Servicio de Anatomia Patologica

Salamanca, Spain

Servicio de Anatomia Patologica

Salamanca, Spain
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Natrajan R.,The Institute of Cancer Research | Mackay A.,The Institute of Cancer Research | Wilkerson P.M.,The Institute of Cancer Research | Lambros M.B.,The Institute of Cancer Research | And 10 more authors.
Breast Cancer Research | Year: 2012

Introduction: The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification.Methods: We investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification.Results: 19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival.Conclusions: The 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers. © 2012 Natrajan et al.; licensee BioMed Central Ltd.


Galvan J.A.,Instituto Universitario Of Oncologia Del Principado Of Asturias | Astudillo A.,Hospital Universitario Central Of Asturias | Vallina A.,Instituto Universitario Of Oncologia Del Principado Of Asturias | Fonseca P.J.,Hospital Universitario Central Of Asturias | And 3 more authors.
American Journal of Clinical Pathology | Year: 2013

Objectives: To elucidate the role of epithelial-mesenchymal transition markers in gastroenteropancreatic neuroendocrine tumors (GEP NETs) and the potential usefulness in their clinical management. Methods: One hundred ten GEP NET paraffinembedded samples were immunohistochemically analyzed for E-cadherin, N-cadherin, β-catenin, vimentin, Snail1, Snail2, Twist, and Foxc2 protein expression. Results: The 5-year survival rate was reduced for those patients showing high Snail1 protein levels, a cytoplasmic E-cadherin pattern, reduced N-cadherin expression, and loss of E-cadherin/β-catenin adhesion complex integrity at the cell membrane. Interestingly, high β-catenin expression was useful in identifying a grade 1 NET subgroup with a favorable clinical course. Importantly, it also helped to discriminate small-cell vs large-cell grade 3 neuroendocrine carcinomas. Conclusions: β-Catenin and N-cadherin immunohistochemical detection might be a useful tool in the differential diagnosis of small-cell vs large-cell G3 neuroendocrine carcinomas. High Snail1 and Foxc2 expression is associated with the invasion and metastatic spread of GEP NETs. © 2013 American Society for Clinical Pathology.


PubMed | Servicio de Anatomia Patologica, IDIS, Complejo Hospitalario Universitario Of Santiago Chus and CIBER ISCIII
Type: Journal Article | Journal: Oncotarget | Year: 2016

Obestatin, a 23-amino acid peptide encoded by the ghrelin gene, and the GPR39 receptor were reported to be involved in the control of mitogenesis of gastric cancer cell lines; however, the relationship between the obestatin/GPR39 system and gastric cancer progression remains unknown. In the present study, we determined the expression levels of the obestatin/GPR39 system in human gastric adenocarcinomas and explored their potential functional roles. Twenty-eight patients with gastric adenocarcinomas were retrospectively studied, and clinical data were obtained. The role of obestatin/GPR39 in gastric cancer progression was studied in vitro using the human gastric adenocarcinoma AGS cell line. Obestatin exogenous administration in these GPR39-bearing cells deregulated the expression of several hallmarks of the epithelial-mesenchymal transition (EMT) and angiogenesis. Moreover, obestatin signaling promoted phenotypic changes via GPR39, increasingly impacting on the cell morphology, proliferation, migration and invasion of these cells. In healthy human stomachs, obestatin expression was observed in the neuroendocrine cells and GPR39 expression was localized mainly in the chief cells of the oxyntic glands. In human gastric adenocarcinomas, no obestatin expression was found; however, an aberrant pattern of GPR39 expression was discovered, correlating to the dedifferentiation of the tumor. Altogether, our data strongly suggest the involvement of the obestatin/GPR39 system in the pathogenesis and/or clinical outcome of human gastric adenocarcinomas and highlight the potential usefulness of GPR39 as a prognostic marker in gastric cancer.


PubMed | Servicio de Cirugia Infantil, University of Santiago de Chile, Servicio de Endocrinologia Infantil, Servicio de Cirugia and 2 more.
Type: Journal Article | Journal: Revista chilena de pediatria | Year: 2016

Papillary thyroid carcinoma (PTC) is a rare childhood disease. The development of PTC in dyshormonogenetic congenital hypothyroidism (CH) is infrequent, with very few case reports in literature.To report a case of PTC in a boy with dyshormonogenetic CH without goitre and exposed to ionising radiation. To evaluate relationships between these factors and development of PTC.We present a boy with dyshormonogenetic CH since birth. Early hormonal substitution was initiated, with subsequent normal levels of thyrotropin and thyroid hormones. He has also congenital cardiomyopathy, exposed to interventional treatment with 10 heart catheterisations, and approximately 26 chest X-rays at paediatric doses. A thyroid nodule was found in thyroid echography at the age of 6 years old. Fine needle aspiration biopsy confirmed high probability of thyroid carcinoma (Bethesda 5). The pre-surgical thorax and cerebral scan showed no evidence of metastasis. The patient underwent total thyroidectomy. Pathological examination revealed a 0.5cm papillary thyroid micro-carcinoma in the right lobe, with no evidence of dissemination.Genetic mutations and radiation exposure may play an important role in the development of PTC. There may be common pathways between dyshormonogenetic CH and thyroid carcinoma that need further investigation.


Sacnun M.P.,Hospital Provincial Of Rosario | Ferrer J.,Servicio de Anatomia Patologica | Ferrer M.,Servicio de Anatomia Patologica | Pons-Estel B.A.,Instituto Cardiovascular Of Rosario
Reumatologia Clinica | Year: 2011

Paciente de 31 años, con historia de síndrome de superposición de lupus eritematoso sistémico y esclerosis sistémica que desarrolla un cuadro caracterizado por fiebre, pericarditis con derrame pericárdico y enfermedad pulmonar rápidamente progresiva y fatal. Se discuten aspectos diagnósticos e indicaciones terapéuticas. A 31-year-old woman with a prior history of an overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) developed fever, pericarditis with pericardial effusion and a rapidly progressive fatal interstitial lung disease. Diagnostic test and procedures, differential diagnosis and therapeutic approach are discussed. © 2010 Elsevier España, S.L.


PubMed | Servicio de Anatomia Patologica and Servicio de Nefrologia
Type: Journal Article | Journal: Transplantation proceedings | Year: 2016

Antibody-mediated rejection is the main cause of deterioration of kidney transplants and frequently is detected only by means of protocol biopsies. The aim of this study was to relate the presence of albuminuria throughout the 1st year to the histologic findings detected by 1-year protocol biopsies in kidney graft recipients.Retrospective observational study of 86 protocol biopsies 1 year after transplantation. Albuminuria was measured at 3, 6, 9, and 12 months in urine samples and expressed as albumin/creatinine (mg/g).Analysis of biopsies, reflected according to the Banff criteria, the following categories: fibrosis and tubular atrophy, 35 (40.7%); cellular rejection, 13 (15.1%); antibody-mediated rejection, 8 (9.3%); chronic glomerulopathy, 10 (11.6%); normal, 14 (16.3%); recurrence, 1 (1.2%); and other, 5 (5.8%). The proportions of patients with albuminuria for Banff scale scores (0 vs1, respectively) at 6 and 12 months, respectively, after transplantation, were: for marker glomerulitis, 45.5% versus 59.3% (P= .021) and 36.4% versus 70.4% (P< .001); for marker glomerulopathy, 49.1% versus 50.0% (P= .051) and 42.1% versus 58.3% (P= .019); for marker peritubular capillaritis, 45.8% versus 60.9% (P= .047) and 39.0% versus 69.6% (P= .276); and for marker C4d, 49.2% versus 56.3% (P= .894) and 46.2% versus 56.3% (P= .774).The presence of albuminuria after renal transplantation is common, especially in patients with proteinuria. Persistent albuminuria after transplantation, even at low levels, can be indicative of subclinical antibody-mediated rejection. Additional broader studies to relate the albuminuria to histologic changes observed in protocol biopsies are required.


Sanchez-Abarca L.I.,Hospital Clinico Universitario Of Salamanca | Gutierrez-Cosio S.,Hospital Clinico Universitario Of Salamanca | Santamaria C.,Hospital Clinico Universitario Of Salamanca | Caballero-Velazquez T.,Servicio de Hematologia | And 12 more authors.
Blood | Year: 2010

Cytokine genes are targets of multiple epigenetic mechanisms in T lymphocytes. 5-azacytidine (5-azaC) is a nucleoside-based DNA methyltransferase inhibitor that induces demethylation and gene reactivation. In the current study, we analyzed the effect of 5-azaC in T-cell function and observed that 5-azaC inhibits T-cell proliferation and activation, blocking cell cycle in the G0 to G1 phase and decreasing the production of proinflammatory cytokines such as tumor necrosis factor-α and interferon-γ. This effect was not attributable to a proapoptotic effect of the drug but to the down-regulation of genes involved in T-cell cycle progression and activation such as CCNG2, MTCP1, CD58, and ADK and up-regulation of genes that induce cell-growth arrest, such as DCUN1D2, U2AF2, GADD45B, or p53. A longer exposure to the drug leads to demethylation of FOXP3 promoter, overexpression of FOXP3, and expansion of regulatory T cells. Finally, the administration of 5-azaC after transplantation prevented the development of graft-versus-host disease, leading to a significant increase in survival in a fully mismatched bone marrow transplantation mouse model. In conclusion, the current study shows the effect of 5-azaC in T lymphocytes and illustrates its role in the allogeneic transplantation setting as an immunomodulatory drug, describing new pathways that must be explored to prevent graft-versus-host disease. © 2010 by The American Society of Hematology.


Santonja C.,Servicio de Anatomia Patologica | Nieto-Gonzalez G.,Hospital Universitario Of Salamanca | Santos-Briz A.,Hospital Universitario Of Salamanca | De Las Nieves Gutierrez Zufiaurre M.,Hospital Universitario Of Salamanca | And 3 more authors.
American Journal of Dermatopathology | Year: 2011

Papular-purpuric "gloves and socks" syndrome is a distinctive dermatosis featuring acral pruritus, edema, and petechiae. It has been attributed in most-but not all-reported cases to Parvovirus B19 infection, on the grounds of serological proof of recent infection or detection of viral DNA by polymerase chain reaction in patient serum or biopsies. We report the immunohistochemical detection of Parvovirus B19 VP2 structural protein in the endothelial lining of dermal blood vessels in 3 examples of Papular-purpuric "gloves and socks" syndrome and review previously described immunohistochemical investigations in cutaneous involvement by this infection. Copyright © 2011 by Lippincott Williams & Wilkins.


Santonja C.,Servicio de Anatomia Patologica | Gonzalo I.,Hospital Infanta Elena | Feito M.,Hospital Universitario La Paz | Beato-Merino M.,Hospital Universitario La Paz | Requena L.,Servicio de Dermatologia
American Journal of Dermatopathology | Year: 2012

We describe the clinical, histopathologic, immunohistochemical, and molecular findings in an additional case of lipoatrophic panniculitis selectively involving the ankles in a 12-year-old boy. This idiopathic, rarely reported entity is presumed to have an autoimmune pathogenesis. Histological findings are a lipophagic lobular panniculits, that in our case featured focally increased numbers of lymphocytes rimming the adipocytes, and infiltration of vascular walls by mildly atypical lymphoid cells, raising the differential diagnosis of subcutaneous panniculitis-like T-cell lymphoma. © 2012 by Lippincott Williams & Wilkins.


Lorenzo V.,Hospital Universitario Of Canarias | Torres A.,Hospital Universitario Of Canarias | Salido E.,Servicio de Anatomia Patologica
Nefrologia | Year: 2014

Primary hyperoxaluria (PH) occurs due to an autosomal recessive hereditary disorder of the metabolism of glyoxylate, which causes excessive oxalate production. The most frequent and serious disorder is due to enzyme deficit of alanine-glyoxylate aminotransferase (PH type I) specific to hepatic peroxisome. As oxalate is not metabolised in humans and is excreted through the kidneys, the kidney is the first organ affected, causing recurrent lithiasis, nephrocalcinosis and early renal failure. With advance of renal failure, particularly in patients on haemodialysis (HD), calcium oxalate is massively deposited in tissues, which is known as oxalosis. Diagnosis is based on family history, the presence of urolithiasis and/or nephrocalcinosis, hyperoxaluria, oxalate deposits in tissue forming granulomas, molecular analysis of DNA and enzyme analysis if applicable. High diagnostic suspicion is required; therefore, unfortunately, in many cases it is diagnosed after its recurrence following kidney transplantation. Conservative management of this disease (high liquid intake, pyridoxine and crystallisation inhibitors) needs to be adopted early in order to delay kidney damage. Treatment by dialysis is ineffective in treating excess oxalate. After the kidney transplant, we normally observe a rapid appearance of oxalate deposits in the graft and the results of this technique are discouraging, with very few exceptions. Pre-emptive liver transplantation, or simultaneous liver and kidney transplants when there is already irreversible damage to the kidney, is the treatment of choice to treat the underlying disease and suppress oxalate overproduction. Given its condition as a rare disease and its genetic and clinical heterogeneity, it is not possible to gain evidence through randomised clinical trials. As a result, the recommendations are established by groups of experts based on publications of renowned scientific rigour. In this regard, a group of European experts (OxalEurope) has drawn up recommendations for diagnosis and treatment, which were published in 2012. © 2014 Revista Nefrología.

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