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p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other's expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2-p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2-p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.
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Carcinogénesis/genética , ARN Largo no Codificante/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Senescencia Celular/genética , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones Desnudos , Biosíntesis de Proteínas , ARN Largo no Codificante/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Transcripción GenéticaRESUMEN
Purpose: Osteoporosis (OP) and diabetes are prevalent diseases in orthopedic and endocrinology departments, with OP potentially arising as a complication of diabetes. However, the mechanism underlying diabetes-induced osteoporosis (DOP) remains enigmatic, and drug discovery in this domain is restricted, hindering research into the DOP's etiology and treatment. With the ultimate goal of preventing OP in diabetic patients, the objective of this study is to mine the genes and pathways linked to DOP using bioinformatics and databases. Method: The present study employed text mining as the initial approach to retrieve genes commonly associated with diabetes and OP. Subsequently, functional annotation was conducted to investigate the roles and functionalities. In order to explore the interactions between proteins relevant to DOP, we constructed protein-protein interaction (PPI) networks. Furthermore, to obtain key genes and candidate drugs for DOP treatment, we conducted drug-gene interaction (DGI) analysis, complemented by a thorough examination of transcriptional factors (TFs)-miRNA co-regulation. Results: The results through text mining revealed 110 genes that are commonly associated with both diabetes and OP. Subsequent enrichment analysis narrowed down the list to 95 symbols that were involved in PPI analysis. After DGI analysis, we identified 7 genes targeted by 11 drugs, which represent candidates for treating DOP. Conclusion: This study unveils ANDECALIXIMAB, SILTUXIMAB, OLOKIZUMAB, SECUKINUMAB, and IXEKIZUMAB as promising potential drugs for DOP treatment, demonstrating the significance of utilizing text mining and pathway analysis to investigate disease mechanisms and explore existing therapeutic options.
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Diabetes Mellitus , MicroARNs , Humanos , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genética , Biología Computacional , Minería de Datos , Descubrimiento de DrogasRESUMEN
The reactivities of o-carborane-fused silylenes toward molecules with C≡E (E = C, P) bonds are reported. The reactions of bis(silylene) [(LSi:)C]2B10H10 (1a, L = PhC(NtBu)2) with arylalkynes afforded bis(silylium) carborane adducts 2 and 3, showing a Si(µ-C2)Si structure with an open-cage nido-carborane backbone. In contrast, the reaction of 1a with a phosphaalkyne AdC≡P (Ad = 1-adamantyl) smoothly furnished compound 4, comprising fused CPSi rings with a C=Si double bond and Si-Si single bond, and the related formation mechanism was investigated by DFT calculations. Furthermore, when monosilylene [(LSi:)C]CHB10H10 (1b) was employed to react with AdC≡P, compound 5 was isolated. The structure of 5 features a 1,2,3-triphosphetene core. All products were characterized by NMR spectroscopy and/or X-ray crystallography.
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Cristalografía por Rayos X , Teoría Funcional de la DensidadRESUMEN
Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial-mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Factor 4 Similar a Kruppel , Proteínas Asociadas a Microtúbulos , Procesos Neoplásicos , PronósticoRESUMEN
Accumulating evidence suggests that p53 plays a suppressive role in cancer metastasis, yet the underlying mechanism remains largely unclear. Regulation of actin dynamics is essential for the control of cell migration, which is an important step in metastasis. The Arp2/3 complex is a major nucleation factor to initiate branched actin polymerization that drives cell migration. However, it is unknown whether p53 could suppress metastasis through modulating Arp2/3 function. Here, we report that WDR63 is transcriptionally upregulated by p53. We show with migration assays and mouse xenograft models that WDR63 negatively regulates cell migration, invasion, and metastasis downstream of p53. Mechanistically, WDR63 interacts with the Arp2/3 complex and inhibits Arp2/3-mediated actin polymerization. Furthermore, WDR63 overexpression is sufficient to dampen the increase in cell migration, invasion, and metastasis induced by p53 depletion. Together, these findings suggest that WDR63 is an important player in the regulation of Arp2/3 function and also implicate WDR63 as a critical mediator of p53 in suppressing metastasis.
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Actinas , Neoplasias , Complejo 2-3 Proteico Relacionado con la Actina/genética , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Actinas/genética , Actinas/metabolismo , Animales , Ratones , Polimerizacion , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The reactions of amidinate silylene chloride LSi(:)Cl (L = PhC(NtBu)2) with TMS- and Ph-ethynyl lithium salts gave rise to silacycles 1 and 4, respectively. The formation of 1 and 4 may undergo cyclo-condensations of transient ethynylsilylene intermidiates and the activation of an amidinate backbone. The distinct structures of 1 and 4 may be derived from the different electronic or steric properties of ethynyl substituents, and their formation mechanisms were investigated by density functional theory (DFT) calculations. Moreover, a sequential reaction of LSi(:)Cl with BH3·SMe2 and TMSC≡CLi as well as a reaction of LSi(:)Cl with TMSC≡CLi under O2 exclusively obtained ethynylsilanes 2 and 3, respectively, which indicated that either blocking a lone pair of a Si(II) atom or oxidizing Si(II) to Si(IV) prevents the further conversion of ethynylsilylenes to silacycle 1. All products were characterized by NMR spectroscopy and X-ray crystallography.
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Deregulated expression of c-Myc is an important molecular hallmark of cancer. The oncogenic function of c-Myc has been largely attributed to its intrinsic nature as a master transcription factor. Here, we report the long noncoding RNA (lncRNA) E2F1 messenger RNA (mRNA) stabilizing factor (EMS) as a direct c-Myc transcriptional target. EMS functions as an oncogenic molecule by promoting G1/S cell cycle progression. Mechanistically, EMS cooperates with the RNA binding protein RALY to stabilize E2F1 mRNA, and thereby increases E2F1 expression. Furthermore, EMS is able to connect c-Myc to cell cycle control and tumorigenesis via modulating E2F1 mRNA stability. Together, these findings reveal a previously unappreciated mechanism through which c-Myc induces E2F1 expression and also implicate EMS as an important player in the regulation of c-Myc function.
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Carcinogénesis/genética , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Neoplasias/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Largo no Codificante/genética , Células A549 , Animales , Factor de Transcripción E2F1/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Ribonucleoproteína Heterogénea-Nuclear Grupo C/metabolismo , Humanos , Ratones , Neoplasias/patología , Proteínas Proto-Oncogénicas c-myc/genética , Estabilidad del ARN/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Previous studies have suggested the role of CD4+Foxp3+ regulatory T cells (Tregs) in protection against kidney ischemia reperfusion injury via their immunosuppressive properties. Unfortunately, the associated mechanisms of Tregs in kidney ischemia reperfusion injury have not been fully elucidated. Semaphorin 4A (Sema4A) is essential for maintaining the immunosuppressive capacity of Tregs in tumors. However, whether Sema4A can alleviate kidney ischemia reperfusion injury through Tregs has not yet been demonstrated. Here, we investigated the effect and mechanism of Sema4A on the development of kidney ischemia reperfusion injury. Administration of recombinant human Sema4A-Fc chimera protein prior to ischemia reperfusion injury promoted the expansion and function of Tregs and decreased the accumulation of neutrophils and proinflammatory macrophages thereby attenuating functional and histological injury of the injured kidneys. Depletion of Tregs abrogated the protective effect of Sema4A on kidney ischemia reperfusion injury, suggesting Tregs as the main target cell type for Sema4A in the development of this injury. Mechanistically, Sema4A bound to neuropilin 1 (Nrp1), a cell surface receptor for Sema4A and other ligands and a key regulator of Tregs, which then promoted recruitment of phosphatase and tensin homologue and suppressed the Akt-mTOR pathway in Foxp3Cre mice but not in Nrp1f/fFoxp3Cre mice. Consistently, Treg-specific deletion of Nrp1 blocked the effect of Sema4A on the expansion and function of Treg cells. Thus, our results demonstrate that the Sema4A-Nrp1 axis alleviates the development of ischemia reperfusion injury by promoting the stability and function of Tregs in mouse kidneys.
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Daño por Reperfusión , Semaforinas , Animales , Riñón , Ratones , Ratones Endogámicos C57BL , Neuropilina-1/genética , Daño por Reperfusión/prevención & control , Semaforinas/genética , Linfocitos T ReguladoresRESUMEN
The reaction of amidinatosilylene LSi(:)Cl [L = PhC(NtBu)2] with N-heterocyclic carbene IAr [:C{N(Ar)CH}2, where Ar = 2,6-iPr2C6H3] and NaOTf in tetrahydrofuran (THF) facilely afforded a silicon(II) cation [LSi(:)-aIAr]+OTf- (1+OTf-), where IAr isomerizes to abnormal N-heterocyclic carbene aIAr, coordinating to the silicon(II) center. Its Ge homologue, [LGe(:)-aIAr]+OTf- (2+OTf-), was also accessed via the same protocol. For the formation of 1+, we propose that an in situ-generated Si(II) cation [LSi(:)]+ under the treatment of LSi(:)Cl with NaOTf may isomerize IAr in THF. In contrast, the replacement of IAr with cyclic alkyl(amino) carbene (cAAC) furnished a cAAC-silanyl radical ion [LSi(H)-cAAC]â¢+(LiOTf2)- [3â¢+(LiOTf2)-], which may undergo an abstraction of the H radical from THF. All of the products were characterized by nuclear magnetic resonance spectroscopy, electron paramagnetic resonance, and X-ray crystallography, and their bonding scenarios were investigated by density functional theory calculations. These studies provide new perspective on carbene-silicon chemistry.
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The tumor suppressor p53 plays a prominent role in the protection against cancer. The activity of p53 is mainly controlled by the ubiquitin E3 ligase Mdm2, which targets p53 for proteasomal degradation. However, the regulation of Mdm2 remains not well understood. Here, we show that MARCH7, a RING domain-containing ubiquitin E3 ligase, physically interacts with Mdm2 and is essential for maintaining the stability of Mdm2. MARCH7 catalyzes Lys63-linked polyubiquitination of Mdm2, which impedes Mdm2 autoubiquitination and degradation, thereby leading to the stabilization of Mdm2. MARCH7 also promotes Mdm2-dependent polyubiquitination and degradation of p53. Furthermore, MARCH7 is able to regulate cell proliferation, DNA damage-induced apoptosis, and tumorigenesis via a p53-dependent mechanism. These findings uncover a novel mechanism for the regulation of Mdm2 and reveal MARCH7 as an important regulator of the Mdm2-p53 pathway.
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Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Daño del ADN/genética , Daño del ADN/fisiología , Células HCT116 , Células HEK293 , Humanos , Masculino , Ratones , Ratones Desnudos , Unión Proteica , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación/genética , Ubiquitinación/fisiologíaRESUMEN
The unique physical structure and chemical and electrical properties of graphene make it an ideal choice for sensor materials. The sensing platform of biomolecule functionalized graphene has received extensive attention due to its high sensitivity and selectivity, especially the biosensors constructed by combining antibodies, nucleic acids and enzymes that efficiently recognize specific targets with graphene having a large specific surface area and a fast electron transfer rate, which has become a significant research direction. In this paper, electrochemical biosensors based on graphene materials developed in recent years are summarized. The methods of functional modification of graphene, graphene oxide and reduced graphene oxide with antibodies, nucleic acids and enzymes are briefly described. In addition, the advantages and disadvantages of the constructed electrochemical biosensors in detecting pathogens and disease markers are also reviewed. Finally, we are optimistic about this prospect for the development direction and application prospects of such electrochemical biosensors.
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Anticuerpos/química , Biomarcadores/análisis , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Enzimas/química , Grafito/química , Ácidos Nucleicos/química , Enfermedad/clasificación , HumanosRESUMEN
BACKGROUND This study aimed to use cumulative sum analysis of the operator learning curve for robot-assisted Mayo Clinic level I-IV inferior vena cava (IVC) thrombectomy associated with renal carcinoma, and describes the development of an optimized operative procedure at a single center. MATERIAL AND METHODS A retrospective study included 120 patients with Mayo Clinic level I-IV IVC thrombus who underwent robotic surgery between 2013 and 2018. Points in the learning curve were identified using cumulative sum analysis, and their impact was assessed by multiple regression analysis. Perioperative indicators analyzed included operative time, estimated blood loss, early complications, and the 90-day progression rate. RESULTS Cumulative sum analysis identified three phases in the learning curve of robot-assisted IVC thrombectomy. The median operative time decreased from 265 min (range, 212-401 min) to 207 min (range, 146-276 min) (p=0.003), the median estimated blood loss decreased from 775 ml (range, 413-1500 ml) to 300 ml (range, 163-813 ml) (p=0.006), and the early complication rate decreased from 52.5% to 15.0% (p<0.001). Multivariate analysis showed that for an initial 40 cases and a further 80 cases, the learning phase, the affected side, the Mayo Clinic level, and the surgical method were independent factors that affected operative time, estimated blood loss, and the rate of early complications. CONCLUSIONS Experience from an initial 40 cases and a further 80 cases of Mayo Clinic level I-IV IVC thrombectomy associated with renal carcinoma were found to provide acceptable surgical and clinical outcomes.
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Carcinoma de Células Renales/patología , Trombectomía/métodos , Vena Cava Inferior/cirugía , Adulto , Anciano , Pérdida de Sangre Quirúrgica , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/cirugía , China , Femenino , Humanos , Neoplasias Renales/patología , Curva de Aprendizaje , Masculino , Persona de Mediana Edad , Células Neoplásicas Circulantes/patología , Nefrectomía/métodos , Tempo Operativo , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/métodos , Robótica , Trombosis de la Vena/etiologíaRESUMEN
Learning accurate Bayesian Network (BN) structures of high-dimensional and sparse data is difficult because of high computation complexity. To learn the accurate structure for high-dimensional and sparse data faster, this paper adopts a divide and conquer strategy and proposes a block learning algorithm with a mutual information based K-means algorithm (BLMKM algorithm). This method utilizes an improved K-means algorithm to block the nodes in BN and a maximum minimum parents and children (MMPC) algorithm to obtain the whole skeleton of BN and find possible graph structures based on separated blocks. Then, a pruned dynamic programming algorithm is performed sequentially for all possible graph structures to get possible BNs and find the best BN by scoring function. Experiments show that for high-dimensional and sparse data, the BLMKM algorithm can achieve the same accuracy in a reasonable time compared with non-blocking classical learning algorithms. Compared to the existing block learning algorithms, the BLMKM algorithm has a time advantage on the basis of ensuring accuracy. The analysis of the real radar effect mechanism dataset proves that BLMKM algorithm can quickly establish a global and accurate causality model to find the cause of interference, predict the detecting result, and guide the parameters optimization. BLMKM algorithm is efficient for BN learning and has practical application value.
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Liposomes are extensively used in drug delivery, while alginates are widely used in tissue engineering. However, liposomes are usually thermally unstable and drug-leaking when in liquids, while the drug carriers made of alginates show low loading capacities when used for drug delivery. Herein, we developed a type of thermo-responsible liposome-alginate composite hydrogel (TSPMAH) by grafting thermo-responsive liposomes onto alginates by using Ca2+ mediated bonding between the phosphatidic serine (PS) in the liposome membrane and the alginate. The temperature-sensitivity of the liposomes was actualized by using phospholipids comprising dipalmitoylphosphatidylcholine (DPPC) and PS and the liposomes were prepared by a thin-film dispersion method. The TSPMAH was then successfully prepared by bridge-linking the microcapsules onto the alginate hydrogel via PS-Ca2+-Carboxyl-alginate interaction. Characterizations of the TSPMAH were carried out using scanning electron microscopy, transform infrared spectroscopy, and laser scanning confocal microscopy, respectively. Their rheological property was also characterized by using a rheometer. Cytotoxicity evaluations of the TSPMAH showed that the composite hydrogel was biocompatible, safe, and non-toxic. Further, loading and thermos-inducible release of model drugs encapsulated by the TSPMAH as a drug carrier system was also studied by making protamine-siRNA complex-carrying TSPMAH drug carriers. Our results indicated that the TSPMAH described herein has great potentials to be further developed into an intelligent drug delivery system.
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Alginatos/química , Hidrogeles/síntesis química , Fosfolípidos/química , 1,2-Dipalmitoilfosfatidilcolina/química , Calcio/química , Cápsulas , Estabilidad de Medicamentos , Hidrogeles/química , Liposomas , Fosfatidilcolinas/química , TermodinámicaRESUMEN
Metal-organic frameworks (MOFs) as sensing materials have experienced explosive growth in recent years due to their intrinsic merits, such as structural diversity, high porosity, large surface area, extraordinary adsorption affinities, etc. Biomolecules such as DNA, protein, and vitamins play vital roles in metabolism. Moreover, the sensitive detection of biomolecules is of importance in the disease prevention and treatment. This review intends to provide an update on the recent progress in the detection of various biomolecules via MOF-based luminescent sensors. MOFs are successful in the detection of DNA, RNA, protein, and other biomolecules. MOF-based luminescent sensors function by utilizing different mechanisms, including luminescent responses of enhancement and quenching, which are defined as "turn-on" and "turn-off" responses, respectively. Then, a short comparison of the "turn-on" and "turn-off" types of sensors is also made.
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Sustancias Luminiscentes/química , Estructuras Metalorgánicas/química , Adsorción , ADN/análisis , Mediciones Luminiscentes , Porosidad , Proteínas/análisis , ARN/análisisRESUMEN
OBJECTIVE: The aim of this study was to examine the effect of low dose heavy ion irradiation on the subset percentage and expression of cytokines of peripheral blood lymphocytes(PBL) in patients with pancreatic cancer. METHODS: PBL from 21 patients with pancreatic cancer were divided into three groups: sham, X-ray and ¹²C6⺠irradiation groups, and the cell responses were measured at 24 hours after radiation exposure. The percentages of T and NK cell subsets were detected by flow cytometry. The mRNA expression of interleukin (IL)-2, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were examined by real-time quantitative RT-PCR (qRT-PCR). The cytokine protein levels in supernatant of cultured cells were assayed by enzyme-linked immunosorbent assays (ELISA). RESULTS: The percentage of T lymphocyte subsets was significantly increased at 24 hours after exposure to low dose radiation, and the effect was more pronounced in the group receiving 0.05 Gy ¹²C6⺠ion irradiation than that in the group receiving X-ray irradiation [CD3⺠T cells: (67.15 ± 4.36)% vs. (60.81 ± 8.35)%; CD3⺠CD4⺠T cells: (19.02 ± 2.35)% vs. (17.21 ± 2.86)%; CD3⺠CD8⺠T cells: (46.59 ± 6.07)% vs. (41.18 ± 6.35)%. (P < 0.05 for all)]. However, there were no significant changes in the CD3⺠CD4âº/CD3⺠CD8⺠ratio (0.67 for sham, 0.65 for X-ray, and 0.68 for ¹²C6⺠groups) and percentage of NK cell subsets (P > 0.05 for all). Expression levels of IFN-γ mRNA (cycle threshold/CT value was 23.35 ± 3.16 for ¹²C6âº, CT value was 27.25 ± 2.15 for X-ray) and IL-2 (CT value was 24.19 ± 3.56 for ¹²C6âº, CT value was 27.85 ± 4.08 for X-ray) in PBL, and their protein levels in the supernatant were significantly increased at 24 hours after exposure to the low dose radiation (P < 0.05). The effects were more pronounced in the group receiving 0.05 Gy ¹²C6⺠ion irradiation than that in the group receiving X-ray irradiation. However, there was no significant change in the TNF-α production of PBL. CONCLUSIONS: Low dose irradiation may alleviate the immune suppression caused by tumor burden and that the effect is more pronounced for 0.05 Gy high linear energy transfer (LET) ¹²C6⺠irradiation. The percentage of T cell subsets and cytokines production could be used as sensitive indicators of acute response to low dose irradiation.
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Citocinas/metabolismo , Iones Pesados , Linfocitos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/radioterapia , Relación CD4-CD8 , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Relación Dosis-Respuesta en la Radiación , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Interleucina-2/metabolismo , Células Asesinas Naturales , Linfocitos/efectos de la radiación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Reactions of o-carborane-fused bis-silylene 1 with isocyanate/isothiocyanate molecules furnished a series of SiN/SiS-heterocycles, which show distinct styles of cyclization and were theoretically studied.
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Traumatic cervical spinal cord injury (TCSCI) often causes varying degrees of motor dysfunction, common assessed by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), in association with the American Spinal Injury Association (ASIA) Impairment Scale. Accurate prediction of motor function recovery is extremely important for formulating effective diagnosis, therapeutic and rehabilitation programs. The aim of this study is to investigate the validity of a novel nested ensemble algorithm that uses the very early ASIA motor score (AMS) of ISNCSCI examination to predict motor function recovery 6 months after injury in TCSCI patients. This retrospective study included complete data of 315 TCSCI patients. The dataset consisting of the first AMS at ≤ 24 h post-injury and follow-up AMS at 6 months post-injury was divided into a training set (80%) and a test set (20%). The nested ensemble algorithm was established in a two-stage manner. Support Vector Classification (SVC), Adaboost, Weak-learner and Dummy were used in the first stage, and Adaboost was selected as second-stage model. The prediction results of the first stage models were uploaded into second-stage model to obtain the final prediction results. The model performance was evaluated using precision, recall, accuracy, F1 score, and confusion matrix. The nested ensemble algorithm was applied to predict motor function recovery of TCSCI, achieving an accuracy of 80.6%, a F1 score of 80.6%, and balancing sensitivity and specificity. The confusion matrix showed few false-negative rate, which has crucial practical implications for prognostic prediction of TCSCI. This novel nested ensemble algorithm, simply based on very early AMS, provides a useful tool for predicting motor function recovery 6 months after TCSCI, which is graded in gradients that progressively improve the accuracy and reliability of the prediction, demonstrating a strong potential of ensemble learning to personalize and optimize the rehabilitation and care of TCSCI patients.
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Algoritmos , Recuperación de la Función , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/diagnóstico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Médula Cervical/lesiones , Médula Cervical/fisiopatología , Anciano , Adulto Joven , Pronóstico , Vértebras Cervicales/lesiones , Vértebras Cervicales/fisiopatologíaRESUMEN
OBJECTIVES: Pancreatic cancer is one of the most aggressive and lethal cancers worldwide and there are few effective treatments. Recently, salinomycin (Sal) was reported to alter proliferation and apoptosis in various tumors. This prompted us to investigate the effect of Sal on pancreatic cancer cells and to explore the possible molecular mechanism in vitro. METHODS: After treatment with Sal, pancreatic cancer cell viability and apoptosis were analyzed by Hoechst 33342 staining and flow cytometry, respectively. Invasion and metastasis of pancreatic cancer cells were assayed by a Transwell migration assay. Flow cytometry was also used to assessed the fraction of CD133(+) cell subpopulations. The expression of proliferating cell nuclear antigen (PCNA), Bcl-2, E-cadherin, and Wnt/ß-catenin signaling-related proteins were detected by RT-PCR and western blot. RESULTS: Sal inhibited the growth and migration of pancreatic cancer cells in vitro in a dose- and time-dependent manner. We found that the proportion of CD133(+) cell subpopulations decreased after treatment with Sal in pancreatic cancer cell lines at the same time. The percentage of apoptotic cells was increased after Sal treatment. Compared with control groups, Bax and E-cadherin were significantly upregulated, and Bcl-2 and PCNA were significantly downregulated in Sal-treated cells. The expression of Wnt/ß-catenin signaling-related proteins (ß-catenin and p-GSK-3ß) was inhibited. CONCLUSIONS: These results indicate that Sal could influence the cell growth and migration in pancreatic cancer cells in vitro, which may occur by inhibition of Wnt/ß-catenin signaling.
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Antibióticos Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Piranos/farmacología , Antígeno AC133 , Antígenos CD , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Glicoproteínas/antagonistas & inhibidores , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Péptidos/antagonistas & inhibidoresRESUMEN
A dynamic model of soil erosion along hillslopes considering soil detachment and sediment transport is still a major challenge in terms of its applicability to field conditions. Data availability for model calibration and validation is very limited for physically process models. An improved hillslope erosion dynamic model (HED) with a simple structure and strong application on field plots was established based on the sediment feedback mechanism in this study. Observed runoff and sediment data from field plots with slope gradients of 14.1 %-62.5 % and slope lengths of 7.9-64.7 m within runoff events for the Chagagou catchment on the Loess Plateau of China were used to evaluate the HED. We confirmed that the power function can reproduce the soil detachment capacity (Φ) and sediment transport capacity (Tc) under varying field slope conditions (gradients and lengths). The two parameters associated with the power function of Φ or Tc are consistent across the variable conditions. When the HED model simulates the process and event sediment discharge, the unified model parameters could be obtained. The simulation precision of above results ranged from 0.44 to 0.95 for Nash-Sutcliffe simulation efficiency (NSE), from 0.65 to 0.96 for R2 and from -32.37 % to 31.61 % for relative error (RE). The feedback term of HED was close to one as the slope length approached zero. Decreasing of sediment yield as slope length increased was quite consistent with the measured data due to the reasonable sediment feedback term. The critical slope lengths were more easily reached, and the feedback term value along the slope decreased more rapidly at steeper slopes and higher runoff events. HED can be further integrated into distributed watershed models for predicting sediment discharge within runoff events.