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The rational design of multifunctional biomaterials with hierarchical porous structure and on-demand biological activity is of great consequence for bone tissue engineering (BTE) in the contemporary world. The advanced combination of trace element cerium ions (Ce3+) with bone repair materials makes the composite material capable of promoting angiogenesis and enhancing osteoblast activity. Herein, a living and phosphorylated injectable porous hydrogel microsphere (P-GelMA-Ce@BMSCs) is constructed by microfluidic technology and coordination reaction with metal ion ligands while loaded with exogenous BMSCs. Exogenous stem cells can adhere to and proliferate on hydrogel microspheres, thus promoting cell-extracellular matrix (ECM) and cell-cell interactions. The active ingredient Ce3+ promotes the proliferation, osteogenic differentiation of rat BMSCs, and angiogenesis of endotheliocytes by promoting mineral deposition, osteogenic gene expression, and VEGF secretion. The enhancement of osteogenesis and improvement of angiogenesis of the P-GelMA-Ce scaffold is mainly associated with the activation of the Wnt/ß-catenin pathway. This study could provide novel and meaningful insights for treating bone defects with biofunctional materials on the basis of metal ions.
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This study aimed to identify neural biomarkers for schizophrenia (SZ) and bipolar disorder (BP) by analyzing multimodal neuroimaging. Utilizing data from structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI), multiclass classification models were created for SZ, BP, and healthy controls (HC). A total of 113 participants (BP: 31, SZ: 39, and HC: 43) were recruited under strict enrollment control, from which 272, 200, and 1875 features were extracted from sMRI, DTI, and rs-fMRI data, respectively. A support vector machine (SVM) with recursive feature elimination (RFE) was employed to build the models using a one-against-one approach and leave-one-out cross-validation, achieving a classification accuracy of 70.8%. The most discriminative features were primarily from rs-fMRI, along with significant findings in sMRI and DTI. Key biomarkers identified included the increased thickness of the left cuneus cortex and decreased regional functional connectivity strength (rFCS) in the left supramarginal gyrus as shared indicators for BP and SZ. Additionally, decreased fractional anisotropy in the left superior fronto-occipital fasciculus was suggested as specific to BP, while decreased rFCS in the left inferior parietal area might serve as a specific biomarker for SZ. These findings underscore the potential of multimodal neuroimaging in distinguishing between BP and SZ and contribute to the understanding of their neural underpinnings.
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Trastorno Bipolar , Esquizofrenia , Humanos , Imagen de Difusión Tensora , Neuroimagen , Imagen por Resonancia Magnética/métodos , Biomarcadores , EncéfaloRESUMEN
The periosteum plays a vital role in the regeneration of critical-size bone defects and highly comminuted fractures, promoting the differentiation of osteoblasts, accelerating the reconstruction of the vascular network, and guiding bone tissue regeneration. However, the materials loaded with exogenous growth factors are limited by the release and activity of the elements. Therefore, the material structure must be carefully designed for the periosteal function. Here, a self-adaptive biomimetic periosteum strategy is proposed, which is a novel interpenetrating double network hydrogel consisting of diselenide-containing gelatin and calcium alginate (modified natural collagen and polysaccharide) to enhance the stability, anti-swelling, and delayed degradation of the hydrogel. The diselenide bond continuously releases nitric oxide (NO) by metabolizing endogenous nitrosated thiols (RSNO), activates the nitric oxide-cycle guanosine monophosphate (NO-cGMP) signal pathway, coordinates the coupling effect of angiogenesis and osteogenesis, and accelerates the repair of bone defects. This self-adaptive biomimetic periosteum with the interpenetrating double network structure formed by the diselenide-containing gelatin and calcium alginate has been proven to be safe and effective in repairing critical-size bone defects and is expected to provide a promising strategy for solving clinical problems.
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Óxido Nítrico , Periostio , Periostio/química , Óxido Nítrico/análisis , Gelatina/farmacología , Gelatina/química , Biomimética , Angiogénesis , Regeneración Ósea , Osteogénesis , Alginatos , Hidrogeles/química , Andamios del Tejido/química , Ingeniería de TejidosRESUMEN
Full-range therapeutic regimens for osteoarthritis (OA) should consider organs (joints)-tissues (cartilage)-cells (chondrocytes)-organelles cascade, of which the subcellular mitochondria dominate eukaryotic cells' fate, and thus causally influence OA progression. However, the dynamic regulation of mitochondrial rise and demise in impaired chondrocytes and the exact role of mitochondrial metronome sirtuins 3 (SIRT3) is not clarified. Herein, chondrocytes are treated with SIRT3 natural agonist dihydromyricetin (DMY) or chemical antagonist 3-TYP, respectively, to demonstrate the positive action of SIRT3 on preserving cartilage extracellular matrix (ECM). Molecular mechanical investigations disclose that SIRT3-induced chondroprotection depended on the repression of mitochondrial apoptosis (mtApoptosis) and the activation of mitophagy. Inspired by the high-level matrix proteinases and reactive oxygen species (ROS) in the OA environment, by anchoring gelatin methacrylate (GelMA) and benzenediboronic acid (PBA) to hyaluronic acid methacrylate (HAMA) with microfluidic technology, a dual-responsive hydrogel microsphere laden with DMY is tactfully fabricated and named as DMY@HAMA-GelMA-PBA (DMY@HGP). In vivo injection of DMY@HGP ameliorated cartilage abrasion and subchondral bone sclerosis, as well as promoted motor function recovery in post-traumatic OA (PTOA) model via recouping endogenous mtApoptosis and mitophagy balance. Overall, this study unveils a novel mitochondrial dynamic-oriented strategy, holding great promise for the precision treatment of OA.
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Osteoartritis , Sirtuina 3 , Humanos , Mitofagia/fisiología , Sirtuina 3/metabolismo , Sirtuina 3/uso terapéutico , Hidrogeles/uso terapéutico , Microesferas , Osteoartritis/tratamiento farmacológico , Condrocitos/metabolismo , Mitocondrias , Apoptosis , Ácido Hialurónico/metabolismo , Metacrilatos/químicaRESUMEN
Duodenal ulcer significantly reduces quality of life and safety in children; however, the mechanism of the pathogenesis in children with duodenal ulcer remains unclear. S100A8/A9, which plays a critical role in the occurrence and development of inflammation, has attracted a lot of interest recently. Here, we identified that S100A8/A9 are highly expressed in the serum of children with duodenal ulcers, and this is of excellent diagnostic value. Animal experiments have proved that inhibition of S100A8/A9 can repair ulcer progression. In addition, further study has shown that S100A8/A9, mainly produced by neutrophil, can enhance the apoptosis of intestinal epithelial cells and promote the growth in children with duodenal ulcers. Thus, our research proves the value of S100A8/A9 in the diagnosis and treatment of children with duodenal ulcers.
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Úlcera Duodenal , Neutrófilos , Animales , Calgranulina B , Calidad de Vida , Calgranulina A , Células Epiteliales , ApoptosisRESUMEN
Congenital heart disease (CHD) is a malformation present from birth caused by the abnormal development of the heart and large blood vessels during the prenatal development. The TGF-ß activated kinase 1 (MAP3K7) binding protein 2 (TAB2) gene plays an important role in the embryonic development of heart tissue. When haploid dosage is insufficient, it can lead to CHD or cardiomyopathy. The present study reported a case study of a Chinese child with growth restriction and CHD. The results of whole exome sequencing suggested that a novel frameshift mutation (c.1056delC/p.Ser353fsTer8) occurred in TAB2. The parents of this patient are wild-type at this locus; therefore, it may be a de novo mutation. The mutant plasmid was constructed in vitro, and the western blotting results showed that the mutation may cease protein expression. This indicated the pathogenic harmfulness of this mutation. In conclusion, the present study emphasizes that TAB2 defects should be investigated in patients with unexplained short stature and CHD, irrespective of family history regarding CHD or cardiomyopathy. The current study provided new data on the mutation spectrum and provided information for second pregnancies and genetic counseling of the parents of patients.
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Mitochondrial homeostasis is of great importance for cartilage integrity and associated with the progression of osteoarthritis (OA); however, the underlying mechanisms are unknown. This study aims to investigate the role of mitochondrial deacetylation reaction and investigate the mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation with the severity of OA in both human arthritic cartilage and mice inflammatory chondrocytes. Global SIRT3 deletion accelerates pathological phenotype in post-traumatic OA mice, as evidenced by cartilage extracellular matrix collapse, osteophyte formation, and synovial macrophage M1 polarization. Mechanistically, SIRT3 prevents OA progression by targeting and deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2) to maintain mitochondrial homeostasis at the post-translational level. The activation of SIRT3 by honokiol restores cartilage metabolic equilibrium and protects mice from the development of post-traumatic OA. Collectively, the loss of mitochondrial SIRT3 is essential for the development of OA, whereas SIRT3-mediated proteins deacetylation of COX4I2 rescues OA-impaired mitochondrial respiratory chain functions to improve the OA phenotype. Herein, the induction of SIRT3 provides a novel therapeutic candidate for OA treatment.
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Osteoartritis , Sirtuina 3 , Humanos , Ratones , Animales , Sirtuina 3/genética , Sirtuina 3/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Oxidorreductasas/metabolismo , Transporte de Electrón , Osteoartritis/metabolismoRESUMEN
OBJECTIVE: This study investigated the factors associated with the high susceptibility of perimenopausal women to depression. METHODS: A total of 66 perimenopausal women participated in this study. The Zung self-rating depression scale (SDS) was used to evaluate the intensity of depressive symptoms. The modified Kupperman index (KI) was used to assess common perimenopausal symptoms. Psychosocial factors were assessed via the Eysenck Personality Questionnaire, attitudes toward menopause checklist, and metacognition questionnaire (MCQ). Levels of serum estradiol, testosterone, and progesterone were determined. RESULTS: There were statistically significant associations between SDS standard score and the KI scale score (ß = .361, p = .001), years of education (ß = -.309, p = .005), and F3 cognitive self-consciousness score of MCQ (ß = -.234, p = .032; adjusted R2 = .264, F = 8.759, p < .001). CONCLUSIONS: High susceptibility to depression of perimenopausal women may be related to lower educational level, more severe perimenopausal symptoms, and altered metacognition.
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Perimenopausia , Testosterona , Femenino , Humanos , Perimenopausia/psicología , Encuestas y CuestionariosRESUMEN
Long non-coding RNAs (lncRNAs) can potentially regulate all aspects of cellular activity including differentiation and development, metabolism, proliferation, apoptosis, and activation, and benefited from advances in transcriptomic and genomic research techniques and database management technologies, its functions and mechanisms in physiological and pathological states have been widely reported. Liver fibrosis is typically characterized by a reversible wound healing response, often accompanied by an excessive accumulation of extracellular matrix. In recent years, a range of lncRNAs have been investigated and found to be involved in several cellular-level regulatory processes as competing endogenous RNAs (ceRNAs) that play an important role in the development of liver fibrosis. A variety of lncRNAs have also been shown to contribute to the altered cell cycle, proliferation profile associated with the accelerated development of liver fibrosis. This review aims to discuss the functions and mechanisms of lncRNAs in the development and regression of liver fibrosis, to explore the major lncRNAs involved in the signaling pathways regulating liver fibrosis, to elucidate the mechanisms mediated by lncRNA dysregulation and to provide new diagnostic and therapeutic strategies for liver fibrosis.
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BACKGROUND: Schizophrenia (SZ) and bipolar disorder with psychosis (BDP) can be clinically confusing. The specific connectomic changes in SZ compared with BDP may lead to a deeper comprehension of the pathophysiological core of SZ. Therefore, this study explored the common and distinct white matter (WM) structural connectomic alterations between these two diseases. METHOD: Diffusion tensor imaging data were collected from 19 drug-naïve patients with first episode SZ, 19 drug-naïve patients with BDP, and 19 healthy controls (HC). A graph theoretical approach was used to assess the brain WM network properties. RESULTS: Except for the clustering coefficients, no significant differences in the global parameters was found between SZ and BDP. Five brain regions, the right precentral, right post-cingulum, right insula, left superior occipital, and left inferior temporal gyri, showed specific differences in the nodal parameters in SZ compared with BDP and HC. Nine brain regions, the left rectus, left lingual, right inferior parietal, left superior temporal, right precentral, right postcentral, bilateral middle frontal, and right post-cingulum gyri, showed specific differences in the nodal parameters in BDP. Significant correlations between clinical symptoms and connectomic changes were detected in the right insula and left superior occipital gyrus in patients with SZ but in the left lingual gyrus in patients with BDP. CONCLUSIONS: Identifying shared and distinct WM structural networks between SZ and BDP may improve the understanding of the neuroanatomy of mental diseases. Specifically, the insula, the inferior temporal, superior temporal, and the lingual gyri may help to distinguish between SZ and BDP.
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Trastorno Bipolar , Conectoma , Trastornos Psicóticos , Esquizofrenia , Sustancia Blanca , Trastorno Bipolar/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Imagen de Difusión Tensora , Humanos , Imagen por Resonancia Magnética , Esquizofrenia/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagenRESUMEN
OBJECTIVE: To investigate the association between gene polymorphism of vesicular monoamine transporter type 2(VMAT2) and schizophrenia in Han Chinese population. METHODS: 430 patients with schizophrenia and 470 age-sex matched controls were recruited from four mental health centers. All patients were diagnosed by two psychiatrists based on the Structured Clinical Interview for DSM Disorders (SCID). The ligase detection reactions (LDR) method was used to assess the polymorphism of the two SNPs (rs363371 and rs363324) of VMAT2. RESULTS: No associations of two SNPs with schizophrenia was found. When we stratified males and females for the analysis, we found that that in the recessive model of rs363371, there was an obvious significant association between rs363371 and schizophrenia in males (OR=0.564, 95% CI=0.357-0.892, p=0.014) but not females. For the association between rs363324 and schizophrenia, no association was found in either males or females. No association was found when stratifying early-onset schizophrenia and late-onset schizophrenia. CONCLUSION: Our findings indicate that both rs363371 and rs363324 were not associated with schizophrenia, while it seemed that the AA genotype of rs363371 plays a protective effect in male Chinese in developing schizophrenia.
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OBJECTIVES: To evaluate the efficacy of immuno-oncology combinational therapy (IOCT) versus monotherapy with programmed cell death 1 (PD-1) or PD-ligand 1 (PD-L1) inhibitors or conventional therapies, i.e., non-IOCT, in patients with advanced solid tumors. METHODS: We systematically searched the PubMed, Embase, and Cochrane Library databases from January 2015 to October 2018 for eligible studies. We included randomized trials of IOCT with available hazard ratios (HR) for death. The random effects model was used to calculate pooled HR for death; heterogeneity was assessed using I 2 statistics. The main outcome measure was overall survival (OS). RESULTS: After screening 483 relevant articles, we identified twelve trials comprising 5388 patients for quantitative analysis. IOCT-treated patients had significantly higher tumor response rate (relative risk (RR): 2.51, 95% confidence interval (CI): 1.82-3.47), prolonged progression-free survival (HR 0.62, 95% CI: 0.53-0.74), and OS (HR 0.69, 95% CI: 0.61-0.78), compared with non-IOCT-treated patients. Sensitivity analyses also demonstrated the OS advantage of IOCT across different combination modalities, intervention agents, malignancy types, and PD-L1 expression (all P < 0.05). Notably, there were higher odds of high-grade (grade ≥ 3) adverse events with IOCT (RR: 1.81, 95% CI: 1.13-2.90), but the risk of treatment-related death (RR: 1.16, 95% CI: 0.84-1.60) was not increased compared with non-IOCT. CONCLUSIONS: IOCT is a preferable treatment option over PD-1/PD-L1 inhibitor monotherapy and conventional therapy for patients with advanced solid tumors. However, we should note the increased incidence rate of high-grade AEs in IOCT.
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Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Cognitive impairment is one of the core symptoms of schizophrenia, and patients with schizophrenia are at increased risk of metabolic syndrome (MS). However, the role of MS in cognitive impairment of schizophrenia is not established. This study investigated the correlation between neurocognitive, social cognitive performance and MS with schizophrenia. One hundred and fifty eight (158) schizophrenia patients were divided into 3 groups with â normal metabolism, â¡ metabolic disorder (only meeting 1 or 2 MS criteria), and ⢠metabolic syndrome (meeting 3 or more MS criteria). MATRICS Consensus Cognitive Battery)MCCB(and the Brief Psychiatric Rating Scale)BPRS(were used to evaluate cognitive performance and clinical symptoms. Blood samples were obtained to detect glucose and lipid metabolic levels. Overall MCCB and subscale T scores in the normal metabolism and metabolic disorder groups were better than in the MS group. After controlling for the confounding factors including age, sex, the usage of hypolipidemic and hypoglycemic drugs, and disease duration, metabolic deficits had effects on the symbol coding and spatial span scores. The results suggest that a defective metabolic state might play a role in neurocognitive performance of schizophrenia patients.
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Síndrome Metabólico/epidemiología , Síndrome Metabólico/psicología , Trastornos Neurocognitivos/epidemiología , Trastornos Neurocognitivos/psicología , Esquizofrenia/epidemiología , Psicología del Esquizofrénico , Adolescente , Adulto , Escalas de Valoración Psiquiátrica Breve , Estudios Transversales , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Síndrome Metabólico/terapia , Persona de Mediana Edad , Trastornos Neurocognitivos/terapia , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Esquizofrenia/terapia , Conducta Social , Adulto JovenRESUMEN
Fingerprints remain topologically unchanged in one's whole life, and therefore, have been used as a means to biometrically identify individuals in forensic investigations, law enforcement and access control. Appropriate methods are essential to obtain high-quality fingerprint images. In this contribution, an aggregation-induced emission luminogen tetraphenylethene-based dye FLA-2 was synthesized and characterized for the visualization of latent fingerprints (LFPs). LFPs can be directly visualized by incubating with the dye FLA-2 solution. And, after a cyanoacrylate fuming method pre-treatment stage, fine fingerprint structures can be obtained from level-1 to level-3 details. Two methods were compared using resolution, fluorescence intensity, and scanning electron microscopy imaging to investigate the influence of the cyanoacrylate fuming method pre-treatment stage. Furthermore, the visualization of old LFPs (7 d, 16 d and 30 d) on glass slides, aluminum foil and coin substrates also became effective after the pre-treatment step. The fluorescent LFP images mentioned above were all validated by using an automated fingerprint identification system obtaining positive matches. These results demonstrate the potential of this method to be applied to visualizing LFPs in the field of public security.
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Antipsicóticos/efectos adversos , Clozapina/efectos adversos , Diabetes Mellitus , Síndrome Metabólico , Esquizofrenia/tratamiento farmacológico , Adolescente , Adulto , Diabetes Mellitus/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/epidemiología , Síndrome Metabólico/genética , Persona de Mediana Edad , Padres , Esquizofrenia/epidemiología , Adulto JovenRESUMEN
Previous studies have revealed that expression of allograft inflammatory factor-1 (AIF-1) protein appears to be increased in malignancies and is correlated with a poorer prognosis in cervical cancer, while its role in gastric cancer has not been reported. We analyzed the expression of AIF-1 in 78 cancer lesions and the corresponding non-cancerous tissues by immunohistochemistry. In contrast with other cancers, we found that AIF-1 protein levels were significantly decreased in 53 of the 78 (67.9%) gastric cancer tissues when compared with the matched normal tissues. This was further confirmed using 7 pairs of fresh gastric cancer tissues and matched adjacent normal tissues. Low tumoral AIF-1 expression was significantly correlated with less favorable clinicopathological characteristics, as well as with reduced overall survival (P<0.001) in the gastric cancer patients. Furthermore, knockdown of AIF-1 obviously increased proliferation, migration and ß-catenin expression in BGC-823 and SGC-7901 gastric cancer cells. Taken together, for the first time, we provide evidence that the level of AIF-1 expression may serve as a protective prognostic indicator for gastric cancer.
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Proteínas de Unión al ADN/genética , Neoplasias Gástricas/genética , Proteínas Supresoras de Tumor/genética , beta Catenina/biosíntesis , Anciano , Biomarcadores de Tumor , Proteínas de Unión al Calcio , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Masculino , Proteínas de Microfilamentos , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño , Neoplasias Gástricas/mortalidad , SobrevidaRESUMEN
JWA, a multifunctional microtubule-binding protein, plays an important role in regulating tumor metastasis via inhibition of matrix metalloproteinase-2 (MMP-2). Recent investigations suggest that MMP-2 is an angiogenesis-associated molecule. In this study, we provide novel evidence that JWA inhibits tumor angiogenesis in gastric cancer (GC). In two independent retrospective GC cohorts, we found that the expression of JWA was downregulated and that of MMP-2 was upregulated in GC tissues compared with the same in normal gastric mucosa. For patients treated with surgery alone, a strong and independent negative prognostic value was shown for low JWA and high MMP-2 expressions separately, which was even stronger when combined (hazard ratio = 7.75, P < 0.001, in the training cohort; hazard ratio = 2.31, P < 0.001, in the validation cohort). Moreover, we found that loss of JWA expression was strongly correlated with increased GC angiogenesis. In vitro, JWA inhibited MMP-2 at both messenger RNA and protein levels by modulating Sp1 activity. Knockdown of endogenous JWA resulted in enhanced human umbilical vein endothelial cell tube formation and MMP-2 expression. Furthermore, JWA was found to inhibit Sp1 activity via an ubiquitin-proteasome-dependent mechanism and to downregulate the expression of the proangiogenic MMP-2. Our findings imply that JWA and MMP-2 may serve as promising prognostic markers in resectable GC, with JWA as a useful biomarker of angiogenesis in GC and a potential therapeutic target by MMP-2 modulation.
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Proteínas de Choque Térmico/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Neovascularización Patológica/prevención & control , Factor de Transcripción Sp1/metabolismo , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/patología , Anciano , Animales , Apoptosis , Western Blotting , Movimiento Celular , Proliferación Celular , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/metabolismo , Membrana Corioalantoides/patología , Ensayo de Cambio de Movilidad Electroforética , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/genética , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Técnicas para Inmunoenzimas , Inmunoprecipitación , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Metaloproteinasa 2 de la Matriz/genética , Proteínas de Transporte de Membrana , Ratones Endogámicos BALB C , Ratones Desnudos , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción Sp1/genética , Neoplasias Gástricas/metabolismoRESUMEN
BACKGROUND: The multifunctional protein JWA was previously identified as a novel regulator of focal adhesion kinase (FAK/PTK2) in suppressing cancer cell adhesion, invasion and metastasis. JWA is downregulated in gastric cancer (GC) and a prognostic and predictive biomarker for resectable GC. However, the value of FAK combined with JWA for GC patients as a biomarker has not been studied. Here we evaluated the roles of FAK alone and combined with JWA in GC patients treated with surgery alone or combined with adjuvant platinum-based chemotherapy. METHODS: Two tissue microarrays were constructed of specimens from resected GC (n = 709 in total) for detection of FAK and JWA expression by immunohistochemistry. Correlations between both proteins and clinicopathological features as well as prognostic and predictive values were evaluated. RESULTS: Compared with adjacent non-cancerous tissues, FAK protein levels were remarkably up-regulated in GC lesions (P < 0.001). High FAK alone or combined with low JWA expression significantly correlated with worse overall survival (OS) (both P < 0.001 in two cohorts). Simultaneously, JWA plus FAK expression was a more valuable prognostic biomarker than JWA or FAK alone. Moreover, the patients with high FAK only or combined with low JWA had significant benefit from adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) therapy compared with those with surgery alone (P = 0.003); however, the cases with adjuvant fluorouracil-leucovorin-cisplatin (FLP) therapy did not show these effects. CONCLUSION: FAK plus JWA may serve as a more prognostic and predictive biomarker for GC than each separately with a potential clinical application.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Quinasa 2 de Adhesión Focal/metabolismo , Proteínas de Choque Térmico/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Anciano , Quimioterapia Adyuvante , Femenino , Fluorouracilo/administración & dosificación , Gastrectomía , Humanos , Leucovorina/administración & dosificación , Masculino , Proteínas de Transporte de Membrana , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugíaRESUMEN
Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.
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Biomarcadores de Tumor/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Neoplasias Gástricas/metabolismo , Anciano , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Quimioterapia Adyuvante/métodos , Estudios de Cohortes , Femenino , Fluorouracilo/farmacología , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Leucovorina/farmacología , Masculino , Proteínas de Transporte de Membrana , Compuestos Organoplatinos/farmacología , Oxaliplatino , Pronóstico , Proteínas Proto-Oncogénicas c-mdm2/genética , Estudios Retrospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Resultado del Tratamiento , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). METHODS: The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. RESULTS: CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis. CONCLUSIONS: Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.