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1.
Development ; 151(11)2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38770916

RESUMEN

Prolyl hydroxylase domain (PHD) proteins are oxygen sensors that use intracellular oxygen as a substrate to hydroxylate hypoxia-inducible factor (HIF) α proteins, routing them for polyubiquitylation and proteasomal degradation. Typically, HIFα accumulation in hypoxic or PHD-deficient tissues leads to upregulated angiogenesis. Here, we report unexpected retinal phenotypes associated with endothelial cell (EC)-specific gene targeting of Phd2 (Egln1) and Hif2alpha (Epas1). EC-specific Phd2 disruption suppressed retinal angiogenesis, despite HIFα accumulation and VEGFA upregulation. Suppressed retinal angiogenesis was observed both in development and in the oxygen-induced retinopathy (OIR) model. On the other hand, EC-specific deletion of Hif1alpha (Hif1a), Hif2alpha, or both did not affect retinal vascular morphogenesis. Strikingly, retinal angiogenesis appeared normal in mice double-deficient for endothelial PHD2 and HIF2α. In PHD2-deficient retinal vasculature, delta-like 4 (DLL4, a NOTCH ligand) and HEY2 (a NOTCH target) were upregulated by HIF2α-dependent mechanisms. Inhibition of NOTCH signaling by a chemical inhibitor or DLL4 antibody partially rescued retinal angiogenesis. Taken together, our data demonstrate that HIF2α accumulation in retinal ECs inhibits rather than stimulates retinal angiogenesis, in part by upregulating DLL4 expression and NOTCH signaling.


Asunto(s)
Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Células Endoteliales , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Receptores Notch , Neovascularización Retiniana , Transducción de Señal , Regulación hacia Arriba , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ratones , Receptores Notch/metabolismo , Receptores Notch/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/genética , Neovascularización Retiniana/patología , Células Endoteliales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Retina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Vasos Retinianos/metabolismo , Angiogénesis
2.
Development ; 148(23)2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34874450

RESUMEN

Under normoxia, hypoxia inducible factor (HIF) α subunits are hydroxylated by PHDs (prolyl hydroxylase domain proteins) and subsequently undergo polyubiquitylation and degradation. Normal embryogenesis occurs under hypoxia, which suppresses PHD activities and allows HIFα to stabilize and regulate development. In this Primer, we explain molecular mechanisms of the oxygen-sensing pathway, summarize HIF-regulated downstream events, discuss loss-of-function phenotypes primarily in mouse development, and highlight clinical relevance to angiogenesis and tissue repair.


Asunto(s)
Embrión de Mamíferos/embriología , Desarrollo Embrionario , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Oxígeno/metabolismo , Ubiquitinación , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones
3.
Development ; 146(8)2019 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-30910827

RESUMEN

Vascular pruning is crucial for normal development, but its underlying mechanisms are poorly understood. Here, we report that retinal vascular pruning is controlled by the oxygen-sensing mechanism in local astrocytes. Oxygen sensing is mediated by prolyl hydroxylase domain proteins (PHDs), which use O2 as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labeling them for polyubiquitylation and proteasomal degradation. In neonatal mice, astrocytic PHD2 deficiency led to elevated HIF-2α protein levels, expanded retinal astrocyte population and defective vascular pruning. Although astrocytic VEGF-A was also increased, anti-VEGF failed to rescue vascular pruning. However, stimulation of retinal astrocytic growth by intravitreal delivery of PDGF-A was sufficient to block retinal vascular pruning in wild-type mice. We propose that in normal development, oxygen from nascent retinal vasculature triggers PHD2-dependent HIF-2α degradation in nearby astrocytic precursors, thus limiting their further growth by driving them to differentiate into non-proliferative mature astrocytes. The physiological limit of retinal capillary density may be set by astrocytes available to support their survival, with excess capillaries destined for regression.This article has an associated 'The people behind the papers' interview.


Asunto(s)
Astrocitos/citología , Astrocitos/metabolismo , Oxígeno/metabolismo , Retina/citología , Retina/metabolismo , Animales , Apoptosis/fisiología , Movimiento Celular/genética , Movimiento Celular/fisiología , Proliferación Celular/genética , Proliferación Celular/fisiología , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Ratones , Seudópodos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
4.
Cytokine ; 142: 155500, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33810947

RESUMEN

We quantified the serum levels of 34 cytokines/chemokines in 30 patients with SARS-CoV-2 infection. Elevated levels of IP-10 and IL-7 were detected in the acute and convalescent stages of the infection and were highly associated with disease severity.


Asunto(s)
COVID-19/sangre , Quimiocina CXCL10/sangre , Interleucina-7/sangre , SARS-CoV-2/metabolismo , Índice de Severidad de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad
6.
Am J Pathol ; 184(4): 1240-1250, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24508125

RESUMEN

Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1α and 2α, tagging them for pVHL-dependent polyubiquitination and proteasomal degradation. In this study, albumin Cre (Alb(Cre))-mediated, hepatocyte-specific triple disruption of Phd1, Phd2, and Phd3 (Phd(1/2/3)hKO) promoted liver erythropoietin (EPO) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels. In Phd(1/2/3)hKO mice, hematocrit levels reached 82.4%, accompanied by severe vascular malformation and steatosis in the liver. In mice double-deficient for hepatic PHD2 and PHD3 (Phd(2/3)hKO), liver EPO increase and renal EPO loss both occurred but were much less dramatic than in Phd(1/2/3)hKO mice. Hematocrit levels, vascular organization, and liver lipid contents all appeared normal in Phd(2/3)hKO mice. In a chronic renal failure model, Phd(2/3)hKO mice maintained normal hematocrit levels throughout the 8-week time course, whereas floxed controls developed severe anemia. Maintenance of normal hematocrit levels in Phd(2/3)hKO mice was accomplished by sensitized induction of liver EPO expression. Consistent with such a mechanism, liver HIF-2α accumulated to higher levels in Phd(2/3)hKO mice in response to conditions causing modest systemic hypoxia. Besides promoting erythropoiesis, EPO is also known to modulate retinal vascular integrity and neovascularization. In Phd(1/2/3)hKO mice, however, neonatal retinas remained sensitive to oxygen-induced retinopathy, suggesting that local EPO may be more important than hepatic and/or renal EPO in mediating protective effects in the retina.


Asunto(s)
Anemia/metabolismo , Eritropoyetina/metabolismo , Fallo Renal Crónico/metabolismo , Hígado/enzimología , Prolil Hidroxilasas/deficiencia , Enfermedades de la Retina/metabolismo , Anemia/patología , Animales , Western Blotting , Modelos Animales de Enfermedad , Fallo Renal Crónico/patología , Ratones , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Enfermedades de la Retina/patología
7.
Am J Pathol ; 184(3): 686-96, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24440788

RESUMEN

Deficiencies in prolyl hydroxylase domain proteins (PHDs) may lead to the accumulation of hypoxia-inducible factor-α proteins, the latter of which activate local angiogenic responses by paracrine mechanisms. Here, we investigate whether a keratinocyte-specific PHD deficiency may promote vascular survival and growth in a distantly located ischemic tissue by a remote signaling mechanism. We generated mice that carry a keratinocyte-specific Phd2 knockout (kPhd2KO) and performed femoral artery ligation. Relative to wild-type controls, kPhd2KO mice displayed improved vascular survival and arteriogenesis in ischemic hind limbs, leading to the accelerated recovery of hindlimb perfusion and superior muscle regeneration. Similar protective effects were also seen in type 1 and type 2 diabetic mice. Molecularly, both abundance of hypoxia-inducible factor-1α protein and expression of vascular endothelial growth factor-A were increased in epidermal tissues of kPhd2KO mice, accompanied by increased plasma concentration of vascular endothelial growth factor-A. Contrary to kPhd2KO mice, which are PHD2 deficient in all skin tissues, localized kPhd2KO in hindlimb skin tissues did not have similar effects, excluding paracrine signaling as a major mechanism. Confirming the existence of remote effects, hepatocyte-specific Phd2 knockout also protected hind limbs from ischemia injury. These data indicate that vascular survival and growth in ischemia-injured tissue may be stimulated by suppressing PHD2 in a remotely located tissue and may provide highly effective angiogenesis therapies without the need for directly accessing target tissues.


Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Miembro Posterior/irrigación sanguínea , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Isquemia/fisiopatología , Transducción de Señal , Animales , Modelos Animales de Enfermedad , Arteria Femoral/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Masculino , Ratones , Ratones Noqueados , Factor A de Crecimiento Endotelial Vascular/metabolismo
8.
Circulation ; 126(6): 741-52, 2012 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-22753193

RESUMEN

BACKGROUND: Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. Whereas germline Vegfr-1(-/-) embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain appear healthy. METHODS AND RESULTS: We performed Cre-loxP-mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice and analyzed developmental, pathophysiological, and molecular consequences. VEGFR-1 deficiency promoted tip cell formation and endothelial cell proliferation and facilitated angiogenesis of blood vessels that matured and perfused properly. Vascular permeability was normal at the basal level but elevated in response to high doses of exogenous VEGF-A. In the postinfarct ischemic cardiomyopathy model, VEGFR-1 deficiency supported robust angiogenesis and protected against myocardial infarction. VEGFR-1 knockout led to abundant accumulation of VEGFR-2 at the protein level, increased VEGFR-2 tyrosine phosphorylation transiently, and enhanced serine phosphorylation of Akt and ERK. Interestingly, increased angiogenesis, tip cell formation, vascular permeability, VEGFR-2 accumulation, and Akt phosphorylation could be partially rescued or suppressed by one or more of the following manipulations, including injection of the VEGFR-2 selective inhibitor SU1498, anti-VEGF-A, or introduction of Vegfr-2(+/-) heterozygosity into Vegfr-1 somatic knockout mice. CONCLUSIONS: Upregulation of VEGFR-2 abundance at the protein level contributes in part to increased angiogenesis in VEGFR-1-deficient mice.


Asunto(s)
Neovascularización Fisiológica/genética , Regulación hacia Arriba , Receptor 1 de Factores de Crecimiento Endotelial Vascular/deficiencia , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Animales , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Regulación hacia Arriba/genética , Regulación hacia Arriba/fisiología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/fisiología
9.
Biol Open ; 12(1)2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36625299

RESUMEN

Tailless (TLX, an orphan nuclear receptor) and hypoxia inducible factor-2α (HIF2α) are both essential for retinal astrocyte and vascular development. Tlx-/- mutation and astrocyte specific Hif2α disruption in Hif2αf/f/GFAPCre mice are known to cause defective astrocyte development and block vascular development in neonatal retinas. Here we report that TLX and HIF2α support retinal angiogenesis by cooperatively maintaining retinal astrocytes in their proangiogenic states. While Tlx+/- and Hif2αf/+/GFAPCre mice are phenotypically normal, Tlx+/-/Hif2αf/+/GFAPCre mice display precocious retinal astrocyte differentiation towards non-angiogenic states, along with significantly reduced retinal angiogenesis. In wild-type mice, TLX and HIF2α coexist in the same protein complex, suggesting a cooperative function under physiological conditions. Furthermore, astrocyte specific disruption of Phd2 (prolyl hydroxylase domain protein 2), a manipulation previously shown to cause HIF2α accumulation, did not rescue retinal angiogenesis in Tlx-/- background, which suggests functional dependence of HIF2α on TLX. Finally, the expression of fibronectin and VEGF-A is significantly reduced in retinal astrocytes of neonatal Tlx+/-/Hif2αf/+/GFAPCre mice. Overall, these data indicate that TLX and HIF2α cooperatively support retinal angiogenesis by maintaining angiogenic potential of retinal astrocytes.


Asunto(s)
Astrocitos , Neuroglía , Animales , Ratones , Astrocitos/metabolismo , Animales Recién Nacidos , Retina/metabolismo , Hipoxia/metabolismo
10.
Front Oncol ; 13: 1247682, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38074651

RESUMEN

Purpose: This bi-institutional study aimed to establish a robust model for predicting clinically significant prostate cancer (csPCa) (pathological grade group ≥ 2) in PI-RADS 3 lesions in the transition zone by comparing the performance of combination models. Materials and methods: This study included 243 consecutive men who underwent 3-Tesla magnetic resonance imaging (MRI) and ultrasound-guided transrectal biopsy from January 2020 and April 2022 which is divided into a training cohort of 170 patients and a separate testing cohort of 73 patients. T2WI and DWI images were manually segmented for PI-RADS 3 lesions for the mean ADC and radiomic analysis. Predictive clinical factors were identified using both univariate and multivariate logistic models. The least absolute shrinkage and selection operator (LASSO) regression models were deployed for feature selection and for constructing radiomic signatures. We developed nine models utilizing clinical factors, radiological features, and radiomics, leveraging logistic and XGboost methods. The performances of these models was subsequently compared using Receiver Operating Characteristic (ROC) analysis and the Delong test. Results: Out of the 243 participants with a median age of 70 years, 30 were diagnosed with csPCa, leaving 213 without a csPCa diagnosis. Prostate-specific antigen density (PSAD) stood out as the only significant clinical factor (odds ratio [OR], 1.068; 95% confidence interval [CI], 1.029-1.115), discovered through the univariate and multivariate logistic models. Seven radiomic features correlated with csPCa prediction. Notably, the XGboost model outperformed eight other models (AUC of the training cohort: 0.949, and validation cohort: 0.913). However, it did not surpass the PSAD+MADC model (P > 0.05) in the training and testing cohorts (AUC, 0.949 vs. 0.888 and 0.913 vs. 0.854, respectively). Conclusion: The machine learning XGboost model presented the best performance in predicting csPCa in PI-RADS 3 lesions within the transitional zone. However, the addition of radiomic classifiers did not display any significant enhancement over the compound model of clinical and radiological findings. The most exemplary and generalized option for quantitative prostate evaluation was Mean ADC+PSAD.

11.
Nat Cell Biol ; 25(7): 950-962, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37400498

RESUMEN

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.


Asunto(s)
Necroptosis , Receptores Tipo I de Factores de Necrosis Tumoral , Humanos , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Hidroxilación , Hipoxia , Prolina/metabolismo , Inflamación , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo
12.
Am J Pathol ; 178(4): 1881-90, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21435465

RESUMEN

Retinopathy of prematurity is a major side effect of oxygen therapy for preterm infants, and is a leading cause of blindness in children. To date, it remains unclear whether the initial microvascular obliteration is triggered by degradation of hypoxia inducible factor (HIF) α proteins or by other mechanisms such as oxidative stress. Here we show that prolyl hydroxylase domain protein 2 (PHD2), an enzyme mostly responsible for oxygen-induced degradation of HIF-α proteins, plays a major role in oxygen-induced retinopathy in mice. In neonatal mice expressing normal amounts of PHD2, exposure to 75% oxygen caused significant degradation of retinal HIF-α proteins, accompanied by massive losses of retinal microvessels. PHD2 deficiency significantly stabilized HIF-1α, and to some extent HIF-2α, in neonatal retinal tissues, and protected retinal microvessels from oxygen-induced obliteration. After hyperoxia-treated neonatal mice were returned to ambient room air, retinal vasculature in PHD2-deficient mice remained mostly intact and showed very little neoangiogenesis. These findings demonstrate a close association between PHD2-dependent HIF-α degradation and oxygen-induced retinal microvascular obliteration, and imply that PHD2 may be a promising therapeutic target to prevent oxygen-induced retinopathy.


Asunto(s)
Oxígeno/metabolismo , Procolágeno-Prolina Dioxigenasa/fisiología , Enfermedades de la Retina/metabolismo , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Hiperoxia/metabolismo , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Inmunohistoquímica/métodos , Ratones , Ratones Noqueados , Pericitos/metabolismo , Procolágeno-Prolina Dioxigenasa/metabolismo , Estructura Terciaria de Proteína , Vasos Retinianos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
13.
Front Immunol ; 13: 923647, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35711457

RESUMEN

Immunotherapy has become the breakthrough strategies for treatment of cancer in recent years. The application of messenger RNA in cancer immunotherapy is gaining tremendous popularity as mRNA can function as an effective vector for the delivery of therapeutic antibodies on immune targets. The high efficacy, decreased toxicity, rapid manufacturing and safe administration of mRNA vaccines have great advantages over conventional vaccines. The unprecedent success of mRNA vaccines against infection has proved its effectiveness. However, the instability and inefficient delivery of mRNA has cast a shadow on the wide application of this approach. In the past decades, modifications on mRNA structure and delivery methods have been made to solve these questions. This review summarizes recent advancements of mRNA vaccines in cancer immunotherapy and the existing challenges for its clinical application, providing insights on the future optimization of mRNA vaccines for the successful treatment of cancer.


Asunto(s)
Inmunoterapia , Neoplasias , Humanos , Neoplasias/terapia , ARN Mensajero , Vacunas Sintéticas , Vacunas de ARNm
14.
Invest Ophthalmol Vis Sci ; 63(9): 30, 2022 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-36036912

RESUMEN

Purpose: Tight junctions (TJs) form the structural basis of retinal pigment epithelium (RPE) barrier functions. Although oxidative stress contributes to age-related macular degeneration, it is unclear how RPE TJ integrity is controlled by redox balance. In this study, we investigated the protective roles of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor, and heme oxygenase-1 (HO1), a heme-degrading enzyme encoded by the NRF2 target gene HMOX1. Methods: ARPE19 cell cultures and mice, including wild-type, Nrf2-/-, and RPE-specific NRF2-deficient mice, were treated with chemicals that impose oxidative stress or impact heme metabolism. In addition, NRF2 and HO1 expression in ARPE19 cells was knocked down by siRNA. TJ integrity was examined by anti-zonula occludens-1 staining of cultured cells or flatmount RPE tissues from mice. RPE barrier functions were evaluated by transepithelium electrical resistance in ARPE19 cells and immunofluorescence staining for albumin or dextran in eye histological sections. Results: TJ structures and RPE barrier functions were compromised due to oxidant exposure and NRF2 deficiency but were rescued by HO1 inducer. Furthermore, treatment with HO1 inhibitor or heme precursor is destructive to TJ structures and RPE barrier properties. Interestingly, both NRF2 and HO1 were upregulated under oxidative stress, probably as an adaptive response to mitigate oxidant-inflicted damages. Conclusions: Our data indicate that the NRF2-HO1 axis protects TJ integrity and RPE barrier functions by driving heme degradation.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Epitelio Pigmentado de la Retina , Animales , Hemo/metabolismo , Hemo/farmacología , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Oxidantes/farmacología , Estrés Oxidativo/fisiología , Epitelio Pigmentado de la Retina/patología
15.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 42(5): 730-2, 744, 2011 Sep.
Artículo en Zh | MEDLINE | ID: mdl-22007508

RESUMEN

OBJECTIVE: To investigate the clinical features and perioperational managements of craniophayngiomas located in posterior fossa. METHODS: Nine patients with craniopharyngioma situated in posterior fossa were included in the study. The clinical manifestations, neuroimage features, operational treatment, and perioperational managments were retrospectively analyzed. RESULTS; All tumors associated with big or huge volume, arised from sellar/suprasellar region and extended into posterior fossa. Tumors showed cystic lesions in 2 cases and cystic-solid lesions in 7 cases. Headache was the most common symptoms (6/9), followed by cranial nerve deficit (4/9) and endocrine dysfunction(3/9). The supra- and infra-tentorial approaches were the optimal approaches for removal these tumors (7/9). Cranial nerves deficit was the most common complication in perioperative period. No perioperational death occured, most of the patients showed good recovery during the fellow-up period. CONCLUSION: Craniophayngiomas in posterior fossa shows different clinical manifestations, radiological features, surgical complications to the tumor in sellar/suprasellar region.


Asunto(s)
Craneofaringioma/diagnóstico , Neoplasias Infratentoriales/diagnóstico , Atención Perioperativa , Neoplasias Hipofisarias/diagnóstico , Adolescente , Adulto , Niño , Craneofaringioma/cirugía , Femenino , Humanos , Neoplasias Infratentoriales/cirugía , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/cirugía , Adulto Joven
16.
Pathol Res Pract ; 216(4): 152848, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32051106

RESUMEN

Piwi-interacting RNAs (piRNAs) dysregulation occurs frequently in extensive cancers. However, there was no report about piRNA expression in esophageal cancer (EC). In this study, the expression levels of piR-823 and DNMT1, DNMT3A, DNMT3B were detected in 54 pairs of ESCC tissues and adjacent normal tissues using the quantitative real-time polymerase chain reaction method. Pearson's chi-squared test and receiver operating characteristic curves were established to evaluate the diagnostic and prognostic value of piR-823 in ESCC. Spearman's correlation analysis was used to evaluate the association between piR-823 and DNMTs. We found that piR-823 was significantly upregulated in ESCC tissues compared with matched normal tissues (P = 0.0213), the level of piR-823 was significantly associated with lymph node metastasis (P = 0.042). The ROC curve analysis of piR-823 expression level yielded an area under the ROC curve value of 0.713 (P = 0.0001). DNMT3B was upregulated in ESCC tissues compared with matched normal tissues (P = 0.0286). There was an obvious positive correlation between piR-823 and DNMT3B expression (r = 0.6420, P < 0.0001). In conclusion, for the first time, we provided evidence about piRNA expression in EC. piRNA-823 and DNMT3B were both upregulated in ESCC and positively correlated with each other, suggesting the tumor oncogenic role of piR-823 in ESCC to epigenetically induce aberrant DNA methylation through DNMT3B. In addition, piRNA-823 showed high specificity in detecting ESCC and higher piRNA-823 level indicated higher risk of lymph node metastasis, suggesting its diagnostic and prognostic biomarker potential.


Asunto(s)
Biomarcadores de Tumor/genética , ADN (Citosina-5-)-Metiltransferasas/biosíntesis , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica/genética , ARN Interferente Pequeño/metabolismo , Adulto , Anciano , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Interferente Pequeño/genética , ADN Metiltransferasa 3B
17.
Mol Cell Biol ; 26(22): 8336-46, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16966370

RESUMEN

PHD1, PHD2, and PHD3 are prolyl hydroxylase domain proteins that regulate the stability of hypoxia-inducible factor alpha subunits (HIF-alpha). To determine the roles of individual PHDs during mouse development, we disrupted all three Phd genes and found that Phd2(-/-) embryos died between embryonic days 12.5 and 14.5 whereas Phd1(-/-) or Phd3(-/-) mice were apparently normal. In Phd2(-/-) mice, severe placental and heart defects preceded embryonic death. Placental defects included significantly reduced labyrinthine branching morphogenesis, widespread penetration of the labyrinth by spongiotrophoblasts, and abnormal distribution of trophoblast giant cells. The expression of several trophoblast markers was also altered, including an increase in the spongiotrophoblast marker Mash2 and decreases in the labyrinthine markers Tfeb and Gcm1. In the heart, trabeculae were poorly developed, the myocardium was remarkably thinner, and interventricular septum was incompletely formed. Surprisingly, while there were significant global increases in HIF-alpha protein levels in the placenta and the embryo proper, there was no specific HIF-alpha increase in the heart. Taken together, these data indicate that among all three PHD proteins, PHD2 is uniquely essential during mouse embryogenesis.


Asunto(s)
Sistema Cardiovascular/embriología , Cardiopatías Congénitas/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Placenta/patología , Procolágeno-Prolina Dioxigenasa/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipoxia de la Célula , Marcación de Gen , Células Gigantes/patología , Cardiopatías Congénitas/inducido químicamente , Cardiopatías Congénitas/embriología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placenta/embriología , Placenta/metabolismo , Procolágeno-Prolina Dioxigenasa/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
18.
Oncol Lett ; 18(2): 1267-1277, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31423187

RESUMEN

Metabolic gene variants, smoking, and alcohol consumption are important upper digestive tract cancer (UDTC) risk factors. However, the gene-gene and gene-environment interactions remain unclear. A case-control study in a high incidence area for upper digestive tract cancer was conducted in China. DNA was extracted from buffy coat samples for PCR or PCR-restriction fragment length polymorphism. Smoking and alcohol drinking status was determined by questionnaires. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the associations. After adjusting for confounding factors, smoking increased esophageal cancer (EC), gastric cardia cancer (GCC) and gastric antral carcinoma (GAC) risk by 3.594, 4.658, and 3.999-fold, respectively. Alcohol consumption increased EC, GCC and GAC risk by 1.953, 2.442 and 1.765-fold, respectively. The cytochrome P4501A1 (CYP1A1) rs4646903 T>C polymorphism increased GCC risk, the cytochrome P4502E1 (CYP2E1) rs2031920 C>T polymorphism increased EC risk, while the GSTM1 null genotype decreased EC risk. An association existed between the following: CYP1A1 rs4646903 and smoking in EC, GCC and GAC; CYP1A1 rs4646903 and alcohol consumption in EC and GCC; CYP2E1 rs2031920 and smoking in EC, GCC and GAC and CYP2E1 rs2031920 and alcohol consumption in EC and GCC. No association was observed between CYP1A1 and CYP2E1. The glutathione S-transferase mu 1 (GSTM1) null genotype decreased EC risk (OR=0.510). Smoking/drinking are upper digestive tract cancer risk factors. The CYP1A1 rs4646903 and CYP2E1 rs2031920 polymorphisms were risk factors of GCC or EC, and the GSTM1 null genotype may serve a protective role against EC. The results of the present study indicated that gene-environment interactions increase the risk of UDTC.

19.
Medicine (Baltimore) ; 98(8): e14454, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30813145

RESUMEN

BACKGROUND: Our previous studies demonstrate that the major histocompatibility complex (MHC) is associated with the progression of esophageal squamous cell carcinoma (ESCC). HLA-DQA1, which belongs to the MHC Class II family, may be a potential biomarker in ESCC progression. However, the association between HLA-DQA1 and ESCC in high-incidence area of northern China has not been well characterized. The purpose of this study is to investigate the relationship of HLA-DQA1 expression with the progression and prognosis of ESCC. METHODS: We analyzed the expression profiles of HLA-DQA1 in esophageal cancer (EC) samples in the TCGA database and validated HLA-DQA1 expression by immunohistochemistry, western blotting, and quantitative reverse-transcription polymerase chain reaction in matched EC and normal tissues, respectively. The correlation between HLA-DQA1 expression and clinicopathologic characteristics of ESCC was further analyzed. RESULT: Immunohistochemical analysis indicated that the expression level of HLA-DQA1 in ESCC tissues was significantly higher than the matched normal tissues (P < .001). HLA-DQA1 mRNA and protein expression were significantly higher in ESCC tissues compared to the matched normal tissues. Patients with family history negative or with tumor sizes >4 cm were associated with higher HLA-DQA1 expression levels. A prognostic significance of HLA-DQA1 was also found by the Log-rank method, in which high expression of HLA-DQA1 was correlated with a shorter overall survival time. The receiver operating characteristic (ROC) curve analysis yielded the area under the ROC curve value of 0.693. Univariate and multivariate analyses also suggest that high expression of HLA-DQA1 is a potential indicator for poor prognosis of ESCC. CONCLUSIONS: Our results demonstrate that HLA-DQA1 plays an important role in ESCC progression and may be a biomarker for ESCC diagnosis and prognosis, as well as a potential target for the treatment of patients with ESCC.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Cadenas alfa de HLA-DQ/metabolismo , Anciano , Western Blotting , China , Bases de Datos Factuales , Progresión de la Enfermedad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Tasa de Supervivencia
20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(4): 1005-1010, 2018 Aug.
Artículo en Zh | MEDLINE | ID: mdl-30111398

RESUMEN

OBJECTIVE: To investigate the clinical characteristics and clinical prognostic factors of patients with acute lymphoblastic leukemia (ALL). METHODS: Ninety-six ALL patients in our hospital from June 2012 to August 2014 were selected and their clinical data were collected. The related clinical data of patients were recorded, and the relation between clinical characteristics and therapeutic efficacy was analyzed. The COX analysis was used to reveal the risk factors affecting the patient's OS and DFS time. RESULTS: Among 96 ALL patients, 65 patients achieved complete remission (CR) after treatment. The age, immunophenotype, central nervous system leukemia (CNSL) and peripheral blood WBC count correlated with complete remission (P<0.05). The age, WBC count, platelet level, immune typing and consolidation therapy were the prognostic factors (P<0.05), the 2 year OS rate was influenced by age, WBC count, CD34 and consolidation therapy (P<0.05), the 2 year DFS rate was influenced by age, CD34 and consolidation therapy (P<0.05). CONCLUSION: Age, WBC counts, CD34 and consolidated treatment after remission are prognostic factors for ALL patients, which has guiding significance for clinical treatment of ALL.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Enfermedad Aguda , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Nervioso Central , Humanos , Pronóstico , Inducción de Remisión
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