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Supplementary Figures 5-8 from Thyroid Hormone Receptor β1 Acts as a Potent Suppressor of Tumor Invasiveness and Metastasis

Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. We show here that expression of TRβ1 in hepatocarcinoma and breast cancer cells reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice. In cultured cells, TRβ1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-I, and transforming growth factor β, and regulates expression of genes that play a key role in tumorigenicity and metastatic growth. The receptor disrupts the mitogenic action of growth factors by suppressing activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways that are crucial for cell proliferation and invasiveness. Furthermore, increased aggressiveness of skin tumors is found in genetically modified mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression. These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer. [Cancer Res 2009;69(2):501–9]

Supplementary Figure 1-4 from Thyroid Hormone Receptor β1 Acts as a Potent Suppressor of Tumor Invasiveness and Metastasis

The modulation of the host’s metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas., This work was funded by grants SAF2017-83289-R to S.A. and A.A., SAF2017-90604REDT to A.A. supported by the The European Regional Development Fund (FEDER) and BIO2016-77430-R to J.M.B. from the Ministerio de Economía y Competitividad; B2017/BMD-3724 to S.A. and A.A. from the Comunidad de Madrid; and CIBERONC CB/16/00228 to A.A. from the Instituto de Salud Carlos III.

Hypothyroidism is often associated with anemia and immunological disorders. Similar defects are found in patients and in mice with a mutated dominant-negative thyroid hormone receptor α (TRα) and in knockout mice devoid of this receptor, suggesting that this isoform is responsible for the effects of the thyroid hormones in hematopoiesis. However, the hematological phenotype of mice lacking also TRβ has not yet been examined. We show here that TRα1/TRβ-knockout female mice, lacking all known thyroid hormone receptors with capacity to bind thyroid hormones, do not have overt anemia and in contrast with hypothyroid mice do not present reduced Gata1 or Hif1 gene expression. Similar to that found in hypothyroidism or TRα deficiency during the juvenile period, the B-cell population is reduced in the spleen and bone marrow of ageing TRα1/TRβ-knockout mice, suggesting that TRβ does not play a major role in B-cell development. However, splenic hypotrophy is more marked in hypothyroid mice than in TRα1/TRβ-knockout mice and the splenic population of T-lymphocytes is not significantly impaired in these mice in contrast with the reduction found in hypothyroidism. Our results show that the overall hematopoietic phenotype of the TRα1/TRβ-knockout mice is milder than that found in the absence of hormone. Although other mechanism/s cannot be ruled out, our results suggest that the unoccupied TRs could have a negative effect on hematopoiesis, likely secondary to repression of hematopoietic gene expression.

Introduction Enterocystoplasties are associated to complications. We developed a surgical technique for bladder autoaugmentation using autologous uterine flap in the rat, to try and improve the post-surgical evolution. Methods 36 female Wistar rats were randomly allocated into following groups: Group 1: Control ( n = 12) for analytical parameters, Group 2: Sham-operation hysterocystorrhaphy ( n = 12) and Group 3: Bladder autoaugmentation with autologous uterine flap ( n = 12). Two weeks after surgery ultrasound examination of the bladder was performed. At 8 weeks and 24 weeks, blood and urine samples were taken. Post-mortem evaluation was performed and urogenital apparatus removed for gross and microscopic examination. The statistical analysis was done using the Kruskall–Wallis and the extension of the Fisher's exact test. Significance was set at 5% ( p Results Serum chemistry, blood count and peripheral blood smears, electrolytes and urinary parameters were all within the normal range for the rat. No abnormal findings were observed during ultrasound examination. There was no mortality or other surgical complications. Post-mortem evaluation revealed no dilation of bladder, uterus or upper urinary tract. Uroliths were not observed. Histology of the augmented area demonstrated an excellent union between the bladder and the protective uterine flap. A normal urothelial layer was maintained. Conclusions The use of autologous uterine flap to perform bladder autoaugmentation in the rat proved a safe and suitable surgical technique to augment the bladder. The major advantage is the avoidance of the complications observed in other surgical techniques for bladder augmentation, like enterocystoplasties, where gastrointestinal tract epithelium is incorporated into the urinary tract.

Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30-65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile., This study was supported by grants from Spanish Ministry of Science and Innovation (BFU2011-25303), Spanish Institute of Health Carlos III (CP15/00129), UCM groups (GR-921641), SESCAMET, Fundación Mutua Madrileña, Fundación Eugenio Rodríguez Pascual and Fondos FEDER.

Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-ΰ B and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections., This work was supported by Grants: BFU2011-28058, BFU2014-53610P and SAF2015-71878-REDT from Ministerio de Economía y Competitividad; S2011/BMD-2328 from the Comunidad de Madrid and RD12/0036/0030 from the Instituto de Salud Carlos III

TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases., This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER funds

Although gonadotropins and testosterone are high in the fetal/early postnatal periods, Sertoli cells remain immature and spermatogenesis does not progress. We hypothesized that Sertoli cells do not respond to testosterone because they do not express the androgen receptor.The objective of the study was to describe the precise ontogeny of androgen receptor expression in the human testis from fetal life through adulthood.This was an immunohistochemical study on testicular biopsies from fetal, neonatal, prepubertal, pubertal, and adult human testes.Quantification of androgen receptor expression in Sertoli cells was measured. Evaluation of androgen receptor expression in peritubular and interstitial cells as well as anti-Müllerian hormone and inhibin-alpha was also performed.Androgen receptor expression was first observed in the nuclei of few Sertoli cells at the age of 5 months. Labeling was weak in 2-15% of Sertoli cells until 4 yr of age and progressively increased thereafter. High levels of androgen receptor expression were observed in more than 90% from the age of 8 yr through adulthood. Androgen receptor was positive in peritubular cells and variable in interstitial cells. Anti-Müllerian hormone immunolabeling was strong in all Sertoli cells from fetal life throughout prepuberty and weakened progressively as spermatogenesis developed. Inhibin-alpha expression was detected in all Sertoli cells from fetal life through adulthood.A lack of androgen receptor expression could explain a physiological Sertoli cell androgen insensitivity during fetal and early postnatal life, which may serve to protect the testis from precocious Sertoli cell maturation, resulting in proliferation arrest and spermatogenic development.

Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies., This work was supported by Grants BFU2011-28058 and BFU2014-53610-P from Ministerio de Economía y Competitividad; Grant S2011/BMD-2328 from the Comunidad de Madrid; Grant RD12/0036/0030 from the Instituto de Salud Carlos III (to A.A.); Grants PI080971 and RD12 0036/0064 from the Instituto de Salud Carlos III (to J.P.); and Grant PI12/00386 from the Instituto de Salud Carlos III (to I.I.d.C.). O.A.M.-I. is supported by an Asociación Española Contra el Cáncer contract.

Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 µg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA., This work was funded by the Pedro Laín Entralgo Agency (NDG7/09) and the Moving Ataxias Foundation. Lucía Calatrava-Ferreras and Rafael Gonzalo-Gobernado were the recipients of a Pedro Laín Entralgo Agency and a Research Supporting Staff Grant Contract [Instituto de Salud Carlos III], respectively

Vascular Endotelial Growth Factors C and D (VEGF-C and VEGF-D) are crucial regulators of lymphangiogenesis, a main event in the metastatic spread of breast cancer tumors. Although inhibition of lymphangiogenic gene expression might be a useful therapeutic strategy to restrict the progression of cancer, the factors involved in the transcriptional repression of these genes are still unknown. We have previously shown that Nuclear Receptor Corepressor 1 (NCoR) and the thyroid hormone receptor β1 (TRβ) inhibit tumor invasion. Here we show that these molecules repress VEGF-C and VEGF-D gene transcription in breast cancer cells, reducing lymphatic vessel density and sentinel lymph node invasion in tumor xenografts. The clinical significance of these results is stressed by the finding that NCoR and TRβ transcripts correlate negatively with those of the lymphangiogenic genes and the lymphatic vessel marker LYVE-1 in human breast tumors. Our results point to the use of NCoR and TRβ as potential biomarkers for diagnosis or prognosis in breast cancer and suggest that further studies of these molecules as potential targets for anti-lymphangiogenic therapy are warranted., This work was supported by Grants: BFU2014-53610-P and SAF2015-71878-REDT from Ministerio de Economía y Competitividad; S2011/BMD-2328, from the Comunidad de Madrid and RD12/0036/0030 from the Instituto de Salud Carlos III (to A.A), by a Grant from the European Thyroid Association (to O.M-I), by grants RD120036/0064 from Instituto de Salud Carlos III (to J.P) and SAF2014-56868-R (to M.S.S). M.S.S is also funded by the Asociación Española Contra el Cancer (AECC) and by the Melanoma Research Alliance (MRA). This work is partially supported by FEDER funds. O.M.I is supported by an AECC contract.

Objective: Liver growth factor (LGF), a mitogen for liver cells, reduces fibrosis in a rat model of cirrhosis. The present study assesses the possible vascular antifibrotic and antihypertensive effects of LGF treatment on spontaneously hypertensive rats (SHR). Methods: Six-month-old male SHR and normotensive Wistar Kyoto rats (WKY) were treated with LGF (4.5 μg LGF/rat i.p. twice a week for 2 weeks). Haemodynamic parameters were measured in anaesthetized rats. Vascular structure and function were studied in carotid arteries using optical and confocal microscopy, radioimmunoassay for desmosine, and isometric tension recording. Results: LGF reduced systolic and diastolic blood pressure only in SHR. When compared to those of untreated SHR, carotid arteries from LGF-treated SHR showed: 1) a 50% reduction in collagen area and an increase in vascular smooth muscle cell number in the media, 2) no difference in total elastin content, but an increase in size of fenestrae in the internal elastic lamina, and 3) enhanced relaxation to acetylcholine, sodium nitroprusside, and forskolin. These effects were specific for SHR, since no changes were observed in LGF-treated WKY. Conclusion: Short-term treatment with a low dose of LGF induced a large improvement in vascular structure and function and significantly reduced blood pressure in a rat model of essential hypertension. The present results could open future research to explore the vascular effects of this endogenous factor in order to determine its potential as an antifibrotic and antihypertensive agent in humans.

Objective To characterize lysosomes and histochemical function of granular Sertoli cells in developmental alterations. Design Prospective and retrospective study. Setting University hospital and research centers. Patient(s) Nineteen infantile and pubertal patients undergoing testicular biopsy; four rat testes for lysosomal study. Intervention(s) CD-68, α-1-antitrypsin, vimentin, inhibin α subunit, and anti-mullerian hormone antibodies were evaluated. Morphometric measures in seminiferous tubules with and without granular Sertoli cells were obtained. Ultrastructural data of lysosomes in human and rat Sertoli cells were compared. Main Outcome Measure(s) Quantification of mean diameter of seminiferous tubules, tubular fertility index, and germ and Sertoli cell indexes were obtained in human testis. Result(s) Granular changes in Sertoli cells are due to the accumulation of large amounts of lysosomes. Vimentin immunoexpression in infantile and pubertal granular Sertoli cells was lower than in adjacent nongranular Sertoli cells. Inhibin was negative in granular cells. Anti-mullerian hormone–positive and -negative granular Sertoli cells were present within the same tubules. Conclusion(s) The presence of early granular changes in Sertoli cells in childhood and pubertal cryptorchidic patients, associated with other developmental alterations, suggests an intense and irreversible dysfunction of phagocytosis in the granular Sertoli cells. These alterations might be considered primary and irreversible anomalies of Sertoli cells, which might be contributing factors in the infertility seen in these patients.

Two patients with xanthogranulomatous inflammation are described, one with involvement of the spermatic cord and the other with 1 testicle and epididymis affected. To our knowledge, only 12 cases of xanthogranulomatous orchiepididymitis have been reported previously, one of which also presented a xanthogranulomatous funiculitis. Clinically, our patients presented with spermatic cord enlargement (case 1) and chronic orchitis that did not respond to treatment with antibiotics (case 2). Histopathologically, both cases showed extensive xanthogranulomatous inflammation with numerous foamy macrophages that were associated with colonies of microorganisms suggestive of actinomyces in case 1. Additionally, Escherichia coli was cultured from the surgical specimen of case 2. The possible underlying pathology may be diabetes in case 1 and phlebitis associated with chronic orchitis in case 2. Differential diagnoses with other lesions that are rich in macrophages, such as malakoplakia, and those testicular neoplasms without serologic tumor markers are discussed.

et al., [Aims]: Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of oxidant and xenobiotic metabolism, but it is unknown how it is regulated to provide basal expression of this defense system. Here, we studied the putative connection between NRF2 and the canonical WNT pathway, which modulates hepatocyte metabolism. [Results]: WNT-3A increased the levels of NRF2 and its transcriptional signature in mouse hepatocytes and HEK293T cells. The use of short interfering RNAs in hepatocytes and mouse embryonic fibroblasts which are deficient in the redox sensor Kelch-like ECH-associated protein 1 (KEAP1) indicated that WNT-3A activates NRF2 in a β-Catenin- and KEAP1-independent manner. WNT-3A stabilized NRF2 by preventing its GSK-3-dependent phosphorylation and subsequent SCF/β-TrCP-dependent ubiquitination and proteasomal degradation. Axin1 and NRF2 were physically associated in a protein complex that was regulated by WNT-3A, involving the central region of Axin1 and the Neh4/Neh5 domains of NRF2. Axin1 knockdown increased NRF2 protein levels, while Axin1 stabilization with Tankyrase inhibitors blocked WNT/NRF2 signaling. The relevance of this novel pathway was assessed in mice with a conditional deletion of Axin1 in the liver, which showed upregulation of the NRF2 signature in hepatocytes and disruption of liver zonation of antioxidant metabolism. [Innovation]: NRF2 takes part in a protein complex with Axin1 that is regulated by the canonical WNT pathway. This new WNT-NRF2 axis controls the antioxidant metabolism of hepatocytes. [Conclusion]: These results uncover the participation of NRF2 in a WNT-regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism., This work was funded by SAF2013-43271-R of the Spanish Ministry of Economy and Competitiveness.

et al., Type 2 diabetes has a complex pathology that involves a chronic inflammatory state. Emerging evidence suggests a link between the innate immune system receptor NOD1 (nucleotide-binding and oligomerization domain 1) and the pathogenesis of diabetes, in monocytes and hepatic and adipose tissues. The aim of the present study was to assess the role of NOD1 in the progression of diabetic cardiomyopathy. We have measured NOD1 protein in cardiac tissue from Type 2 diabetic (db) mice. Heart and isolated cardiomyocytes from db mice revealed a significant increase in NOD1, together with an up-regulation of nuclear factor κB (NF-κB) and increased apoptosis. Heart tissue also exhibited an enhanced expression of pro-inflammatory cytokines. Selective NOD1 activation with C12-γ -D-glutamyl-m-diaminopimelic acid (iEDAP) resulted in an increased NF-κB activation and apoptosis, demonstrating the involvement of NOD1 both in wild-type and db mice. Moreover, HL-1 cardiomyocytes exposed to elevated concentrations of glucose plus palmitate displayed an enhanced NF-κB activity and apoptotic profile, which was prevented by silencing of NOD1 expression. To address this issue in human pathology, NOD1 expression was evaluated in myocardium obtained from patients with Type 2 diabetes (T2DMH) and from normoglycaemic individuals without cardiovascular histories (NH). We have found that NOD1 was expressed in both NH and T2DMH; however, NOD1 expression was significantly pronounced in T2DMH. Furthermore, both the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) and the apoptosis mediator caspase-3 were up-regulated in T2DMH samples. Taken together, our results define an active role for NOD1 in the heightened inflammatory environment associated with both experimental and human diabetic cardiac disease.

El estudio de la hipoxia hipobárica (HH) determina un problema de salud pública y laboral en poblaciones que habitan en zonas de altura. La disminución del oxígeno afecta a diferentes órganos, incluyendo el testículo. El organismo responde frente a la hipoxia estimulando la angiogénesis, el flujo sanguíneo testicular e incrementa la temperatura intraescrotal, lo cual produce un daño de la espermatogénesis. Nuestro estudio valoró el efecto que produce la HH sobre el testículo del ratón. Se utilizó una cámara hipobárica regulada a 4.200 metros sobre el nivel del mar (msnm), en periodos de hipoxia durante 8,3; 16,6 y 24,9 días, en comparación a un grupo control en normoxia (500 msnm). En estos tres grupos, a unos ratones se administró melatonina, a otros maca (Lepidium meyenii) y a otros la combinación de melatonina y maca. Los objetivos fueron evaluar si la ingesta de maca protege al testículo, reduciendo el daño generado por la hipoxia, y determinar un posible efecto sinérgico de la melatonina y de la maca. La exposición a HH continua produjo una disminución del diámetro de los túbulos seminíferos y del lumen tubular; además, el seminograma demostró una reducción del recuento espermático, un aumento de la teratozoospermia y una reducción de la calidad del ADN espermático. La administración de maca aislada o la combinación de maca y melatonina en animales sometidos a HH produjo una notable mejoría de los parámetros relacionados con la función de los espermatozoides, siendo significativos la disminución del número de espermatozoides con morfología anormal y de la compactación del DNA, alcanzando en algunos casos valores próximos a los de los animales normóxicos. Los datos del presente modelo de HH corroboran los excelentes beneficios que la ingesta de maca tiene sobre la capacidad reproductiva de poblaciones que viven en áreas geográficas de grandes alturas, Hypobaric hypoxia (HH) is a decisive factor in human health in populations that reside at high altitude levels. Low oxygen rate affects most tissues and organs, including the testis. In humans, hypoxia stimulates angiogenesis, testicular blood flow and increases intrascrotal temperature which determines negative effects on sperm production. Our study researched the effects of HH in mice testicle. Mice were housed in a hypobaric chamber with a setting at 4,200 m above sea level during three different periods of hypoxia (8.3, 16.6 and 24.9 days). Control groups were housed at normoxic conditions (500 m above sea level). Hypoxic mice were treated with melatonin, maca plant (Lepidium meyenii) and melatonin and maca combination. The aim of present study was to determine if maca consumption protects testis against harmful effects of hypoxia and to determine a possible synergistic effect between melatonin and maca administration. In this article we have demonstrated that hypoxia produces a considerable decrease of seminiferous tubules diameter and lumen diameter. Moreover, seminogram showed a reduced sperm count, increased teratozoospermia and a reduction of DNA quality. The HH mice treatment with maca or maca-melatonin combination showed statistically significant improvement at sperm function parameters, and in the reduction of sperm morphology abnormalities and DNA compaction, in some cases attaining rates closer to those registered in normoxic mice. Our experimental data corroborates that maca consumption improves reproductive capacity of populations that inhabit high altitude regions, Este trabajo fue financiado por la Universidad de Tarapacá (Arica, Chile) Proyecto Mayor de Investigación Científica y Tecnológica UTA, código 4711-13.

Androgen receptor (AR) immunohistochemistry was performed in an archival collection of adult human cryptorchid testes to determine whether AR cellular distribution and intensity of immunostaining were functions of the severity of cellular dysgenesis. The seminiferous tubule histology of cryptorchid testes collected from adults is marked by three specific patterns. 1) Seminiferous tubules are characterized as maintaining focal areas of germinal cell differentiation (albeit incomplete) that are interspersed with 2) tubules composed of Sertoli cells only, these latter cells being principally of the adult type, although dysgenetic and immature Sertoli cells may also be detected. 3) In contrast, there is a class of tubule that is characterized as being composed exclusively of Sertoli cells that are extremely dysgenetic in appearance. The majority of adult-type Sertoli cells found in the first types of tubules exhibited either robust or moderate AR staining intensity. Peritubular cells of these tubules also expressed a similar AR staining intensity. In contrast, in the more dysgenetic and immature type Sertoli cells found in the second type of tubules, the intensity of AR staining was significantly less, if not missing altogether. Finally, in the most dysgenetic tubules, Sertoli cell AR staining was never detected. To our knowledge, this is the first report in the literature that addresses the intensity of AR immunostaining in Sertoli cells of cryptorchid testes. The results presented herein are consistent with the interpretation that the intensity of AR staining in Sertoli cells diminishes as a function of the severity to which the cells are afflicted within a cryptorchid testis and that focal absence of AR expression in Sertoli cells correlates with a lack of local spermatogenesis in the tubules.

Objective.—To evaluate the morphometric, immunohistochemical, and ultrastructural lesions of the testes in prepubertal and adult patients with androgen insensitivity syndrome. Methods.—We examined the testicular biopsy using immunohistochemistry for vimentin, smooth muscle actin, and collagen IV antigens. Quantification of seminiferous tubules and testicular interstitium was performed in prepubertal and adult patients with androgen insensitivity syndrome and results were compared with normal testes from both infants and adults. Results.—The adult testes presented nodular and diffuse lesions that consisted of Sertoli-cell-only seminiferous tubules. Two types of Sertoli cells could be distinguished, namely, immature vimentin-positive Sertoli cells and nearly mature Sertoli cells. In the nodules, the lamina propria was thin and contained a scant number of actin-positive peritubular cells. Leydig cells were hyperplastic. The prepubertal patients showed only diffuse lesions characterized by Sertoli cell hyperplasia, decreased germ cell numbers, and a discontinuous immunoreaction to collagen IV. Conclusions.—The testicular lesions in androgen insensitivity syndrome are probably caused by primary alterations that begin during gestation. These lesions become progressively more pronounced at puberty, when the nodular lesion pattern (adenomas) is completely developed.

The immunohistochemical reaction to oncostatin M (OSM) was studied in normal human testes at different ages (fetuses, newborns, children, pubertal boys, adults, and elderly men), as well as in several testicular disorders including carcinoma-in-situ cells (CIS), germ cell tumors, benign functioning Leydig cell tumor, androgen insensitivity syndrome, Klinefelter's syndrome, and cryptorchidism. Positive OSM immunostained Sertoli cells were only observed in fetuses. In normal testes, intense OSM immunoreaction was found in the Leydig cells of fetuses, newborns, and adults. Leydig cell immunoreaction was weak in elderly men and absent in children and pubertal boys. In some testicular disorders (Leydig cell tumor, cryptorchidism, and CIS), Leydig cell immunoreaction was as intense as in normal adult testes. This immunoreaction was heterogeneous in androgen insensitivity syndrome and was absent in Klinefelter's syndrome and intratubular seminoma. No recognizable Leydig cells were observed in the other testicular tumors. The findings of our study suggest that, in humans, the down-regulation of OSM immunoexpression in Sertoli cells occurs early, and that OSM immunoreaction in the Leydig cells is associated with functionally active and differentiated Leydig cells.

The distribution of the androgen receptor (AR) in archival human testes was determined immunocytochemically using an affinity-purified peptide-specific rabbit antibody, PG21, and employing a modified biotin-streptavidin-immunoperoxidase method that incorporated a biotin amplification step. In combination with microwave epitope retrieval, the biotin amplification step increased the sensitivity of the immunostaining assay approximately 20-fold. Thus, the useful range at which PG21 rendered a robust, specific immunostaining signal without also increasing nonspecific background was extended dramatically. Broadening the useful range of the PG21 antibody made it possible to resolve the relative amounts of immunopositive AR in different cell types of the human testis. At a high PG21 concentration, for example, all AR-positive cells exhibited a robust immunostaining intensity, but it was not possible to distinguish between nuclei exhibiting either high or moderate immunostaining intensities. In contrast, as the concentration of PG21 was decreased, distinct populations of testicular cells exhibited differential AR immunostaining intensities in their nuclei. AR immunostaining of Sertoli cell nuclei was present at low PG21 concentrations at which no immunostaining of peritubular myoid cells or Leydig cells could be detected. In turn, AR immunostaining of peritubular myoid cells was detected at PG21 concentrations that did not immunostain Leydig cells. Moreover, within the seminiferous epithelium, Sertoli cell nuclear AR staining intensity was less at stages V and VI of the cycle of the seminiferous epithelium than that at stage III, and stage III staining intensity was greater than that at stages I and II. This AR immunostaining pattern in human Sertoli cell nuclei as a function of the cycle of the seminiferous epithelium is reminiscent of the pattern observed in rodent species. Finally, no AR immunostaining of germ cells was observed at any of the PG21 concentrations examined.

[Background]: Maternal diabetes influences fetal pancreas development. As there are some controversial reports, we studied the morphometric changes of the fetal insular pancreas and insulin immunostain of beta cells as well as the proliferative activity of insular cells in 21-day-old fetuses from control, diabetic, and insulin-treated diabetic pregnant rats. [Methods]: Streptozotocin was injected into 7-day-pregnant rats (controls were not injected). Some rats were either left untreated (diabetic) or injected with insulin. Animals were killed at 21 days of gestation. Fetal pancreas were fixed in toto for the morphometry and immunohistochemistry studies using anti-insulin, anti-Ki-67 and anti-proliferating cell nuclear antigen (PCNA) antibodies. [Results]: Diabetic status was determined by measuring maternal and fetal serum glucose and insulin levels. The morphometric studies showed hyperplasia of the diabetic fetal insular tissue which had not been normalized by insulin therapy. Diabetes caused an increase of both insulin- positive and insulin-negative cells. The increase in insulin-positive cells was not corrected by insulin treatment, although the number of non-beta cells became normal. The nuclear area in beta cells increased in diabetic rats but was not corrected by insulin. The cytoplasmic area decreased in diabetic rats and was normalized by insulin administration. Diabetes increased the expression of the nuclear antigen Ki-67 in fetal insular pancreas, and insulin treatment returned it to the normal state. [Conclusions]: Maternal diabetes leads to hyperstimulation of fetal beta cells, with increased proliferative activity. Insulin administration to the dams corrects some of the changes observed., Grant sponsor: DGICYT PM 91/0220; Grant sponsor: FISS 92-0888.

We investigated the possible role of a tissular renin-angiotensin system in promoting the growth of vascular smooth muscle cells (VSMCs) from hypertensive transgenic rats (TGRs) with the mouse renin gene Ren-2. Mean arterial pressure values were 99.4 +/- 2.8 and 186.7 +/- 5.0 mm Hg for control Sprague-Dawley rats (SDs) and TGRs, respectively (p < 0.05). The tunica media of femoral arteries obtained from hypertensive TGRs was found to be thickened compared to that of age-matched normotensive SDs. Angiotensin II could be detected by dot blot and immunocytochemistry and quantified by radioimmunoassay in transgenic VSMCs, but not in control SD ones. Under serum-free conditions, VSMCs derived from TGRs showed a higher protein content than those derived from SDs (337 +/- 19 vs. 269 +/- 14 pg/cell, p < 0.05, n = 3). Under the same basal conditions, the mean planar cell surface area was significantly higher in TGR VSMCs than in SD ones (4,764 +/- 204 vs. 4,074 +/- 238 micron 2, p < 0.05). In addition, TGR VSMCs showed an enhanced [14C]-leucine uptake but SD VSMCs did not (13,188 +/- 663 vs. 7,633 +/- 713 dpm/well, p < 0.05). VSMCs showed a concentration-dependent proliferative response to fetal calf serum (FCS) that was more marked in TGRs than in SDs. In the absence of FCS, c-fos and c-jun mRNAs were expressed only in transgenic cultures. From the present results, we can hypothesize that cultured TGR VSMCs are able to synthesize angiotensin II that, being almost exclusive into the cells, contributes to produce VSMC growth in the absence of FCS stimulation.

Splanchnic and systemic low-grade inflammation has been proposed to be a consequence of long-term prehepatic portal hypertension. This experimental model causes minimal alternations in the liver, thus making a more selective study possible for the pathological changes characteristic of prehepatic portal hypertension. Low-grade splanchnic inflammation after long-term triple partial portal vein ligation could be associated with liver steatosis and portal hypertensive intestinal vasculopathy. In fact, we have previously shown that prehepatic portal hypertension in the rat induces liver steatosis and changes in lipid and carbohydrate metabolism similar to those produced in chronic inflammatory conditions described in metabolic syndrome in humans. Dysbiosis and bacterial translocation in this experimental model suggest the existence of a portal hypertensive intestinal microbiome implicated in both the splanchnic and systemic alterations related to prehepatic portal hypertension. Among the systemic impairments, aortopathy characterized by oxidative stress, increased levels of proinflammatory cytokines and profibrogenic mediators stand out. In this experimental model of long-term triple portal vein ligated-rats, the abdominal aortic proinflammatory response could be attributed to oxidative stress. Thus, the increased aortic reduced-nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase activity could be associated with reactive oxygen species production and promote aortic inflammation. Also, oxidative stress mediated by NAD(P)H oxidase has been associated with risk factors for inflammation and atherosclerosis. The splanchnic and systemic pathology that is produced in the long term after triple partial portal vein ligation in the rat reinforces the validity of this experimental model to study the chronic low-grade inflammatory response induced by prehepatic portal hypertension.

Resumen del trabajo presentado al 38th Annual Meeting of the European Thyroid Association celebrado en Santiago de Compostela (Espana) del 6 al 10 de septiembre de 2014.

[Background]: MAP3K8 (Cot/tpl2) activates MKK1/2-Erk1/2 upon stimulation of receptors from the Toll-like/interleukin-1 receptor superfamily. [Results]: Cot/tpl2 plays an essential role in acetaminophen-induced liver injury by modulating the generation of inflammatory signals induced by necrotic cells. [Conclusion]: Sterile inflammatory processes triggered by tissue damage are modulated by Cot/tpl2. [Significance]: Cot/tpl2 contributes to the development of pathologies associated with inflammation triggered by damage-associated molecular patterns., This work was supported by Grants SAF 2011-24481 (to S. A.) and SAF 2012-33283 (to A. M. V.) from MINECO (Spain) Comunidad de Madrid S2010/BMD-2423, EFSD/Amylin Programme 2011 (to A. M. V.) and a grant from the Mutua Madrileña (to S. A.).

FUNDING: Universidad Autonoma de Madrid (UAM/32 IMADE) METHODS Varicose veins are an important cause of morbidity with a prevalence of 10 to 50%. Risk factors: advanced age, female gender, diets, obesity, physical activity, standing ocupations, connective tissue altrations, genetic predisposition. The aetiology and pathogenesis: Two hypothesis have been proposed: 1. Valvular dysfunction causing venous reflux in early state of pathology 2. A primary change in varicose vein wall (structural and biochemical changes). We hypothesize that the formation of varicose vein is secondary to defects in cellular and extracellular matrix components, causing wall weakness and altered tone.

Liver growth factor (LGF) is an endogenous albumin-bilirubin complex with antihypertensive effects in spontaneously hypertensive rats (SHR). We assessed the actions of LGF treatment on SHR mesenteric resistance and intramyocardial arteries (MRA and IMA, respectively), heart, and vascular smooth muscle cells (VSMC). SHR and Wistar-Kyoto (WKY) rats treated with vehicle or LGF (4.5 μg LGF/rat, 4 ip injections over 12 days) were used. Intra-arterial blood pressure was measured in anesthetized rats. The heart was weighted and paraffin-embedded. Proliferation, ploidy, and fibronectin deposition were studied in carotid artery-derived VSMC by immunocytochemistry. In MRA, we assessed: 1) geometry and mechanics by pressure myography; 2) function by wire myography; 3) collagen by sirius red staining and polarized light microscopy, and 4) elastin, cell density, nitric oxide (NO), and superoxide anion by confocal microscopy. Heart sections were used to assess cell density and collagen content in IMA. Left ventricular hypertrophy (LVH) regression was assessed by echocardiography. LGF reduced blood pressure only in SHR. LGF in vitro or as treatment normalized the alterations in proliferation and fibronectin in SHR-derived VSMC with no effect on WKY cells. In MRA, LGF treatment normalized collagen, elastin, and VSMC content and passive mechanical properties. In addition, it improved NO availability through reduction of superoxide anion. In IMA, LGF treatment normalized perivascular collagen and VSMC density, improving the wall-to-lumen ratio. Paired experiments demonstrated a partial regression of SHR LVH by LGF treatment. The effective cardiovascular antifibrotic and regenerative actions of LGF support its potential in the treatment of hypertension and its complications.

In addition to the well-known role of the thyroid hormone receptors (TRs) in growth, development and metabolism, there is increasing evidence that they have profound effects on cell proliferation and malignant transformation. TRs repress transcriptional induction of cyclin D1 by the ras oncogene and block transformation and tumor formation by Ras-transformed fibroblasts in nude mice. Mutant receptors that do not bind coactivators are able to display these actions, whereas receptors defective in corepressors binding are unable to antagonize the responses to the ras oncogene. Furthermore, expression of TRΒ 1 in hepatocarcinoma and breast cancer cells abolishes anchorage-independent growth and migration, blocks responses to growth factors and represses expression of prometastatic genes, reducing tumor growth and strongly inhibiting invasiveness, extravasation and metastasis formation in euthyroid mice. By contrast, when cells are inoculated into hypothyroid host, tumor growth is retarded, but tumors are more invasive and metastatic growth is enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs, showing that changes secondary to hypothy-roidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. Finally, increased malignancy of skin tumors is found in mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression and suggesting that they represent a potential therapeutic target in cancer., Research in this laboratory has been supported by grant BFU2007- 62402 from the Ministerio de Ciencia e Innovación, grant RD06/ 0020/0036 from the Fondo de Investigaciones Sanitarias and from the European Project CRESCENDO (grant FP6-018652). The authors have no conflict of interest to declare

To study the ability of human adipose-derived mesenchymal stem cells (AMSCs) to survive over the short and long term, their biodistribution and their biosafety in vivo in tumor-prone environments.We subcutaneously injected human AMSCs from different human donors into immunodeficient SCID mice over both short- (2 and 4 mo) and long- (17 mo) term in young, and aged tumor-prone mice. Presence of human cells was studied by immunohistochemistry and polymerase chain reaction analysis in all organs of injected mice.Subcutaneously injected AMSCs did not form teratomas at any time point. They did not migrate but remained at the site of injection regardless of animal age, and did not fuse with host cells in any organ examined. AMSCs survived in vivo for at least 17 mo after injection, and differentiated into fibroblasts of the subdermic connective tissue and into mature adipocytes of fat tissue, exclusively at the site of injection.Our results support the assertion that AMSC may be safe candidates for therapy when injected subcutaneously because of their long term inability to form teratomas.

Cot/tpl2 (also known as MAP3K8) has emerged as a new and potentially interesting therapeutic anti-inflammatory target. Here, we report the first study of Cot/tpl2 involvement in acute peripheral inflammation in vivo. Six hours after an intraplantar injection of zymosan, Cot/tpl2−/− mice showed a 47% reduction in myeloperoxidase activity, concomitant with a 46% lower neutrophil recruitment and a 40% decreased luminol-mediated bioluminescence imaging in vivo. Accordingly, Cot/tpl2 deficiency provoked a 25–30% reduction in luminol-mediated bioluminescence and neutrophil recruitment together with a 65% lower macrophage recruitment 4 h following zymosan-induced peritonitis. Significantly impaired levels of G-CSF and GM-CSF and of other cytokines such as TNFα, IL-1β, and IL-6, as well as some chemokines such as MCP-1, MIP-1β, and keratinocyte-derived chemokine, were detected during the acute zymosan-induced intraplantar inflammatory response in Cot/tpl2−/− mice. Moreover, Cot/tpl2 deficiency dramatically decreased the production of the hypernociceptive ligand NGF at the inflammatory site during the course of inflammation. Most importantly, Cot/tpl2 deficiency significantly reduced zymosan-induced inflammatory hypernociception in mice, with a most pronounced effect of a 50% decrease compared with wild type (WT) at 24 h following intraplantar injection of zymosan. At this time, Cot/tpl2−/− mice showed significantly reduced NGF, TNFα, and prostaglandin E2 levels compared with WT littermates. In conclusion, our study demonstrates an important role of Cot/tpl2 in the NGF, G-CSF, and GM-CSF production and myeloperoxidase activity in the acute inflammatory response process and its implication in inflammatory hypernociception., This work was supported by Comunidad de Madrid Grants SAF 2008-00819 and Mutua Madrileña.

Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. We show here that expression of TRβ1 in hepatocarcinoma and breast cancer cells reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice. In cultured cells, TRβ1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-I, and transforming growth factor β, and regulates expression of genes that play a key role in tumorigenicity and metastatic growth. The receptor disrupts the mitogenic action of growth factors by suppressing activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways that are crucial for cell proliferation and invasiveness. Furthermore, increased aggressiveness of skin tumors is found in genetically modified mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression. These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer. ©2009 American Association for Cancer Research., MEC grants BFU2004 03165 and BFU2007-62402, FIS grants RD06/0020/0036, Acción Transversal de Cáncer and PIO40682, and EU Project CRESCENDO grant FP6-018652.

11 pages, 9 figures., [Background]: Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients [Methodology/Principal Findings]: In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRβ1–expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRβ–expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs. [Conclusions/Significance]: These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer., This work was supported by grants BFU2007-62402 from MEC; RD06/0020/0036 from FIS and from the EU Project CRESCENDO (FP6-018652.

To counter the global threat caused by Plasmodium falciparum malaria, new drugs and vaccines are urgently needed. However, there are no practical animal models because P. falciparum infects human erythrocytes almost exclusively. Here we describe a reliable falciparum murine model of malaria by generating strains of P. falciparum in vivo that can infect immunodeficient mice engrafted with human erythrocytes. We infected NOD(scid/beta2m-/-) mice engrafted with human erythrocytes with P. falciparum obtained from in vitro cultures. After apparent clearance, we obtained isolates of P. falciparum able to grow in peripheral blood of engrafted NOD(scid/beta2m-/-) mice. Of the isolates obtained, we expanded in vivo and established the isolate Pf3D7(0087/N9) as a reference strain for model development. Pf3D7(0087/N9) caused productive persistent infections in 100% of engrafted mice infected intravenously. The infection caused a relative anemia due to selective elimination of human erythrocytes by a mechanism dependent on parasite density in peripheral blood. Using this model, we implemented and validated a reproducible assay of antimalarial activity useful for drug discovery. Thus, our results demonstrate that P. falciparum contains clones able to grow reproducibly in mice engrafted with human erythrocytes without the use of myeloablative methods.

Objetivo: Presentar un caso de metástasis ovárica secundaria a un carcinoma de células claras renal. Método/Resultados: Mujer de 52 años que consultó por metrorragias siendo inicialmente diagnosticada de carcinoma primario de ovario. En los estudios de extensión se informa de masa renal sugestiva de metástasis ovárica. La intervención quirúrgica consistió en histerectomía con doble anexectomía y nefrectomía radical. El diagnóstico final fue de carcinoma de células claras renal con metástasis ovárica. Conclusión: Las metástasis tumorales en el ovario presentan un problema diagnóstico en su interpretación, especialmente cuando las metástasis presentan una histología similar al primario de ovario. Debido a las implicaciones terapéuticas y pronósticas es muy importante diferenciar si se trata de un tumor ovárico primario o un metástasis de un carcinoma renal.

La Terapia Fotodinámica (TFD) es una modalidad terapéutica mínimamente invasiva y de extraordinaria utilidad. En Urología, la TFD, es muy útil y puede ser aplicada mediante endoscopia o directamente, habiéndose obtenido excelentes resultados en el diagnóstico y tratamiento de lesiones tumorales de vejiga, en el tratamiento de carcinoma de próstata y de sus recidivas y en el tratamiento de lesiones dermatológicas precancerosas y tumorales del pene. La TFD se fundamenta en el uso de compuestos fotosensibilizadores (FSs) que se acumulan selectivamente en los tejidos tumorales. La irradiación posterior de éstos tejidos con luz de longitud de onda apropiada (generalmente de la región del rojo del espectro visible λ > 600nm) produce la formación de especies reactivas de oxígeno (ROS) con efectos citotóxicos, que conducen a la muerte selectiva de las células neoplásicas y en consecuencia a la regresión del tumor. La principal ventaja de la TFD es que el daño celular queda restringido a la zona irradiada, con la consiguiente disminución de efectos secundarios sobre los tejidos sanos próximos al tumor, al contrario de lo que ocurre con otras terapias convencionales de algunos tumores del tracto urinario. Además, la TFD puede utilizarse en combinación con radioterapia y quimioterapia.

OBJETIVOS Realizar una evaluacion a largo plazo de 15 pacientes con hematuria esencial unilateral, con el fin de determinar las causas del sangrado y la respuesta obtenida con el tratamiento endoscopico efectuado. Disenar un algoritmo diagnostico-terapeutico para los pacientes con hematuria esencial unilateral. METODOS Revisamos de forma retrospectiva los datos medicos de 15 pacientes con hematuria esencial unilateral que fueron evaluados mediante ureteroscopia rigida (15 casos), ureteropielocalicoscopia flexible (15 casos) y nefroscopia percutanea (3 casos). En 4 pacientes se realizo electrocoagulacion de las lesiones encontradas en el sistema pielocalicial. RESULTADOS De los 15 pacientes, 14 fueron tratados con exito mediante endoscopia. En un solo paciente se observo la recidiva de la hematuria. El tiempo de seguimiento medio (a estos pacientes) ha sido de 64 meses (rango 4 a 168 meses). Ningun paciente ha sufrido complicacion relevante en relacion con el tratamiento endoscopico. CONCLUSIONES En los pacientes con hematuria esencial unilateral la causa del sangrado se determina en pocos de ellos, pero el tratamiento endoscopico resulta exitoso en un alto porcentaje de casos. Consideramos que la endoscopia del tracto urinario superior, pero sobre todo, la ureteropielocalicoscopia flexible, ha impactado fuertemente en el diagnostico y tratamiento de la hematuria esencial unilateral. Exponemos un nuevo algoritmo diagnostico y terapeutico de esta entidad clinica, basado en la utilidad practica de la instrumentacion flexible.

OBJETIVOS Mujer de 79 anos que consulta por dolores colicos abdominales inespecificos. La ecografia solicitada por el servicio de digestivo es informada como formacion polipoidea exofitica de unos 3 cm. en vejiga, que infiltra la pared vesical y los tejidos adyacentes...