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Find video protocols related to scientific articles indexed in Pubmed.
KRAS, EGFR, PDGFR-?, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE).
Diagn Pathol
PUBLISHED: 05-15-2014
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CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid.
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Inter- and intra-observer agreement on Miller's classification of gingival tissue recessions.
Odontology
PUBLISHED: 01-28-2014
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Miller's is the most commonly used classification of gingival tissue recessions, defined as the displacement of the soft tissue margin apical to the cemento-enamel junction. However, data on the reliability of this classification are missing so far, although reliability, which reflects the consistency of repeated measurements, is regarded as a prerequisite for judging the utility of a classification. The aim of the present study was to evaluate inter- and intra-observer agreement on Miller's classification of gingival tissue recessions. Two hundred photographs (50 of each region: maxillary/mandibular anterior/posterior teeth) of gingival tissue recessions were evaluated twice by four observers with different degrees of experience in Miller's classification, gingival phenotype, tooth shape, and identifiability of the cemento-enamel junction. The following inter- and intra-observer agreements were found: Miller's classification, 0.72 and 0.73-0.95; gingival phenotype, 0.29 and 0.45-0.58; tooth shape, 0.39 and 0.44-0.59; and identifiability of the cemento-enamel junction, 0.21 and 0.30-0.59. A higher agreement was detected for anterior teeth. Further, gingival phenotype (thin-high scalloping) significantly correlated with tooth shape (long-narrow) (? = 0.662, p < 0.001). Miller's classification of gingival tissue recessions was evaluated by four examiners using 200 clinical photographs and yielded substantial to almost perfect agreement, with higher agreement for anterior teeth. Although limited to photographic assessment, the present study offers the so far missing proof on the sufficient inter- and intra-observer agreement of this classification.
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Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.
Cell
PUBLISHED: 01-21-2014
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Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
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Environmentally relevant bouts of cooling stimulate corticosterone secretion in free-living eastern bluebird (Sialia sialis) nestlings: Potential links between maternal behavior and corticosterone exposure in offspring.
Gen. Comp. Endocrinol.
PUBLISHED: 08-01-2013
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In vertebrates, exposure to stressful stimuli or to elevated glucocorticoids early in development can contribute to phenotypic variation that may have significant fitness consequences. In species with altricial young, offspring may be partially buffered from elevations in glucocorticoids by a period of low glucocorticoid responsiveness to stressors coupled with high levels of parental care. Because altricial young depend heavily on their parents for warmth, parental brooding behavior could buffer offspring from glucocorticoid exposure associated with cooling. We studied eastern bluebirds (Sialia sialis) with two goals: (1) to determine whether an experimental drop in body temperature such as that which might occur when a brooding female is off the nest was sufficient to stimulate glucocorticoid secretion in young chicks, and (2) to examine the extent to which chicks experienced such bouts of cooling in the field. We subjected chicks to treatments simulating nest temperatures while females were brooding or absent from the nest. We also recorded chick surface temperatures and ambient temperatures at nests during the first week of the brood period. Reductions of surface temperature of less than 10°C significantly elevated corticosterone secretion in chicks as young as 5days old, and thermal and hormonal responses of chicks to cooling increased in an age-dependent manner. One quarter of broods experienced repeated, natural bouts of cooling of this magnitude or greater in the nest. Our data suggest that natural variations in maternal brooding patterns can result in differential exposure of offspring to glucocorticoids, and this may have important phenotypic consequences later in life.
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Assessing the effectiveness and cost effectiveness of subcutaneous nerve stimulation in patients with predominant back pain due to failed back surgery syndrome (SubQStim study): study protocol for a multicenter randomized controlled trial.
Trials
PUBLISHED: 06-05-2013
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Chronic radicular pain can be effectively treated with spinal cord stimulation, but this therapy is not always sufficient for chronic back pain. Subcutaneous nerve stimulation (SQS) refers to the placement of percutaneous leads in the subcutaneous tissue within the area of pain. Case series data show that failed back surgery syndrome (FBSS) patients experience clinically important levels of pain relief following SQS and may also reduce their levels of analgesic therapy and experience functional well-being. However, to date, there is no randomized controlled trial evidence to support the use of SQS in FBSS.
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Neonatal handling alters the development of the adrenocortical response to stress in a wild songbird (eastern bluebird, Sialia sialis).
Gen. Comp. Endocrinol.
PUBLISHED: 03-02-2013
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Neonatal handling of captive vertebrates can shape the development of their hypothalamo-pituitary-adrenal (HPA) axis and alter their ability to respond to stressful stimuli later in life. However, the long-term effects of such handling on this endocrine axis in free-living species are not well understood. We investigated the effects of age and neonatal handling on corticosterone secretion in response to restraint in eastern bluebird (Sialia sialis) chicks. We found that unhandled ("naïve") and handled ("experienced") chicks exhibited no corticosterone response to handling early in development. Thereafter, naïve individuals exhibited the progressive development of a corticosterone response with age, and by day 12 post-hatch, the response resembled that of adult bluebirds. Experienced nestlings, which were handled every other day from the day of hatch, showed a similar pattern of HPA development until day 12 post-hatch, when their corticosterone response was significantly reduced compared to that of naïve nestlings. In contrast, chicks that were handled only once, when 10days old, did not show a reduced corticosterone response at 12days old. Taken together, our data suggest that a certain threshold of accumulated neonatal handling episodes is necessary to depress corticosterone secretion, and/or that the cumulative effects of several handling episodes only manifest themselves once the HPA axis is fully developed. Our findings, in concert with studies on two other wild species, indicate that routine handling of nestlings in the field can alter their responses to stress in a species-specific manner, potentially leading to important fitness consequences.
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Peripheral Nerve Field Stimulation (PNFS) in Chronic Low Back Pain: A Prospective Multicenter Study.
Neuromodulation
PUBLISHED: 01-16-2013
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The goal of this study was to evaluate the long-term efficacy and safety of peripheral nerve field stimulation (PNFS) for chronic low back pain (cLBP).
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Green tea extract ameliorates reperfusion injury to rat livers after warm ischemia in a dose-dependent manner.
Mol Nutr Food Res
PUBLISHED: 03-25-2011
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Polyphenolic constituents of green tea (Camellia sinensis) have been shown to be potent scavengers of reactive oxygen species (ROS). Thus, this study was designed to assess its effects after liver ischemia-reperfusion.
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Central nervous system dysfunction in a mouse model of FA2H deficiency.
Glia
PUBLISHED: 03-03-2011
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Fatty acid 2-hydroxylase (FA2H) is responsible for the synthesis of myelin galactolipids containing hydroxy fatty acid (hFA) as the N-acyl chain. Mutations in the FA2H gene cause leukodystrophy, spastic paraplegia, and neurodegeneration with brain iron accumulation. Using the Cre-lox system, we developed two types of mouse mutants, Fa2h(-/-) mice (Fa2h deleted in all cells by germline deletion) and Fa2h(flox/flox) Cnp1-Cre mice (Fa2h deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of Fa2h(-/-) mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected. Fa2h(-/-) mice also exhibited histological and functional disruption in the cerebellum at 12 months of age. In a time course study, significant deterioration of cerebellar function was first detected at 7 months of age. Further behavioral assessments in water T-maze and Morris water maze tasks revealed significant deficits in spatial learning and memory at 4 months of age. These data suggest that various regions of the CNS are functionally compromised in young adult Fa2h(-/-) mice. The cerebellar deficits in 12-month-old Fa2h(flox/flox) Cnp1-Cre mice were indistinguishable from Fa2h(-/-) mice, indicating that these phenotypes likely stem from the lack of myelin hFA-galactolipids. In contrast, Fa2h(flox/flox) Cnp1-Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in Fa2h(-/-) mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS.
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Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors.
Clin. Cancer Res.
PUBLISHED: 03-03-2011
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The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.
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The nude mutant gene Foxn1 is a HOXC13 regulatory target during hair follicle and nail differentiation.
J. Invest. Dermatol.
PUBLISHED: 12-30-2010
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Among the Hox genes, homeobox C13 (Hoxc13) has been shown to be essential for proper hair shaft differentiation, as Hoxc13 gene-targeted (Hoxc13(tm1Mrc)) mice completely lack external hair. Because of the remarkable overt phenotypic parallels to the Foxn1(nu) (nude) mutant mice, we sought to determine whether Hoxc13 and forkhead box N1 (Foxn1) might act in a common pathway of hair follicle (HF) differentiation. We show that the alopecia exhibited by both the Hoxc13(tm1Mrc) and Foxn1(nu) mice is because of strikingly similar defects in hair shaft differentiation and that both mutants suffer from a severe nail dystrophy. These phenotypic similarities are consistent with the extensive overlap between Hoxc13 and Foxn1 expression patterns in the HF and the nail matrix. Furthermore, DNA microarray analysis of skin from Hoxc13(tm1Mrc) mice identified Foxn1 as significantly downregulated along with numerous hair keratin genes. This Foxn1 downregulation apparently reflects the loss of direct transcriptional control by HOXC13 as indicated by our results obtained through co-transfection and chromatin immunoprecipitation (ChIP) assays. As presented in the discussion, these data support a regulatory model of keratinocyte differentiation in which HOXC13-dependent activation of Foxn1 is part of a regulatory cascade controlling the expression of terminal differentiation markers.
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CD95 and TNF?-induced apoptosis in liver metastases of colorectal carcinoma.
In Vivo
PUBLISHED: 10-19-2010
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Therapeutic options in patients with metastatic colorectal cancer are still limited. As apoptosis contributes to the overall sensitivity to radiotherapy or chemotherapy, a better understanding of the apoptotic process in metastatic tumour tissues is necessary.
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COX-2 expression and effects of COX-2 inhibition in colorectal carcinomas and their liver metastases.
Anticancer Res.
PUBLISHED: 07-24-2010
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Nonsteroidal anti-inflammatory drugs are known to reduce the risk and mortality from colorectal carcinoma by inhibiting cyclo-oxygenases (COX). COX-2 expression was investigated immunohistologically in 57 patients with colorectal carcinomas and in the corresponding liver metastases using tissue microarray analysis. Ex vivo COX-2 inhibition with assessment of apoptosis was performed using precision-cut tissue slices of three human liver metastases. Following stimulation with different concentrations of the selective COX-2 inhibitor meloxicam, apoptosis was assessed immunohistochemically after 6 h and 12 h. All primary carcinomas and 56 out of the 57 liver metastases showed various degrees of cytoplasmatic COX-2 expression being with a reduction and in the liver metastases. There was a time- and concentration-dependent change in the number of apoptotic cells in tissue slices, however, this was without statistical significance. COX-2 is constantly involved in the carcinogenesis and metastatic process of colorectal cancer. The antineoplastic effect of COX-2 inhibition may be based on different pathways, including changes in sensitivity to apoptosis.
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Her2 overexpression is a rare event in anorectal melanoma.
Melanoma Res.
PUBLISHED: 06-22-2010
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Anorectal melanomas (AMs) are very rare and highly malignant tumors that are often diagnosed in advanced stages. After the differentiation between cutaneous melanoma (CM) and AM on the molecular level based on the presence of BRAF mutations, further modes of differentiation opened up, such as the recently discovered immunohistologically relevant protein deleted in malignant brain tumors 1 (DMBT1). Over the past several years, increasingly specific therapies have been developed on the basis of new therapy principles. Tyrosin kinase receptors such as Her2 and EGFR have been awarded a large role in this context. The goal of this study was to examine AMs for a possible expression or overexpression of these markers. Expression analyses of Her2 and EGFR were performed immunohistologically on 25 primary AMs. An overexpression of Her2 (score: 3+) was found in one AM from a 68-year-old female patient among these samples. In contrast, EGFR expression was not found in any of the AMs. The results presented here show that isolated cases of AM may benefit from an additive Her2-directed therapy, as the overexpression of Her2 was found in one of our AM patients.
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Expression of L1CAM, COX-2, EGFR, c-KIT and Her2/neu in anaplastic pancreatic cancer: putative therapeutic targets?
Histopathology
PUBLISHED: 05-13-2010
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Undifferentiated (anaplastic) pancreatic cancer and undifferentiated pancreatic carcinoma with osteoclast-like giant cells (giant cell tumour) are rare variants of pancreatic ductal adenocarcinoma. Representing biologically highly aggressive neoplasms, they are frequently diagnosed at an advanced stage. The response to established chemo- or radiochemotherapeutic treatment regimens is poor, and undifferentiated pancreatic cancer generally has a dismal prognosis. As additional therapeutic options have not yet been investigated in undifferentiated pancreatic cancer, the aim was to analyse the expression of putative therapeutic targets that have shown promising results in various other neoplasms.
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Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms.
Hepatology
PUBLISHED: 03-25-2010
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The A kinase anchor protein 12 (AKAP12) is a central mediator of protein kinase A and protein kinase C signaling. Although AKAP12 has been described to act as a tumor suppressor and its expression is frequently down-regulated in several human malignancies, the underlying molecular mechanisms responsible for the AKAP12 reduction are poorly understood. We therefore analyzed the expression of AKAP12 and its genetic and epigenetic regulatory mechanisms in human hepatocarcinogenesis. Based on tissue microarray analyses (n = 388) and western immunoblotting, we observed a significant reduction of AKAP12 in cirrhotic liver (CL), premalignant lesions (DN), and hepatocellular carcinomas (HCCs) compared to histologically normal liver specimens (NL). Analyses of array comparative genomic hybridization data (aCGH) from human HCCs revealed chromosomal losses of AKAP12 in 36% of cases but suggested additional mechanisms underlying the observed reduction of AKAP12 expression in hepatocarcinogenesis. Quantitative methylation analysis by MassARRAY of NL, CL, DN, and HCC tissues, as well as of various tumorigenic and nontumorigenic liver cell lines revealed specific hypermethylation of the AKAP12? promoter but not of the AKAP12? promoter in HCC specimens and in HCC cell lines. Consequently, restoration experiments performed with 5-aza-2deoxycytidine drastically increased AKAP12? mRNA levels in a HCC cell line (AKN1) paralleled by AKAP12? promoter demethylation. As hypermethylation is not observed in CL and DN, we investigated microRNA-mediated posttranscriptional regulation as an additional mechanism to explain reduced AKAP12 expression. We found that miR-183 and miR-186 are up-regulated in CL and DN and are able to target AKAP12. Conclusion: In addition to genetic alterations, epigenetic mechanisms are responsible for the reduction of the tumor suppressor gene AKAP12 in human hepatocarcinogenesis.
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Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.
Cardiovasc. Res.
PUBLISHED: 01-18-2010
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Left ventricular non-compaction (LVNC) is caused by mutations in multiple genes. It is still unclear whether LVNC is the primary determinant of cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte dysfunction being the actual cause of the disease. Here, we describe a family with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T gene (TNNT2).
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Expression and mutational status of PDGFR in thymic tumours.
Anticancer Res.
PUBLISHED: 10-23-2009
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There is an ongoing search for new therapeutic targets in invasive non-resectable thymic tumours because of the low response rates in current chemotherapeutic treatment modalities. In this study, the possibility that platelet-derived growth factor receptor A (PDGFRA) and/ or PDGFRB may represent potential therapeutic targets in epithelial tumours of the thymus was investigated.
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Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma.
Hepatology
PUBLISHED: 05-15-2009
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The inhibition of heat shock protein 90 (Hsp90) has emerged as a promising antineoplastic strategy in diverse human malignancies. Hsp90 has been predicted to be involved in hepatocellular carcinoma (HCC) development; however, its role in hepatocarcinogenesis remains elusive. Using chemically distinctive Hsp90 inhibitors, we show that Hsp90 capacitates the aberrant expression and activity of crucial hepatocarcinogenesis-driving factors (e.g., insulin-like growth factor receptor 1, hepatocyte growth factor receptor, protein kinase B, v-raf-1 murine leukemia viral oncogene homolog 1, and cyclin-dependent kinase 4). In vitro, Hsp90 inhibition with both geldanamycin analogs (17-allylamino-17-desmethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-desmethoxygeldanamycin (17-DMAG)) and the non-quinone compound 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (PU-H71) reduced the viability of various HCC cell lines, induced the simultaneous degradation of numerous hepatocarcinogenic factors, and caused substantial cell cycle arrest and apoptosis. In contrast, nontumorigenic hepatocytes were less susceptible to Hsp90 inhibition. Because conventional geldanamycin-derivate Hsp90 inhibitors induce dose-limiting liver toxicity, we tested whether novel Hsp90 inhibitors lacking the benzoquinone moiety, which has been deemed responsible for hepatotoxicity, can elicit antineoplastic activity without causing significant liver damage. In HCC xenograft mouse models, PU-H71 was retained in tumors at pharmacologically relevant concentrations while being rapidly cleared from nontumorous liver. PU-H71 showed potent and prolonged in vivo Hsp90 inhibitory activity and reduced tumor growth without causing toxicity. Conclusion: Hsp90 constitutes a promising therapeutic target in HCC. Non-quinone Hsp90 inhibitors exhibit tumor-specific accumulation and exert potent antineoplastic activity without causing significant hepatotoxicity.
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Melatonin protects from hepatic reperfusion injury through inhibition of IKK and JNK pathways and modification of cell proliferation.
J. Pineal Res.
PUBLISHED: 04-28-2009
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Reactive oxygen species (ROS) are involved in pathophysiology of ischemia/reperfusion injury. Melatonin is a potent scavenger of ROS. Thus, this study was designed to elucidate its effects in a combined hepatic warm ischemia and resection model. The right lateral and caudate lobes (32% of liver volume) of Sprague-Dawley rats underwent warm ischemia for 30 min followed by reperfusion and subsequent resection of the nonischemic liver tissue. Some rats were gavaged with 50 mg/kg melatonin 2 hr before the onset of experiments. Controls received the same volume of microcrystalline cellulose. Survival, transaminases, histology, flow cytometry, inducible nitric oxide synthase (iNOS) expression, and activation of signal transduction pathways [c-Jun N-terminal kinase (JNK), cJUN, IkappaB kinase alpha (IKKalpha), proliferating cell nuclear antigen (PCNA), and Ki67] were assessed for hepatic injury, oxidative stress, and cell proliferation. Melatonin significantly improved animal survival and decreased transaminase levels, the indices for necrosis, liver damage, leukocyte infiltration, and iNOS expression. In parallel, the expression of IKKalpha, JNK1, and cJUN decreased by 35-50% after melatonin (P < 0.05). At the same time, melatonin reduced the expression of both PCNA and Ki67 in liver (P < 0.05). Melatonin is hepatoprotective most likely via mechanisms including inhibition of IKK and JNK pathways and regulation of cell proliferation.
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Periostin promotes a fibroblastic lineage pathway in atrioventricular valve progenitor cells.
Dev. Dyn.
PUBLISHED: 04-01-2009
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Differentiation of prevalvular mesenchyme into valve fibroblasts is an integral step towards the development of functionally mature cardiac valves. Although clinically relevant, little is known regarding the molecular and cellular mechanisms by which this process proceeds. Genes that are regulated in a spatio-temporal pattern during valve remodeling are candidates for affecting this differentiation process. Based on its expression pattern, we have focused our studies on the role of the matricellular gene, periostin, in regulating the differentiation of cushion mesenchymal cells into valve fibroblasts. Herein, we demonstrate that periostin expression is coincident with and regulates type I collagen protein production, a major component of mature valve tissue. Adenoviral-mediated knock-down of periostin in atrioventricular mesenchyme resulted in a decrease in collagen I protein expression and aberrant induction of myocyte markers indicating an alteration in AV mesenchyme differentiation. In vitro analyses using a novel "cardiotube" assay further demonstrated that expression of periostin regulates lineage commitment of valve precursor cells. In these cells, expression of periostin and collagen I are regulated, in part, by TGFbeta-3. We further demonstrate that TGFbeta-3, through a periostin/collagen pathway, enhances the viscoelastic properties of AV cushion tissue surface tension and plays a crucial role in regulating valve remodeling. Thus, data presented here demonstrate that periostin, a TGFbeta-3 responsive gene, functions as a crucial mediator of chick AV valve maturation via promoting mesenchymal-to-fibroblast differentiation while blocking differentiation of alternative cell types (myocytes).
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Danshen protects kidney grafts from ischemia/reperfusion injury after experimental transplantation.
Transpl. Int.
PUBLISHED: 03-20-2009
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Danshen (DS) is used for treatment of various ischemic events in the traditional Chinese medicine. Hence, this study was designed to investigate its effect on ischemia/reperfusion injury (IRI) after experimental kidney transplantation (eKTx). Nephrectomized Sprague-Dawley rats underwent eKTx. Some animals were infused with 1.5 ml DS 10 min before surgery. Kidney grafts were transplanted after cold storage for 20 h in Histidine-Tryptophane-Ketoglutarate solution. After reperfusion blood samples were collected for blood urinary nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and alanine transaminase. Further, tissue was assessed for morphologic and pathophysiologic changes. Donor preconditioning with DS (DS-d) significantly decreased BUN, creatinine, LDH, and aspartate aminotransferase to 65-97% of controls while preconditioning of the recipient (DS-r) decreased values to 58-82% (P < 0.05). Tubular damage and caspase-3 decreased significantly in both DS-d and DS-r (DS-d: 96% and 67%, DS-r: 83% and 75% of controls) while heat shock protein 72 and superoxide dismutase increased significantly (DS-d: 143% and 173%, DS-r: 166% and 194% of controls). Further, inducible nitric oxide synthase and tumor necrosis factor-alpha decreased (DS-d: 84% and 61%, DS-r: 79% and 67% of controls) after DS. Preconditioning of both donors and recipients with DS significantly reduces IRI and thus improves graft function after eKTx.
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Expression pattern and functional relevance of epidermal growth factor receptor and cyclooxygenase-2: novel chemotherapeutic targets in pancreatic endocrine tumors?
Am. J. Gastroenterol.
PUBLISHED: 02-25-2009
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Pancreatic endocrine tumors represent morphologically and biologically heterogeneous neoplasms. Well-differentiated endocrine tumors (benign or of uncertain behavior) can be distinguished from well-differentiated and poorly differentiated endocrine carcinomas. Although many well-differentiated endocrine carcinomas show rather low rates of tumor growth, more than two-thirds of pancreatic endocrine carcinomas display distant metastases at the time of diagnosis. As the currently applied therapies beyond surgery only achieve partial or complete response rates of approximately 15%, additional chemotherapeutic targets are needed, especially in the therapy of inoperable and progressive pancreatic endocrine carcinomas.
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Statins may not protect against vasospasm in subarachnoid haemorrhage.
J Clin Neurosci
PUBLISHED: 02-23-2009
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Statins have been shown in two recent small phase I/II trials to be associated with a marked reduction in clinical and transcranial Doppler (TCD) evidence of vasospasm after aneurysmal subarachnoid haemorrhage (SAH). The purpose of this study was to assess the clinical impact of this treatment in a larger number of patients. Fifty-eight individuals were treated in the year before, and 72 patients treated in the year after, the introduction of a 2week course of 40mg/day pravastatin therapy for SAH. Statins did not result in reduced TCD velocities, clinical or angiographic vasospasm, or improvements in global outcome at the time of hospital discharge. A measurable reduction in the rates of vasospasm was expected, based on the size of the effect of statin therapy in the previous small studies. There remains significant uncertainty as to the role of statins in preventing vasospasm after SAH.
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DMBT1 expression distinguishes anorectal from cutaneous melanoma.
Histopathology
PUBLISHED: 02-12-2009
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Anorectal melanoma (AM) forms a rare but highly malignant subset of mucosal melanoma with an extremely poor prognosis. Although AMs display histological and immunohistochemical features very similar to cutaneous melanoma (CM), no association exists either with exposure to ultraviolet light or with melanocytic naevi. While AMs are clearly distinguished from CM by displaying few BRAF mutations, they are commonly indistinguishable from CM at the level of gene expression. The aim was to carry out expression analyses of classical immunohistochemical markers and of the protein deleted in malignant brain tumours 1 (DMBT1) in cases of primary anorectal malignant melanoma and CM.
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Fundamental differences in the neural invasion behavior of pancreatic endocrine tumors: relevance for local recurrence rates?
Hum. Pathol.
PUBLISHED: 01-07-2009
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Neural invasion represents an important prognostic factor in pancreatic cancer, and it is thought to be one of the main causes for the high rate of postoperative local recurrences in pancreatic ductal adenocarcinomas. In contrast to the latter, systematic investigations of the mode and extent of neural invasion in pancreatic endocrine tumors have not yet been carried out, although this process represents an important feature in the classification of these tumors. In the present study, a total of 48 pancreatic endocrine tumors were analyzed including 10 well-differentiated endocrine tumors of uncertain behavior, 33 well-differentiated endocrine carcinomas, and 5 poorly differentiated endocrine carcinomas. Neural invasion was found in a large subset (73%) of pancreatic endocrine tumors. The frequency of neural invasion correlated with the grade of malignancy but occurred irrespective of functional activity, hormone phenotype, or histomorphology. Analogous to pancreatic ductal adenocarcinoma, the expression of epidermal growth factor receptor and nerve growth factor, which were expressed in 50% and 100% of the tumors, respectively, seemed to be associated with the frequency of neural invasion. However, in contrast to pancreatic ductal adenocarcinoma, neural invasion in pancreatic endocrine tumors was only detected within the tumor boundaries and did not reach beyond the tumor invasion front. This phenomenon may explain the low rate of local relapses after tumor resection in pancreatic endocrine tumors despite the high frequency of neural invasion.
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Changing topographic Hox expression in blood vessels results in regionally distinct vessel wall remodeling.
Biol Open
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The distinct topographic Hox expression patterns observed in vascular smooth muscle cells (VSMCs) of the adult cardiovascular system suggest that these transcriptional regulators are critical for maintaining region-specific physiological properties of blood vessels. To test this proposition, we expanded the vascular Hoxc11 expression domain normally restricted to the lower limbs by utilizing an innovative integrated tetracycline regulatory system and Transgelin promoter elements to induce Hoxc11 expression universally in VSMCs of transgenic mice. Ectopic Hoxc11 expression in carotid arteries, aortic arch and descending aorta resulted in drastic vessel wall remodeling involving elastic laminae fragmentation, medial smooth muscle cell loss, and intimal lesion formation. None of these alterations were observed upon induction of Hoxc11 transgene expression in the femoral artery, i.e. the natural Hoxc11 activity domain, although this vessel was greatly enlarged, comparable to the topographically restricted vascular changes seen in Hoxc11(-/-) mice. To begin defining Hoxc11-controlled pathways of vascular remodeling, we performed immunolabeling studies in conjunction with co-transfection and chromatin immunoprecipitation (ChIP) assays using mouse vascular smooth muscle (MOVAS) cells. The results suggest direct transcriptional control of two members of the matrix metalloproteinase (Mmp) family, including Mmp2 and Mmp9 that are known as key players in the inception and progression of vascular remodeling events. In summary, the severe vascular abnormalities resulting from the induced dysregulated expression of a Hox gene with regional vascular patterning functions suggest that proper Hox function and regulation is critical for maintaining vascular functional integrity.
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"Pollical palmar interosseous muscle" (musculus adductor pollicis accessorius): attachments, innervation, variations, phylogeny, and implications for human evolution and medicine.
J. Morphol.
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Most atlases and textbooks dealing with human anatomy do not refer to the "pollical palmar interosseous" (PPI) muscle of Henle. In order to undertake a fresh and detailed study of this muscle and to thus better understand human comparative anatomy and evolution, we: 1) analyze the frequency of the PPI in a large sample of human hands; 2) describe the attachments, innervation and varieties of the PPI in these hands; 3) compare the data obtained with the information available in the literature; and 4) discuss the phylogenetic origin of the PPI and the implications of our observations and comparisons for medicine and for the understanding of human evolutionary history. Within the 72 hands dissected by us, the PPI is present in 67 hands (93%), commonly having a single muscular branch, originating from the medial side of the base of metacarpal I only, inserting onto the medial side of the base of the pollical proximal phalanx and/or surrounding structures (e.g., ulnar sesamoid bone, wing tendon of extensor apparatus), and passing at least partially, and usually mainly, medial to the princeps pollicis artery. A careful study of the human PPI, as well as a detailed comparison with other mammals, strongly suggest that the muscle is evolutionarily derived from the adductor pollicis, and namely from its oblique head. Therefore, we propose that PPI should be designated by the name musculus adductor pollicis accessorius, which indicates that the muscle is most likely a de novo structure derived from the adductor pollicis.
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Examining faking on personality inventories using unfolding item response theory models.
J Pers Assess
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A concern about personality inventories in diagnostic and decision-making contexts is that individuals will fake. Although there is extensive research on faking, little research has focused on how perceptions of personality items change when individuals are faking or responding honestly. This research demonstrates how the delta parameter from the generalized graded unfolding item response theory model can be used to examine how individuals perceptions about personality items might change when responding honestly or when faking. The results indicate that perceptions changed from honest to faking conditions for several neuroticism items. The direction of the change varied, indicating that faking can operate to increase or decrease scores within a personality factor.
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MKP-1 is essential for canonical vitamin D-induced signaling through nuclear import and regulates RANKL expression and function.
Mol. Endocrinol.
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Vitamin D(3,) and its most active form, 1,25(OH)(2)D(3), are well known to stimulate osteoclastogenesis through stromal cell induction of the receptor activator of nuclear factor-?B ligand (RANKL). MAPK phosphatase-1 (MKP-1) is a phosphatase classically known to negatively regulate the innate immune response through dephosphorylation of p38, ERK, and c-Jun N-terminal kinase activity. This paper describes a new function of MKP-1 in permitting genomic 1,25(OH)(2)D(3) signaling and downstream osteoclastogenesis through RANKL. Initially, quantitative RT-PCR (qRT-PCR) and immunoblot analysis comparing bone marrow stromal cells (BMSC) revealed that 1,25(OH)(2)D(3)-induced vitamin D receptor (VDR), cytochrome P 45024a1, and RANKL mRNA expression and protein were significantly attenuated or absent in MKP-1(-/-) BMSC. Immunoblot analysis from cellular fractions of wild type and MKP-1(-/-) BMSC stimulated with 10(-7) m 1,25(OH)(2)D(3) revealed retinoid X receptor (RXR)? nuclear import was impaired in MKP-1(-/-) BMSC, whereas VDR import was not. Proximity ligation assays revealed that baseline VDR-RXR? heterodimer translocation was unchanged, yet 1,25(OH)(2)D(3)-induced nuclear translocation of VDR-RXR? heterodimers was reduced in MKP-1(-/-) BMSC. A functional consequence was observed as BMSC from MKP-1(-/-) mice treated with 1,25(OH)(2)D(3) and cocultured with RAW 264.7 cells had a 91% decrease in osteoclastogenesis and a 94.5% decrease in mineralized matrix resorption compared with wild-type cocultures (P < 0.01). These results reveal an unexpected, permissive role for MKP-1 in canonical 1,25(OH)(2)D(3) signaling via VDR-RXR? heterodimer nuclear import and downstream osteoclastogenesis through stromal cell RANKL expression.
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