tbuckley/cabot-search huggingface dataset:
ME-17 * JAK 1/2 INHIBITION FOLLOWING BONE MARROW TRANSPLANTATION MITIGATES Cd11b + /GR1+ MEDIATED LOW-GRADE GLIOMA NEOANGIOGENESIS
Authors: P. Rajappa, Y. Huang, E. Vartanian, D. Pisapia, D. Lyden, J. Bromberg, J. Greenfield
Journal: Neuro-Oncology (2014)

INTRODUCTION: Low grade gliomas lack neovascularization when compared to their high grade counterparts. Bone marrow-derived cells (BMDCs) are recruited to the tumor site and mediate the angiogenic switch during malignant transformation. This process ultimately supports the exponential growth kinetics displayed by high grade tumors that often exhibit aberrant vasculature. In order to elucidate the functional consequence of impairing BMDCs, in particular myeloid-derived suppressor cells (MDSC), we employed JAK 1/2 inhibitors. JAK 1/2 inhibition prior to the angiogenic switch in low grade glial tumors resulted in reduced neo-vascularization (CD31) and cellular proliferation (Ki67+). To conclusively prove impaired MDSC recruitment, we pursued a series of bone marrow transplant studies to demonstrate the effect of interrogated JAK 1/2 signaling on GFP+ BMDCs recruitment to the tumor core and periphery. METHODS: A spontaneous, transgenic PDGF-driven murine glioma model was utilized to recapitulate low-grade to high-grade progression. Tumor bearing animals were lethally irradiated (10Gy) at 2 weeks old and transplanted with age appropriate bone marrow from GFP donor mice. After a 4 week bone marrow reconstitution, the animals were treated with JAK1/2 inhibitors via oral gavage for 4 weeks. Immunofluorescence was used to characterize the impact on GFP+ BMDC recruitment at the tumor site. Flow cytometry was then used to quantify GFP+ BMDCs at the tumor site and periphery (blood and bone marrow). RESULTS: The number of GFP + BMDCs recruited to the tumor core is markedly reduced in post-transplant JAK treated animals. These animals demonstrate a significant survival advantage and exhibit delayed transformation on MRI and histologically, consistent with our previous findings. Flow cytometry and immunofluorescence demonstrates impaired Cd11b + /GR1+ mobilization in the bone marrow, peripheral blood and at the tumor core. CONCLUSION: The utility of GFP+ bone marrow transplant model system proves that JAK 1/2 Inhibition plays a direct role in impairment of MDSC infiltration.
The Effect of Hexamethonium Bromide Upon Coronary Flow, Cardiac Work and Cardiac Efficiency in Normotensive and Renal Hypertensive Dogs
Authors: CHARLES W. CRUMPTON, GEORGE G. ROWE, GEORGE O'BRIEN, QUILLIAN R. MURPHY
Journal: Circulation Research (1954)

Hexamethonium bromide in normotensive and renal hypertensive dogs resulted in significant reductions in arterial blood pressure, cardiac output and cardiac work. The decrease in cardiac output relative to that in blood pressure suggests that the blood pressure reduction was largely due to the decrease in cardiac output. There was a decrease in coronary flow accompanied by an increase in myocardial oxygen extraction of such Degrees that cardiac oxygen consumption remained unchanged. Since myocardial oxygen consumption remained unchanged despite the decrease in cardiac work the calculated cardiac efficiency was decreased.
Anti-CD8 Monoclonal Antibody Therapy Is Effective in the Prevention and Treatment of Experimental Autoimmune Glomerulonephritis
Authors: John Reynolds, Vicki A. Norgan, Upinder Bhambra, Jennifer Smith, H. Terence Cook, Charles D. Pusey
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Experimental autoimmune glomerulonephritis (EAG), which is an animal model of Goodpasture's disease, can be induced in Wistar Kyoto rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, focal necrotizing glomerulonephritis with crescent formation, and glomerular infiltration by T cells and macrophages. Our hypothesis was that T cell-mediated immunity, in addition to humoral immunity, was necessary for the development of crescentic nephritis in this model. To investigate the role of CD8+ T cells in the pathogenesis of EAG, the in vivo effects of an anti-CD8 monoclonal antibody (OX8) were examined, with administration starting at the time of immunization (prevention) or 2 wk after immunization, when glomerular abnormalities were first detected (treatment). When administered intraperitoneally at 5 mg/kg, three times per week, from week 0 to week 4 (prevention), OX8 completely inhibited the development of albuminuria, deposits of fibrin in the glomeruli, glomerular and interstitial abnormalities, the influx of CD8+ T cells and macrophages, and glomerular expression of granzyme B and inducible nitric oxide synthase. Circulating anti-GBM antibody levels were not reduced, but there was a reduction in the intensity of antibody deposition on the GBM. When administered at the same dose from week 2 to week 4 (treatment), OX8 greatly reduced the severity of EAG; in particular, the formation of crescents was prevented. These studies demonstrate that anti-CD8 monoclonal antibody therapy is effective in both the prevention and treatment of EAG. They confirm the importance of T cell-mediated immunity in the pathogenesis of this model of Goodpasture's disease. Similar therapeutic approaches may be worth investigating in human crescentic glomerulonephritis.
Evaluation of a proposed technique to assess unscheduled DNA synthesis and genotoxicity.
Authors: R A Goodlad, C Y Lee, M R Alison, C E Sarraf, M A Ghatei, S R Bloom, N A Wright
Journal: Gut (1993)

Results from a recent, new assay suggest that omeprazole, a potent inhibitor of gastric acid secretion, is genotoxic. The principle of this assay is that the non-proliferating zone of surface gastric epithelial cells can be selectively removed by controlled digestion so that any incorporation of tritiated thymidine into these cells represents unscheduled DNA synthesis. Parietal cells (which are located below the uppermost proliferating cells) and proliferating cells in semiconservative, regular DNA synthesis could always be shown in the digested fraction, and as regular DNA synthesis takes up a thousand fold more thymidine than unscheduled DNA synthesis, any signal from unscheduled synthesis would therefore be swamped. The digestion process was also uneven, as histological analysis showed denuded patches of mucosa, and gland like structures were seen in the digest. Quantification of the number of silver grains over the nuclei showed no increase in low level labelling after omeprazole administration, indicating that there was no unscheduled DNA synthesis. The labelling index of undigested gastric tissue from omeprazole treated rats was not significantly different from that of the control group, despite an increase in the plasma gastrin value.
Highly Selective Escape from KSHV-mediated Host mRNA Shutoff and Its Implications for Viral Pathogenesis
Authors: Britt Glaunsinger, Don Ganem
Journal: The Journal of Experimental Medicine (2004)

During Kaposi's sarcoma (KS)–associated herpesvirus (KSHV) lytic infection, many virus-encoded signaling molecules (e.g., viral G protein–coupled receptor [vGPCR]) are produced that can induce host gene expression in transiently transfected cells, and roles for such induced host genes have been posited in KS pathogenesis. However, we have recently found that host gene expression is strongly inhibited by 10–12 h after lytic reactivation of KSHV, raising the question of whether and to what extent de novo host gene expression induced by viral signaling molecules can proceed during the lytic cycle. Here, we show by microarray analysis that expression of most vGPCR target genes is drastically curtailed by this host shutoff. However, rare cellular genes can escape the host shutoff and are potently up-regulated during lytic KSHV growth. Prominent among these is human interleukin-6, whose striking induction may contribute to the overexpression of this cytokine in several disease states linked to KSHV infection.
Inhibition of fluorouracil-induced stomatitis by oral cryotherapy.
Authors: D J Mahood, A M Dose, C L Loprinzi, M H Veeder, L M Athmann, T M Therneau, J M Sorensen, D K Gainey, J A Mailliard, N L Gusa
Journal: Journal of Clinical Oncology (1991)

Mucositis is a significant dose-limiting toxicity associated with fluorouracil (5FU), particularly when it is combined with leucovorin. We hypothesized that oral cryotherapy would cause local vasoconstriction and would temporarily decrease blood flow to the oral mucous membranes. If cryotherapy were used during the time of peak serum 5FU levels, then the oral mucous membranes would have less exposure to 5FU and thus develop less mucositis. To test this hypothesis, 95 patients scheduled to receive their first cycle of 5FU plus leucovorin were randomized to have oral cryotherapy at the time of chemotherapy administration or to serve as a control group. Subsequent mucositis was significantly reduced in the group assigned to receive cryotherapy as judged by the attending physicians (P = .0002) and by the patients themselves (P = .0001). We now routinely recommend this cryotherapy procedure for our patients receiving daily bolus 5FU plus leucovorin.
Hemoglobin Malmö β-97 (FG-4) Histidine→Glutamine: A Cause of Polycythemia
Authors: Samuel H. Boyer, Samuel Charache, Virgil F. Fairbanks, Jorge E. Maldonado, Andrea Noyes, Esther E. Gayle
Journal: Journal of Clinical Investigation (1972)

A striking history of familial polycythemia led to a search for an abnormal hemoglobin. None could be demonstrated by routine electrophoretic methods, but the propositus' hemolysate had increased oxygen affinity. Manipulation of the conditions of electrophoresis, and chromatographic methods, permitted identification of hemoglobin Malmö. Studies of hemolysates demonstrated a normal Bohr effect, decreased heme-heme interaction (n=1.58), and a p50 of 1.3 mm Hg at 10 degrees C and pH 7.2. The amino acid substitution occurs in the same position (FG-4) as that of hemoglobin Chesapeake, but in the beta-chain rather than the alpha-chain. The two types of hemolysate have different pathophysiologic properties, and carriers of hemoglobin Malmö exhibit more striking hematologic abnormalities.
TGF-beta 1 genotype and accelerated decline in lung function of patients with cystic fibrosis
Authors: P. D Arkwright
Journal: Thorax (2000)

Polymorphisms in transforming growth factor (TGF)-beta(1) associated with variations in cytokine levels are linked to fibrosis in a number of tissues. However, the contribution of this cytokine to organ fibrosis in patients with cystic fibrosis is presently unclear. This study was undertaken to examine the association between TGF-beta(1) gene polymorphisms and the development of pulmonary dysfunction in patients with cystic fibrosis.Polymorphisms in the TGF-beta(1) gene defining amino acids of codons 10 and 25 were determined by ARMS-PCR using DNA stored on 171 Caucasian patients who were homozygous for the DeltaF508 mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clinical information on the patients was obtained from medical records.Patients with cystic fibrosis of a TGF-beta(1) high producer genotype for codon 10 had more rapid deterioration in lung function than those with a TGF-beta(1) low producer genotype. The relative risk of accelerated decline in forced expiratory volume in one second (FEV(1)) to 50% predicted and forced vital capacity (FVC) to 70% predicted of patients with a high producer genotype was 1.74 (95% CI 1.11 to 2. 73) compared with 1.95 (95% CI 1.24 to 3.06) for those with a low producer genotype.TGF-beta(1) genotypes may have a role in mediating pulmonary dysfunction in patients with cystic fibrosis. Further work is required to determine whether inhibition of TGF-beta(1) activity in these patients may slow disease progression.
Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients
Authors: Shenhong Wu, Christi Kim, Lea Baer, Xiaolei Zhu
Journal: Journal of the American Society of Nephrology (2010)

Treatment with the chemotherapeutic agent bevacizumab, a humanized mAb that neutralizes vascular endothelial growth factor, can lead to proteinuria and renal damage. The risk factors and clinical outcomes of renal adverse events are not well understood. We performed a systematic review and meta-analysis of published randomized, controlled trials to assess the overall risk for severe proteinuria with bevacizumab. We analyzed data from 16 studies comprising 12,268 patients with a variety of tumors. The incidence of high-grade (grade 3 or 4) proteinuria with bevacizumab was 2.2% (95% confidence interval [CI] 1.2 to 4.3%). Compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria (relative risk 4.79; 95% CI 2.71 to 8.46) and nephrotic syndrome (relative risk 7.78; 95% CI 1.80 to 33.62); higher dosages of bevacizumab associated with increased risk for proteinuria. Regarding tumor type, renal cell carcinoma associated with the highest risk (cumulative incidence 10.2%). We did not detect a significant difference between platinum- and non–platinum-based concurrent chemotherapy with regard to risk for high-grade proteinuria (P = 0.39). In conclusion, the addition of bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome.
Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve
Authors: Misha D. Luyer, Jan Willem M. Greve, M'hamed Hadfoune, Jan A. Jacobs, Cornelis H. Dejong, Wim A. Buurman
Journal: The Journal of Experimental Medicine (2005)

The immune system in vertebrates senses exogenous and endogenous danger signals by way of complex cellular and humoral processes, and responds with an inflammatory reaction to combat putative attacks. A strong protective immunity is imperative to prevent invasion of pathogens; however, equivalent responses to commensal flora and dietary components in the intestine have to be avoided. The autonomic nervous system plays an important role in sensing luminal contents in the gut by way of hard-wired connections and chemical messengers, such as cholecystokinin (CCK). Here, we report that ingestion of dietary fat stimulates CCK receptors, and leads to attenuation of the inflammatory response by way of the efferent vagus nerve and nicotinic receptors. Vagotomy and administration of antagonists for CCK and nicotinic receptors significantly blunted the inhibitory effect of high-fat enteral nutrition on hemorrhagic shock-induced tumor necrosis factor-α and interleukin-6 release (P &amp;lt; 0.05). Furthermore, the protective effect of high-fat enteral nutrition on inflammation-induced intestinal permeability was abrogated by vagotomy and administration of antagonists for CCK and nicotinic receptors. These data reveal a novel neuroimmunologic pathway, controlled by nutrition, that may help to explain the intestinal hyporesponsiveness to dietary antigens, and shed new light on the functionality of nutrition.
Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling
Authors: Alfiya Distler, Lisa Deloch, Jingang Huang, Clara Dees, Neng-Yu Lin, Katrin Palumbo-Zerr, Christian Beyer, Alexander Weidemann, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Canonical Wnt signalling has recently emerged as a key mediator of fibroblast activation and tissue fibrosis in systemic sclerosis. Here, we investigated tankyrases as novel molecular targets for inhibition of canonical Wnt signalling in fibrotic diseases. <h3>Methods</h3> The antifibrotic effects of the tankyrase inhibitor XAV-939 or of siRNA-mediated knockdown of tankyrases were evaluated in the mouse models of bleomycin-induced dermal fibrosis and in experimental fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (Ad-TBRI). <h3>Results</h3> Inactivation of tankyrases prevented the activation of canonical Wnt signalling in experimental fibrosis and reduced the nuclear accumulation of β-catenin and the mRNA levels of the target gene c-myc. Treatment with XAV-939 or siRNA-mediated knockdown of tankyrases in the skin effectively reduced bleomycin-induced dermal thickening, differentiation of resting fibroblasts into myofibroblasts and accumulation of collagen. Potent antifibrotic effects were also observed in Ad-TBRI driven skin fibrosis. Inhibition of tankyrases was not limited by local or systemic toxicity. <h3>Conclusions</h3> Inactivation of tankyrases effectively abrogated the activation of canonical Wnt signalling and demonstrated potent antifibrotic effects in well-tolerated doses. Thus, tankyrases might be candidates for targeted therapies in fibrotic diseases.
Paroxetine Is an Effective Treatment for Hot Flashes: Results From a Prospective Randomized Clinical Trial
Authors: Vered Stearns, Rebecca Slack, Nancy Greep, Ronda Henry-Tilman, Michael Osborne, Craig Bunnell, Lynda Ullmer, Ann Gallagher, Jennifer Cullen, Edmund Gehan, Daniel F Hayes, Claudine Isaacs
Journal: Journal of Clinical Oncology (2005)

In an open-label trial we have previously demonstrated that paroxetine reduces hot flashes. We initiated a stratified, randomized, double-blind, cross-over, placebo-controlled trial to investigate the efficacy of paroxetine 10 mg and 20 mg compared to placebo in reducing hot flash frequency and composite score. A secondary objective was to evaluate quality of life (QOL) parameters.Women who suffered at least two hot flashes a day for 1 month or longer were eligible. Women were randomly assigned to 4 weeks of paroxetine 10 mg or 20 mg followed by placebo for 4 weeks, or placebo for 4 weeks followed by paroxetine 10 mg or 20 mg for 4 weeks. Participants completed baseline daily hot flash diaries for one week prior to the start of the study and throughout the study, and QOL questionnaires at baseline, week 5 and week 9.279 women were screened, and 151 were randomly assigned. Paroxetine 10 mg reduced hot flash frequency and composite score by 40.6% and 45.6%, respectively, compared to 13.7% and 13.7% for placebo (P = .0006 and P = .0008, respectively). Paroxetine 20 mg reduced hot flash frequency and composite score by 51.7% and 56.1%, respectively, compared with 26.6% and 28.8% for placebo (P = .002 and P = .004, respectively). Efficacy was similar between the two doses, but women were less likely to discontinue low-dose paroxetine. Paroxetine 10 mg was associated with a significant improvement in sleep compared with placebo (P = .01).Paroxetine is an effective treatment for hot flashes in women with or without a prior breast cancer.
Nursing home-acquired pneumonia: a 10 year single-centre experience
Authors: E Polverino, P Dambrava, C Cilloniz, V Balasso, M A Marcos, C Esquinas, J Mensa, S Ewig, A Torres
Journal: Thorax (2010)

<h3>Background</h3> Pneumonia among nursing home (NH) residents has increased considerably in recent years, but it remains unclear whether it should be considered as community-acquired pneumonia (CAP) or a new category of infection. <h3>Methods</h3> 150 consecutive cases of NH-acquired pneumonia (NHAP) (from 1 February 1997 to 1 July 2007) were analysed. <h3>Results</h3> Patients (median age, 82 years; range, 77–87 years) showed numerous co-morbidities, (neurological, 55%; pulmonary, 38%; cardiac, 35%) and severe disability for daily activities (partial, 32%; total, 31%). Cases of NHAP were mainly classified as mild to moderate according to the CRB-65 score (CRB-65 classes 0–1 and 2, 41% each). In-hospital and 30-day mortality were 8.7% and 20%, respectively. Aetiology was defined in 57 cases (38%). The most common isolates were <i>Streptococcus pneumoniae</i> (58%), <i>Enterobacteriaceae</i> (Gram-negative bacteria (GNB)) (9%), atypical bacteria (7%), respiratory viruses (5%), methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) (5%) and <i>Legionella pneumophila</i> (5%). The most frequent causes of treatment inadequacy were use of β-lactams alone (25%) and lack of aspiration assessment (15%). Prognostic factors of 1-month mortality were neurological comorbidities (OR 4.5; 95% CI 1.3 to 15.7; p=0.020), septic shock (OR 6.6; 95% CI 1.3 to 34.0; p=0.025), pleural effusion (OR 3.6; 95% CI 1.1 to 11.7; p=0.036) and isolation of GNB or MRSA (OR 16.4; 95% CI 2.1 to 128.9; p=0.008). <h3>Conclusions</h3> The patients show clinical characteristics (eg, age and co-morbidities) comparable with those with hospital-acquired pneumonia. However, microbiological and mortality data of patients with NHAP are more similar to the data of those with CAP. Isolation of GNB or MRSA was associated with increased mortality risk. CAP empirical antibiotic coverage is still indicated in NHAP, although specific risk factors for multidrug-resistant infections should be assessed on an individual basis.
Conditional Activation of RET/PTC3 and BRAFV600E in Thyroid Cells Is Associated with Gene Expression Profiles that Predict a Preferential Role of BRAF in Extracellular Matrix Remodeling
Authors: Cleo Mesa, Mana Mirza, Norisato Mitsutake, Maureen Sartor, Mario Medvedovic, Craig Tomlinson, Jeffrey A Knauf, Georg F. Weber, James A. Fagin
Journal: Cancer Research (2006)

Abstract Papillary thyroid cancers (PTC) are associated with nonoverlapping mutations of genes coding for mitogen-activated protein kinase signaling effectors (i.e., the TK receptors RET or NTRK and the signaling proteins RAS and BRAF). We examined the pattern of gene expression after activation of these oncoproteins in thyroid PCCL3 cells, with the goal of identifying pathways or gene subsets that may account for the phenotypic differences observed in human cancers. We hybridized cDNA from cells treated with or without doxycycline to induce expression of BRAFV600E, RET/PTC3, or RET/PTC3 with small interfering RNA–mediated knockdown of BRAF, respectively, to slides arrayed with a rat 70-mer oligonucleotide library consisting of 27,342 oligos. Among the RET/PTC3-induced genes, 2,552 did not require BRAF as they were similarly regulated by RET/PTC3 with or without BRAF knockdown and not by expression of BRAFV600E. Immune response and IFN-related genes were highly represented in this group. About 24% of RET/PTC3-regulated genes were BRAF dependent, as they were similarly modified by RET/PTC3 and BRAFV600E but not in cells expressing RET/PTC3 with knockdown of BRAF. A gene cluster coding for components of the mitochondrial electron transport chain pathway was down-regulated in this group, potentially altering regulation of cell viability. Metalloproteinases were also preferentially induced by BRAF, particularly matrix metalloproteinase 3 (MMP3), MMP9, and MMP13. Accordingly, conditional expression of BRAF was associated with markedly increased invasion into Matrigel compared with cells expressing RET/PTC3. The preferential induction of MMPs by BRAF could explain in part the more invasive behavior of thyroid cancers with BRAF mutations. (Cancer Res 2006; 66(13): 6521-9)