tbuckley/cabot-search huggingface dataset:
The angiopietin-1–Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice
Authors: Lakshmi Kugathasan, Julie Basu Ray, Yupu Deng, Effat Rezaei, Daniel J. Dumont, Duncan J. Stewart
Journal: The Journal of Experimental Medicine (2009)

The role of the angiopoietin-1 (Ang1)–Tie2 pathway in the pathogenesis of pulmonary arterial hypertension (PAH) is controversial. Although Ang1 is well known to prevent endothelial activation and injury in systemic vascular beds, this pathway has been suggested to mediate pulmonary vascular remodeling in PAH. Therefore, we used transgenic models to determine the effect of increased or decreased Tie2 activity on the development of PAH. We now report modest spontaneous elevation in right ventricular systolic pressure in Tie2-deficient mice (Tie2+/−) compared with wild-type (WT) littermate controls, which was exacerbated upon chronic exposure to the clinically relevant PAH triggers, serotonin (5-HT) or interleukin-6 (IL-6). Moreover, overexpression of Ang1 in transgenic mice had no deleterious effect on pulmonary hemodynamics and, if anything, blunted the response to 5-HT. Exposure to 5-HT or IL-6 also decreased lung Ang1 expression, further reducing Tie2 activity and inducing pulmonary apoptosis in the Tie2+/− group only. Similarly, cultured pulmonary artery endothelial cells subjected to Tie2 silencing demonstrated increased susceptibility to apoptosis after 5-HT treatment. Finally, treatment of Tie2-deficient mice with Z-VAD, a pan-caspase inhibitor, prevented the pulmonary hypertensive response to 5-HT. Thus, these findings firmly establish that endothelial survival signaling via the Ang1–Tie2 pathway is protective in PAH.
Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across all CRB-65 classes
Authors: S. Kruger, S. Ewig, R. Marre, J. Papassotiriou, K. Richter, H. von Baum, N. Suttorp, T. Welte
Journal: European Respiratory Journal (2007)

The aim of the present study was to investigate the prognostic value, in patients with community-acquired pneumonia (CAP), of procalcitonin (PCT) compared with the established inflammatory markers C-reactive protein (CRP) and leukocyte (WBC) count alone or in combination with the CRB-65 (confusion, respiratory rate ≥30 breaths·min<sup>−1</sup>, low blood pressure (systolic value &lt;90 mmHg or diastolic value ≤60 mmHg) and age ≥65 yrs) score. In total, 1,671 patients with proven CAP were enrolled in the study. PCT, CRP, WBC and CRB-65 score were all determined on admission and patients were followed-up for 28 days for survival. In contrast to CRP and WBC, PCT levels markedly increased with the severity of CAP, as measured by the CRB-65 score. In 70 patients who died during follow-up, PCT levels on admission were significantly higher compared with levels in survivors. In receiver operating characteristic analysis for survival, the area under the curve (95% confidence interval) for PCT and CRB-65 was comparable (0.80 (0.75–0.84) <i>versus</i> 0.79 (0.74–0.84)), but each significantly higher compared with CRP (0.62 (0.54–0.68)) and WBC (0.61 (0.54–0.68)). PCT identified low-risk patients across CRB classes 0–4. In conclusion, procalcitonin levels on admission predict the severity and outcome of community-acquired pneumonia with a similar prognostic accuracy as the CRB-65 score and a higher prognostic accuracy compared with C-reactive protein and leukocyte count. Procalcitonin levels can provide independent identification of patients at low risk of death within CRB-65 (confusion, respiratory rate ≥30 breaths·min<sup>−1</sup>, low blood pressure (systolic value &lt;90 mmHg or diastolic value ≤60 mmHg) and age ≥65 yrs) risk classes.
Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts
Authors: Antonio Mazzocca, Francesco Dituri, Luigi Lupo, Michele Quaranta, Salvatore Antonaci, Gianluigi Giannelli
Journal: Hepatology (2011)

Hepatocellular carcinoma (HCC) occurs in fibrotic liver as a consequence of underlying cirrhosis. The goal of this study was to investigate how the interaction between HCC cells and stromal fibroblasts affects tumor progression. We isolated and characterized carcinoma-associated fibroblasts (CAFs) and paired peritumoral tissue fibroblasts (PTFs) from 10 different patients with HCC and performed coculture experiments. We demonstrated a paracrine mechanism whereby HCC cells secrete lysophostatidic acid (LPA), which promotes transdifferentiation of PTFs to a CAF-like myofibroblastic phenotype. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype. After transdifferentiation, PTFs expressed α-smooth muscle actin (α-SMA) and enhanced proliferation, migration, and invasion of HCC cells occur. A pan-LPA inhibitor (α-bromomethylene phosphonate [BrP]-LPA), or autotaxin gene silencing, inhibited this PTF transdifferentiation and the consequent enhanced proliferation, migration, and invasion of HCC cells. In vivo, PTFs coinjected with HCC cells underwent transdifferentiation and promoted tumor progression. Treatment with BrP-LPA blocked transdifferentiation of PTFs, down-regulated myofibroblast-related genes, and slowed HCC growth and progression. Patients with larger and metastatic HCC and shorter survival displayed higher serum levels of LPA. Analysis of microdissected tissues indicated that stroma is the main target of the LPA paracrine loop in HCC. As a consequence, α-SMA-positive cells were more widespread in tumoral compared with paired peritumoral stroma.Our data indicate that LPA accelerates HCC progression by recruiting PTFs and promoting their transdifferentiation into myofibroblasts. Inhibition of LPA could prove effective in blocking transdifferentiation of myofibroblasts and tumor progression.
Human neutrophil lipocalin, a highly specific marker for acute exacerbation in cystic fibrosis
Authors: I Eichler, M Nilsson, R Rath, I Enander, P Venge, DY Koller
Journal: European Respiratory Journal (1999)

Cystic fibrosis (CF) is characterized by the production of abnormally thick secretions in the airways, chronic bacterial endobronchial infections and a chronic, predominantly neutrophilic inflammatory response. Therefore, myeloperoxidase (MPO) and lactoferrin are frequently used as inflammatory markers. Recently, a new protein in the neutrophil granules, human neutrophil lipocalin (HNL) has been discovered. The aim of the present study was to investigate HNL in sera of patients with CF and its relation to MPO and lactoferrin as well as to acute pulmonary exacerbation. Serum concentrations of HNL, MPO and lactoferrin were determined in 42 patients with CF and in 25 healthy subjects. Patients with CF were divided into groups with and without acute pulmonary exacerbation (APE) and also with and without colonization with Pseudomonas aeruginosa (Pa). Median serum levels of HNL (200.5 microg x L(-1)), MPO (595 microg x L(-1)) and lactoferrin (1,356.5 microg x L(-1)) were significantly increased in patients with CF compared to control subjects (57.7, 178 and 478 microg x L(-1), respectively; p<0.0001). CF patients with APE had significantly increased serum concentrations of HNL (321 versus 97.7 microg x L(-1); p<0.0001), MPO (1,125 versus 300 microg x L(-1); p<0.005) and lactoferrin (4,936 versus 980 microg x L(-1); p<0.001) compared with patients in stable clinical condition. Similarly, patients colonized with Pa had significantly higher concentrations of HNL, MPO and lactoferrin than Pa negative patients. These results indicate that in patients with cystic fibrosis, serum concentrations of human neutrophil lipocalin are markedly increased with a strong relationship to myeloperoxidase and lactoferrin. Thus, determination of serum human neutrophil lipocalin concentrations may be another useful diagnostic tool to monitor neutrophil inflammation in cystic fibrosis. The more marked difference in human neutrophil lipocalin compared with myeloperoxidase concentrations with no overlap between patients with acute pulmonary exacerbation and those in stable condition even suggests that human neutrophil lipocalin may be a more sensitive and specific discriminator.
THE PITUITARY BODY AND THE THERAPEUTIC VALUE OF THE INFUNDIBULAR EXTRACT IN SHOCK, UTERINE ATONY, AND INTESTINAL PARESIS
Authors: W. B. Bell
Journal: BMJ (1909)

Two years ago I had the honour of reading a paper' before -the Liverpool Medical Institution on the calcium metabolism, with special reference to the ductless glands and the female genital organs; and I then indicated some of the lines on x which our work was being carried i out, and hinted at the results already ( obtained in regard to the pituitary body.An account of the experi- ments carried out by Dr. Hick and myself up to the end of July, 1908, was published in the BRITISH MEDI.-CAL JOURNAL2 early in this year;and although in these papers it was pointed out in what way clinical mLnnlinat.innawargY Pnn A;l T hn.vA _ evident that we have no right to regard as rudimentary those portions of man's anatomy which present, when submitted to a very casual naked eye and microscopical examination, if not a higher and more complex formation than is seen in the lower animals, at least one that is of equal development.In connexion with the structure under discussion, I may point out that there is little, if any, development of the posterior portion of the pituitary body in elasmobranchs, whereas it is well developed in the higher manmmals and in man.It was not until 1894 that the wonderful properties of the extract made from the adrenals were described by Oliver and Schafer.8In 1895 these workers investigated also the physiological effects pro- duced by an extract made from the W^A --;:j zpituitary body, and certain other extracts, such as those made from the spleen and thyroid.4While A adrenalin sprang into fame, the @ pituitary body, which undoubtedly B deserves a nimbus of its own, re- mained with its light.hidden beneath the very brains that should have recognized its virtues.
Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice.
Authors: K L Bruner, L M Matrisian, W H Rodgers, F Gorstein, K G Osteen
Journal: Journal of Clinical Investigation (1997)

Matrix metalloproteinases of the stromelysin family are expressed in the human endometrium as a consequence of cellular events during the menstrual cycle that require extracellular matrix remodeling. We have recently documented the presence of these enzymes in lesions of endometriosis, a benign disease that presents as persistent ectopic sites of endometrial tissue, usually within the peritoneal cavity. Endometriosis can develop after retrograde menstruation of endometrial tissue fragments, and establishment of ectopic sites within the peritoneal cavity requires breakdown of extracellular matrix. To examine whether matrix metalloproteinases might contribute to the steroid-dependent epidemiology and cellular pathophysiology of endometriosis, we have developed an experimental model of endometriosis using athymic nude mice as recipients of human endometrial tissue. Our results demonstrate that estrogen treatment of human endometrial tissue in organ culture maintains secretion of matrix metalloproteinases, and promotes establishment of ectopic peritoneal lesions when injected into recipient animals. In contrast, suppressing metalloproteinase secretion in vitro with progesterone treatment, or blocking enzyme activity with a natural inhibitor of metalloproteinases, inhibits the formation of ectopic lesions in this experimental model.
Cloning and characterization of a cDNA for murine macrophage inflammatory protein (MIP), a novel monokine with inflammatory and chemokinetic properties.
Authors: G Davatelis, P Tekamp-Olson, S D Wolpe, K Hermsen, C Luedke, C Gallegos, D Coit, J Merryweather, A Cerami
Journal: The Journal of Experimental Medicine (1988)

In the course of studies on cachectin/TNF being conducted in our laboratory, a novel macrophage product has been detected and characterized. Termed macrophage inflammatory protein or MIP, this protein appears to be an endogenous mediator of the inflammatory events induced by endotoxin. A cDNA cloned probe for this protein has been isolated from a lambda gt10 phage library prepared from poly(A)+ RNA obtained of endotoxin-induced RAW264.7 cells. The sequence codes for a 92 amino acid-long polypeptide, of which 69 amino acids correspond to the mature product. The sequence predicts a molecular weight of 7,889 and structural analysis of the protein indicates a characteristic signal sequence alpha-helix and a hydrophobic core. Sequence data also confirm no sequence similarity to any other protein listed in the Dayhoff data base.
Lymphocyte subsets in peripheral blood and pleural fluid
Authors: G Lucivero, G Pierucci, L Bonomo
Journal: European Respiratory Journal (1988)

We have examined the distribution of B and T lymphocytes, T-cells with helper/inducer (T4+) or suppressor/cytotoxic (T8+) phenotypes and a subset of cells with natural killer (NK) activity and positive for the Leu 7 (HNK-1) surface antigen in peripheral blood and in lymphocyte-rich pleural effusions of patients with tuberculosis or malignancies (mesothelioma and lung cancer with pleural metastasis). In individual patients, the percentages of T lymphocytes were uniformly higher in pleural effusions than in peripheral blood; however, lower percentages of B lymphocytes and cells positive for the Leu 7 antigen were present in pleural fluids. The analysis of T-cell subpopulations demonstrated a selective enrichment of T lymphocytes with helper/inducer phenotype in pleural effusions, while the percentages of T-cells with suppressor/cytotoxic phenotype were similar in pleural fluid and peripheral blood. These results indicate that in lymphocytic pleural effusions the main lymphoid cell population is represented by T lymphocytes with helper/inducer phenotype, regardless of whether the effusion is due to tuberculosis or malignancies such as mesothelioma or lung cancer.
<i>Maternally Expressed Gene 3</i>, an Imprinted Noncoding RNA Gene, Is Associated with Meningioma Pathogenesis and Progression
Authors: Xun Zhang, Roger Gejman, Ali Mahta, Ying Zhong, Kimberley A. Rice, Yunli Zhou, Pornsuk Cheunsuchon, David N. Louis, Anne Klibanski
Journal: Cancer Research (2010)

Abstract Meningiomas are common tumors, representing 15% to 25% of all central nervous system tumors. NF2 gene inactivation on chromosome 22 has been shown as an early event in tumorigenesis; however, few factors underlying tumor growth and progression have been identified. The chromosomal abnormalities of 14q32 are often associated with meningioma pathogenesis and progression; therefore, it has been proposed that an as yet unidentified tumor suppressor is present at this locus. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 which encodes a noncoding RNA with an antiproliferative function. We found that MEG3 mRNA is highly expressed in normal arachnoidal cells. However, MEG3 is not expressed in the majority of human meningiomas or the human meningioma cell lines IOMM-Lee and CH157-MN. There is a strong association between loss of MEG3 expression and tumor grade. Allelic loss at the MEG3 locus is also observed in meningiomas, with increasing prevalence in higher grade tumors. In addition, there is an increase in CpG methylation within the promoter and the imprinting control region of MEG3 gene in meningiomas. Functionally, MEG3 suppresses DNA synthesis in both IOMM-Lee and CH157-MN cells by ∼60% in bromodeoxyuridine incorporation assays. Colony-forming efficiency assays show that MEG3 inhibits colony formation in CH157-MN cells by ∼80%. Furthermore, MEG3 stimulates p53-mediated transactivation in these cell lines. Therefore, these data are consistent with the hypothesis that MEG3, which encodes a noncoding RNA, may be a tumor suppressor gene at chromosome 14q32 involved in meningioma progression via a novel mechanism. Cancer Res; 70(6); 2350–8
Effects of Exenatide Plus Rosiglitazone on β-Cell Function and Insulin Sensitivity in Subjects With Type 2 Diabetes on Metformin
Authors: Ralph A. DeFronzo, Curtis Triplitt, Yongming Qu, Michelle S. Lewis, David Maggs, Leonard C. Glass
Journal: Diabetes Care (2010)

OBJECTIVE Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on β-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin. RESEARCH DESIGN AND METHODS In this 20-week, randomized, open-label, multicenter study, participants (mean age, 56 ± 10 years; weight, 93 ± 16 kg; A1C, 7.8 ± 0.7%) continued their metformin regimen and received either EXE 10 μg b.i.d. (n = 45), ROSI 4 mg b.i.d. (n = 45), or EXE 10 μg b.i.d. + ROSI 4 mg b.i.d. (n = 47). Seventy-three participants underwent clamp procedures to quantitate insulin secretion and insulin sensitivity. RESULTS A1C declined in all groups (P &amp;lt; 0.05), but decreased most with EXE+ROSI (EXE+ROSI, −1.3 ± 0.1%; ROSI, −1.0 ± 0.1%, EXE, −0.9 ± 0.1%; EXE+ROSI vs. EXE or ROSI, P &amp;lt; 0.05). ROSI resulted in weight gain, while EXE and EXE+ROSI resulted in weight loss (EXE, −2.8 ± 0.5 kg; EXE+ROSI, −1.2 ± 0.5 kg; ROSI, + 1.5 ± 0.5 kg; P &amp;lt; 0.05 between and within all groups). At week 20, 1st and 2nd phase insulin secretion was significantly higher in EXE and EXE+ROSI versus ROSI (both P &amp;lt; 0.05). Insulin sensitivity (M value) was significantly higher in EXE+ROSI versus EXE (P = 0.014). CONCLUSIONS Therapy with EXE+ROSI offset the weight gain observed with ROSI and elicited an additive effect on glycemic control with significant improvements in β-cell function and insulin sensitivity.
Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy
Authors: Gregory J. Keir, Toby M. Maher, David M. Hansell, Christopher P. Denton, Voon H. Ong, Suveer Singh, Athol U. Wells, Elisabetta A. Renzoni
Journal: European Respiratory Journal (2012)

In very severe interstitial lung disease associated with connective tissue disease (CTD-ILD), progressing despite maximal conventional immunosuppression, there is no effective medical rescue therapy. The aim of the present study was to test whether rituximab, a monoclonal antibody that depletes peripheral B lymphocytes, is effective as rescue therapy in very severe CTD-ILD, unresponsive to conventional immunosuppression. We performed a retrospective assessment of eight patients with severe and progressive CTD-ILD treated with rituximab. In six patients, change in pulmonary function tests (PFTs) compared with pre-rituximab levels, was assessed at 9-12 months post-treatment. In two patients, who were mechanically ventilated at the time of treatment, clinical and HRCT changes were assessed. Seven out of eight patients had a favourable treatment response to rituximab, while in one patient disease severity did not change. In contrast with previous progression, we observed a median significant improvement of 22% in diffusing capacity for carbon monoxide (from a median baseline of 25%; range 16-32%; p=0.04), and a median significant improvement of 18% in forced vital capacity (from a median baseline of 45%; range 37-59%; p=0.03), in the 9-12 months following treatment with rituximab. In very severe CTD-ILD unresponsive to conventional immunosuppression, rituximab may represent an effective, potentially life-saving, therapeutic intervention.
Systemic release of interleukin-10 during orthotopic liver transplantation
Authors: Olivier Le Moine, Arnaud Marchhant, François Durand, Brigitte Ickx, Olrvier Pradier, Jacques Belghiti, Daniel Abramowicz, Michel Gelin, Michel Goldman, Jacques Devière
Journal: Hepatology (1994)

Experimental and clinical observations indicate that the liver allograft is less immunogenic than other organ transplants and can promote immune tolerance. Because interleukin-10 recently emerged as a macrophage and T-cell-derived cytokine with potent immunosuppressive properties, we studied its production in 28 patients undergoing orthotopic liver transplantation. Plasma levels of immunoreactive interleukin-10 dramatically increased within 2 hr after liver allograft reperfusion, with peak levels ranging between 214 and 4998 pg/ml (median = 677 pg/ml). This systemic release of interleukin-10 was transient because it returned to low levels by 48 hr (range = 26 to 51 pg/ml). The higher interleukin-10 levels measured in right atrial blood as compared with portal blood indicated that interleukin-10 was most likely synthesized within the liver graft. To get insight into the cellular origin of interleukin-10, we also measured serum levels of interleukin-4 and interferon-gamma, both produced by T cells, and interleukin-8, a cytokine secreted by macrophages, in eight patients. Interleukin-4 and interferon-gamma levels remained undetectable in most of the patients, whereas interleukin-8 levels paralleled those of interleukin-10. Portal endotoxemia was probably not involved in interleukin-10 production because endotoxin levels remained low (< 20 pg/ml) before and after liver allograft reperfusion. Interleukin-10 plasma levels did not correlate either with cold ischemia time or with the occurrence of rejection episodes. We conclude that orthotopic liver transplantation is associated with a massive release of interleukin-10 and interleukin-8, most likely produced by allograft macrophages.
Prevention of Glomerulonephritis and Prolonged Survival in New Zealand Black/New Zealand White F1 Hybrid Mice Fed an Essential Fatty Acid-deficient Diet
Authors: Eric R. Hurd, John M. Johnston, Janice R. Okita, Paul C. MacDonald, Morris Ziff, James N. Gilliam
Journal: Journal of Clinical Investigation (1981)

Female B/W mice spontaneously develop an autoimmune disease that is similar to systemic lupus erythematosus. Antibodies to doublestranded DNA (dsDNA) and antinuclear antibodies develop in aging animals; death from immune complex-mediated glomerulonephritis occurs from 8 to 12 mo of age. It has been reported that prostaglandin (PG)E1 treatment of such mice prolongs survival. In the present study, four groups of female B/W mice were studied beginning at 6-11 wk of age on the following regimens: (a) a synthetic diet that contained 20% safflower oil, (b) a standard laboratory chow diet, (c) a standard diet together with injections of PGE1, and (d) an essential fatty acid-deficient synthetic diet that contained 20% coconut oil. All animals were tested monthly for antinuclear antibodies and anti-dsDNA. Kidney tissue was obtained for light and immunofluorescence microscopy when animals were dying. All disease manifestations were altered strikingly in the essential fatty acid (EFA)-deficient animals. Intermediate benefit was seen in PGE1-treated animals. 7% of the control animals and 18% of safflower oil-fed animals survived to 10 mo. In contrast, the PGE1-treated and EFA-deficient mice had a similar survival rate (78-88%). At age 16 mo, 78% of EFA-deficient mice and 45% of PGE1-treated mice were alive. 25% of the PGE1-treated and 55% of the EFA-deficient animals survived to 20 mo. Serum anti-dsDNA appeared at age 5 mo in safflower oil-fed and control animals, but not until 9 and 12 mo for PGE1-treated and EFA-deficient animals, respectively. All kidneys from 7- to 9-mo-old safflower oil-fed and control animals and the majority of kidneys from PGE1-treated animals were abnormal by light and immunofluorescence microscopy. Kidneys from EFA-deficient animals were essentially normal at 10 mo. At 13 mo, all PGE1-treated animals examined had significant kidney involvement, whereas none of the EFA-deficient animals had glomerulonephritis. These findings demonstrate that an EFA-deficient diet has a beneficial effect on murine lupus erythematosus.
Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck
Authors: J. Bernier, J Bonner, J.B. Vermorken, R.-J. Bensadoun, R. Dummer, J. Giralt, G. Kornek, A. Hartley, R. Mesia, C. Robert, S. Segaert, K.K. Ang
Journal: Annals of Oncology (2007)