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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,783 records · Page 99
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Feeding Arteries of Primary Tongue Cancers on Intra-arterial Infusion Chemotherapy

PurposeTo evaluate the frequency and the predictive factor of each feeding artery on intra-arterial infusion chemotherapy (IAIC) in primary tongue cancer.Materials and MethodsWe retrospectively evaluated 20 patients who received IAIC for primary tongue cancer. The main and accompanying feeding arteries were identified on super-selective angiography of the branches of the external carotid artery. Tumor diameter, and extension to the contralateral side, tongue extrinsic muscles (TEMs), and lateral mesopharyngeal wall were determined based on magnetic resonance imaging or computed tomography findings.ResultsThe main feeding artery was the ipsilateral lingual artery (LA) in 15 of the 20 examined tumors and the contralateral LA in the other 5. Ten cancers had only one feeding artery, and multiple feeding arteries were detected in the remaining 10. Tumors >4 cm (n = 9), those with extension to the contralateral side (n = 13), and those with extension to TEMs (n = 15) were supplied by significantly larger numbers of feeding arteries compared to tumors without these features (P = 0.01, 0.049, and 0.02, respectively). The frequency of feeding from the contralateral LA was 64 % (9/14) and 17 % (1/6) in tumors with and without extension to the contralateral side, respectively. Feeding from a facial artery (FA) was not detected in tumors ≤4 cm, while 5 of the 9 (56 %) tumors >4 cm were supplied by a FA (P = 0.01).ConclusionA careful search for feeding arteries is required, especially in large tumors with extension to the contralateral side or to TEMs.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Prostatic Artery Embolization (PAE) for Symptomatic Benign Prostatic Hyperplasia (BPH): Part 2, Insights into the Technical Rationale

Rationale of prostatic artery embolization (PAE) in the treatment of symptomatic benign prostatic hyperplasia is conventionally believed to include two parts: shrinkage of the enlarged prostate gland as a result of PAE-induced ischemic infarction and potential effects to relax the increased prostatic smooth muscle tone by reducing the number and density of α{sub 1}-adrenergic receptor in the prostate stroma. This review describes new insights into the likely mechanisms behind PAE, such as ischemia-induced apoptosis, apoptosis enhanced by blockage of androgens circulation to the embolized prostate, secondary denervation following PAE, and potential effect of nitric oxide pathway immediately after embolization. Studies on therapeutic mechanisms in PAE may shed light on potentially new treatment strategies and development of novel techniques.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Percutaneous Management of Accidentally Retained Foreign Bodies During Image-Guided Non-vascular Procedures: Novel Technique Using a Large-Bore Biopsy System

ObjectiveTo describe a novel percutaneous image-guided technique using a large-bore biopsy system to retrieve foreign bodies (FBs) accidentally retained during non-vascular interventional procedures.Materials and MethodsBetween May 2013 and October 2015, five patients underwent percutaneous retrieval of five iatrogenic FBs, including a biopsy needle tip in the femoral head following osteoblastoma biopsy and radiofrequency ablation (RFA); a co-axial needle shaft within a giant desmoid tumour following cryoablation; and three post-vertebroplasty cement tails within paraspinal muscles. All FBs were retrieved immediately following original procedures under local or general anaesthesia, using combined computed tomography (CT) and fluoroscopic guidance. The basic technique involved positioning a 6G trocar sleeve around the FB long axis and co-axially advancing an 8G biopsy needle to retrieve the FB within the biopsy core. Retrospective chart review facilitated analysis of procedures, FBs, technical success, and complications.ResultsMean FB size was 23 mm (range 8–74 mm). Four FBs were located within 10 mm of non-vascular significant anatomic structures. The basic technique was successful in 3 cases; 2 cases required technical modifications including using a stiff guide-wire to facilitate retrieval in the case of the post-cryoablation FB; and using the central mandrin of the 6G trocar to push a cement tract back into an augmented vertebra when initial retrieval failed. Overall technical success (FB retrieval or removal to non-hazardous location) was 100 %, with no complications.ConclusionPercutaneous image-guided retrieval of iatrogenic FBs using a large-bore biopsy system is a feasible, safe, effective, and versatile technique, with potential advantages over existing methods.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

MRI-guided Wire Localization Surgical Biopsy in an Adolescent Patient with a Difficult to Diagnose Case of Lymphoma

A 17-year-old previously healthy female presented with a progressive soft tissue infiltrative process involving the neck and thorax. Extensive diagnostic evaluation including multiple imaging, laboratory, and biopsy studies was nondiagnostic. Due to an urgent need to establish a diagnosis and several previous nondiagnostic biopsies, she was referred to interventional radiology for MRI-guided wire localization immediately prior to open surgical biopsy. Under general anesthesia, wires were placed in the areas of increased T2 signal within the bilateral splenius capitis muscles using intermittent MRI-guidance followed by immediate surgical biopsy down to the wires. Pathology confirmed the diagnosis of diffuse large B-cell lymphoma.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Development and Evaluation of a Novel Curved Biopsy Device for CT-Guided Biopsy of Lesions Unreachable Using Standard Straight Needle Trajectories

PurposeTo evaluate the feasibility of a novel curved CT-guided biopsy needle prototype with shape memory to access otherwise not accessible biopsy targets.Methods and MaterialsA biopsy needle curved by 90° with specific radius was designed. It was manufactured using nitinol to acquire shape memory, encased in a straight guiding trocar to be driven out for access of otherwise inaccessible targets. Fifty CT-guided punctures were conducted in a biopsy phantom and 10 CT-guided punctures in a swine corpse. Biposies from porcine liver and muscle tissue were separately gained using the biopsy device, and histological examination was performed subsequently.ResultsMean time for placement of the trocar and deployment of the inner biopsy needle was ~205 ± 69 and ~93 ± 58 s, respectively, with a mean of ~4.5 ± 1.3 steps to reach adequate biopsy position. Mean distance from the tip of the needle to the target was ~0.7 ± 0.8 mm. CT-guided punctures in the swine corpse took relatively longer and required more biopsy steps (~574 ± 107 and ~380 ± 148 s, 8 ± 2.6 steps). Histology demonstrated appropriate tissue samples in nine out of ten cases (90%).ConclusionsTargets that were otherwise inaccessible via standard straight needle trajectories could be successfully reached with the curved biopsy needle prototype. Shape memory and preformed size with specific radius of the curved needle simplify the target accessibility with a low risk of injuring adjacent structures.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Cytological Characteristics of a Heterogeneous Population of Hepatocellular Carcinoma-29 Cells after Injection of Lithium Carbonate in the Experiment

Five cytological types of hepatocellular carcinoma-29 (G-29) grown in the muscle tissue of the thigh of experimental animals were identified by transmission electron microscopy; 89% of these were poorly differentiated type I-III cells. Lithium in a concentration of 20 mM produced a damaging effect on poorly differentiated G-29 cells: the number of cells with zones of intracellular component destruction and volume density of these zones increased, while volume density of cisterns of endoplasmic reticulum decreased. These results suggest that lithium carbonate can cause destructive changes in the heterogeneous population of G-29 cells during in vivo tumor development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Focal mass-like cardiac uptake on oncologic FDG PET/CT: Real lesion or atypical pattern of physiologic uptake?

Background: Cardiac uptake on oncologic FDG PET/CT can be unpredictable. Focal or mass-like cardiac uptake not confined to normal pattern is a real challenge for interpretation due to great variability in physiologic uptake and rarity of either primary or metastatic cardiac neoplasms. Methods and Results: Eight patients with suspicious mass-like cardiac uptake on oncologic FDG PET/CT were retrospectively analyzed with correlation to cardiac workups including contrast CT, echocardiography, and repeat PET/CT. Four patients had real cardiac lesions or metastases. Focal uptake was benign and might represent papillary muscle in the other four. SUV{sub max} ratio between the cardiac focus and surrounding background cardiac uptake was statistically higher in the true-positive group than that in the false-positive group. In addition, the patients with true-positive cardiac uptake had more diffuse distant metastases compared to those with false-positive cardiac uptake. Conclusions: Focal suspicious cardiac uptake on oncology FDG PET/CT warranted further evaluation. SUV{sub max} ratio between the cardiac focus and surrounding background cardiac uptake and status of distant metastases might help to differentiate malignant from benign nature of the focal cardiac uptake on FDG PET/CT. Focal uptake of the right ventricle on oncologic FDG PET/CT is more likely suggestive of a neoplasm.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Hepatitis B virus e antigen induces activation of rat hepatic stellate cells

Highlights: •HBeAg expression in HSCs induced production of ECM protein and liver fibrotic markers. •The activation and proliferation of HSCs were mediated by TGF-β. •HBeAg protein purified from cell medium directly activated HSCs. -- Abstract: Chronic hepatitis B virus infection is a major cause of hepatic fibrosis, leading to liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus e antigen (HBeAg) is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. Hepatic stellate cells (HSCs) are the major producers of excessive extracellular matrix during liver fibrogenesis. Therefore, we examined the influence of HBeAg on HSCs. The rat HSC line HSC-T6 was transfected with HBeAg plasmids, and expression of α-smooth muscle actin, collagen I, transforming growth factor-β1 (TGF-β), and tissue inhibitors of metalloproteinase 1 (TIMP-1) was investigated by quantitative real-time PCR. The proliferation of HSCs was determined by MTS analysis. HBeAg transduction induced up-regulation of these fibrogenic genes and proliferation of HSCs. We found that HBeAg induced TGF-β secretion in HSCs, and the activation of HSCs was prevented by a neutralizing anti-TGF-β antibody. Depletion and addition of HBeAg protein in conditioned medium from HSC-T6 cells transduced with HBeAg indicated that HBeAg directly induced the activation and proliferation of rat primary HSCs. Taken together, HBeAg induces the activation and proliferation of HSCs, mainly mediated by TGF-β, and HBeAg protein purified from cell medium can directly activate HSCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Identification of FAM96B as a novel prelamin A binding partner

Highlights: •We screen the binding protein of prelamin A by yeast two-hybrid screen. •FAM96B colocalizes with prelamin A in HEK-293 cells. •FAM96B physically interacts with prelamin A. -- Abstract: Prelamin A accumulation causes nuclear abnormalities, impairs nuclear functions, and eventually promotes cellular senescence. However, the underlying mechanism of how prelamin A promotes cellular senescence is still poorly understood. Here we carried out a yeast two-hybrid screen using a human skeletal muscle cDNA library to search for prelamin A binding partners, and identified FAM96B as a prelamin A binding partner. The interaction of FAM96B with prelamin A was confirmed by GST pull-down and co-immunoprecipitation experiments. Furthermore, co-localization experiments by fluorescent confocal microscopy revealed that FAM96B colocalized with prelamin A in HEK-293 cells. Taken together, our data demonstrated the physical interaction between FAM96B and prelamin A, which may provide some clues to the mechanisms of prelamin A in premature aging.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Localization and proliferation of lymphatic vessels in the tympanic membrane in normal state and regeneration

Highlights: •We newly developed the whole-mount imaging method of the tympanic membrane. •Lymphatic vessel loops were localized around the malleus handle and annulus tympanicus. •In regeneration, abundant lymphatic vessels were observed in the pars tensa. •Site-specific lymphatic vessels may play an important role in the tympanic membrane. -- Abstract: We clarified the localization of lymphatic vessels in the tympanic membrane and proliferation of lymphatic vessels during regeneration after perforation of the tympanic membrane by using whole-mount imaging of the tympanic membrane of Prox1 GFP mice. In the pars tensa, lymphatic vessel loops surrounded the malleus handle and annulus tympanicus. Apart from these locations, lymphatic vessel loops were not observed in the pars tensa in the normal tympanic membrane. Lymphatic vessel loops surrounding the malleus handle were connected to the lymphatic vessel loops in the pars flaccida and around the tensor tympani muscle. Many lymphatic vessel loops were detected in the pars flaccida. After perforation of the tympanic membrane, abundant lymphatic regeneration was observed in the pars tensa, and these regenerated lymphatic vessels extended from the lymphatic vessels surrounding the malleus at day 7. These results suggest that site-specific lymphatic vessels play an important role in the tympanic membrane.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

PPAR-γ agonist stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination

Highlights: •PPAR-γ increases KLF4 protein level but does not influence KLF4 gene transcription. •The increase of KLF4 protein levels induced by pioglitazone is PPAR-γ-dependent. •Pioglitazone stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination. -- Abstract: Peroxisome proliferator activated receptor γ (PPAR-γ) plays important roles in cell cycle regulation, differentiation and apoptosis. Krüppel-like factor 4 (KLF4) modulates vascular smooth muscle cell (VSMC) phenotype. Both KLF4 and PPAR-γ are involved in VSMC proliferation and differentiation. However, the actual relationship between KLF4 and PPAR-γ in VSMCs is not clear. In this study, we found that PPAR-γ agonist pioglitazone increases KLF4 protein levels but does not influence KLF4 gene transcription. PPAR-γ overexpression increases, while PPAR-γ knockdown reduces KLF4 expression, suggesting that the increase in KLF4 protein levels induced by pioglitazone is PPAR-γ-dependent. Further study showed that pioglitazone enhances KLF4 protein stability through reducing KLF4 ubiquitination. Furthermore, we demonstrated that stabilization of KLF4 by pioglitazone was related to the activation of Akt signaling pathway. Taken together, we revealed that PPAR-γ agonist pioglitazone stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination, providing further insights into PPAR-γ and KLF4 in regulating each other’s expression in VSMCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Overexpression of Snail in retinal pigment epithelial triggered epithelial–mesenchymal transition

Highlights: • First reported overexpression of Snail in RPE cells could directly trigger EMT. • Further confirmed the regulator role of Snail in RPE cells EMT in vitro. • Snail may be a potential therapeutic target to prevent the fibrosis of PVR. - Abstract: Snail transcription factor has been implicated as an important regulator in epithelial–mesenchymal transition (EMT) during tumourigenesis and fibrogenesis. Our previous work showed that Snail transcription factor was activated in transforming growth factor β1 (TGF-β1) induced EMT in retinal pigment epithelial (RPE) cells and may contribute to the development of retinal fibrotic disease such as proliferative vitreoretinopathy (PVR). However, whether Snail alone has a direct role on retinal pigment epithelial–mesenchymal transition has not been investigated. Here, we analyzed the capacity of Snail to drive EMT in human RPE cells. A vector encoding Snail gene or an empty vector were transfected into human RPE cell lines ARPE-19 respectively. Snail overexpression in ARPE-19 cells resulted in EMT, which was characterized by the expected phenotypic transition from a typical epithelial morphology to mesenchymal spindle-shaped. The expression of epithelial markers E-cadherin and Zona occludin-1 (ZO-1) were down-regulated, whereas mesenchymal markers a-smooth muscle actin (a-SMA) and fibronectin were up-regulated in Snail expression vector transfected cells. In addition, ectopic expression of Snail significantly enhanced ARPE-19 cell motility and migration. The present data suggest that overexpression of Snail in ARPE-19 cells could directly trigger EMT. These results may provide novel insight into understanding the regulator role of Snail in the development of retinal pigment epithelial–mesenchymal transition.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Adipocyte induced arterial calcification is prevented with sodium thiosulfate

Highlights: • High phosphorus can induce calcification of adipocytes, even when fully differentiated. • Adipocytes can induce vascular calcification in an autocrine manner. • Sodium thiosulfate inhibits adipocyte calcification. - Abstract: Background: Calcification can occur in fat in multiple clinical conditions including in the dermis, breasts and in the abdomen in calciphylaxis. All of these are more common in patients with advanced kidney disease. Clinically, hyperphosphatemia and obesity are risk factors. Thus we tested the hypothesis that adipocytes can calcify in the presence of elevated phosphorus and/or that adipocytes exposed to phosphorus can induce vascular smooth muscle cell (VSMC) calcification. Methods: 3T3-L1 preadipocytes were induced into mature adipocytes and then treated with media containing high phosphorus. Calcification was assessed biochemically and PCR performed to determine the expression of genes for osteoblast and adipocyte differentiation. Adipocytes were also co-cultured with bovine VSMC to determine paracrine effects, and the efficacy of sodium thiosulfate was determined. Results: The results demonstrated that high phosphorus induced the calcification of differentiated adipocytes with increased expression of osteopontin, the osteoblast transcription factor Runx2 and decreased expression of adipocyte transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (CEBPα), indicating that high phosphorus led to a phenotypic switch of adipocytes to an osteoblast like phenotype. Sodium thiosulfate, dose dependently decreased adipocyte calcification and inhibited adipocyte induced increase of VSMC calcification. Co-culture studies demonstrated that adipocytes facilitated VSMC calcification partially mediated by changes of secretion of leptin and vascular endothelial growth factor (VEGF) from adipocytes. Conclusion: High phosphorus induced calcification of mature adipocytes, and adipocytes exposed to elevated phosphorus can induce calcification of VSMC in a paracrine manner. Sodium thiosulfate inhibited this calcification and decreased the secretin of leptin and VEGF from adipocytes. These results suggest that adipocyte exposure to elevated phosphorus may be a pathogenic factor in calcification observed in the skin in calciphylaxis and other diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Myomaker mediates fusion of fast myocytes in zebrafish embryos

Highlights: • Myomaker is transiently expressed in fast myocytes during embryonic myogenesis. • Myomaker is essential for fast myocyte fusion in zebrafish. • The function of myomaker is conserved among Teleostomi. - Abstract: Myomaker (also called Tmem8c), a new membrane activator of myocyte fusion was recently discovered in mice. Using whole mount in situ hybridization on zebrafish embryos at different stages of embryonic development, we show that myomaker is transiently expressed in fast myocytes forming the bulk of zebrafish myotome. Zebrafish embryos injected with morpholino targeted against myomaker were alive after yolk resorption and appeared morphologically normal, but they were unable to swim, even under effect of a tactile stimulation. Confocal observations showed a marked phenotype characterized by the persistence of mononucleated muscle cells in the fast myotome at developmental stages where these cells normally fuse to form multinucleated myotubes. This indicates that myomaker is essential for myocyte fusion in zebrafish. Thus, there is an evolutionary conservation of myomaker expression and function among Teleostomi.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Over-expression of Oct4 and Sox2 transcription factors enhances differentiation of human umbilical cord blood cells in vivo

Highlights: • Gene and cell-based therapies comprise innovative aspects of regenerative medicine. • Genetically modified hUCB-MCs enhanced differentiation of cells in a mouse model of ALS. • Stem cells successfully transformed into micro-glial and endothelial lines in spinal cords. • Over-expressing oct4 and sox2 also induced production of neural marker PGP9.5. • Formation of new nerve cells, secreting trophic factors and neo-vascularisation could improve symptoms in ALS. - Abstract: Gene and cell-based therapies comprise innovative aspects of regenerative medicine. Even though stem cells represent a highly potential therapeutic strategy, their wide-spread exploitation is marred by ethical concerns, potential for malignant transformation and a plethora of other technical issues, largely restricting their use to experimental studies. Utilizing genetically modified human umbilical cord blood mono-nuclear cells (hUCB-MCs), this communication reports enhanced differentiation of transplants in a mouse model of amyotrophic lateral sclerosis (ALS). Over-expressing Oct4 and Sox2 induced production of neural marker PGP9.5, as well as transformation of hUCB-MCs into micro-glial and endothelial lines in ALS spinal cords. In addition to producing new nerve cells, providing degenerated areas with trophic factors and neo-vascularisation might prevent and even reverse progressive loss of moto-neurons and skeletal muscle paralysis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Age-dependent changes in diastolic Ca{sup 2+} and Na{sup +} concentrations in dystrophic cardiomyopathy: Role of Ca{sup 2+} entry and IP{sub 3}

Highlights: • Age-dependent increase in [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} in mdx cardiomyocytes. • Gadolinium significantly reduced both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} at all ages. • IP{sub 3}-pathway inhibition reduced cations concentrations in dystrophic cardiomyocytes. - Abstract: Duchenne muscular dystrophy (DMD) is a lethal X-inherited disease caused by dystrophin deficiency. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with a dilated cardiomyopathy that leads to progressive heart failure at the end of the second decade. The aim of the present study was to characterize the diastolic Ca{sup 2+} concentration ([Ca{sup 2+}]{sub d}) and diastolic Na{sup +} concentration ([Na{sup +}]{sub d}) abnormalities in cardiomyocytes isolated from 3-, 6-, 9-, and 12-month old mdx mice using ion-selective microelectrodes. In addition, the contributions of gadolinium (Gd{sup 3+})-sensitive Ca{sup 2+} entry and inositol triphosphate (IP{sub 3}) signaling pathways in abnormal [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} were investigated. Our results showed an age-dependent increase in both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} in dystrophic cardiomyocytes compared to those isolated from age-matched wt mice. Gd{sup 3+} treatment significantly reduced both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} at all ages. In addition, blockade of the IP{sub 3}-pathway with either U-73122 or xestospongin C significantly reduced ion concentrations in dystrophic cardiomyocytes. Co-treatment with U-73122 and Gd{sup 3+} normalized both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} at all ages in dystrophic cardiomyocytes. These data showed that loss of dystrophin in mdx cardiomyocytes produced an age-dependent intracellular Ca{sup 2+} and Na{sup +} overload mediated at least in part by enhanced Ca{sup 2+} entry through Gd{sup 3+} sensitive transient receptor potential channels (TRPC), and by IP{sub 3} receptors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Assessment of DNA synthesis in Islet-1{sup +} cells in the adult murine heart

Highlights: • Islet-1 was expressed in the adult heart. • Islet-1-positive cells did not proliferate in the adult heart. • Sinoatrial node cells did not proliferate in the adult heart. - Abstract: Rationale: Islet-1 positive (Islet-1{sup +}) cardiac progenitor cells give rise to the right ventricle, atria and outflow tract during murine cardiac development. In the adult heart Islet-1 expression is limited to parasympathetic neurons, few cardiomyocytes, smooth muscle cells, within the proximal aorta and pulmonary artery and sinoatrial node cells. Its role in these cells is unknown. Here we tested the hypothesis that Islet-1{sup +} cells retain proliferative activity and may therefore play a role in regenerating specialized regions in the heart. Methods and results: DNA synthesis was analyzed by the incorporation of tritiated thymidine ({sup 3}H-thymidine) in Isl-1-nLacZ mice, a transgenic model with an insertion of a nuclear beta-galactosidase in the Islet-1 locus. Mice received daily injections of {sup 3}H-thymidine for 5 days. DNA synthesis was visualized throughout the heart by dipping autoradiography of cryosections. Colocalization of an nLacZ-signal and silver grains would indicate DNA synthesis in Islet-1{sup +} cells. Whereas Islet{sup −} non-myocyte nuclei were regularly marked by accumulation of silver grains, colocalization with nLacZ-signals was not detected in >25,000 cells analyzed. Conclusions: Islet-1{sup +} cells are quiescent in the adult heart, suggesting that, under normal conditions, even pacemaking cells do not proliferate at higher rates than normal cardiac myocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Platelet-derived growth factor-D modulates extracellular matrix homeostasis and remodeling through TIMP-1 induction and attenuation of MMP-2 and MMP-9 gelatinase activities

Platelet-derived growth factor-D (PDGF-D) is a more recent recognized growth factor involved in the regulation of several cellular processes, including cell proliferation, transformation, invasion, and angiogenesis by binding to and activating its cognate receptor PDGFR-β. After bile duct ligation or in the carbon tetrachloride-induced hepatic fibrosis model{sub ,} PDGF-D showed upregulation comparable to PDGF-B. Moreover, adenoviral PDGF-D gene transfer induced hepatic stellate cell proliferation and liver fibrosis. We here investigated the molecular mechanism of PDGF-D involvement in liver fibrogenesis. Therefore, the GRX mouse cell line was stimulated with PDGF-D and evaluated for fibrotic markers and PDGF-D signaling pathways in comparison to the other PDGF isoforms. We found that PDGF-D failed to enhance Col I and α-smooth muscle actin (α-SMA) production but has capacity to upregulate expression of the tissue inhibitor of metalloprotease 1 (TIMP-1) resulting in attenuation of MMP-2 and MMP-9 gelatinase activity as indicated by gelatinase zymography. This phenomenon was restored through application of a PDGF-D neutralizing antibody. Unexpectedly, PDGF-D incubation decreased both PDGFR-α and -β in mRNA and protein levels, and PDGF-D phosphorylated typrosines specific for PDGFR-α and -β. We conclude that PDGF-D intensifies fibrogenesis by interfering with the fibrolytic activity of the TIMP-1/MMP system and that PDGF-D signaling is mediated through both PDGF-α and -β receptors. - Highlights: • PDGF-D signals through PDGF receptor type α and β. • PDGF-D modulates extracellular matrix homeostasis and remodeling. • Like PDGF-B, PDGF-D triggers phosphorylation of PLC-γ, Akt/PKB, JNK, ERK1/2, and p38. • PDGF-D induces TIMP-1 expression through ERK and p38 MAPK. • PDGF-D attenuates MMP-2 and MMP-9 gelatinase activities.

60 APPLIED LIFE SCIENCES↗