tbuckley/cabot-search huggingface dataset:
Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis
Authors: I S Woolhouse
Journal: Thorax (2002)

<b>Background:</b> Sputum analysis is used increasingly to assess airway inflammation in patients with chronic obstructive pulmonary disease, including those with chronic bronchitis and bronchiectasis. However, it is not known whether dithiothreitol (DTT), a reducing mucolytic agent regularly used to homogenise sputum, affects the detection of inflammatory mediators in the sputum soluble phase from such patients. <b>Methods:</b> Thirty two spontaneous sputum samples were collected from 13 patients with chronic bronchitis and 17 with bronchiectasis. An aliquot from each sample was treated with either freshly prepared 0.1% DTT plus normal saline (NaCl) or NaCl alone, then ultracentrifuged to obtain the sputum sol phase. Interleukin (IL)-1β, IL-6, IL-8, leukotriene B<sub>4</sub> (LTB<sub>4</sub>), secretory leukoprotease inhibitor (SLPI), alpha-1-antitrypsin (α<sub>1</sub>-AT), and tumour necrosis factor alpha (TNFα) were measured by ELISA, and neutrophil elastase (NE) and myeloperoxidase (MPO) by chromogenic substrate assay. The effect of DTT on the detection of assay standards was also determined. <b>Results:</b> Median levels of IL-1β, IL-6, IL-8, SLPI, and NE were similar in the DTT and NaCl treated samples. There was a significant reduction in median (IQR) levels of detectable TNFα (0.07 (0.00–0.47) pM <i>v</i> 0.90 (0.06–6.98) pM, p&lt;0.001), LTB<sub>4</sub> (1.67 (1.31–2.64) nM <i>v</i> 2.29 (0.95–4.22) nM, p&lt;0.05) and MPO (0.00 (0.00–0.00) mg/l <i>v</i> 4.48 (0.00–33.66) mg/l, p&lt;0.001) and a small increase in the median α<sub>1</sub>-AT concentration (0.05 (0.03–0.08) nM <i>v</i> 0.03 (0.02–0.08) nM, p&lt;0.01) in the DTT treated samples. DTT had no effect on the assay standards for IL-1β, IL-8 or TNFα, but at higher concentrations it did affect IL-6, SLPI, NE, and LTB<sub>4</sub> standards (43%, 70%, 76% and 643% of control value for top standard, respectively) and at all concentrations DTT completely abolished MPO activity. <b>Conclusions:</b> Sputum processing with DTT significantly reduces the detectable concentration of TNFα, LTB<sub>4</sub> and MPO, and produces a small but significant increase in median α<sub>1</sub>-AT levels. To avoid this problem we recommend that an untreated aliquot of sputum be retained for cytokine analysis, unless the assay has been specifically validated.
Tpeak-Tend and Tpeak-Tend Dispersion as Risk Factors for Ventricular Tachycardia/Ventricular Fibrillation in Patients With the Brugada Syndrome
Authors: Jesus Castro Hevia, Charles Antzelevitch, Francisco Tornés Bárzaga, Margarita Dorantes Sánchez, Francisco Dorticós Balea, Roberto Zayas Molina, Miguel A. Quiñones Pérez, Yanela Fayad Rodríguez
Journal: Journal of the American College of Cardiology (2006)
Neuro-oncology and palliative care: a challenging interface
Authors: E. Lin, M. A. Rosenthal, B. H. Le, P. Eastman
Journal: Neuro-Oncology (2012)

atients with high-grade gliomas almost invariably develop disease progression despite recent advances in anticancer therapy.Increasingly, the value of formal palliative care consultation and management has been recognized in both cancer and noncancer medicine.However, there is a paucity of data to definitively guide the provision of palliative care for neuro-oncology patients.This paper aims to review the existing evidence for and describe the interface between palliative care and neuro-oncology, with a particular focus on glioblastoma multiforme (GBM).We also discuss the role of palliative care in nonmalignant neurologic disease where parallels with neuro-oncology might be drawn. GlioblastomaGBM remains an uncommon diagnosis.However, for those patients and carers affected, it is life-changing from first diagnosis.The median overall survival for patients receiving GBM therapy is 14 months, and fewer than 10% of patients are alive at 5 years following diagnosis. 1,2Further, patients older than 70 years and/or those with poor KPS may not benefit from current palliative anticancer therapies and can have significantly worse outcomes.Indeed, population-based management surveys document median survivals of ,10 months and negligible 5-year survival rates. 3any clinicians view GBM as having the worst of all cancer prognoses; however, median and long-term survival of GBM patients compare favorably with those of patients with other incurable cancers, such as metastatic pancreatic and metastatic lung. 2 GBM results in significant morbidity, which can be challenging for patients and their carers, as well as for health professionals.Physical symptoms include headache, nausea, vomiting, easy fatigue, and excessive somnolence. 4Local tumor effects, depending on site, may result in focal or generalized neurologic problems such as seizure, motor weakness, aphasia, and impaired vision. 5,6Mood and cognitive disturbance are common. 7 multidisciplinary approach including neurosurgery, radiation oncology, neuro-oncology, and allied health is recommended to optimize treatment outcomes. 3,4However, few of these multidisciplinary teams would routinely include palliative care, despite the lack of curative treatment options and significant symptom burden.The palliative care needs of patients with GBM can be complex, with a paucity of published data in this area. 5 -9 Parallels do exist, however, between the needs of patients with GBM and those of patients with other, more common cancer diagnoses and nonmalignant chronic neurologic illness.
Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages.
Authors: Z Werb, M J Banda, P A Jones
Journal: The Journal of Experimental Medicine (1980)

We have investigated the ability of neutral and lysosomal enzymes of mouse macrophages to degrade the insoluble extracellular matrices secreted by smooth muscle cells, endothelial cells, and fibroblasts. Matrices produced by smooth muscle cells contained glycoproteins, elastin, and collagens, but matrices of endothelial cells and fibroblasts contained no elastin. Sequential enzyme digestion of residual matrix revealed that plasmin, a product of macrophage plasminogen activation, degraded 50-70% of the glycoprotein in the matrices but did not degrade the elastin or the collagens. Purified macrophage elastase degraded glycoprotein and elastin components but had no effect on the collagens. The rate of elastin degradation by macrophage elastase was decreased in the presence of the glycoproteins. In contrast, human granulocyte elastase effectively degraded the matrix glycoproteins, elastin, and, to a lesser extent, collagens, Mammalian collagenase degraded only collagens. Conditioned medium from resident and inflammatory macrophages, containing mixtures of the secreted proteinases, degraded the glycoprotein and elastin components of the matrices. However, conditioned medium was less effective in degrading matrix than comparable amounts of purified macrophage elastase because &amp;gt; 90% of the elastase in the medium was in a latent form. Inclusion of plasminogen in the assays accelerated degradation. In the presence of plasminogen, glycoproteins were degraded readily by medium from P388D1, pyran copolymer-, thioglycollate-, and periodate-elicited macrophages and, to a lesser extent, by medium from endotoxin-elicited and resident macrophages; medium from P388D1, thioglycollate-, and periodate-elicited macrophages was most effective in elastin degradation, and resident, endotoxin-elicited and pyran copolymer-elicited macrophages degraded almost no elastin. The macrophage cathepsins D and B degraded all the matrix components at an optimum pH of 5.5 and acted with the secreted neutral proteinases to degrade the connective tissue macromolecules to amino acids and oligopeptides. These data indicate that macrophages at inflammatory sites contain and secrete proteolytic enzymes that could degrade the extracellular matrix.
Regulatory modules in the developing heart
Authors: P Habets
Journal: Cardiovascular Research (2003)

Fragments of regulatory DNA of cardiac genes drive reporter gene expression in sometimes unexpected subdomains of the heart. These patterns have revealed that the regulatory DNA of genes consists of distinct subfragments (regulatory modules) that are active in different regions of the developing heart. In this review we give an overview of the activity of regulatory modules in vivo. Furthermore, we investigated the relationship between the activity domains of the regulatory modules, the building blocks of the heart and the developmental patterning of the myocardium. Most of the regulatory modules show a domain of activity broader than the morphological boundary of a cardiac compartment and seem to respond to a patterning program along the antero-posterior axis.
Incorporation of &lt;sup&gt;125&lt;/sup&gt;I-iododeoxyuridine Into Target Cells as an Assay for Cell Immunity&lt;xref ref-type="fn" rid="fn2"&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/xref&gt;
Authors: F Fish, M Yaakubovicz, I P Witz
Journal: JNCI Journal of the National Cancer Institute (1974)

We assayed cell immunity by measuring the decrease of 125I-iododeoxyuridine (125IUDR) uptake into target cells when incubated with sensitized effector cells. This method was suitable for target .cells in monolayer or in suspension cultures. A labeling regimen was used in which 125IUDR was added after a short exposure of the target cells to effector cells. This obviated the need to preplate the target cells in the culture vessel a day before or to prelabel them. Thereby, the test was further simplified and shortened. This method was used successfully in allogeneic and syngeneic (tumor-specific) systems. In the syngeneic systems, lymph node cells (LNC) from mice with a syngeneic 3-methylcholanthrene-induced tumor inhibited 125IUDR incorporation into the corresponding tumor cells. LNC from mice with a different syngeneic 3-methylcholanthrene-induced tumor did not inhibit 125IUDR incorporation into the first tumor cells.
Kinome Profiling of Chondrosarcoma Reveals Src-Pathway Activity and Dasatinib as Option for Treatment
Authors: Yvonne M. Schrage, Inge H. Briaire-de Bruijn, Noel F.C.C. de Miranda, Jolieke van Oosterwijk, Antonie H.M. Taminiau, Tom van Wezel, Pancras C.W. Hogendoorn, Judith V.M.G. Bovée
Journal: Cancer Research (2009)

Abstract Chondrosarcomas are notorious for their resistance to conventional chemotherapy and radiotherapy, indicating there are no curative treatment possibilities for patients with inoperable or metastatic disease. We therefore explored the existence of molecular targets for systemic treatment of chondrosarcoma using kinome profiling. Peptide array was performed for four chondrosarcoma cell lines and nine primary chondrosarcoma cultures with GIST882, MSCs, and colorectal cancer cell lines as controls. Activity of kinases was verified using immunoblot, and active Src- and platelet-derived growth factor receptor (PDGFR) signaling were further explored using imatinib and dasatinib on chondrosarcoma in vitro. The AKT1/GSK3B pathway was clearly active in chondrosarcoma. In addition, the PDGFR pathway and the Src kinase family were active. PDGFR and Src kinases can be inhibited by imatinib and dasatinib, respectively. Although imatinib did not show any effect on chondrosarcoma cell cultures, dasatinib showed a decrease in cell viability at nanomolar concentrations in seven of nine chondrosarcoma cultures. However, inhibition of phosphorylated Src (Y419) was found both in responsive and nonresponsive cells. In conclusion, using kinome profiling, we found the Src pathway to be active in chondrosarcoma. Moreover, we showed in vitro that the inhibitor of the Src pathway, dasatinib, may provide a potential therapeutic benefit for chondrosarcoma patients who are not eligible for surgery. [Cancer Res 2009;69(15):6216–22]
IKK-ϵ Coordinates Invasion and Metastasis of Ovarian Cancer
Authors: Sarah Hsu, Marianne Kim, Lidia Hernandez, Valentina Grajales, Anne Noonan, Miriam Anver, Ben Davidson, Christina M. Annunziata
Journal: Cancer Research (2012)

Abstract Inhibitor of IκB kinases (IKK) are key regulators of NF-κB signaling. Three IKK isoforms—α, β, and ϵ—have been linked to oncogenesis, yet the precise components of NF-κB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-ϵ expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P = 0.03). Therefore, we hypothesized that IKK-ϵ drives ovarian cancer metastasis. IKK-ϵ was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ovarian cancer–specific IKK-ϵ–regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-ϵ. Pathway analysis of the signature indicated that IKK-ϵ regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-ϵ depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-ϵ in mice showed decreased aggressiveness, whereas overexpression of IKK-ϵ in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-ϵ is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-ϵ signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway. Cancer Res; 72(21); 5494–504. ©2012 AACR.
IT-06 * PERSONALIZED IMMUNOTHERAPY FOR THE TREATMENT OF GLIOBLASTOMA
Authors: G. De Leon, S. Nair, W. Xie, J. Drake, D. Mitchell
Journal: Neuro-Oncology (2014)

BACKGROUND: Immunotherapy harnesses the immune system to specifically attack malignant cells thereby offering a targeted treatment option without systemic toxicity for patients with GBM. However, immunotherapy remains limited by the relative dearth of antigen specific tumor targets. Since GBMs have been shown to express cytomegalovirus (CMV) antigens, we can use these viral epitopes as a novel, effective, and specific targets in conjunction with other tumor associated antigens (TAAs) for effective glioma therapy. We hypothesize that elucidating a more full antigenic profile of CMV and other TAAs for use in a multi-component immunotherapeutic approach will provide robust immunologic responses against GBM. METHODS: We designed a multiplex RT-qPCR SYBR array (Bio-Rad) containing 27 CMV genes that were shown to be associated with immune reactivity. Agilent 4x44k custom gene expression arrays were designed and developed to screen GBM patient tumor samples for the presence of human TAA genes. RT-qPCR products were verified via Sanger sequencing and select TAA microarray genes were validated via RT-qPCR. Targets identified within GBM specimens were evaluated for immunogenicity in vitro using RNA-pulsed dendritic cells. RESULTS/CONCLUSIONS: As expected, there was significant heterogeneity in the expression of CMV and TAA antigens within primary GBM tumors. The capacity to effectively target GBM tumors using autologous T cells stimulated by antigen pulsed DCs was demonstrated in vitro. In summary, given differences in antigenic profiles of GBM patients, a personalized targeted approach will allow us to select the appropriate RNA transcripts for use in a multi-component dendritic cell based therapy. The enrichment for personalized tumor antigens using transcript specific autologous RNA amplification may further refine immunologic targeting and we have demonstrated the feasibility and immunologic potency of this novel therapeutic approach.
Tonicity-Responsive Enhancer Binding Protein Is an Essential Regulator of Aquaporin-2 Expression in Renal Collecting Duct Principal Cells
Authors: Udo Hasler, Un Sil Jeon, Jeong Ah Kim, David Mordasini, H. Moo Kwon, Eric Féraille, Pierre-Yves Martin
Journal: Journal of the American Society of Nephrology (2006)

Tonicity-responsive enhancer binding protein (TonEBP) plays a key role in protecting renal cells from hypertonic stress by stimulating transcription of specific genes. Under hypertonic conditions, TonEBP activity is enhanced via increased nuclear translocation, transactivation, and abundance. It was reported previously that hypertonicity exerted a dual, time-dependent effect on vasopressin-inducible aquaporin-2 (AQP2) expression in immortalized mouse collecting duct principal cells (mpkCCDcl4). Whereas AQP2 abundance decreased after 3 h of hyperosmotic challenge, it increased after 24 h of hypertonic challenge. This study investigated the role that TonEBP may play in these events by subjecting mpkCCDcl4 cells to 3 or 24 h of hypertonic challenge. Hypertonic challenge increased TonEBP mRNA and protein content and enhanced TonEBP activity as illustrated by both increased TonEBP-dependent luciferase activity and mRNA expression of several genes that are targeted by TonEBP. Irrespective of the absence or presence of vasopressin, decreased TonEBP activity in cells that were transfected with either TonEBP small interfering RNA or an inhibitory form of TonEBP strongly reduced AQP2 mRNA and protein content under iso-osmotic conditions and blunted the increase of AQP2 abundance that was induced after 24 h of hypertonic challenge. Conversely, decreased TonEBP activity did not significantly alter reduced expression of AQP2 mRNA that was induced by 3 h of hypertonic challenge. Mutation of a TonE enhancer element located 489 bp upstream of the AQP2 transcriptional start site abolished the hypertonicity-induced increase of luciferase activity in cells that expressed AQP2 promoter-luciferase plasmid constructs, indicating that TonEBP influences AQP2 transcriptional activity at least partially by acting directly on the AQP2 promoter. These findings demonstrate that in collecting duct principal cells, TonEBP plays a central role in regulating AQP2 expression by enhancing AQP2 gene transcription.
CD45RA and CD45RBhigh expression induced by thymic selection events.
Authors: V A Wallace, W P Fung-Leung, E Timms, D Gray, K Kishihara, D Y Loh, J Penninger, T W Mak
Journal: The Journal of Experimental Medicine (1992)

CD45 is a protein tyrosine phosphatase involved in T and B cell signaling. While peripheral T cells switch CD45 isoforms upon activation, events leading to exon switching during T cell development in the thymus have not been determined. The expression of high molecular weight isoforms of CD45 was examined on thymocytes from nontransgenic and T cell receptor (TCR) transgenic mice. All thymocytes from nontransgenic mice were CD45RB+ as assessed by staining with MB23G2, an anti-CD45RB-specific monoclonal antibody. Interestingly, there was a small population (1-3%) of thymocytes that displayed a higher intensity of staining with MB23G2, CD45RBhigh. CD45RBhigh thymocytes were found in all subsets defined by CD4 and CD8 expression and were also present within the TCR-alpha/beta high population. To analyze whether or not CD45 expression correlated with thymic selection events, expression of CD45RBhigh and a second isoform, CD45RA, was examined on thymocytes from H-Y and 2C TCR transgenic mice and found to correlate with positive and negative selection events but did not occur in nonselecting backgrounds. CD45RA and CD45RBhigh upregulation was also not observed in transgenic mice backcrossed into CD8-deficient mice, a scenario in which there is no positive selection of transgene-expressing thymocytes. These data suggest that modulation of CD45 isoform expression may be involved in thymic selection events.
Heterogeneity of Breast Cancer Metastases: Comparison of Therapeutic Target Expression and Promoter Methylation Between Primary Tumors and Their Multifocal Metastases
Authors: Julie M. Wu, Mary Jo Fackler, Marc K. Halushka, Diana W. Molavi, M. Evangeline Taylor, Wei Wen Teo, Constance Griffin, John Fetting, Nancy E. Davidson, Angelo M. De Marzo, Jessica L. Hicks, Dhananjay Chitale, Marc Ladanyi, Saraswati Sukumar, Pedram Argani
Journal: Clinical Cancer Research (2008)

Abstract Purpose: A comprehensive comparison of biomarker expression between patients' primary breast carcinoma (PBC) and their metastatic breast carcinomas (MBC) has not been done. Experimental Design: We did rapid autopsies (postmortem intervals, 1-4 hours) on 10 consenting patients who died of MBC. We constructed single-patient tissue microarrays from the patients' archived PBC and multiple different MBCs harvested at autopsy, which were immunohistochemically labeled for multiple biomarkers. Methylation of multiple gene promoters was assessed quantitatively on dissected PBC and MBC samples. Results: Extensive heterogeneity was observed between PBC and their paired MBC, as well as among multiple MBC from the same patient. Estrogen and progesterone receptors tended to be uniformly down-regulated in metastases. E-cadherin was down-regulated in a subset of the MBC of one case. Variable overexpression in MBC compared with the PBC was observed for cyclooxygenase-2 (five cases), epidermal growth factor receptor (EGFR; four cases), MET (four cases), and mesothelin (four cases). No case strongly overexpressed HER-2/neu by immunohistochemistry, but eight cases showed variable protein expression ranging from negative to equivocal (2+) in different MBC. In one case, variable low-level HER-2/neu gene amplification was found. EGFR and MET overexpression were restricted to the four basal-type cancers. EGFR protein overexpression did not correlate with EGFR gene amplification. Multigene promoter hypermethylation of RASSF1a, HIN1, cyclin D2, Twist, estrogen receptor α, APC1, and RARβ was overall very similar in the PBC and all MBCs in all cases. Conclusions: Therapeutic targets identified in the PBC or even some MBC may not reflect targets present in all metastatic sites.
Changing strategies of lung biopsies in diffuse lung diseases: the impact of video-assisted thoracoscopy
Authors: M Ravini, G Ferraro, B Barbieri, P Colombo, G Rizzato
Journal: European Respiratory Journal (1998)

The aims of this report were: 1) to compare the strategy of bioptic approach in Italy during the last 4 yrs with a previous period; and 2) to compare efficacy and safety of video-assisted thorascopic lung biopsy (VTLB) versus OLB. We retrospectively evaluated: 1) the strategy of the bioptic approach in the Milan Sarcoid Clinic in the years 1992-1995 (201 patients) versus 1988-1991 (197 patients); and 2) data from 65 VTLB procedures in the years 1992-1995 versus 68 OLB procedures in the years 1988-1991 performed in patients with diffuse lung disease. It was found that the use of OLB (17-9%), mediastinoscopy (15-5%), and scalene node biopsy (20-7%) decreased, whereas transbronchial biopsy (TBB) increased (11-17%). VTLB biopsy is now performed in 17% of patients. VTLB compares favourably with OLB as there is less need for analgesia (7.5+/-7.5 versus 17.5+/-8.0 methadone mg i.m.: p&lt;0.001), lower blood loss (61+/-58 versus 156+/-84 mL in the first postoperative day: p&lt;0.001), and shorter postoperative stay (4.7+/-1.6 versus 5.7+/-1.4 days: p&lt;0.001). Specimen adequacy (98.6 versus 985%) and diagnostic accuracy (86.1% VTLB, versus 92.6% OLB: p&gt;0.05) were the same in the two groups. In conclusion, video-assisted thoracoscopic lung biopsy is replacing both mediastinoscopy and open lung biopsy. It is at present the best option when a surgical procedure is required for histological confirmation of diffuse lung disease.
Soft tissue sarcoma: from molecular diagnosis to selection of treatment. Pathological diagnosis of soft tissue sarcoma amid molecular biology and targeted therapies
Authors: E. Wardelmann, H.-U. Schildhaus, S. Merkelbach-Bruse, W. Hartmann, P. Reichardt, P. Hohenberger, R. Büttner
Journal: Annals of Oncology (2010)