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BACKGROUND: Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of hereditary diseases caused by the gradual degeneration of the lower motor neuron. More than 30 genes associated with dHMN have been reported, while 70-80% of those with the condition are still unable to receive a genetic diagnosis. METHODS: A 26-year-old man experiencing gradual weakness in his lower limbs was referred to our hospital, and data on clinical features, laboratory tests, and electrophysiological tests were collected. To identify the disease-causing mutation, we conducted whole exome sequencing (WES) and then validated it through Sanger sequencing for the proband and his parents. Silico analysis was performed to predict the pathogenesis of the identified mutations. A literature review of all reported mutations of the related gene for the disease was performed. RESULTS: The patient presented with dHMN phenotype harboring a novel homozygous variant c.361G > C (p.Ala121Pro) in SORD, inherited from his parents, respectively. A121 is a highly conserved site and the mutation was categorized as "likely pathogenic" according to the criteria and guidelines of the American College of Medical Genetics and Genomics (ACMG). A total of 13 published articles including 101 patients reported 18 SORD variants. Almost all described cases have the homozygous deletion variant c.757delG (p.A253Qfs*27) or compound heterozygous state of a combination of c.757delG (p.A253Qfs*27) with another variant. The variant c.361G > C (p.Ala121Pro) detected in our patient was the second homozygous variant in SORD-associated hereditary neuropathy. CONCLUSION: One novel homozygous variant c.361G > C (p.Ala121Pro) in SORD was identified in a Chinese patient with dHMN phenotype, which expands the mutation spectrum of SORD-associated hereditary neuropathy and underscores the significance of screening for SORD variants in patients with undiagnosed hereditary neuropathy patients.
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Mutación , Humanos , Masculino , Adulto , Secuenciación del Exoma , Neuropatía Hereditaria Motora y Sensorial/genética , Linaje , FenotipoRESUMEN
Natural rubber (NR) exhibits good elasticity, flexural resistance, wear resistance, and excellent mechanical properties, and it has been widely used in aerospace, transportation, medical, and health fields. For NR, however, the resistance to thermal-oxidation and ozone aging is fairly poor. Although aging properties of NR can be significantly improved with the incorporation of chloroprene rubber (CR) according to some references, the miscibility between NR and CR, the morphologies of the binary blends, and so on are revealed ambiguously. In this work, molecular dynamics simulation (MD) and dissipative particle dynamics (DPD) simulation were carried out to predict the compatibility between natural rubber and chloroprene rubber in view of Flory-Huggins parameters. The morphologies of the blends were obtained with the use of the DPD method. The simulation results were furtherly examined by means of Fourier transform infrared spectroscopy (FT-IR) and dynamic mechanical analysis (DMA). It was found that the miscibility between NR and CR is poor. Nevertheless, the miscibility could be improved when the content of CR is 50% or 90%. In addition, spinodal decomposition with a critical temperature of 390 K would take place according to the phase diagram. Microphase structure such as spherical, lamellar, and bicontinuous phases can be found with different contents of CR in the blends with the results of morphologies analysis.
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The role and mechanism of insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) in the metastasis of esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, IGF2BP3 mRNA and protein expression levels were evaluated in ESCC tissues. Small interfering RNAs (siRNAs), plasmid overexpression, and stable lentivirus transfection were used to manipulate intracellular IGF2BP3 expression levels. The role of IGF2BP3 in ESCC tumorigenesis was investigated in vitro and in vivo. IGF2BP3 target transcripts were detected, and the acetylation effect ratios of the IGF2BP3 promoter region by H3K27ac were determined. IGF2BP3 mRNA expression levels were significantly higher in ESCC tissues than in normal esophageal tissues. Increased IGF2BP3 expression levels were detected in node-negative ESCC tissues and correlated with greater lesion depth in ESCC. Overexpression of IGF2BP3 promoted ESCC development in vitro and in vivo, and IGF2BP3 knockdown caused an opposite effect. IGF2BP3 was found to directly bind to the zinc finger E-box-binding homeobox 1 (Zeb1) mRNA, and the downregulation of IGF2BP3 reduced the stability of Zeb1 mRNA. IGF2BP3 induced epithelial-mesenchymal transition in ESCC cells in a Zeb1-dependent manner. IGF2BP3 was transcriptionally activated in ESCC cell lines via H3K27 acetylation. Our results demonstrate that IGF2BP3 plays a vital role in ESCC cell proliferation, invasion, and metastasis and is a potential therapeutic target for treating ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Somatomedinas , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas/metabolismo , Transición Epitelial-Mesenquimal/genética , ARN Mensajero/genética , Línea Celular Tumoral , Movimiento Celular/genética , Somatomedinas/genética , Somatomedinas/metabolismo , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Invasividad Neoplásica/genéticaRESUMEN
BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.
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Enfermedad de Parkinson , Edad de Inicio , Pueblo Asiatico/genética , China , Proteínas de Unión al ADN/genética , Humanos , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/genética , Factores de Transcripción/genéticaRESUMEN
Interleukin (IL)-4 and IL-13 are closely related class I cytokines that play key roles in the T helper (Th)-2 immune response via heterodimeric receptors. IL-4 signals via both the type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes, while IL-13 signals only via the type II receptor complex. IL-13Rα2 is traditionally considered a "decoy" receptor for IL-13. However, the IL-4/13 system and its response to pathogenic infection are still not fully understood in fish. In this study, we identiï¬ed four IL-4/13 receptor subunit genes in the large yellow croaker (Larimichthys crocea): LcIL-4Rα1, LcIL-4Rα2, LcIL-13Rα1, and LcIL-13Rα2. Sequence analysis showed that these receptors possessed typical characteristic domains, including a signal peptide, two fibronectin type III (FN III)-like domains, and a transmembrane domain, but their cytoplasmic regions were not well conserved. The mRNA and protein of the four IL-4/13 receptors were constitutively expressed in all examined tissues of large yellow croaker. Their mRNAs were also detected in primary head kidney macrophages (PKMs), primary head kidney granulocytes (PKGs), and primary head kidney lymphocytes (PKLs). Immunofluorescence assay further showed that LcIL-4Rα and LcIL-13Rα1 were expressed on the membrane of IgM + B cells. After stimulation by Vibrio alginolyticus and poly (I:C) (a viral dsRNA mimic), the mRNA levels of LcIL-4/13 receptors were significantly upregulated in the head kidney and spleen. Their mRNA levels were also upregulated in head kidney leukocytes in response to poly (I:C) and lipopolysaccharide (LPS) treatment. Moreover, both recombinant LcIL-4/13A and LcIL-4/13B upregulated LcIL-4Rα1 and LcIL-4Rα2 in primary leukocytes, but only recombinant LcIL-4/13A upregulated LcIL-13Rα1 and LcIL-13Rα2. These results indicated that LcIL-4/13 receptors, containing conserved functional domains, may be involved in the IL-4/13-mediated immune response to pathogenic infections in the large yellow croaker.
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Proteínas de Peces , Perciformes , Receptores de Interleucina-13 , Receptores de Interleucina-4 , Animales , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Regulación de la Expresión Génica , Interleucina-13 , Interleucina-4 , Perciformes/genética , Perciformes/inmunología , Filogenia , Poli I-C/farmacología , ARN Mensajero , Receptores de Interleucina-13/genética , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/genética , Receptores de Interleucina-4/metabolismoRESUMEN
Colorectal cancer (CRC) is among the top five most common malignant tumors worldwide and has a high mortality rate. Identification of the mechanism of CRC and potential therapeutic targets is critical for improving survival. In the present study, we observed high expression of RAN binding protein 1 (RANBP1) in CRC tissues. Upregulated RANBP1 expression was strongly associated with TNM stages and was an independent risk factor for poor prognosis. In vitro and in vivo functional experiments demonstrated that RANBP1 promoted the proliferation and invasion of CRC cells and inhibited the apoptosis of CRC cells. Low RANBP1 expression reduced the expression levels of hsa-miR-18a, hsa-miR-183, and hsa-miR-106 microRNAs (miRNAs) by inhibiting the nucleoplasmic transport of precursor miRNAs (pre-miRNAs), thereby promoting the accumulation of the latter in the nucleus and reducing the expression of mature miRNAs. Further experiments and bioinformatic analyses demonstrated that RANBP1 promoted the expression of YAP by regulating miRNAs and the Hippo pathway. We also found that YAP acted as a transcriptional cofactor to activate RANBP1 transcription in combination with TEAD4 transcription factor. Thus, RANBP1 further promoted the progression of CRC by forming a positive feedback loop with YAP. Our results revealed the biological role and mechanism of RANBP1 in CRC for the first time, suggesting that RANBP1 can be used as a diagnostic molecule and a potential therapeutic target in CRC.
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MicroARNsRESUMEN
BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Humanos , Mutación/genética , Superóxido Dismutasa-1/genéticaRESUMEN
The present study was designed to systemically evaluate changes in the diffusion tensor imaging (DTI)-derived parameters of iNPH (idiopathic normal pressure hydrocephalus) patients with different responses to the tap test (TT), and to correlate cognitive impairment with white matter (WM) degeneration. This study included 22 iNPH patients and 14 healthy controls with structural magnetic resonance imaging (MRI) and DTI scanning. DTI was used to explore the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for all participants. DTI parameters were evaluated using an ROI (region of interest)-based and tract-based spatial statistics (TBSS) approach. Neuropsychological assessments and the idiopathic normal pressure hydrocephalus grading scoring scale (iNPHGS) were performed. Compared to the TT non-responders, the TT responders group had significantly lower FA values in the corpus callosum, cingulum cingulate gyrus, superior longitudinal fasciculus, and lower AD values in the right cingulum cingulate gyrus and the left posterior thalamic radiation. Besides, the MD values were significantly increased in the corpus callosum, left anterior corona radiata, and the RD values in the corpus callosum and cingulum cingulate gyrus. In addition, the cognitive improvement was negatively correlated with FA of the corpus callosum, cingulum cingulate gyrus, and MD values of the genu of corpus callosum. While, the cognitive improvement was positively related to the AD of the cingulum cingulate gyrus, superior longitudinal, and RD values of the corpus callosum, cingulum cingulate gyrus and uncinate fasciculus. The ROI specific WM lesions in iNPH patients are the underlying basis for cognitive impairment.
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ATG12, a core autophagy protein, forms a conjugate with ATG5 to promote the formation of autophagosome membrane, and plays an important role in antiviral immunity. However, little is known about the function of ATG12 in fish. Here, we cloned the open reading frame (ORF) of large yellow croaker (Larimichthys crocea) ATG12 (LcATG12), which is 354 nucleotides long and encodes a protein of 117 amino acids. The deduced LcATG12 possesses a conserved APG12 domain (residues 31 to 117), and shares 91.45% identities with ATG12 in orange-spotted grouper (Epinephelus coioides). LcATG12 was constitutively expressed in all examined tissues, with the highest level in intestine. Its transcript was also detected in primary head kidney granulocytes (PKG), primary head kidney macrophages (PKM), primary head kidney lymphocytes (PKL), and large yellow croaker head kidney (LYCK) cell line, and was significantly up-regulated by poly(I:C). LcATG12 was regularly distributed in both cytoplasm and nucleus of LYCK and epithelioma papulosum cyprinid (EPC) cells. Overexpression of LcATG12 in EPC cells significantly inhibited the replication of spring viremia of carp virus (SVCV). Further studies reveled that LcATG12 could induce the occurrence of autophagy in LYCK cells. Furthermore, overexpression of LcATG12 in LYCK cells increased the expression levels of large yellow croaker type I interferons (IFNs, IFNc, IFNd, and IFNh), IFN regulatory factors (IRF3 and IRF7), and IFN-stimulated genes (PKR, Mx, and Viperin). All these data indicated that LcATG12 plays a role in the antiviral immunity possibly by inducing both autophagy and type I IFN response in large yellow croaker.
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Enfermedades de los Peces , Perciformes , Secuencia de Aminoácidos , Animales , Antivirales , Proteínas de Peces/genética , Regulación de la Expresión Génica , Inmunidad , Inmunidad Innata/genética , Perciformes/genética , FilogeniaRESUMEN
BACKGROUND: Cognitive impairment is a common non-motor symptom in patients with Parkinson's disease (PD). Mild cognitive impairment (MCI) is also prevalent in nondemented PD patients, even in newly diagnosed PD patients. The possible impacts of MCI on brain function activities for PD patients need more investigation, and the potential of emerging technologies for detecting underlying pathophysiology of cognitive signs in PD can be further improved. METHOD: Forty-seven newly diagnosed drug-naïve PD patients (28 PD-MCI patients and 19 PD patients with cognitively unimpaired (PD-CU)) and 28 healthy controls (HCs) underwent resting-state functional MRI. The connectivity patterns of specific networks were investigated through the independent component analysis among PD-MCI, PD-CU and HCs groups. RESULTS: The independent component analysis revealed significantly decreased functional connectivity (FC) of the default mode network, visual network and sensorimotor network in the PD-MCI subgroup compared with the HC group. Furthermore, FC of the default mode network was positively correlated with memory scores from the brief visuospatial memory test-revised, and FC of the visual network was positively correlated with visuospatial scores from the clock copying test in the PD-MCI group. In all patients with PD, FC of the sensorimotor network negatively correlated with motor severity scores from the Unified PD Rating Scale (UPDRS) part III. On the other hand, the potential damage was more likely to occur in FC between the sensorimotor network and limbic network, and between the ventral attention network and visual network in all PD patients. CONCLUSIONS: Newly diagnosed drug-naïve PD-MCI patients showed characteristic damage of FC within the default mode network, visual network and sensorimotor network, and all PD patients presented impaired FC between the sensorimotor network and limbic network, and FC between the ventral attention network and visual network. These network-wide functional aberrations may underline the pathophysiology of PD.
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Disfunción Cognitiva , Enfermedad de Parkinson , Preparaciones Farmacéuticas , Mapeo Encefálico , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Humanos , Imagen por Resonancia Magnética , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagenRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a common tumor characterized by its high mortality. However, the underlying molecular mechanisms that drive CRC tumorigenesis are unclear. Clock genes have important roles in tumor development. In the present study, the expression and functions of clock gene TIMELESS (encoding the Timeless protein) in CRC were investigated. METHODS: Immunohistochemistry, cell proliferation, migration, invasion, EMT and xenograft tumor experiments were used to prove the function of Timeless in the tumorigenesis of CRC. Immunoprecipitation, mass spectrometry, Immunofluorescence and Chromatin immunoprecipitation (ChIP) were utilized to clarify the mechanism of Timeless in regulating CRC tumorigenesis. RESULTS: We found that Timeless was upregulated in CRC tissues compared with corresponding normal tissues and its expression was closely associated with the TNM stages and overall survival of CRC patients. Functional studies demonstrated that Timeless promoted the proliferation, invasion, and EMT of CRC cells in vitro and in vivo. Mechanistic investigations showed that Timeless activated the ß-catenin signal pathway by binding to Myosin-9, which binds to ß-catenin to induce its nuclear translocation. The upregulation of Timeless was attributed to CREB-binding protein (CBP)/p300-mediated H3K27 acetylation of the promoter region of Timeless. CONCLUSION: Timeless regulates the tumorigenesis of CRC by binding to and regulating myosin-9, suggesting Timeless might be a potential prognostic biomarker and therapeutic target for CRC.
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Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorrectales/metabolismo , Histonas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Vía de Señalización Wnt , Acetilación , Animales , Células CACO-2 , Carcinogénesis , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/fisiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Células HCT116 , Células HT29 , Xenoinjertos , Histonas/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Cadenas Pesadas de Miosina/genética , Pronóstico , Regulación hacia ArribaRESUMEN
A 6-week feeding strategy experiment was conducted to investigate the effects of time-dependent protein restriction and subsequent recovery on shrimp. Diets with protein levels of 43 and 36% were used as adequate and restricted diets, respectively. Shrimp with an initial body weight of 6.52 ± 0.46 g were given four feeding strategies: feeding on an adequate diet for six weeks (T1, the control), having protein-restricted diet in weeks 1 and 4 (T2), being given a protein-restricted diet in weeks 1, 3, and 5 (T3), and having protein-restricted diet in weeks 1, 2, 4, and 5 (T4). WG, SGR, FE, and PER of shrimp in T1-T3 showed no significant difference (P > 0.05), these indicators of T4 were significantly reduced (P < 0.05). No significant differences were found in digestive enzyme activities of shrimp among all treatments (P > 0.05). Crude protein content of shrimp muscle in T4 was lower than that of T1-T3. The expression level of tor in T4 was lower than that in other treatments, while 4e-bp was higher than that of other treatments. To balance saving on feeding cost and growth performance, giving the shrimp a protein-restricted diet for 1 week with subsequent refeeding (T2 and T3) is suitable for shrimp under high-density conditions.
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Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman's correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval No. 2015(236)) on December 23, 2015.
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Chemoresistance is a major obstacle in non-small cell lung cancer (NSCLC) treatment. The pseudogene keratin 17 pseudogene 3 (KRT17P3) has been previously shown to be upregulated in lung cancer tissues of patients with cisplatin resistance. In the present study, RT-qPCR was performed to evaluate KRT17P3 levels in plasma samples collected from 30 cisplatin-resistant and 32 cisplatin-sensitive patients. We found that the plasma level of KRT17P3 is upregulated in cisplatin-resistant patients, and the increased expression of plasma KRT17P3 is associated with poor chemotherapy response. Functional studies demonstrated that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment in vitro and in vivo, while KRT17P3 knockdown has the opposite effect. Mechanistically, bioinformatics analysis, RNA immunoprecipitation, and dual luciferase reporter assay indicated that KRT17P3 acts as a molecular sponge for miR-497-5p and relieves the binding of miR-497-5p to its target gene mTOR. Rescue experiments validated the functional interaction between KRT17P3, miR-497-5p, and mTOR. Taken together, our findings indicate that KRT17P3/miR-497-5p/mTOR regulates the chemosensitivity of NSCLC, suggesting a potential therapeutic target for cisplatin-resistant NSCLC patients. KRT17P3 may be a potential peripheral blood marker of NSCLC patients resistant to cisplatin.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Seudogenes/genética , Serina-Treonina Quinasas TOR/genética , Anciano , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Cisplatino/uso terapéutico , Femenino , Xenoinjertos , Humanos , Queratina-17/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Persona de Mediana Edad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Background: Impaired dopamine metabolism is associated with Parkinson's disease (PD). Considering the overlap in the clinical and pathological characteristics between PD and multiple system atrophy (MSA), we investigated the effect of five potential functional polymorphisms in dopamine metabolism-related genes on disease susceptibility, phenotypes, and responses to dopamine in a large sample of PD and MSA patients. Methods: A total of 1506 PD patients, 496 MSA patients, and 894 healthy controls were included in this study. Five variants (rs6356 in TH, rs921451 in DDC, rs4680 in COMT, rs1799836 in MAOB, and rs1611115 in DBH) were genotyped in all cases using Sequenom iPLEX Assay technology. Results: After adjusting for gender and age at onset, except for DDC rs921451, which was associated with an increased risk of MSA (p = 0.001, OR = 1.21), no significant differences were found in genotype distribution or minor allele frequencies for the other four variants between PD and MSA patients and healthy controls. In the subgroup analysis, DDC rs921451 was associated with an increased risk for late-onset PD as well as for PD onset in males (p = 0.002 [OR = 1.13] p = 0.003 [OR = 1.15], respectively). In addition, patients harboring the risk allele DDC rs921451 required lower levodopa equivalent daily doses of dopaminergic medication than those without the risk allele (52.00 ± 21.31 mg/day, p = 0.015). Conclusion: None of the five candidate functional variants is a major determinant of the risk for PD or MSA. The modified PD phenotypes associated with these variants requires further confirmation.
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The powerful ability of human amnion-derived mesenchymal stem cells (hAMSCs) to promote angiogenesis suggests that they may facilitate angiogenesis-associated therapeutic strategies. However, the molecular mechanisms underlying hAMSC-induced angiogenesis remain largely unknown. The present study results suggested that enhanced migration and tube formation in human umbilical vein endothelial cells (HUVECs) was induced by conditioned medium from hAMSCs (hAMSC-CM). In addition, culture with this conditioned medium resulted in the increased expression of circular RNA ATP binding cassette subfamily B member 10 (circ-ABCB10) and vascular endothelial growth factor A (VEGFA). In the present study genes related to thecirc-ABCB10/microRNA (miR)-29b-3p/VEGFA pathway were predicted using bioinformatics software, and further investigated using in vitro luciferase reporter assays. Loss-of-function assays were performed using small interfering RNAs (siRNAs). The results suggested that siRNA-silencing of circ-ABCB10 in HUVECs weakened migration and tube formation of HUVECs following hAMSC-CM treatment and reduced the levels of VEGFA expression. Treatment with an miR-29b-3p inhibitor could largely rescue these effects in HUVECs, following circ-ABCB10 silencing. The present study results suggest that the circ-ABCB10/miR-29b-3p/VEGFA pathway may be involved in the pro-angiogenic role of hAMSC-CM in HUVECs.
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Certain conflicting conclusions have been drawn that gastric xanthelasma is related to H. pylori, atrophic gastritis, intestinal metaplasia, and early gastric cancer. The aim of this study was to examine the relationship between gastric xanthelasma and upper gastrointestinal (GI) endoscopic or pathological features. A crosssectional study was completed. A total of 8,634 patients who underwent stomach biopsy and who had no gastrectomy history were enrolled in the study. The patients were divided into two groups according to the presence or absence of gastric xanthelasma. The relationship between gastric xanthelasma and demographic characteristics (including age and sex), endoscopic features (including peptic ulcer, bile reflux, and gastric poly), or pathological features (including atrophy, intestinal metaplasia, H. pylori, dysplasia, and gastric cancer) was analyzed. Age/sex matched analysis was also performed to exclude the influence of age and sex. The results revealed that out of the 8,634 patients, 3.54% patients had xanthelasma. Gastric xanthelasma was significantly associated with age (55.76 vs. 49.17 years, P<0.0001), duodenal ulcer (OR 0.860, 95% CI 0.3690.923), atrophy (OR 1.839, 95% CI 1.4322.362), and intestinal metaplasia (OR 3.296, 95% CI 2.6124.159). Binary logistic analysis revealed that age (OR 1.027, 95% CI 1.0171.037) and intestinal metaplasia (OR 2.700, 95% CI 2.0903.487) were independently related to gastric xanthelasma. Age/sex matched control binary logistic analysis revealed that gastric xanthelasma was significantly associated with presence of intestinal metaplasia (OR 2.338, 95% CI 1.6593.297). There was no difference in the number (P=0.427) and location (P>0.05) of gastric xanthelasma for intestinal metaplasia. In conclusion, gastric xanthelasma may be an independent endoscopic warning sign of intestinal metaplasia.
Asunto(s)
Intestinos/patología , Gastropatías/patología , Xantomatosis/patología , Biopsia , Estudios de Casos y Controles , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Metaplasia/patología , Persona de Mediana Edad , Estudios Retrospectivos , Gastropatías/epidemiología , Xantomatosis/epidemiologíaRESUMEN
The powerful pro-angiogenic capacity of human amnion-derived mesenchymal stem cells (hAMSCs) could be a valuable therapeutic angiogenesis strategy for bone regeneration. However, the molecular mechanisms underlying this process remain largely unknown. Herein, we report upregulated expression of circular RNA 100290 (circ-100290) and an enhanced angiogenic phenotype of human umbilical vein endothelial cells (HUVECs) incubated with conditioned medium from hAMSCs (hAMSC-CM), whereas downregulation of circ-100290 reversed the pro-angiogenic capacity of HUVECs induced by hAMSC-CM. Circ-100290/microRNA 449a (miR-449a)/endothelial nitric oxide synthase (eNOS) and circ-100290/miR-449a/vascular endothelial growth factor A (VEGFA) axes were predicted by a bioinformatics method and subsequently verified by luciferase reporter assays in vitro. Gain- or loss-of-function assays were then performed using small interfering RNAs (siRNAs) targeting circ-100290, or a plasmid overexpressing circ-100290. As expected, downregulation of circ-100290 in HUVECs led to weakened tube formation and migration of HUVECs following hAMSC-CM treatment, along with decreased expression of eNOS and VEGFA. In contrast, upregulation of circ-100290 led to enhanced tube formation and migration of HUVECs following hAMSC-CM treatment, along with increased expression of eNOS and VEGFA. Furthermore, a miR-449a inhibitor could largely rescue the effect of circ-100290 silencing on HUVECs, whereas a miR-449a mimic could significantly rescue the effect of overexpressing circ-100290 on HUVECs. Functional assays using eNOS or VEGF receptor inhibitors indicated eNOS and VEGFA may be important targets of miR-449a. Finally, a Matrigel plug assay revealed weakened angiogenesis when circ-100290 was silenced in HUVECs, but enhanced angiogenesis when circ-100290 was overexpressed in vivo. Our results suggest that circ-100290 might function via miR-449a/eNOS and miR-449a/VEGFA axes in the pro-angiogenic role of hAMSC-CM on HUVECs.