Histology and histopathology Vol.30, nº2 (2015)
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- PublicationOpen AccessThe combination of strong immunohistochemical mtTFA expression and a high survivin index predicts a shorter diseasespecific survival in pancreatic ductal adenocarcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Kimura, Tomoko; Kitada, Shohei; Uramoto, Hidetaka; Zhi, Li; Kawatsu, Yuichiro; Takeda, Toru; Horie, Seichi; Nabeshima, Atsunori; Noguchi, Hirotsugu; Sasaguri, Yasuyuki; Izumi, Hiroto; Kohno, Kimitoshi; Yamada, SohsukeMitochondrial transcription factor A (mtTFA) plays a crucial role in both the transcription and maintenance of mitochondrial DNA. A high expression of mtTFA has been demonstrated in several solid tumors, and is closely associated with cancer cell survival/apoptosis and growth. However, its expression pattern in pancreatic ductal adenocarcinoma (PAC) remains to be elucidated. Additionally, our groups have recently revealed that a subset of apoptosis-related genes is strongly regulated by mtTFA, and that two putative mtTFA binding sites are present in the promoter region of the survivin gene, which is a member of the inhibitorof-apoptosis protein family. We therefore investigated the correlation of the immunohistochemical mtTFA expression and the survivin index with various clinicopathological variables and the prognosis, using 70 paraffin-embedded tumor samples from patients with surgically-resected PAC. The mtTFA expression or survivin index was considered to be strong or high when ≥30% or 10% of the PAC cells showed positive staining, respectively. Strong mtTFA expression and/or a high survivin index was revealed to have a significant relationship to a pathologically high tumor grading and advanced tumor stage. Moreover, mtTFA showed significantly high co-expression with survivin. Univariate and multivariate analyses demonstrated that both the strong mtTFA expression and high survivin index groups had significantly shorter survival rates, especially within the first two years postoperatively. The combination of strong mtTFA expression and a high survivin index may predict a poor prognosis in patients with PAC, and these new biomarkers might offer useful information for the early clinical management.
- PublicationOpen AccessTumor heterogeneity has important consequences for personalized medicine in ovarian cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Gui, Ting; Cao, Dongyan; Yang, Jiaxin; Shen, KengMost patients with ovarian cancers relapse, and treatment failure has often been attributed to chemoresistance in tumor cells. Emerging evidence indicates that tumor heterogeneity may play an equally important role. Although the idea of tumor heterogeneity is not new, little attention has been focused on applying it to understand and control ovarian cancer progression. Recent advances in understanding its generation model, original basis, consequent problems, and derived therapies provide great potential for tumor heterogeneity to be a new insight in treatment of ovarian cancers.
- PublicationOpen AccessSpatio-temporal expression patterns of microRNAs in remodelling and repair of the infarcted heart(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Chiarella-Redfern, H.H.; Rayner, K.J.; Suuronen, E.J.MicroRNAs (miRNAs) are small, nonmessenger RNAs, 20-22 nucleotides in size, which regulate gene expression at the post-transcriptional level. Typically, miRNAs target the 3’ untranslated region (3'UTR) of mRNA transcripts leading to mRNA degradation or translational repression. The known dysregulation of miRNAs during cardiac ischemia and the crucial role of miRNA-dependent regulation of angiogenesis, fibrosis and hypertrophy present interesting therapeutic opportunities for repairing and regenerating the heart after myocardial infarction (MI). An understanding of the expression pattern and localization of deleterious and beneficial miRNAs during cardiac ischemia is necessary for the development of therapeutics designed to specifically treat the affected tissue and cell populations. This review focuses on the role and localization of key miRNAs implicated in MI while highlighting how their manipulation may promote cardiac repair.
- PublicationOpen AccessFOXO1 expression in villous trophoblast of preeclampsia and fetal growth restriction placentas(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Sheridan, Rachel; Belludi, Chethan; Khoury, Jane; Stanek, Jerzy; Handwerger, StuartOxidative stress and increased apoptosis are implicated in the pathogenesis of many disorders of pregnancy, including preeclampsia (PE) and fetal growth restriction (FGR). Since the transcription factor FOXO1 (forkhead box protein O1) is implicated in the regulation of a variety of cellular processes, including resistance to oxidative stress, apoptosis and morphogenesis of the placenta, we examined whether FOXO1 expression is abnormal in placentas from patients with PE or FGR. Paracentral sections from grossly unremarkable areas of 9 or 10 placentas each from early third trimester patients (31.7±5.0 weeks) with mild PE, severe PE, FGR and a gestational age-matched comparison group (GA controls) were double immunostained for FOXO1 and E-cadherin, the latter distinguishing villous cytotrophoblast cells (CTB) from syncytiotrophoblast (STB). The numbers of FOXO1-positive and FOXO1 negative STB and CTB nuclei were determined on ten 20x objective fields of each placenta section by three observers who were blinded to the clinical outcome. The results were evaluated by a generalized linear mixed model. In mild PE, FOXO1-positive STB nuclei were significantly decreased in number and FOXO1-negative STB nuclei were increased as compared to GA controls. However, the number of FOXO1-positive and FOXO1- negative CTB nuclei were not significantly changes as compared to GA controls. In severe PE and FGR, the numbers of FOXO-positive and FOXO1-negative STB and CTB were not statistically different from GA controls. Since FOXO1 is critical for placental cellular morphogenesis, abnormal FOXO1 expression may contribute in part to the abnormal trophoblast differentiation in mild PE. The differences in FOXO1 expression in mild and severe PE are consistent with other studies suggesting that the two forms of PE are different disease processes.
- PublicationOpen AccessBCR-ABL negative myeloproliferative neoplasia: a review of involved molecular mechanisms(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Koopmans, Suzanne M.; Schouten, Harry C.; van Mario, Ariënne M.W.The clonal bone marrow stem cell disorders essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) belong to the group of Philadelphia chromosome negative myeloproliferative neoplasia (Ph- MPN). In 2005 the JAK2V617F mutation was discovered which has generated more insight in the pathogenetic mechanism of the MPNs. More mutations have been detected in MPN patients since. However, the underlying cause of MPN has not been discovered so far. The mechanism of increased angiogenesis in MPNs and the development of fibrosis in the bone marrow in PMF patients and in some ET and PV patients is still not known. This review will focus on the most important molecular pathogenetic mechanisms in MPN patients.
- PublicationOpen AccessInflammatory risk factors and pathologies promoting Alzheimer’s disease progression: is RAGE the key?(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Matrone, Carmela; Djellou, Mehdi; Taglialatela, Giulio; Perrone, LorenaEpidemiological studies reveal growing evidence that most cases of Alzheimer’s Disease (AD) likely involve a combination of genetic and environmental risk factors. Identifying and validating these risk factors remains one of the most critical scientific challenges. Several diseases appear to have strong implications for neurodegeneration leading to dementia. This risk encompasses different forms of cardiovascular disease, carotid atherosclerosis, history of hypertension or high cholesterol, Type II diabetes, stroke or transient ischemic attack and brain trauma. However, the molecular pathways that are common and central in the progression of these diseases and AD are not yet elucidated. Unveiling these critical mechanisms at the molecular level is necessary for the development of therapeutic strategies aimed at preventing AD progression. The Receptor for Advanced Glycation Endproducts (RAGE) plays a key role in all the diseases that represent a risk for AD. RAGE-mediated signaling also contributes to neurodegeneration in AD, suggesting that it may mediate the effect of risk factors in promoting AD. We will summarize the current knowledge on the role of RAGE in pathologies promoting AD and in AD progression. We will also provide evidence showing the relevance of RAGEinduced inflammation as a risk pathway that is implicated in AD pathophysiology.
- PublicationOpen AccessWnt signaling in kidney tubulointerstitium during disease(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Maarouf, Omar H.; Ikeda, Yoichiro; Humphreys, Benjamin D.The evolutionary conserved Wnt signaling transduction pathway plays essential roles in a wide array of biologic processes including embryonic development, branching morphogenesis, proliferation and carcinogenesis. Over the past ten years it has become increasingly clear that Wnt signaling also regulates the response of adult organs to disease processes, including kidney disease. This review will focus on the growing literature implicating important roles for Wnt signaling during disease in two separate kidney compartments: the tubular epithelium and the interstitium.
- PublicationOpen AccessUtility of immunohistochemical investigation of SDHB and molecular genetic analysis of SDH genes in the differential diagnosis of mesenchymal tumors of GIT(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Dubova, M.; Sedivcova, M.; Michal, M.; Kokoskova, B.; Ryska, A.; Smid, D.; Daum, OndrejLoss of expression of beta subunit of succinate dehydrogenase (SDHB) was proved to be present in a subgroup of KIT/PDGFRA wt gastrointestinal stromal tumors (GISTs). To evaluate possible diagnostic utility of SDHB immunohistochemistry in the differential diagnostics of mesenchymal tumors of gastrointestinal tract (GIT), 11 cases of KIT/PDGFRA wt GISTs, 12 gastric schwannomas (GSs), 20 solitary fibrous tumors (SFTs), 4 leiomyomas (LMs), 16 leiomyosarcomas (LMSs), 5 synovial sarcomas (SSs), 3 endometrioid stromal sarcomas (ESSs), and 1 ileal inflammatory myofibroblastic tumor (IMT) were investigated for SDHB immunoexpression together with molecular genetic analysis of genes encoding succinate dehydrogenase (SDH). Three recent cases of KIT/PDGFRA mutant GISTs were used as controls. Among the 11 KIT/PDGFRA wt GISTs, 6 expressed SDHB, 1 of them harboring a sequence change of SDHD. All SDHB-negative cases were SDHB-D wt. In 1 of the control GIST cases molecular genetic analysis revealed an SDHD sequence change in addition to a mutation in KIT exon 11. No SFT was truly SDHBnegative, but in 2 of them the staining was impossible to analyze. Furthermore, 1 SFT carried an SDHB and another 1 SDHD sequence change. All GSs, LMs, LMSs, SSs, ESSs, and IMT were SDHB-positive or nonanalyzable, and SDHB-D wt. Additional factors may play a role in regulating expression of SDHB. Furthermore, SDHB immunohistochemistry alone may be misleading in excluding tumors other than GIST (especially SFT) in the differential diagnosis of KIT/PDGFRA wt mesenchymal tumors of GIT.
- PublicationOpen AccessAngiogenesis: a new surrogate histopathological marker is capable of differentiating between mild and significant portal hypertension(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Hu, Dou-dou; Habib, Sohail; Li, Xin-min; Wang, Tai-ling; Wang, Bao-en; Zhao, Xin-yanAim: Angiogenesis is considered an important pathophysiological feature of portal hypertension. We investigated the ability of angiogenesis, as CD34-positive microvessel density (MVD), to differentiate portal pressure in a CCl 4-induced rat cirrhosis model. Methods: Cirrhosis was induced by intraperitoneal injection of carbon tetrachloride in 46 male adult Sprague-Dawley rats. A catheter connected to a highly sensitive pressure transducer was inserted into the portal vein to continuously record portal pressure. Fibrosis area, nodule size and MVD were assessed by image morphometry. Results: Of 42 rats in which portal pressure was measured successfully, 27 (64%) had portal pressure ≥10 mmHg, defined as significant portal hypertension. MVD was 4.5-fold higher and fibrosis area 13.0-fold higher in rats with significant portal hypertension than in rats with portal pressure <10 mmHg. Portal pressure was significantly correlated with MVD (r=0.491, p<0.001) and fibrosis area (r=0.545, p﹤ 0.001) in all animals, but only MVD correlated with portal pressure (r=0.731 p<0.001) in rats with significant portal hypertension. The area under receiver operating characteristic curve for MVD in all rats was 0.953 (95% CI: 0.875-1.031) and optimum cutoff for MVD was 18/mm2, with 96.3% sensitivity and 93.3% specificity. Conclusions: We found that MVD, measured by CD34 immunostaining, was better able than the fibrosis area to discriminate significant portal hypertension in rats, suggesting that MVD could be a surrogate marker for portal hypertension in patients with liver diseases.
- PublicationOpen AccessIn vivo confocal microscopy assessment of the corneoscleral limbal stem cell niche before and after biopsy for cultivated limbal epithelial transplantation to restore corneal epithelium(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Ramírez, Beatriz E.; Victoria, Darío A.; Murillo, Giovana M.; Herreras, José M.; Calonge, MargaritaAutologous cultivated limbal epithelial transplantation (CLET) is a successful therapy to restore corneal epithelium when limbal epithelial stem cells are damaged unilaterally, which can result in corneal blindness. We used in vivo confocal microscopy (IVCM) to identify the best location in the corneoscleral limbal niche and to harvest autologous epithelial stem cells for CLET. We also ascertained the completeness of limbal structure removal after biopsy and followed the healing process for any evidence of limbal structure reappearance. The 4 meridians of the corneoescleral limbus of 5 healthy donor eyes were scanned clinically and by IVCM before biopsy and 1 week, 1, 3, and 6 months after. IVCM detected palisades of Vogt, the limbal niche hallmark, more efficiently (100%) than clinically (60%), and were consistently better defined at the 12 o’clock meridian, and so this was the site selected for biopsy. The depth of palisades was 80.4±19.8 µm, and of the limbal biopsies was 136.8±19.1 µm, thus assuring that the limbal niche was completely harvested in all cases. Re-epithelialization of the donor site was complete at 1 week. The limbal wound was refilled with fibrovascular tissue, and no limbal-like structures reappeared. The study shows that clinical absence of palisades of Vogt is not necessarily an exclusionary criterion for autologous CLET. IVCM was useful to select the best place for limbal biopsy and identified features not visible clinically. IVCM also confirmed complete removal of limbal tissue by the biopsy. Limbal niche structures did not reappear by 6 months after surgery.
- PublicationOpen AccessEndoglin is not expressed with cell adhesion molecules in aorta during atherogenesis in apoE-deficient mice(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2020) Rathouska, Jana; Jezkova, Katerina; Nemeckova, Ivana; Zemankova, Lenka; Varejckova, Michala; Nachtigal, PetrEndoglin (TGF-β receptor III), has been demonstrated to affect vascular endothelium and atherosclerosis. Moreover, it was also demonstrated that endoglin is involved in inflammation and plays a role in leukocyte adhesion and transmigration in vitro and in vivo but not in atherosclerosis related vessels. In this study, we wanted to evaluate endoglin expression in two different parts of the aorta (heart aortic sinus and ascending aorta) and assess its potential simultaneous expression with cell adhesion molecules in nonatherosclerotic and atherosclerotic aortas of apoEdeficient mice. Ten-week–old female apolipoprotein E-deficient mice on a C57BL/6J background (n=24) were randomly subdivided into three groups and were fed either chow diet (for another two months) or Western type diet (for another two or four months). Immunohistochemical staining of endoglin, VCAM-1 and P-selectin in aortic sinus and ascending aorta was performed. Endoglin expression was detected only in endothelial cells and varied during atherogenic process in aorta but not in aortic sinus. Moreover, its expression seemed to be weaker in aorta when compared to aortic sinus and the positivity was detected only in endothelium covering atherosclerotic lesions but not in non-atherosclerotic endothelium regardless of the plaque size. Endoglin was not expressed with P-selectin and VCAM-1 in aortic endothelium in any studied group. This study shows that endothelial expression of endoglin is related to the atherogenic process predominantly in aorta outside the heart. Moreover, endoglin is not localized with cell adhesion molecules involved in atherosclerosis, suggesting it might not participate in leukocyte accumulation in aorta of apoEdeficient mice during atherogenesis.
- PublicationOpen AccessEpendymal damage in a Plasmodium yoelii yoelii lethal murine malaria model(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2020) Rivera Fernández, Norma; Colin-Barenque, Laura; Romero Silva, Samanta E.; Salas Garrido, Gerardo; Jiménez Rosey, Samantha G.; Zepeda Rodríguez, Armando; Romero Romero, Laura P.; Menchaca Gómez, ÁngelesMalaria continues to be a major global health problem, and over 40% of the world’s population is at risk. Severe or complicated malaria is defined by clinical or laboratory evidence of vital organ dysfunction, including dysfunction of the central nervous system (CNS). The pathogenesis of complicated malaria has not been completely elucidated; however, the development of the multiorgan affection seems to play an important role in the disruption of the blood brain barrier (BBB) that protects the CNS against chemical insults. Historically, the BBB has received more attention in the pathogenesis of malaria than have the cerebrospinal fluid-brain barrier (CSFBB) and ependymal cells. This perspective may be misguided because, in the context of disease or toxicity, the CSFBB is more vulnerable to many foreign invaders than are the capillaries. Given the lack on studies of the damage to the CSFBB and ependymal epithelium in experimental murine malaria, the present study evaluated morphological changes in the ependymal cells of CD-1 male mice infected with lethal Plasmodium yoelii yoelii (Pyy) via histopathology and scanning electron microscopy (SEM). Samples were taken two, four and six days post-infection (PI). No lesions were observed upon the initial infection. By the fourth day PI, fourth ventricle ependymal samples exhibited disruptions and roughened epithelia. More severe injuries were observed at six days PI and included thickened cilia and deep separations between the ependymal intercellular spaces. In some of the analyzed areas, the absence of microvilli and cell layer detachment were observed, and some areas exhibited blebbing surfaces. The ependymal cell lesions observed in the CD1 male mice infected with lethal Pyy seemed to facilitate the paracellular permeability of the CSFBB and consequently promote the access of inflammatory mediators and toxic molecules through the barrier, which resulted in damage to the brain tissue. Understanding the mechanism of ependymal disruption during lethal murine malaria could help to elucidate the local and systemic factors that are involved in the pathogenesis of the disease and may provide essential clues for the prevention and treatment of complicated human malaria.