compared to observation. However, the total benefit of blood transfusion therapy, as assessed by the parents, was not measured against the burden of monthly blood transfusion therapy. In this planned ancillary study, we tested the hypothesis that a patient centered outcome, health-related quality of life (HRQL), would be greater in participants randomly assigned to the blood transfusion therapy group than the observation group. A total of 89% (175 of 196) of the randomly allocated participants had evaluable entry and exit HRQL evaluations. The increase in Change in Health, measured as the child's health being better, was significantly greater for the transfusion group than the observation group (difference estimate = -0.54, P ≤ 0.001). This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy.
The role of protein phosphatase type-2A in the cell cycle: initiation of the G2/M transition
Authors: Tina H. Lee
Journal: Seminars in Cancer Biology (1995)

The last several years has seen an explosion in the identification of a multiplicity of serine/threonine protein kinases with important functions in eukaryotic cell cycle progression. Although the major serine/threonine phosphoprotein phosphatases, that must oppose the action of the kinases, have been identified and extensively characterized for their involvement in metabolic processes, the functions of the phosphatases in cell cycle regulation is less well established. This paper focuses on the role of the type-2A protein phosphatase (PP2A) in the regulation of the G2/M transition in theXenopuscell cycle. Although a role for PP2A in regulating G2/M has been suggested by studies in various systems, it is the relative simplicity of thein-vitrocell cycle extracts ofXenopusthat has allowed the clearest dissection of the mechanism by which PP2A regulates this transition.
The clinical significance of<i>BRAF</i>and<i>NRAS</i>mutations in a clinic-based metastatic melanoma cohort
Authors: H. Ekedahl, H. Cirenajwis, K. Harbst, A. Carneiro, K. Nielsen, H. Olsson, L. Lundgren, C. Ingvar, G. Jönsson
Journal: British Journal of Dermatology (2013)

BRAF and NRAS mutations are frequently found in melanoma tumours, and recently developed BRAF-targeted therapies demonstrate significant clinical benefit.We sought to investigate the clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort.In total, 237 tumours, mostly metastatic lesions, from 203 patients were screened for mutations in exon 15 of BRAF and exon 2 of NRAS using Sanger sequencing. BRAF and NRAS mutation status was analysed in relation to clinical and histopathological characteristics, and outcome.Mutation in BRAF and NRAS was present in 43% (88% V600E, 10% V600K) and 30% (48% Q61K, 40% Q61R) of metastatic melanomas, respectively. We found consistent BRAF and NRAS mutation status in all but one of 27 patients with multiple metastases. BRAF mutation was associated with younger age at primary diagnosis (P = 0.02). Among patients with distant metastatic melanoma, patients with BRAF-mutant tumours without BRAF inhibitor treatment had inferior survival compared with patients with BRAF inhibitor treatment [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.10-5.01, P = 0.03]. We also observed a trend towards better prognosis for patients with wild-type and NRAS-mutant tumours compared with BRAF V600E-mutant tumours (HR 0.64, 95% CI 0.39-1.04, P = 0.07; and HR 0.76, 95% CI 0.48-1.21, P = 0.25, respectively).We were able to confirm the effect of BRAF inhibitor treatment in a single clinical institution. The results suggest further that BRAF mutation is a weak prognostic factor but a strong predictive factor and that BRAF-mutant melanoma might constitute one or more distinct subtypes of the disease with certain aetiology and clinical outcome.
Spontaneous pneumothorax can be associated with <i>TGFBR2</i> mutation
Authors: Joseph E. Chambers, Lucy E. Dalton, Deepak N. Subramanian, Bibek Gooptu, Anu Balan, Soo-Mi Park, Simon Holden, Stefan J. Marciniak
Journal: European Respiratory Journal (2015)

Primary pneumothorax affects 0.01% of the population. 10% of cases have a family history of pneumothorax but in the majority, a definitive genetic diagnosis is not made. We report a 26-year-old, white British woman who presented with left apical pneumothorax (figure 1a). Previously, she had migraines, multiple stress fractures in her right foot, myopia, easy bruising, lumbar scoliosis and spontaneous dislocation of the right patella. She had no previous history of pneumothoraces or any other respiratory problems, and had never smoked. TGFBR2 mutations that cause Loeys-Dietz syndrome can present as pneumothorax <http://ow.ly/SlMkS>
Impaired non-specific delayed cutaneous hypersensitivity in bird fancier's lung.
Authors: R Orriols, F Morell, V Curull, A Roman, G Sampol
Journal: Thorax (1989)

The relation between non-specific delayed cutaneous hypersensitivity and bird fancier9s lung was investigated in 13 patients with the disorder. They were compared with 50 subjects who had no reason to have decreased non-specific delayed cutaneous hypersensitivity (control group) and 34 patients with pulmonary sarcoidosis. In addition, 13 patients with bird fancier9s lung (11 of the original group) were tested at least one year after avoiding exposure to the causal antigen. Five antigens (candidine, staphylococcal toxoid, tuberculin purified protein derivative, trichophyton, and streptokinase-streptodornase) were injected intradermally (0.1 ml) and the mean weal diameter was measured at 48 hours. The mean weal size was significantly less in the subjects with bird fancier9s lung at the time of diagnosis than in the control group (2.23 v 5.66 mm) but did not differ significantly from that of the subjects with sarcoidosis (2.80 mm) or from that of the bird fanciers with no exposure to the causal antigen for one year (2.75 mm). The impairment of non-specific delayed cutaneous hypersensitivity in patients with bird fancier9s lung appears to be quantitatively similar to that occurring in sarcoidosis.
Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells
Authors: John Cardone, Gaelle Le Friec, Pierre Vantourout, Andrew Roberts, Anja Fuchs, Ian Jackson, Tesha Suddason, Graham Lord, John P Atkinson, Andrew Cope, Adrian Hayday, Claudia Kemper
Journal: Nature Immunology (2010)
The deadly connection between endoplasmic reticulum, Ca2+, protein synthesis, and the endoplasmic reticulum stress response in malignant glioma cells
Authors: Guyla G. Johnson, Misti C. White, Jian-He Wu, Matthew Vallejo, Maurizio Grimaldi
Journal: Neuro-Oncology (2014)

The endoplasmic reticulum (ER) is involved in Ca2+ signaling and protein processing. Accumulation of unfolded proteins following ER Ca2+ depletion triggers the ER stress response (ERSR), which facilitates protein folding and removal of damaged proteins and can induce cell death. Unfolded proteins bind to chaperones, such as the glucose-regulated protein (GRP)78 and cause the release of GRP78-repressed proteins executing ERSR. Several glioma cell lines and primary astrocytes were used to analyze ERSR using standard western blots, reverse transcription–PCR, viability assays, and single cell Ca2+ imaging. ERSR induction with thapsigargin results in a more intense ERSR associated with a larger loss of ER Ca2+, activation of ER-associated caspases (4/12) and caspase 3, and a higher rate of malignant glioma cell death than in normal glial cells. Malignant glioma cells have higher levels of protein synthesis and expression of the translocon (a component of the ribosomal complex, guiding protein entry in the ER), the activity of which is associated with the loss of ER Ca2+. Our experiments confirm increased expression of the translocon in malignant glioma cells. In addition, blockade of the ribosome-translocon complex with agents differently affecting translocon Ca2+ permeability causes opposite effects on ERSR deployment and death of malignant glioma cells. Excessive ER Ca2+ loss due to translocon activity appears to be responsible for the enhancement of ERSR, leading to the death of glioma cells. The results reveal a characteristic of malignant glioma cells that could be exploited to develop new therapeutic strategies to treat incurable glial malignancies.
The exit of Trypanosoma cruzi from the phagosome is inhibited by raising the pH of acidic compartments.
Authors: V Ley, E S Robbins, V Nussenzweig, N W Andrews
Journal: The Journal of Experimental Medicine (1990)

The protozoan parasite Trypanosoma cruzi can infect many distinct mammalian cell types. The parasites enter cells through the formation of phagocytic vacuoles, but later are found free in the cytosol, where they multiply as amastigotes. Using transmission electron microscopy we found that within 2 h after infection 70% of the parasites, including examples of both mammalian forms (trypomastigotes and amastigotes), were inside partially disrupted vacuoles or free in the cytosol. We demonstrated that the pH of vacuoles containing recently interiorized parasites is acidic, through immunocytochemical localization of the acidotropic compound DAMP (18) in their interior. Increasing the vacuolar pH with chloroquine, ammonium chloride, methylamine, or monensin significantly inhibited the escape of the parasites into the cytosol. These results are compatible with the hypothesis that an acid-active hemolysin of T. cruzi (15) might be involved in the escape mechanism.
Case of Haemorrhage into the Peritoneal Cavity
Authors: A. W. Tomkins
Journal: BMJ (1873)

cular hypertrophy" of the arterial walls; bat how is one to feel sure that the appearance one sees is really due to " true muscular hypertrophy"?Is this not, in fact, a question of interpretation ?Dr. Johnson feels convinced that the drawing he gives (fig.2,p.4, BRIT.MIED.JOURNAL, January 4th, I873) has been copied from an artery the muscular tissue of which was " hypertrophied"; but I venture to think that some who have studied the small arteries in health and in disease with great care will not acquiesce in that opinion: at any rate, the appearances delineated may be accounted for in more ways than c-ne.
VISPA: a computational pipeline for the identification and analysis of genomic vector integration sites
Authors: Andrea Calabria, Simone Leo, Fabrizio Benedicenti, Daniela Cesana, Giulio Spinozzi, Massimilano Orsini, Stefania Merella, Elia Stupka, Gianluigi Zanetti, Eugenio Montini
Journal: Genome Medicine (2014)

The analysis of the genomic distribution of viral vector genomic integration sites is a key step in hematopoietic stem cell-based gene therapy applications, allowing to assess both the safety and the efficacy of the treatment and to study the basic aspects of hematopoiesis and stem cell biology. Identifying vector integration sites requires ad-hoc bioinformatics tools with stringent requirements in terms of computational efficiency, flexibility, and usability. We developed VISPA (Vector Integration Site Parallel Analysis), a pipeline for automated integration site identification and annotation based on a distributed environment with a simple Galaxy web interface. VISPA was successfully used for the bioinformatics analysis of the follow-up of two lentiviral vector-based hematopoietic stem-cell gene therapy clinical trials. Our pipeline provides a reliable and efficient tool to assess the safety and efficacy of integrating vectors in clinical settings.
Demonstration of a human pyrogen-inducing factor during mixed leukocyte reactions.
Authors: C A Dinarello
Journal: The Journal of Experimental Medicine (1981)

The role of lymphocytes in the pathogenesis of fever was investigated by stimulating human blood mononuclear cells in a two-way mixed leukocyte reaction (MLR). After 2-7 d of incubation, MLR supernates contained a factor that was not pyrogenic itself when injected into rabbits; however, these supernates, when incubated with human blood monocytes from a third donor, induced the synthesis of LP. The pyrogen-inducing activity was stable at 56 degrees C, destroyed at 70 degrees C, and was neither dialyzable nor removable by adsorption by anti-human leukocytic pyrogen (LP) attached to Sepharose 4B. Production of this factor was not always correlated with increased thymidine incorporation in the MLR. Its production was absent when peripheral lymphocytes were purified over nylon wool. The concentration of mononuclear cells in the MLR varied from 5 X 10(5) to 5 X 10(6)/ml in round-bottomed tubes. Under the latter conditions, some donor cells produced this factor without stimulation in the MLR culture, but when these cells were cultured on flat-bottomed containers at low cell concentration, autologous production was not observed. These experiments demonstrate the production of a human lymphocyte factor (lymphokine) that induces LP synthesis. This pyrogen-inducing lymphokine may be important in the pathogenesis of fever in certain immunologically mediated diseases.
Is it really time to look at distal airways to improve asthma phenotyping and treatment?
Authors: T. Perez
Journal: European Respiratory Journal (2011)

Is it really time to look at distal airways to improve asthma phenotyping and treatment?T. Perez I n 2011, severe asthma and/or insufficient control of disease remain major challenges for the pulmonologist [1].Small airway involvement has been demonstrated by a number of studies, particularly in fatal, severe or poorly controlled asthma, and may be a potential target to improve treatment and asthma outcomes [2][3][4][5].Although inhaled corticosteroids (ICSs) remain the cornerstone of asthma treatment, there is a continuing debate on the potential benefit of small-particle formulations.In this context, the recent study by COHEN et al. [6] clearly adds new data to this controversial topic.
Current sustained delivery strategies for the design of local neurotrophic factors in treatment of neurological disorders
Authors: Hongzhuo Liu, Yanyan Zhou, Shichao Chen, Meng Bu, Jiayu Xin, Sanming Li
Journal: Asian Journal of Pharmaceutical Sciences (2013)

Although therapeutic potential of neurotrophic factors (NTFs) has been well recognized for over two decades, attempts to translate that potential to the clinic have been disappointing, largely due to significant obstacles in delivery, including inadequate protein dose/kinetics released at target sites. Considerable efforts have been made to improve the therapeutic performance of NTFs. This articles reviews recent developments in localized delivery systems of NTFs for the neurological disorders treatments with a main focus on sustained delivery strategies. Different non-covalent binding approaches have been employed to immobilize proteins in hydrogels, microspheres, electrospun nanofibers, and their combined systems, which serve as depots for sustained local release of NTFs. The challenges associated with current NTFs delivery systems and how these systems can be applied to neurological diseases and disorders have been discussed in the review. In conclusion, optimal delivery systems for NTFs will be needed for reliable and meaningful clinical benefits; ideally, delivering a time and dose-controlled release of bioactive multi-NTFs at different individual optimal kinetics to achieve multi-functions in target tissues is significant preferred.
Serum Apoptosis Markers in Acute Liver Failure: A Pilot Study
Authors: Anna E. Rutherford, Linda S. Hynan, Carolina B.S. Borges, David G. Forcione, Jason T. Blackard, Wenyu Lin, April R. Gorman, Obaid Shakil Shaikh, Adrian Reuben, Edwyn Harrison, K. Rajender Reddy, William M. Le, Raymond T. Chung
Journal: Clinical Gastroenterology and Hepatology (2007)