tbuckley/cabot-search huggingface dataset:
FGF23 Fails to Inhibit Uremic Parathyroid Glands
Authors: Rocío Canalejo, Antonio Canalejo, Julio Manuel Martinez-Moreno, M. Encarnacion Rodriguez-Ortiz, Jose C. Estepa, Francisco Javier Mendoza, Juan Rafael Munoz-Castaneda, Victoria Shalhoub, Yolanda Almaden, Mariano Rodriguez
Journal: Journal of the American Society of Nephrology (2010)

Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D(3). FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal-regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal-regulated kinase 1/2-mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition.
Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver
Authors: S. Lorenzini, T. G. Bird, L. Boulter, C. Bellamy, K. Samuel, R. Aucott, E. Clayton, P. Andreone, M. Bernardi, M. Golding, M. R. Alison, J. P. Iredale, S. J. Forbes
Journal: Gut (2010)

<h3>Background</h3> Stem/progenitor cell niches in tissues regulate stem/progenitor cell differentiation and proliferation through local signalling. <h3>Objective</h3> To examine the composition and formation of stem progenitor cell niches. <h3>Methods</h3> The composition of the hepatic progenitor cell niche in independent models of liver injury and hepatic progenitor cell activation in rodents and humans was studied. To identify the origin of the progenitor and niche cells, sex-mismatched bone marrow transplants in mice, who had received the choline–ethionine-deficient-diet to induce liver injury and progenitor cell activation, were used. The matrix surrounding the progenitor cells was described by immunohistochemical staining and its functional role controlling progenitor cell behaviour was studied in cell culture experiments using different matrix layers. <h3>Results</h3> The progenitor cell response in liver injury is intimately surrounded by myofibroblasts and macrophages, and to a lesser extent by endothelial cells. Hepatic progenitor cells are not of bone marrow origin; however, bone marrow-derived cells associate intimately with these cells and are macrophages. Laminin always surrounds the progenitor cells. In vitro studies showed that laminin aids maintenance of progenitor and biliary cell phenotype and promotes their gene expression (Dlk1, Aquaporin 1, γGT) while inhibiting hepatocyte differentiation and gene expression (CEPB/α). <h3>Conclusions</h3> During liver damage in rodents and humans a stereotypical cellular and laminin niche forms around hepatic progenitor cells. Laminin helps maintenance of undifferentiated progenitor cells. The niche links the intrahepatic progenitor cells with bone marrow-derived cells and links tissue damage with progenitor cell-mediated tissue repair.
Overexpression of ezrin inactivates NF2 tumor suppressor in glioblastoma
Authors: F. C. Morales, J. R. Molina, Y. Hayashi, M.-M. Georgescu
Journal: Neuro-Oncology (2010)

Glioblastoma is a frequent brain malignancy with a dismal prognosis. The molecular changes causing its aggressive phenotype are under investigation. We report that the cytoskeletal-related proteins neurofibromatosis type 2 (NF2) and ezrin have opposite yet interdependent activities in glioblastoma growth. We show that NF2 is absent in approximately one-third of glioblastoma cell lines and tumors, and that it suppresses growth when expressed in cells. Although ezrin overexpression was previously observed in glioblastoma, we show here that ezrin enhanced cell proliferation and anchorage-independent growth but only in cells expressing NF2. Ezrin interacted and delocalized NF2 from the cortical compartment releasing its inhibition on Rac1. By using swap NF2-ezrin molecules, we identified that the opposite effects on cell growth of NF2 and ezrin depend on their amino-terminal FERM domain. The subcellular cortical localization appeared important for NF2 suppressive activity. In contrast, the ability of ezrin to enhance growth or complex NF2 did not depend on the molecular conformation or subcellular localization. In conclusion, these studies show 2 mechanisms for NF2 inactivation in glioblastoma: (i) decreased protein expression and (ii) increasing dosages of ezrin that disable NF2 by intermolecular association and aberrant intracellular recruitment.
Prevalence and consequences of nutritional depletion in lung transplant candidates
Authors: C. Schwebel, I. Pin, D. Barnoud, G. Devouassoux, P.Y. Brichon, PH. Chaffanjon, O. Chavanon, C. Sessa, D. Blin, M. Guignier, X Leverve, Ch Pison
Journal: European Respiratory Journal (2000)

Nutritional status was studied in lung transplant (LT) candidates. The hypotheses were that nutritional depletion was highly prevalent and lean body mass depletion was a risk factor for a higher mortality both before and after LT. Of 78 consecutive patients listed for LT, 16 (21%) died while on the waiting list, eight (10%) were alive awaiting LT, and 54 (69%) received a graft. Mean age was 42.3+/-4.4 (mean+/-SD). Thirty-eight per cent had a diagnosis of bronchiectasis or cystic fibrosis (BRO/CF), 33% of emphysema, 20% of idiopathic pulmonary fibrosis (IPF) and 8% of primary pulmonary hypertension. Body mass index (BMI) was 20.4+/-4.3 kg.m2, weight was 87.9+/-16.6% of ideal body weight (IBW). Patients were classed into four nutritional groups according to IBW and creatinine height index (CHI): 1: weight <90% IBW and CHI <60% of predicted (28% of cases); II: weight <90% IBW and CHI > or =60% (27%); III: weight > or =90% IBW and CHI <60% (17%); IV: weight > or =90% IBW and CHI > or =60% (28%). Overall, 72% were depleted corresponding to groups 1, II and III. Lean body mass depletion occurred despite normal weight in 17% of the cases (group III). Subjects with BRO/CF were mostly in groups 1, II, III whereas IPF were concentrated in group II. Lean body mass depletion was associated with more severe hypoxaemia, reduced 6-minute walking distance and a higher mortality while awaiting. After LT, duration of mechanical ventilation, time spent in intensive care unit (ICU) was related to initial body composition. Survival after LT was lowest in group III. To conclude, nutritional depletion in lung transplant candidates is highly prevalent and should be more precisely assessed with a special reference to lean body mass since it has specific consequences both while awaiting and after lung transplant. Attempts should be made to increase lean body mass before lung transplant.
Effect of Histamine on the Pulmonary Circulation in Dogs
Authors: OLE STORSTEIN, LÉON CUDKOWICZ, H. D. ATTWOOD
Journal: Circulation Research (1959)

Histamine was administered to dogs by the intravenous route near the right atrium in doses of 9.6 to 19 γ/Kg. body weight. It produced a severe drop in systemic blood pressure, negligible changes in heart rate and respiration, usually a fall in cardiac output and no change in left atrial or pulmonary artery wedge pressure. The pulmonary artery pressure showed an initial rise and then a fall following the drop in systemic blood pressure. Pulmonary arteriolar resistance followed the changes in cardiac output. There appeared to be no consistent evidence of pulmonary vascular constriction following the injection of histamine in the doses used in this study.
Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases
Authors: Anastasia Hadzidimitriou, Andreas Agathangelidis, Nikos Darzentas, Fiona Murray, Marie-Helene Delfau-Larue, Lone Bredo Pedersen, Alba Navarro Lopez, Antonis Dagklis, Paul Rombout, Kheira Beldjord, Arne Kolstad, Martin H. Dreyling, Achilles Anagnostopoulos, Athanasios Tsaftaris, Penelope Mavragani-Tsipidou, Andreas Rosenwald, Maurilio Ponzoni, Patricia Groenen, Paolo Ghia, Birgitta Sander, Theodora Papadaki, Elias Campo, Christian Geisler, Richard Rosenquist, Frederic Davi, Christiane Pott, Kostas Stamatopoulos
Journal: Blood (2011)
Evolution of the Isd11–IscS Complex Reveals a Single α-Proteobacterial Endosymbiosis for All Eukaryotes
Authors: Thomas A. Richards, Mark van der Giezen
Journal: Molecular Biology and Evolution (2006)

Giardia and Trichomonas are eukaryotes without standard mitochondria but contain mitochondrial-type α-proteobacterium–derived iron–sulfur cluster (ISC) assembly proteins, located to mitosomes in Giardia and hydrogenosomes in Trichomonas. Although these data suggest a single common endosymbiotic ancestry for mitochondria, mitosomes, and hydrogenosomes, separate origins are still being proposed. Here, we present a bioinformatic analysis of Isd11, a recently described essential component of the mitochondrial ISC assembly pathway. Isd11 is unique to eukaryotes but functions closely with the α-proteobacterium–derived cysteine desulfurase IscS. We demonstrate the presence of homologues of Isd11 in all 5 eukaryotic supergroups sampled, including hydrogenosomal and mitosomal lineages. The eukaryotic invention of Isd11 as a functional partner to IscS directly implies a single shared α-proteobacterial endosymbiotic ancestry for all eukaryotes. This pinpoints the α-proteobacterial endosymbiosis to before the last common ancestor of all eukaryotes without ambiguity.
Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.
Authors: A Inazu, X C Jiang, T Haraki, K Yagi, N Kamon, J Koizumi, H Mabuchi, R Takeda, K Takata, Y Moriyama
Journal: Journal of Clinical Investigation (1994)

Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.
Thrombin- and Factor Xa–Induced DNA Synthesis Is Mediated by Transactivation of Fibroblast Growth Factor Receptor-1 in Human Vascular Smooth Muscle Cells
Authors: Bernhard H. Rauch, Esther Millette, Richard D. Kenagy, Guenter Daum, Alexander W. Clowes
Journal: Circulation Research (2003)

Thrombin and factor Xa (FXa) are agonists for G protein–coupled receptors (GPRCs) and may contribute to vascular lesion formation by stimulating proliferation of vascular smooth muscle cells (SMCs). Mitogenic signaling of GPCRs requires transactivation of receptor tyrosine kinases (RTKs). In rat SMCs, thrombin transactivates the epidermal growth factor receptor (EGFR) via a pathway that involves heparin-binding EGF-like growth factor (HB-EGF) as ligand for EGFR. The purpose of this study was to investigate in human SMCs the role of receptor transactivation in the mitogenic response to thrombin and FXa. Thrombin (10 nmol/L) and FXa (100 nmol/L) cause a 3.3- and 2.6-fold increase in DNA synthesis, respectively. In human SMCs, neither thrombin nor FXa causes EGFR phosphorylation, and blockade of EGFR kinase does not inhibit DNA synthesis. However, DNA synthesis and phosphorylation of fibroblast growth factor receptor-1 (FGFR-1) induced by thrombin or FXa are inhibited by antibodies neutralizing basic fibroblast growth factor (bFGF) or by heparin. Hirudin inhibits thrombin-, but not FXa-induced mitogenesis, indicating that FXa acts independently of thrombin. We further demonstrate by ELISA that upon thrombin and FXa stimulation, bFGF is released and binds to the extracellular matrix. Our data suggest that in human vascular SMCs, both thrombin and FXa rapidly release bFGF into the pericellular matrix. This is followed by transactivation of the FGFR-1 and increased proliferation. Heparin may inhibit the mitogenic effects of thrombin and FXa in human SMCs by preventing bFGF binding to FGFR-1.
Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group.
Authors: M Gore, P Mainwaring, R A'Hern, V MacFarlane, M Slevin, P Harper, R Osborne, J Mansi, P Blake, E Wiltshaw, J Shepherd
Journal: Journal of Clinical Oncology (1998)

We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy.Two hundred twenty-seven patients were randomized to treatment and eligible for analysis. The dose of carboplatin was calculated according to the Calvert formula. One hundred seventeen patients received carboplatin at an area under the concentration time curve (AUC) of 6 for six courses, administered every 28 days, and 110 patients received carboplatin at an AUC of 12 for four courses, administered every 28 days. Patients were eligible provided they had not received prior chemotherapy or radiotherapy and had International Federation of Gynecology and Obstetrics stages II to IV or relapsed stage I epithelial ovarian cancer.The planned total-dose increase was 33% for the patients treated with carboplatin AUC 12, but the received percentage total-dose increase was 20%. There were no differences in progression-free or overall survival between the two treatment arms; the overall survival rate at 5 years was 31% and 34% of patients treated at AUCs 6 and 12, respectively. There was significantly more toxicity associated with carboplatin AUC 12, which resulted in more treatment delays and/or dose reductions (52% v 18%; P < .001).We have shown that carboplatin can be delivered at an AUC of 12 for four courses without granulocyte colony-stimulating factor support, although significant hematologic toxicity occurs. Nonhematologic toxicities were not clinically significant. Carboplatin offers an opportunity to intensify cisplatin therapy, but a greater than two-fold increase in dose-intensity probably needs to be achieved before significant effects on survival will be produced and hematologic support will be required.
AN INCREASE IN RETICULO-ENDOTHELIAL CELLS IN OUTLYING BONE MARROW CONSEQUENT UPON A LOCAL INCREASE IN TEMPERATURE
Authors: Charles Huggins, W. J. Noonan
Journal: The Journal of Experimental Medicine (1936)

In adult mammals and birds there is a great quantitative difference in the reticulo-endothelial system content of the bone marrow of central bones as compared with distal outlying bones. Experimental procedures reported in the accompanying communication effecting development and increase of hemopoiesis in inactive yellow marrow also effect a reticulo-endothelial cell increase.
<i>M6P/IGF2R</i>tumor suppressor gene mutated in hepatocellular carcinomas in Japan
Authors: Yoshihiko Oka, Robert A. Waterland, J. Keith Killian, Catherine M. Nolan, Hong-Seok Jang, Keiji Tohara, Seigo Sakaguchi, Tsuneyoshi Yao, Akinori Iwashita, Yutaka Yata, Terumi Takahara, Shin-ichiro Sato, Kazuyuki Suzuki, Tomoyuki Masuda, Randy L. Jirtle
Journal: Hepatology (2002)

Mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) tumor suppressor– gene mutation is an early event in human hepatocellular carcinoma (HCC) formation in the United States, but its role in hepatocarcinogenesis in Japan is unclear. We therefore determined M6P/IGF2R mutation frequency in HCCs from patients who resided in the southern, central, and northern regions of Japan. Ten single nucleotide polymorphisms were used to identify HCCs and dysplastic liver nodules with M6P/IGF2R loss of heterozygosity. The retained allele in these tumors was also assessed for point mutations and deletions in the M6P/IGF2R ligand binding domains by direct sequencing of polymerase chain reaction (PCR) amplified DNA products. Fifty-eight percent (54 of 93) of the patients were heterozygous at the M6P/IGF2R locus, and 67% (43 of 64) of the HCCs and 75% (3 of 4) of the dysplastic nodules had loss of heterozygosity. The remaining allele in 21% of the HCCs contained either M6P/IGF2R missense mutations or deletions, whereas such mutations were not found in the dysplastic lesions. In conclusion, M6P/IGF2R is mutated in HCCs from throughout Japan with a frequency similar to that in the United States. Loss of heterozygosity in dysplastic liver nodules provides additional evidence that M6P/IGF2R haploid insufficiency is an early event in human hepatocarcinogenesis.
Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia
Authors: Michele Milella, Steven M. Kornblau, Zeev Estrov, Bing Z. Carter, Hélène Lapillonne, David Harris, Marina Konopleva, Shourong Zhao, Elihu Estey, Michael Andreeff
Journal: Journal of Clinical Investigation (2001)

The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27Kip1 and p21Waf1/CIP1) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.
Tissue Factor Regulation by Epidermal Growth Factor Receptor and Epithelial-to-Mesenchymal Transitions: Effect on Tumor Initiation and Angiogenesis
Authors: Chloe C. Milsom, Joanne L. Yu, Nigel Mackman, Johann Micallef, G. Mark Anderson, Abhijit Guha, Janusz W. Rak
Journal: Cancer Research (2008)

Abstract ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation. Blockade of E-cadherin in vitro, leads to the acquisition of spindle morphology and de novo expression of vimentin, features consistent with epithelial-to-mesenchymal transition. These changes were associated with an increase in EGFR-dependent TF expression, and with enhanced stimulation of vascular endothelial growth factor production, particularly following cancer cell treatment with coagulation factor VIIa. In vivo, cells undergoing epithelial-to-mesenchymal transition exhibited an increased metastatic potential. Furthermore, injections of the TF-blocking antibody (CNTO 859) delayed the initiation of A431 tumors in immunodeficient mice, and reduced tumor growth, vascularization, and vascular endothelial growth factor expression. Collectively, our data suggest that TF is regulated by both oncogenic and differentiation pathways, and that it functions in tumor initiation, tumor growth, angiogenesis, and metastasis. Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies. [Cancer Res 2008;68(24):10068–76]