tbuckley/cabot-search huggingface dataset:
TLRs as miRNA Receptors
Authors: Muller Fabbri
Journal: Cancer Research (2012)

Abstract MicroRNAs (miRNA) are small noncoding RNAs with gene regulatory functions. Their expression is frequently dysregulated in almost all human tumors and they can be found circulating within exosomes secreted by cancer cells. In addition to being promising cancer biomarkers with diagnostic, prognostic, and theranostic implications, circulating miRNAs have also important biologic functions: they can be engulfed by immune cells surrounding cancer cells within the tumor microenvironment and bind to toll-like receptors (TLR7 in mice and TLR8 in human) expressed by the immune cells. As a result, the binding miRNAs function as agonists of these single-stranded RNA-binding TLRs, leading to NF-κB signaling activation and secretion of interleukin (IL)-6 and TNF-α, which promote cancer cell growth and metastasization. This novel miRNA mechanism of action suggests that these small noncoding RNAs can act as hormones (we call these miRNAs hormone miRNAs or H-miRNAs). The discovery that miRNAs released by cancer cells can bind to a receptor in a surrounding immune cell is completely novel. Other receptors (in addition to TLR7 and TLR8) are likely to be found, but this is the first identified miRNA receptor and it is relevant to cancer. This review discusses the meaning of this discovery and comments on the exciting future implications of these findings in the context of tumor microenvironment biology as well as of other human diseases. Cancer Res; 72(24); 6333–7. ©2012 AACR.
Targeting p53 by small molecules in hematological malignancies
Authors: Manujendra N Saha, Lugui Qiu, Hong Chang
Journal: Journal of Hematology & Oncology (2013)

Abstract p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative activities of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor effects in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases.
Rapid Estrogen-Induced Hypercalcemia
Authors: Satinder Swaroop
Journal: JAMA (1973)

Two menopausal patients with metastatic breast cancer and osteolytic bone metastases were treated with diethylstilbestrol in oral doses. In one patient, hypercalcemia developed within 48 hours of treatment with a total dose of 10.0 mg of diethylstilbestrol, and in the second patient hypercalcemia developed within 24 hours of therapy with a single 5.0-mg oral dose.
Intermediate CD14++CD16+ blood monocytes are elevated in preterm neonates
Authors: Marion Frankenberger, Gudrun Kaßner, Prajakta Oak, Kai Förster, Harald Ehrhardt, Christoph Hübener, Oliver Eickelberg, Löms Ziegler-Heitbrock, Anne Hilgendorff
Journal: European Respiratory Journal (2014)

Monocytes are a major part of the innate immune system. Three populations of blood monocyte subsets in humans have been defined according to their differential expression of CD14 and CD16: classical CD14++CD16-, non-classical CD14+CD16++ and intermediate CD14++CD16+ monocytes. In adults these subsets are well described, but very little is known on the development and activity of these cells in very-preterm neonates. Blood samples from preterm neonates born at gestational age from 24 to 32 weeks were taken from day 0 up to 11 weeks after birth and compared with term neonates born by cesarean section and adult controls. At 10 days or less after birth intermediate CD14++CD16+ monocytes were strongly elevated in preterm neonates (49.1±9.2% of all monocytes at 24-26 weeks gestational age), they were still high at 20.7±6.3 % in preterm neonates born at 30-32 weeks gestational age while in term neonates they accounted for 6.9±3.3% compared to 3.3±0.98% in adult control donors. CD62L expression was 4-fold higher in intermediate monocytes from preterm neonates compared to cells from term neonates and adults, but HLA-DR was strongly decreased in preterm intermediate monocytes. While both intermediate monocytes and non-classical monocytes were strong producers of Lipopolysaccharide induced-TNF in preterm and term neonates the level of TNF production was 5-fold lower compared to what is seen in adult monocyte subsets.

The strong expansion and aberrant phenotype of intermediate monocytes in preterm neonates may be explained by the immaturity of the innate immune system in the preterms and this may contribute to the increased susceptibility to infection.
Risk factors for 30-day mortality after resection of lung cancer and prediction of their magnitude
Authors: T.-E. Strand, H. Rostad, R. A M Damhuis, J. Norstein
Journal: Thorax (2007)

<h3>Background:</h3> There is considerable variability in reported postoperative mortality and risk factors for mortality after surgery for lung cancer. Population-based data provide unbiased estimates and may aid in treatment selection. <h3>Methods:</h3> All patients diagnosed with lung cancer in Norway from 1993 to the end of 2005 were reported to the Cancer Registry of Norway (n = 26 665). A total of 4395 patients underwent surgical resection and were included in the analysis. Data on demographics, tumour characteristics and treatment were registered. A subset of 1844 patients was scored according to the Charlson co-morbidity index. Potential factors influencing 30-day mortality were analysed by logistic regression. <h3>Results:</h3> The overall postoperative mortality rate was 4.4% within 30 days with a declining trend in the period. Male sex (OR 1.76), older age (OR 3.38 for age band 70–79 years), right-sided tumours (OR 1.73) and extensive procedures (OR 4.54 for pneumonectomy) were identified as risk factors for postoperative mortality in multivariate analysis. Postoperative mortality at high-volume hospitals (⩾20 procedures/year) was lower (OR 0.76, p = 0.076). Adjusted ORs for postoperative mortality at individual hospitals ranged from 0.32 to 2.28. The Charlson co-morbidity index was identified as an independent risk factor for postoperative mortality (p = 0.017). A prediction model for postoperative mortality is presented. <h3>Conclusions:</h3> Even though improvements in postoperative mortality have been observed in recent years, these findings indicate a further potential to optimise the surgical treatment of lung cancer. Hospital treatment results varied but a significant volume effect was not observed. Prognostic models may identify patients requiring intensive postoperative care.
Molecular Basis of Decreased Kir4.1 Function in SeSAME/EAST Syndrome
Authors: David M. Williams, Coeli M.B. Lopes, Avia Rosenhouse-Dantsker, Heather L. Connelly, Alessandra Matavel, Jin O-Uchi, Elena McBeath, Daniel A. Gray
Journal: Journal of the American Society of Nephrology (2010)

SeSAME/EAST syndrome is a channelopathy consisting of a hypokalemic, hypomagnesemic, metabolic alkalosis associated with seizures, sensorineural deafness, ataxia, and developmental abnormalities. This disease links to autosomal recessive mutations in KCNJ10, which encodes the Kir4.1 potassium channel, but the functional consequences of these mutations are not well understood. In Xenopus oocytes, all of the disease-associated mutant channels (R65P, R65P/R199X, G77R, C140R, T164I, and A167V/R297C) had decreased K(+) current (0 to 23% of wild-type levels). Immunofluorescence demonstrated decreased surface expression of G77R, C140R, and A167V expressed in HEK293 cells. When we coexpressed mutant and wild-type subunits to mimic the heterozygous state, R199X, C140R, and G77R currents decreased to 55, 40, and 20% of wild-type levels, respectively, suggesting that carriers of these mutations may present with an abnormal phenotype. Because Kir4.1 subunits can form heteromeric channels with Kir5.1, we coexpressed the aforementioned mutants with Kir5.1 and found that currents were reduced at least as much as observed when we expressed mutants alone. Reduction of pH(i) from approximately 7.4 to 6.8 significantly decreased currents of all mutants except R199X but did not affect wild-type channels. In conclusion, perturbed pH gating may underlie the loss of channel function for the disease-associated mutant Kir4.1 channels and may have important physiologic consequences.
Risk of Second Malignant Neoplasms After Childhood Leukemia and Lymphoma: An International Study
Authors: M. Maule, G. Scelo, G. Pastore, P. Brennan, K. Hemminki, E. Tracey, R. Sankila, E. Weiderpass, J. H. Olsen, M. L. McBride, D. H. Brewster, V. Pompe-Kirn, E. V. Kliewer, K. S. Chia, J. M. Tonita, C. Martos, J. G. Jonasson, F. Merletti, P. Boffetta
Journal: JNCI Journal of the National Cancer Institute (2007)

Survivors of childhood leukemia and lymphoma experience high risks of second malignant neoplasms. We quantified such risk using a large dataset from 13 population-based cancer registries.The registries provided individual data on cases of leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma occurring in children aged 0-14 years and on subsequent second malignant neoplasms for different time periods from 1943 to 2000. Risks of second malignant neoplasms were assessed through standardized incidence ratios (SIRs) and corresponding 95% confidence intervals (CIs), using the incidence rates in the general populations covered by the registries as a reference. Cumulative absolute risks were also calculated.A total of 133 second malignant neoplasms were observed in 16,540 patients (12,731 leukemias, 1246 Hodgkin lymphomas, and 2563 non-Hodgkin lymphomas) after an average follow-up of 6.5 years. The most frequent second malignancies after leukemia were brain cancer (19 cases, SIR = 8.52, 95% CI = 5.13 to 13.3), non-Hodgkin lymphoma (nine cases, SIR = 9.41, 95% CI = 4.30 to 17.9), and thyroid cancer (nine cases, SIR = 18.8, 95% CI = 8.60 to 35.7); the most frequent after Hodgkin lymphoma were thyroid cancer (nine cases, SIR = 52.5, 95% CI = 24.0 to 99.6), breast cancer (six cases, SIR = 20.9, 95% CI = 7.66 to 45.4), and neoplasms of skin (non-melanoma) (six cases, SIR = 34.0, 95% CI = 12.5 to 74.0); and the most frequent after non-Hodgkin lymphoma were thyroid cancer (six cases, SIR = 40.4, 95% CI = 14.8 to 88.0) and brain cancer (four cases, SIR = 6.97, 95% CI = 1.90 to 17.9). Cumulative incidence of any second malignant neoplasm was 2.43% (95% CI = 1.09 to 3.78), 12.7% (95% CI = 8.29 to 17.2), and 2.50% (95% CI = 1.04 to 3.96) within 30 years from diagnosis of leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma, respectively.This population-based study provides, to our knowledge, the most precise and up-to-date estimates for relative and absolute risks of second malignant neoplasms after childhood leukemia and lymphoma.
Hypersplenism in Wilson's disease
Authors: G. T. Strickland, N-K. Chang, W. M. Beckner
Journal: Gut (1972)

Thirteen patients with Wilson's disease were compared with seven cirrhotic and 13 normal controls to define better the haematological abnormalities in this condition. Hypersplenism (anaemia, leukopenia, thrombocytopenia, and reduced red cell survival) commonly occurred in patients with both Wilson's disease and cirrhosis. These abnormalities correlated with splenic enlargement. Despite reduced haematocrits, red cell mass was greater in these two groups than in normal controls. Plasma volume and the body haematocrit/peripheral haematocrit ratios were also greater in patients with Wilson's disease and cirrhosis. Increased splenic sequestration of (51)Cr-tagged red blood cells was not demonstrated in any subjects. The hypersplenism in patients with Wilson's disease is similar to that found in patients with cirrhosis from other causes.
Exercise peripheral oxygen saturation (Spo2) accurately reflects arterial oxygen saturation (Sao2) and predicts mortality in systemic sclerosis
Authors: J J Swigris, X Zhou, F S Wamboldt, R du Bois, R Keith, A Fischer, G P Cosgrove, S K Frankel, D Curran-Everett, K K Brown
Journal: Thorax (2009)

<h3>Background:</h3> Measures of oxygenation have not been assessed for prognostic significance in systemic sclerosis-related interstitial lung disease (SSc-ILD). <h3>Methods:</h3> 83 subjects with SSc-ILD performed a maximal cardiopulmonary exercise test with an arterial line. The agreement between peripheral oxygen saturation (Spo<sub>2</sub>) and arterial oxygen saturation (Sao<sub>2</sub>) was examined and survival differences between subgroups of subjects stratified on Spo<sub>2</sub> were analysed. Cox proportional hazards analyses were used to examine the prognostic capabilities of Spo<sub>2</sub>. <h3>Results:</h3> At maximal exercise the mean (SD) difference between Spo<sub>2</sub> and Sao<sub>2</sub> was 2.98 (2.98) and only 15 subjects had a difference of &gt;4 points. The survival of subjects with SSc-ILD whose maximum exercise Spo<sub>2</sub> (Spo<sub>2</sub>max) fell below 89% or whose Spo<sub>2</sub>max fell &gt;4 points from baseline was worse than subjects in comparator groups (log rank p = 0.01 and 0.01, respectively). The hazard of death during the median 7.1 years of follow-up was 2.4 times greater for subjects whose Spo<sub>2</sub>max fell below 89% (hazard ratio 2.4, 95% CI 1.1 to 4.9, p = 0.02) or whose Spo<sub>2</sub>max fell &gt;4 points from baseline (hazard ratio 2.4, 95% CI 1.1 to 5.0, p = 0.02). <h3>Conclusion:</h3> In patients with SSc-ILD, Spo<sub>2</sub> is an adequate reflection of Sao<sub>2</sub> and radial arterial lines need not be inserted during cardiopulmonary exercise tests in these patients. Given the ease of measurement and its prognostic value, Spo<sub>2</sub> should be considered as a meaningful clinical and research outcome in patients with SSc-ILD.
RELATIONSHIP BETWEEN EXERCISE TRAINING AND CHANGES IN BIOMARKERS OF MYOCARDIAL STRESS, INJURY AND INFLAMMATION IN PATIENTS WITH CHRONIC HEART FAILURE
Authors: Tariq Ahmad, Mona Fiuzat, Ben Neely, Megan Neely, Kirkwood Adams, David Whellan, Mark Donahue, Dalane Kitzman, Ileana Pina, Faiez Zannad, William Kraus, Christopher O'Connor, G. Michael Felker
Journal: Journal of the American College of Cardiology (2013)
Recurrent ischemia without warning. Analysis of risk factors for in-hospital ischemic events following successful thrombolysis with intravenous tissue plasminogen activator.
Authors: S G Ellis, E J Topol, B S George, D J Kereiakes, D Debowey, K N Sigmon, A Pickel, K L Lee, R M Califf
Journal: Circulation (1989)

Ischemic events after successful thrombolysis have been reported to occur in 18-32% of patients treated for acute myocardial infarction with thrombolytic therapy, and previous studies in which patients received streptokinase suggest that risk of early recurrent ischemia is closely related to the presence of a high-grade residual stenosis. If these events are predictable after intravenous recombinant tissue-plasminogen activator (rt-PA) thrombolytic therapy, then further intervention after its use could be targeted at selected patients. One-hundred ninety-two patients from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) I and TAMI III trials had successful rt-PA-mediated thrombolysis without immediate coronary angioplasty (PTCA). One-hundred seventy-four of these patients (92%) had prehospital discharge angiography. The mean age was 56 +/- 11 years; 81% were men; the infarct-related artery was the left anterior descending in 76 (39.8%), the left circumflex in 24 (12.6%), and the right coronary artery in 91 (47.6%). Thrombolysis with rt-PA resulted in a residual 73 +/- 13% diameter and 0.95 +/- 0.51 mm stenosis by quantitative coronary arteriography, and Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 in 59.2% and 3 in 40.8% of stenoses as assessed on angiograms obtained 90 minutes after the initiation of rt-PA therapy. Recurrent ischemic events (ischemia requiring emergency percutaneous transluminal coronary angioplasty or urgent bypass surgery, reocclusion of the infarct-related artery, or cardiac death) occurred in 41 patients (21.3%).(ABSTRACT TRUNCATED AT 250 WORDS)
Oxidative damage in synovial tissue is associated with in vivo hypoxic status in the arthritic joint
Authors: Monika Biniecka, Aisling Kennedy, Ursula Fearon, Chin Teck Ng, Douglas J Veale, Jacintha N O'Sullivan
Journal: Annals of the Rheumatic Diseases (2009)

To assess levels of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanine; 8-oxo-dG) and lipid peroxidation (4-hydroxy-2-nonenal; 4-HNE) in serum, synovial fluid and tissue of patients with inflammatory arthritis in relation to in vivo hypoxia levels, disease activity and angiogenic markers.Oxygen levels in synovial tissue were assessed using an oxygen/temperature probe. Nuclear and cytoplasmic 8-oxo-dG and 4-HNE levels were assessed in synovial tissue from 23 patients by immunohistochemistry. 8-Oxo-dG and 4-HNE levels in serum and synovial fluid were determined using 8-oxo-dG and hexanoyl-Lys (HEL) adduct ELISAs, respectively. Serum vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) levels were also measured by ELISA.The median oxygen tension in synovial tissue was profoundly hypoxic at 19.35 mm Hg (2.5%). Nuclear 8-oxo-dG levels were significantly higher than nuclear 4-HNE levels in the lining and sublining layers (all p<0.001). In contrast, cytoplasmic 4-HNE levels were higher than cytoplasmic 8-oxo-dG levels in both cell layers (all p<0.001). Reduced in vivo oxygen tension correlated with high lipid peroxidation in synovial fluid (p=0.027; r=0.54) and tissue (p=0.004; r=0.58). Serum VEGF levels were positively correlated with cytoplasmic 4-HNE expression (p=0.05; r=0.43) and intensity (p=0.006; r=0.59) in the lining layer. Serum Ang2 levels were positively correlated with nuclear 4-HNE expression and intensity in both cell layers (all p < or = 0.05). DAS28-C-reactive protein was correlated with nuclear 4-HNE expression in the sublining layer (p=0.02; r=0.48) and DAS28-erythrocyte sedimentation rate was correlated with nuclear 4-HNE expression in both cell layers (p < or = 0.03).Lipid peroxidation is associated with low oxygen tension in vivo, disease activity and angiogenic marker expression in inflammatory arthritis.
Allergen challenge-induced acute exudation of IL-8, ECP and α&lt;SUB&gt;2&lt;/SUB&gt;-macroglobulin in human rhinovirus-induced common colds
Authors: L Greiff, M Andersson, C Svensson, M Linden, S Myint, CG Persson
Journal: European Respiratory Journal (1999)

Rhinovirus infections cause exacerbations of eosinophilic airway disease. The acute effects of allergen-challenge on nasal interleukin-8 (IL-8), eosinophil cationic protein (ECP), and alpha2-macroglobulin were examined in atopic subjects with common cold symptoms. Twenty-three patients with seasonal allergic rhinitis were inoculated with human rhinovirus 16 outside the pollen season. Diluent and allergen challenges, followed by nasal lavages, were carried out about 3 months before and 4 days after virus inoculation. Seventeen patients developed significant common cold symptoms with increased nasal lavage fluid levels of alpha2-macroglobulin, IL-8, and ECP at baseline (p&lt;0.001-0.05 versus before inoculation), and were further increased by allergen challenge (p&lt; 0.001-0.05); IL-8 and ECP levels were correlated (r = 0.63, p&lt;0.001). Before inoculation, the six patients who later did not develop common cold symptoms had high levels of IL-8 and myeloperoxidase (MPO), and exhibited strong allergen-induced plasma exudation responses (alpha2-macroglobulin). After inoculation, IL-8 and ECP did not increase in these symptomless subjects. In conclusion, high nasal interleukin-8 and myeloperoxidase levels and exudative hyperresponsiveness may protect against infection. The association between nasal interleukin-8 and eosinophil cationic protein in common cold, particularly that observed in nasal lavage fluids after allergen-induced acute exudation of plasma, suggests the involvement of interleukin-8 in exacerbation of airway mucosal eosinophil activity.
Airway hyperresponsiveness and bronchial mucosal inflammation in T cell peptide-induced asthmatic reactions in atopic subjects
Authors: F R. Ali, A B. Kay, M. Larche
Journal: Thorax (2007)

<b>Background:</b> Subjects with allergic asthma develop isolated late asthmatic reactions after inhalation of allergen-derived T cell peptides. Animal experiments have shown that airway hyperresponsiveness (AHR) is CD4+ cell-dependent. It is hypothesised that peptide inhalation produces increases in non-specific AHR and a T cell-dominant bronchial mucosal inflammatory response. <b>Methods:</b> Bronchoscopy, with bronchial biopsies and bronchoalveolar lavage (BAL), was performed in 24 subjects with cat allergy 6 h after aerosol inhalation of short overlapping peptides derived from <i>Fel d</i> 1, the major cat allergen. Biopsy specimens and BAL fluid were studied using immunohistochemistry and ELISA. <b>Results:</b> Twelve of the 24 subjects developed an isolated late asthmatic reaction without a preceding early (mast cell/histamine-dependent) reaction characteristic of whole allergen inhalation. These responders had significant between-group differences (responders vs non-responders) in the changes (peptide vs diluent) in AHR (p = 0.007) and bronchial mucosal CD3+ (p = 0.005), CD4+ (p = 0.006) and thymus- and activation-regulated chemokine (TARC)+ (p = 0.003) but not CD8+ or CD25+ cells or eosinophils, basophils, mast cells and macrophages. The between-group difference for neutrophils was p = 0.05 but with a non-significant within-group value (peptide vs diluent, responders, p = 0.11). In BAL fluid there was a significant between-group difference in TARC (p = 0.02) but not in histamine, tryptase, basogranulin, C3a or C5a, leukotrienes C<sub>4</sub>/D<sub>4</sub>/E<sub>4</sub>, prostaglandins D<sub>2</sub> or F<sub>2α</sub>. <b>Conclusions:</b> Direct activation of allergen-specific airway T cells by peptide inhalation in patients with atopic asthma leads to increased AHR with local increases in CD3+ and CD4+ cells and TARC but no significant changes in eosinophils or basophil/mast cell products. These findings support previous animal experiments which showed a CD4+ dependence for AHR.
Adefovir Dipivoxil for the Treatment of Hepatitis B e Antigen–Negative Chronic Hepatitis B
Authors: Stephanos J. Hadziyannis, Nicolaos C. Tassopoulos, E. Jenny Heathcote, Ting-Tsung Chang, George Kitis, Mario Rizzetto, Patrick Marcellin, Seng Gee Lim, Zachary Goodman, Michael S. Wulfsohn, Shelly Xiong, John Fry, Carol L. Brosgart
Journal: New England Journal of Medicine (2003)

Adefovir dipivoxil, a nucleotide analogue, demonstrated clinically significant antiviral activity in patients with chronic hepatitis B in phase 1 and 2 clinical trials.