tbuckley/cabot-search huggingface dataset:
Current Understanding of the Molecular Biology of Pancreatic Neuroendocrine Tumors
Authors: Jianliang Zhang, Rony Francois, Renuka Iyer, Mukund Seshadri, Maria Zajac-Kaye, Steven N. Hochwald
Journal: JNCI Journal of the National Cancer Institute (2013)

Pancreatic neuroendocrine tumors (PanNETs) are complicated and often deadly neoplasms. A recent increased understanding of their molecular biology has contributed to expanded treatment options. DNA sequencing of samples derived from patients with PanNETs and rare genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Von Hippel-Lindau (VHL) syndrome reveals the involvement of MEN1, DAXX/ATRX, and the mammalian target of rapamycin (mTOR) pathways in PanNET tumorigenesis. Gene knock-out/knock-in studies indicate that inactivation of factors including MEN1 and abnormal PI3K/mTOR signaling uncouples endocrine cell cycle progression from the control of environmental cues such as glucose, leading to islet cell overgrowth. In addition, accumulating evidence suggests that further impairment of endothelial-endocrine cell interactions contributes to tumor invasion and metastasis. Recent phase III clinical trials have shown that therapeutic interventions, such as sunitinib and everolimus, targeting those signal transduction pathways improve disease-free survival rates. Yet, cure in the setting of advanced disease remains elusive. Further advances in our understanding of the molecular mechanisms of PanNETs and improved preclinical models will assist in developing personalized therapy utilizing novel drugs to provide prolonged control or even cure the disease.
Early Events in B Cell Activation
Authors: Naomi E. Harwood, Facundo D. Batista
Journal: Annual Review of Immunology (2010)

B cell activation is initiated by the ligation of the B cell receptor (BCR) with antigen and ultimately results in the production of protective antibodies against potentially pathogenic invaders. Here we review recent literature concerned with the spatiotemporal dynamic characterization of the early molecular events of B cell activation, including the initiation of BCR triggering, the formation of BCR microclusters, and the dynamic regulation of BCR signaling. Because these events involve the considerable reorganization of molecules within the membrane, an important role for the cytoskeleton is emerging in the regulation of B cell activation. At each stage we highlight the role of the cytoskeleton, establishing its pivotal position during the initiation and regulation of B cell activation.
A Clinical Algorithm to Diagnose Invasive Pulmonary Aspergillosis in Critically Ill Patients
Authors: Stijn I. Blot, Fabio Silvio Taccone, Anne-Marie Van den Abeele, Pierre Bulpa, Wouter Meersseman, Nele Brusselaers, George Dimopoulos, José A. Paiva, Benoit Misset, Jordi Rello, Koenraad Vandewoude, Dirk Vogelaers
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: The clinical relevance of Aspergillus-positive endotracheal aspirates in critically ill patients is difficult to assess.Objectives: We externally validate a clinical algorithm to discriminate Aspergillus colonization from putative invasive pulmonary aspergillosis in this patient group.Methods: We performed a multicenter (n = 30) observational study including critically ill patients with one or more Aspergillus-positive endotracheal aspirate cultures (n = 524). The diagnostic accuracy of this algorithm was evaluated using 115 patients with histopathologic data, considered the gold standard. Subsequently, the diagnostic workout of the algorithm was compared on the total cohort (n = 524), with the categorization based on the diagnostic criteria of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group.Measurements and Main Results: Among 115 histopathology-controlled patients, 79 had proven aspergillosis. The algorithm judged 86 of 115 cases to have putative aspergillosis. This diagnosis was confirmed in 72 and rejected in 14 patients. The algorithm judged 29 patients to have Aspergillus colonization. This was confirmed in 22 and rejected in 7 patients. The algorithm had a specificity of 61% and a sensitivity of 92%. The positive and negative predictive values were 61 and 92%, respectively. In the total cohort (n = 524), 79 patients had proven invasive pulmonary aspergillosis (15.1%). According to the European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria, 32 patients had probable aspergillosis (6.1%) and 413 patients were not classifiable (78.8%). The algorithm judged 199 patients to have putative aspergillosis (38.0%) and 246 to have Aspergillus colonization (46.9%).Conclusions: The algorithm demonstrated favorable operating characteristics to discriminate Aspergillus respiratory tract colonization from invasive pulmonary aspergillosis in critically ill patients.
Preparedness is crucial for safe care of Ebola patients and to prevent onward transmission in Europe – outbreak control measures are needed at its roots in West Africa
Authors: M. J.W Sprenger, D Coulombier
Journal: Eurosurveillance (2014)

Preview this article: Preparedness is crucial for safe care of Ebola patients and to prevent onward transmission in Europe – outbreak control measures are needed at its roots in West Africa, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/19/40/art20925-en-1.gif
S91 Fungal sensitisation and bronchiectasis in a severe asthma clinic
Authors: G Hayes, M Masoli, B Whalley, R Jones, M Hyland
Journal: Thorax (2013)

<h3>Aims</h3> Allergic bronchopulmonary aspergillosis (ABPA) and Severe asthma with fungal sensitivity (SAFS) are well recognised in the severe asthma population. Sensitisation to other moulds has also been described. Defined radiological, immunological, and physiological features are associated with these conditions. We describe these features within a severe asthma population, identifying radiological airway abnormality and the association with fungal sensitisation, airway obstruction and immunological markers. <h3>Methods</h3> Retrospective database analysis of referrals to a severe/difficult asthma service with comparison of radiological, immunological and physiological features in patients with severe refractory asthma (SRA), with and without fungal sensitivity (FS). <h3>Results</h3> (table1) 141 patients with SRA, defined according to ATS criteria, were identified. 67 patients (47.5%) had an abnormal CT scan; the most common abnormalities being bronchial wall thickening (38.8%), bronchiectasis (28.3%) and mucus plugging (2.9%). 35 patients (24.8%) demonstrated fungal sensitisation (FS), 30 to Aspergillus fumigatus and 5 to “mould mix”. All patients, regardless of fungal senstitivity (FS) demonstrated a strongly eosinophilic phenotype with IgE, ENO and blood eosinophil levels of 1450.03 kU/L, 47.36 ppb and 0.95 x109 for those with FS and 387.88 kU/L, 59.96 ppb and 0.8x109L, for those without FS. Consistent with a diagnosis of SRA obstructive spirometry was seen across both groups with post bronchodilator FEV1:FVC ratios of 0.57 (FS) vs 0.62 (SRA) CT appearances most commonly associated with fungal sensitisation were bronchial wall thickening (22.9%) and bronchiectasis (34.3%). In the presence of bronchiectasis and fungal sensitisation equal incidence of proximal and distal disease distribution was observed. Division of those with fungal sensitivity into ABPA, allergic bronchopulmonary mycosis (ABPM), defined according to criteria by Agrawal <i>et al</i>, SAFS and severe asthma without fungal sensitisation also demonstrated further differences (figure 1). Bronchiectasis was seen most frequently in those with SAFS and of the patients with ABPA and ABPM all patients had a serological diagnosis apart from 2 where peripheral bronchiectasis was demonstrated. <h3>Conclusions</h3> In this population SRA is characterised by a strongly positive eosinophilic phenotype, airflow obstruction and a high prevalence of radiological abnormality regardless of FS. FS is associated with bronchiectasis even when diagnostic criteria for ABPA are not met.
Incidence and risk factors for central nervous system occurrencein elderly patients with diffuse large-B-cell lymphoma: influenceof rituximab
Authors: P. Feugier, J.M. Virion, H. Tilly, C. Haioun, G. Marit, M. Macro, D. Bordessoule, C. Recher, M. Blanc, T. Molina, P. Lederlin, B. Coiffier
Journal: Annals of Oncology (2003)
Expression of homocellular and heterocellular gap junctions in hamster arterioles and feed arteries
Authors: S Sandow
Journal: Cardiovascular Research (2003)

Objectives: Conduction of vasoconstrictor and vasodilator responses in the microcirculation involves electrical coupling through gap junction channels among cells of the vascular wall. The present study determined whether reported differences in the properties of conduction along the arterioles of the epithelial hamster cheek pouch (CPA) and feed arteries of its retractor skeletal muscle (RFA) result from differences in the expression profile of specific connexin (Cx) isoforms and the gap junctions they comprise. Methods: Real-time PCR, immunohistochemistry and serial section electron microscopy were used to compare wall morphology and the distribution of gap junctions between respective vessels. Results: Expression of mRNA for Cx37, 40, 43 and 45 was similar between CPA and RFA. In the endothelium, Cx37, 40 and 43 proteins were expressed abundantly between adjacent cells while Cx37 was present in the smooth muscle. In both vessels, endothelial and smooth muscle cell (SMC) layers were well connected by myoendothelial gap junctions (MEGJs), which were found near endothelial cell (EC) gap junctions. Conclusions: The absence of differential gap junctional expression between CPA and RFA, in spite of documented differences in cellular conduction pathways, supports the hypothesis that conductance of vascular gap junction channels can be differentially modulated in resistance microvessels.
Assessment of reversibility of airway obstruction in patients with chronic obstructive airways disease.
Authors: M Nisar, M Walshaw, J E Earis, M G Pearson, P M Calverley
Journal: Thorax (1990)

Spirometry before and after an inhaled beta agonist or a course of oral prednisolone is widely used to detect reversible airflow limitation in patients with chronic obstructive lung disease. How many of these patients have a response and how the response to beta agonists relates to the response to corticosteroids is not clear. In 127 outpatients (mean (SD) FEV1 0.92 (0.38) 1) who had a clinical diagnosis of chronic obstructive lung disease (continuous breathlessness for more than six months and an FEV1/forced vital capacity (FVC) ratio less than 60%) and who appeared to be stable, the change in FEV1 was measured after salbutamol 200 micrograms from a metered dose inhaler and 5 mg from a nebuliser. Symptoms and spirometric values were recorded before and after two weeks of oral prednisolone 30 mg. Reversibility was defined as a response in FEV1 of 15% or more from baseline alone and as a 15% change and a minimum increase of at least 200 ml. The latter gave results that showed greater internal consistency between the drug regimens. On the basis of this criterion 56 patients (44%) had no response to salbutamol or prednisolone, 71 responded to salbutamol (including all 27 steroid responders), and 25 patients had a response to salbutamol 5 mg but not to 200 micrograms. In general, the largest increase in FEV1 after salbutamol occurred in the subjects with greatest improvement after prednisolone. Subjects showing a response in FEV1 after two weeks' prednisolone had a fall in total symptom score, unlike those who had no response to any treatment or a response to salbutamol only. These data show that reversibility in response to beta agonists is common in patients diagnosed on clinical grounds as having stable chronic obstructive lung disease, that it can be substantial, and that it is best detected by using a larger dose of salbutamol. Salbutamol responders were those most likely to improve after a trial of oral prednisolone. Allowance should be made for the variability of FEV1 in the calculation of the percentage response at low baseline values (less than 1 litre).
Paranormal healing and hypertension
Authors: J. J Beutler, J. T M Attevelt, S. A Schouten, J. A J Faber, E. J D. Mees, G. G Geijskes
Journal: BMJ (1988)

A prospective randomised trial was carried out to see whether paranormal healing by laying on of hands might reduce blood pressure in essential hypertension and whether such an effect might be due to a paranormal, psychological, or placebo factor. Patients were randomised to three treatment groups: paranormal healing by laying on of hands (n=40), paranormal healing at a distance (n=37), and no paranormal healing (controls; n=38). Healing at a distance and no paranormal healing were investigated double blind. Systolic and diastolic blood pressures were significantly reduced in all three groups at week 15 (mean reduction (95% confidence interval) 17·1 (14·0 to 20·2)/8·3 (6·6 to 10·0) mm Hg). Only the successive reductions in diastolic blood pressures among the groups from week to week were significantly different. Each week diastolic pressure was consistently lower (average 1·9 mm Hg) after healing at a distance compared with control, but on paired comparison these differences were not significant. Probably week to week variations among the groups accounted for any differences noted. In this study no treatment was consistently better than another and the data cannot therefore be taken as evidence of a paranormal effect on blood pressure. Probably the fall in blood pressure in all three groups either was caused by the psychosocial approach or was a placebo effect of the trial itself.
Technetium-99m hexakis 2-methoxy-2-isobutyl isonitrile and thallium-201 extraction, washout, and retention at varying coronary flow rates in rabbit heart.
Authors: R C Marshall, E M Leidholdt, D Y Zhang, C A Barnett
Journal: Circulation (1990)

Technetium-99m hexakis 2-methoxy-2-isobutyl isonitrile (Tc-MIBI) and thallium-201 extraction, washout, and retention were investigated and compared in 20 isolated, isovolumic, retrograde blood-perfused rabbit hearts at flow rates ranging from 0.5 to 3.5 ml/g wet wt min-1 in the absence of tracer recirculation. Mean Tc-MIBI peak instantaneous extraction was lower (0.55 +/- 0.10, p less than 0.001) and more affected by flow rate (p less than 0.05) than 201Tl peak instantaneous extraction (0.83 +/- 0.06). In contrast, the rate of 201Tl washout was significantly faster (p less than 0.05) and initially more dependent on perfusion rate (p less than 0.05) than Tc-MIBI washout. Reflecting its higher peak instantaneous extraction, 201Tl retention was 55-79% higher immediately after isotope injection (p less than 0.001) than Tc-MIBI retention, and relative changes in maximal 201Tl net uptake correlated better (p less than 0.05) with relative flow changes than maximal Tc-MIBI net uptake. However, due to its faster washout rate, the superiority of thallium over Tc-MIBI as a perfusion indicator was lost within 10 minutes of tracer injection under the present single-pass experimental conditions. These data were interpreted to indicate that 1) Tc-MIBI is not as well extracted and has a slower washout rate than 201Tl; 2) varying the coronary flow rate has significant but divergent effects on the extraction, washout, and retention of Tc-MIBI and 201Tl; and 3) the present results support continued evaluation of Tc-MIBI as a possible perfusion indicator.
Interleukin-8 and Markers of Neutrophil Degranulation in Pleural Effusions
Authors: ROSA M. SEGURA, JOSÉ ALEGRE, ENCARNA VARELA, RAMON MARTI, JOSEP M. SURIÑACH, JORDI JUFRESA, LLUIS ARMADANS, CARLES PASCUAL, TOMÁS FERNÁNDEZ de SEVILLA
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

In order to know the degree of interleukin-8 (IL-8) production in the pleural space and its relationship to neutrophil activation, IL-8, neutrophil elastase (NE), and myeloperoxidase (MPO) were assessed in blood and pleural fluid (PF) of 219 patients with pleural effusions. Correlations between blood and PF IL-8, NE, and MPO were either absent or weak, except for IL-8 in transudates (r = 0.6745, p < 0.001). PF IL-8, NE, and MPO concentrations in cases of empyema were higher than in cases of effusion of other causes (p < 0.001). No significant differences in inflammatory markers were observed between parapneumonic and tuberculous fluids. IL-8, NE, and MPO levels in malignant, nonspecific, and transudative effusions were lower than in those due to infection, the lowest levels corresponding to transudates. No significant correlation was observed between PF IL-8 and neutrophil count in any group; in contrast, IL-8 was associated with NE and MPO in empyema (r = 0.7545, and r = 0.7283; p < 0.001), tuberculosis (r = 0.4016, p = 0.008 and r = 0.6545, p < 0.001), and nonspecific effusions (r = 0.3748, p = 0.007 and r = 0.3085, p = 0.028). Our results indicate that local production of markers of the nonspecific inflammatory response is high in both chronic and acute pleural infection, and suggest a role for IL-8 in the release of NE and MPO.
ADAM9 is upregulated in human COPD lungs and in human and murine lung in response to cigarette smoke
Authors: Francesca Polverino, Maria Laucho Contreras, Miguel Divo, Victor Pinto-Plata, Bartolome Celli, Caroline Ann Owen
Journal: European Respiratory Journal (2014)

Background:  ADAM9 (A9) is a member of the family of proteinases with a disintegrin and a metalloproteinase domain. It is known to be expressed by cells germane to the pathogenesis of COPD, but it is not clear whether it contributes to COPD pathogenesis. Our goal was to begin to address this knowledge gap.   Methods:  Immunostaining was used to quantify A9 expression in alveolar macrophages (AMs), and alveolar and bronchial epithelial cells in lung sections from 11 smokers with COPD (GOLD I-IV); 5 control smokers (SC), and 5 non-smokers (NSC) undergoing surgery for pulmonary nodules or LVRS. A9 mRNA levels were also quantified using qPCR in lungs from WT mice exposed to air or CS for one month.   Results:  COPD patients had higher A9 expression in AMs (Median, Range: 51.5; 19.1-197 Fl Units/pixel 2 ) when compared to SC (19, 9-168) and NSC (13, 5-31). COPD patients also had higher A9 expression in alveolar (41;16-725) and bronchial (51, 105-31.5) epithelial cells compared with SC (21.5, 9-189; 26, 14-76) and NSC (15, 6-140; 14, 6-26, respectively). Moreover, SC had higher A9 expression compared to NSC (p l 0.001 for all comparisons). Within the COPD group, the expression of A9 in AMs was increased in patients with COPD GOLD III-IV (55, 32-196) vs. GOLD I-II (40.5, 19-122) (p l 0.001). A9 upregulation in response to CS was confirmed in an animal model as CS-exposed C57BL/6 WT mice had 2-fold higher A9 mRNA levels than air-exposed animals.   Conclusions:  ADAM9 expression is increased in alveolar macrophages and lung epithelial cells in COPD patients. A9 is also upregulated in lungs of CS-exposed mice. Thus, ADAM9 may have potential to contribute to COPD pathogenesis.
Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma
Authors: Long Chen, Shuang Zhou, Jie Qin, Heng Hu, Huiying Ma, Binbin Liu, Xuan Wang, Jiaqi Ma, Shenglong Ye, Cuiping Zhong, Guomin Zhou, Chunmin Liang
Journal: Molecular Cancer (2013)

Abstract Background Secondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25 + Foxp3 + regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice. Methods C57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8 + T cells and CD4 + T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro. Results Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8 + T cells and CD4 + T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8 + T cells and CD4 + T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy. Conclusions Our data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8 + T cells and CD4 + T cells in peripheral immune organs.
Cytokine profiles of cultured microvascular endothelial cells from the human intestine
Authors: E M Nilsen, F-E Johansen, F L Jahnsen, K E A Lundin, T Scholz, P Brandtzaeg, G Haraldsen
Journal: Gut (1998)

Cytokine production by endothelial cells, has, for practical reasons, been chiefly studied in human umbilical vein endothelial cells (HUVEC) but, because tissue-specific differences apparently exist, the role of human intestinal microvascular endothelial cells (HIMEC) as a source of mucosal cytokines was also assessed.The expression of cytokine transcripts in HIMEC was screened by means of reverse transcription polymerase chain reaction (RT-PCR) and compared with cytokine profiles of HUVEC. Production of cytokines was investigated by bioassay and enzyme linked immunosorbent assay (ELISA).In the basal unstimulated state, HIMEC and HUVEC cultures contained detectable mRNA for interleukin (IL)-3, IL-7, IL-8, IL-11, IL-14, IL-15, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and granulocytemacrophage colony stimulating factor (GM-CSF). However, message was undetectable for IL-2, IL-4, IL-5, IL-9, IL-10, IL-12p40, IL-13, and interferon (IFN)-gamma in the resting as well as the stimulated state. Stimulation of HIMEC and HUVEC with recombinant human (rh) IL-1 beta or rhTNF-alpha induced cell associated bioactive IL-1 alpha but not IL-1 beta, as well as enhanced secretion of both IL-6 and IL-8. Furthermore, transcript levels for GM-CSF and TNF-alpha were enhanced by rhIL-1 beta or rhTNF-alpha in both cell types. Supernatants from Th1-like or Th0-like gluten reactive intestinal T cell clones derived from patients with coeliac disease elicited cytokine profiles in both HIMEC and HUVEC similar to those revealed after rhIL-1 beta or rhTNF-alpha stimulation.These data demonstrate that the intestinal microvascular endothelium may contribute to the cytokine network of the intestinal mucosa with the ability to respond to locally generated cytokines and to produce potent inflammatory mediators.