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Background: Open thoracotomy has been the traditional surgical approach for patients with bronchogenic cysts (BCs). This study aimed to evaluate the safety and efficacy of video-assisted thoracoscopic surgery (VATS) compared to open surgery for the treatment of BCs in adults. Methods: This single-institution, retrospective cohort study included 117 consecutive adult patients who underwent VATS (group A) or open surgery (group B) for BC resection between February 2019 and January 2023. Data regarding clinical history, operation duration, length of hospital stay, 30-day mortality, and recurrence during follow-up were collected and analyzed. Results: Of the total cohort, 103 (88.0%) patients underwent VATS, while 14 (12.0%) patients underwent open surgery. Patients' age in group B were much older than group A (P=0.014), and no significant differences in other demographic and baseline clinical characteristics were observed between the groups. The VATS group had shorter median operation duration (96 vs. 149.5 min, P<0.001) and shorter mean length of hospital stay (5.0±5.5 vs. 8.6±4.0 days, P<0.001). One death occurred in the open surgery group. During a median follow-up of 34 (interquartile range, 20.8-42.5) months, no instances of BC recurrence were observed in either group. Conclusions: Compared to open surgery, VATS is also a safe and efficacious approach for treating BCs in adults. What's more, VATS offered shorter operative times and hospital stays. Considering the minimally invasive, VATS may be a better choice in most patients with bronchial cysts.
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Lung cancer (LC) is the leading cause of death worldwide, and lung adenocarcinoma (LUAD) is the most common form of LC. The abnormally high expression of myelin protein zero-like 1 (MPZL1) promotes the malignant progression of various tumors. However, there is no relevant report on the functional role of MPZL1 in LUAU. In this study, we applied Illumina sequencing to screen differentially expressed genes. Subsequently, MPZL1 was selected as hub gene for quantitative real-time polymerase chain reaction (qRT-PCR) and CCK8 assay. The expression level of MPZL1 was analyzed by immunohistochemistry, immunofluorescence, western blot, and qRT-PCR. After silencing or overexpressing MPZL1, CCK8, EDU, clone formation, scratch healing, invasion, and nude mouse tumor-bearing experiments were performed to detect the abilities of cell proliferation, migration, invasion, and tumorigenicity. Moreover, qRT-PCR, western blot, coimmunoprecipitation, and scratch healing assays were conducted to explore the transcriptional regulatory factors of MPZL1. Finally, the relationship between MPZL1 and immunotherapy was explored through public databases and validated in vivo. The results show that a total of 196 high-expressed genes and 496 low-expressed genes were screened. Differential genes are mainly enriched in cell proliferation and division, protein binding, and other pathways and functions. MPZL1 was selected as the hub gene and upregulated in LUAD tissues and cells. Silencing MPZL1 inhibited the cell proliferation and cloning formation, and the growth of tumor. Conversely, overexpression of MPZL1 has the opposite effect. In addition, MPZL1 combines with the transforming growth factor-ß1 to promote the progress of LUAD. Finally, we found that high expression of MPZL1 is negatively correlated with infiltration of CD8+ cells and may lead to immunotherapy resistance. In summary, this study revealed a new mechanism by which MPZL1 promotes LUAD progression by enhancing tumor proliferation, invasion, migration, and suppressing immune function.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Animales , Ratones , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Inmunidad , Neoplasias Pulmonares/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , HumanosRESUMEN
Objective: To assess the clinical efficacy of thoracoscopic lobectomy and segmentectomy in the treatment of patients with early-stage lung cancer. Methods: A total of 70 patients with early-stage non-small cell lung cancer who were treated in our hospital from April 2018 to May 2020 were recruited and assigned at a ratio of 1 : 1 to receive either segmentectomy (observation group) or lobectomy (control group). Outcome measures included clinical efficacy, surgery-related indicators, pulmonary function indicators (forced vital capacity (FVC) and forced expiratory volume in one second (FEV1)), postoperative complications, and recurrence and metastasis. Results: There was no significant difference in the clinical efficacy between the two groups (P > 0.05). Segmentectomy was associated with a longer operation time and shorter hospital stay compared to lobectomy (P < 0.05). There was no statistical significance in the amount of intraoperative blood loss and the number of lymph nodes dissected (P > 0.05). Segmentectomy resulted in significantly higher FVC and FEV1 levels in patients compared to lobectomy (P < 0.05). There was no significant difference in the incidence of postoperative complications between the two groups (P > 0.05). The two groups of patients were followed up for 12 months after the operation, and there was no recurrence or metastasis in either group. Conclusion: The two surgical methods have similar efficacy and safety profiles, but for the treatment of patients with early-stage lung cancer, thoracoscopic segmentectomy is associated with a shorter hospital stay and better protection of the lung function of patients compared to lobectomy.
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CircRNAs (circular RNAs) have been implicated in the development and progression of a variety of cancers. The molecular pathways underlying the progression of NSCLC (Non-Small Cell Lung Cancer) and the associated regulation of circRNAs in NSCLC remain to be fully elucidated. In this study, we found that circPLK1 expression was upregulated in serum exosomes and tissues from NSCLC patients. The Kaplan-Meier survival analysis revealed that a high expression level of circPLK1 was associated with a poorer prognosis in NSCLC patients. Exosomes extracted from NSCLC serum could promote the replication, migration, and invasion of NSCLC cells and suppress apoptotic cell death. The overexpression of circPLK1 also promotes the malignant phenotype of NSCLC cells. Molecular analyses demonstrated that circPLK1 directly targets miR-1294 and negatively regulates its activity. And circPLK1 overexpression facilitates the progression of NSCLC by negatively regulating miR-1294 level and maintaining a high-level expression of HMGA1 (High Mobility Group Protein A1). Our study suggests that circPLK1 upregulation plays an important role in NSCLC progression by targeting miR-1294/HMGA1 axis. These data provide a theoretical basis for the development of therapeutic strategy targeting exosomal circPLK1 in NSCLC treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Proteína HMGA1a/genética , Neoplasias Pulmonares , MicroARNs/genética , ARN Circular/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Exosomas/metabolismo , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: To investigate the feasibility and indications of video-assisted thoracic surgery (VATS) in thymoma resection. METHODS: The clinical data of 103 patients undergoing thymoma resection via different approaches [including conventional lateral thoracotomy approach (LTA) in 41 cases, median sternotomy approach (MSA) in 40 cases, and right-sided VATS in 22 cases] were analyzed. Among them, 59, 13, 25, and 6 patients were in Masaoka stage I, II, III, and IV, respectively. Myasthenia gravis (MG) was also found in 54 cases. The patients were followed up for postoperative survival and the improvement in MG. The prognostic indicators of patients undergoing thymoma resection via different surgical approaches (i.e., LTA, MSA, and VATS) were statistically analyzed. RESULTS: Eight of 103 patients died. Six patients underwent unilateral sacral nerve resection, among whom 4 patients developed respiratory dysfunction, and 3 died. Two patients died of MG after surgery, 1 patient died of tumor recurrence and metastasis, 1 patient died of heart disease, and the cause of death was unknown in the remaining patient. The drainage time was shorter in VATS group than in open groups, along with smaller tumor size. The VATS group also had shorter hospital stay in the whole series and the subgroup without accompanying MG. The improvement in MG showed no significant difference among the three surgical groups. Both 5- and 10-year survival rates were 91% in the entire cohort. CONCLUSIONS: VATS is like a conventional surgeries for improving MG in thymoma patients with accompanying MG. VATS resection can still be considered for thymoma that only invades the mediastinal pleura. For thymomas that have intact capsules and have not invaded mediastinal pleura, MSA surgery shall be performed to ensure patient safety if the anteroposterior diameters of the tumors are large and the masses have produced severe compression of the innominate vein, even if the tumors are still in the Masaoka stage II. For thymomas with large left-to-right diameters and with most parts of the tumors located in the left thoracic cavity, a left-sided approach (either VATS or an open approach) may be used in the absence of MG; if MG accompanies the condition, an MT approach or a bilateral VATS may be considered. In patients with unilateral pericardial phrenic nerve and/or local pericardial involvement, right-sided VATS thymectomy may be considered for thymomas located at the right side and bilateral VATS surgery can be performed for tumors located at the left side. In summary, VATS is feasible for the treatment of thymoma complicated by MG. VATS can be performed in patients with Masaoka stage I, II and (a certain portion of) III thymoma; for some patients with Masaoka stage II thymoma, especially those with compression of the innominate vein, the use of VATS should be cautious.
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One approach to improve the targeted therapeutic efficiency of lung cancer is to deliver drugs using nano-scaled systems. In this study, RGD peptide-modified, paclitaxel (PTX) prodrug-based, dual-drugs loaded, and redox-sensitive lipid-polymer nanoparticles were developed and the in vitro and in vivo antitumor efficiency was evaluated in lung cancer cells and tumor bearing animal models. RGD-modified PTX and cisplatin (CDDP) loaded LPNs (RGD-ss-PTX/CDDP LPNs) have sizes around 190â¯nm, and zeta potentials of -35â¯mV. The half-maximal inhibitory concentration (IC50) values were 26.7 and 75.3⯵g/mL for drugs loaded LPNs and free drugs combination, which indicates significantly higher antitumor activity of LPNs than free drugs. RGD-ss-PTX/CDDP LPNs also exhibited the best antitumor efficiency in vivo, which inhibited the tumor size of mice from 1486 mm3 to 263 mm3. The results illustrated that the system could successfully load drugs and achieve synergistic combination lung cancer treatment efficiency with lower systemic toxicity compared with free drugs counterparts. The resulting system could be facilitated as a promising targeted nanomedicine for the treatment of lung cancer.
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Antineoplásicos/administración & dosificación , Portadores de Fármacos , Lípidos/química , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas , Oligopéptidos/metabolismo , Paclitaxel/administración & dosificación , Polímeros/química , Profármacos/administración & dosificación , Células A549 , Animales , Antineoplásicos/sangre , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Liberación de Fármacos , Estabilidad de Medicamentos , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Nanomedicina , Oligopéptidos/química , Oxidación-Reducción , Paclitaxel/análogos & derivados , Paclitaxel/sangre , Paclitaxel/química , Profármacos/química , Profármacos/metabolismo , Tecnología Farmacéutica/métodos , Distribución Tisular , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single-arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC-P) were similar to the MMAC group in the retrospective study (MMAC-R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.
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Suero Antilinfocítico/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Acondicionamiento Pretrasplante , Adolescente , Adulto , Anciano , Plaquetas , Niño , Preescolar , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Femenino , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
The current study examined the role of Raf kinase inhibitor protein (RKIP) in non-small cell lung cancer (NSCLC) metastasis. A total of 100 patients with NSCLC were recruited following pathological diagnosis in the First Affiliated Hospital of Bengbu Medical College. The patients were classified and statistically analyzed according to their clinicopathological characteristics and tumor-node-metastasis stage. Paired tumor tissue and adjacent non-tumor tissue samples were subject to pathological diagnosis and western blot analysis. Transient transfection and lentivirus particle vector-mediated RKIP overexpression, small interfering RNA-mediated silencing, Transwell assays and immunocytochemistry methods were employed to elucidate the role and underlying mechanisms of RKIP and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in NSCLC metastasis. Furthermore, in order to examine the in vivo effects of RKIP, recombinant lentivirus particles containing the RKIP gene were administrated in a mouse NSCLC tumor model via tail vein injection. The results revealed reduced RKIP expression levels in NSCLC tissue compared with corresponding non-cancer tissue. Additionally, RKIP expression levels were inversely associated with NSCLC intra-lung, lymph node and long-distance metastasis. The results also indicated that RKIP was able to block STAT3 activation via phosphorylation and inhibit NSCLC-cell metastasis in vitro. Furthermore, RKIP knockdown was able to promote STAT3 phosphorylation and cell metastasis in NSCLC cell lines. During in vivo experiments, RKIP overexpression was able to suppress xenograft tumor metastasis in nude mice. Therefore, RKIP may be an important factor in cancer cell metastasis in patients with NSCLC, and RKIP may inhibit NSCLC-cell invasion by blocking the activation of the JAK/STAT3 signaling pathway.
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The Testin gene was previously identified in the fragile chromosomal region FRA7G at 7q31.2. It has been implicated in several types of cancers including prostate, ovarian, breast and gastric cancer. In the present study, we investigated the function of the candidate tumor-suppressor Testin gene in non-small cell lung cancer (NSCLC). In NSCLC cell lines, we observed lower expression of Testin compared to that noted in normal human bronchial epithelial cells. MTT assays, flow cytometry, clonogenic assay and invasion assay showed that the overexpression of the Testin gene inhibited cancer cell proliferation, invasion and colony formation. In tumor xenograft models, Testin markedly inhibited lung cancer cell xenograft formation and growth in athymic nude mice. Taken together, these data suggest that Testin plays an important role in the development and progression of NSCLC. Testin may be an effective novel target in NSCLC prevention and treatment.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas del Citoesqueleto/metabolismo , Genes Supresores de Tumor , Proteínas con Dominio LIM/metabolismo , Neoplasias Pulmonares/patología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Proteínas del Citoesqueleto/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas con Dominio LIM/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones Endogámicos BALB C , Proteínas de Unión al ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Blood coagulation is the clotting and subsequent dissolution of the clot following repair to the damaged tissue. However, inducing blood coagulation is difficult for some patients with homeostasis dysfunction or during surgery. In this study, we proposed a method to develop an integrated system that combines optical coherence tomography (OCT) and laser microsurgery for blood coagulation. Also, an algorithm for positioning of the treatment location from OCT images was developed. With OCT scanning, 2D/3D OCT images and angiography of tissue can be obtained simultaneously, enabling to noninvasively reconstruct the morphological and microvascular structures for real-time monitoring of changes in biological tissues during laser microsurgery. Instead of high-cost pulsed lasers, continuous-wave laser diodes (CW-LDs) with the central wavelengths of 450 nm and 532 nm are used for blood coagulation, corresponding to higher absorption coefficients of oxyhemoglobin and deoxyhemoglobin. Experimental results showed that the location of laser exposure can be accurately controlled with the proposed approach of imaging-based feedback positioning. Moreover, blood coagulation can be efficiently induced by CW-LDs and the coagulation process can be monitored in real-time with OCT. This technology enables to potentially provide accurate positioning for laser microsurgery and control the laser exposure to avoid extra damage by real-time OCT imaging.
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Coagulación Sanguínea/efectos de la radiación , Rayos Láser , Microcirugia/instrumentación , Microcirugia/métodos , Tomografía de Coherencia Óptica , Algoritmos , Animales , Hemoglobinas/metabolismo , Ratones , Oxihemoglobinas/metabolismo , Radiografía , Piel/diagnóstico por imagenRESUMEN
BACKGROUND: Obesity is frequently complicated by comorbid conditions, yet how excess adipose contributes is poorly understood. Although adipocytes in obese individuals induce systemic inflammation via secreted cytokines, another potential mediator has recently been identified (i.e., adipocyte-derived exosomes). We hypothesized that adipocyte-derived exosomes contain mediators capable of activating end-organ inflammatory and fibrotic signaling pathways. METHODS: We developed techniques to quantify and characterize exosomes shed by adipocytes from seven obese (age: 12-17.5 y, BMI: 33-50 kg/m(2)) and five lean (age: 11-19 y, BMI: 22-25 kg/m(2)) subjects. RESULTS: Abundant exosomal miRNAs, but no mRNAs, were detected. Comparison of obese vs. lean visceral adipose donors detected 55 differentially expressed miRNAs (P < 0.05; fold change ≥|1.2|). qRT-PCR confirmed downregulation of miR-148b (ratio = 0.2 (95% confidence interval = 0.1, 0.6)) and miR-4269 (0.3 (0.1, 0.8)), and upregulation of miR-23b (6.2 (2.2, 17.8)) and miR-4429 (3.8 (1.1-13.4)). Pathways analysis identified TGF-ß signaling and Wnt/ß-catenin signaling among the top canonical pathways expected to be altered with visceral adiposity based on projected mRNA targets for the 55 differentially expressed miRNAs. A select mRNA target was validated in vitro. CONCLUSION: These data show that visceral adipocytes shed exosomal-mediators predicted to regulate key end-organ inflammatory and fibrotic signaling pathways.
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Adipocitos/metabolismo , Exosomas/química , Regulación de la Expresión Génica/fisiología , Inflamación/etiología , MicroARNs/análisis , Obesidad/complicaciones , Transducción de Señal/fisiología , Adolescente , Línea Celular , Humanos , Inmunohistoquímica , Macrófagos/fisiología , MicroARNs/efectos adversos , Obesidad/fisiopatologíaRESUMEN
Dominant mutations in the valosin-containing protein (VCP) gene cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, which is characterized by progressive muscle weakness, dysfunction in bone remodeling, and frontotemporal dementia. More recently, VCP has been linked to 2% of familial amyotrophic lateral sclerosis cases. VCP plays a significant role in a plethora of cellular functions including membrane fusion, transcription activation, nuclear envelope reconstruction, postmitotic organelle reassembly, and cell cycle control. To elucidate the pathological mechanisms underlying the VCP disease progression, we have previously generated a VCP(R155H/+) mouse model with the R155H mutation. Histological analyses of mutant muscle showed vacuolization of myofibrils, centrally located nuclei, and disorganized muscle fibers. Global expression profiling of VCP(R155H/+) mice using gene annotations by DAVID identified key dysregulated signaling pathways including genes involved in the physiological system development and function, diseases and disorders, and molecular and cellular functions. There were a total of 212 significantly dysregulated genes, several of which are involved in the regulation of proteasomal function and NF-κB signaling cascade. Findings of the gene expression study were validated by using quantitative reverse transcriptase polymerase chain reaction analyses to test genes involved in various signaling cascades. This investigation reveals the importance of the VCP(R155H/+) mouse model in the understanding of cellular and molecular mechanisms causing VCP-associated neurodegenerative diseases and in the discovery of novel therapeutic advancements and strategies for patients suffering with these debilitating disorders.
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Adenosina Trifosfatasas/genética , Sustitución de Aminoácidos , Proteínas de Ciclo Celular/genética , Perfilación de la Expresión Génica , Técnicas de Sustitución del Gen , Degeneración Nerviosa/genética , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Ratones , Músculos/patología , Degeneración Nerviosa/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Proteína que Contiene ValosinaRESUMEN
We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor ß-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues.
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Fibrosis/patología , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/patología , Regeneración/fisiología , Animales , Antiinflamatorios/farmacología , Diferenciación Celular , Células Cultivadas , Distrofina/genética , Humanos , Inflamación/patología , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Músculo Esquelético/citología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Distrofia Muscular Animal/patología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/patología , Prednisona/farmacología , Pregnadienodioles/farmacología , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Estructura Terciaria de Proteína , ARN Mensajero/genética , Células Madre/citología , Factor de Crecimiento Transformador betaRESUMEN
RATIONALE: Asthma prevalence, onset, remission and relapse, and healthcare use have been intensively studied. However, asthma symptom progression through childhood and adolescence has not been well studied, in part due to the challenges in obtaining consistent and robust long-term follow-up data on a large series of subjects with asthma. OBJECTIVES: To use the asthma diary symptom data of the Childhood Asthma Management Program placebo group (5 yr, 418 subjects, and total 564,518 records) to establish sex-specific high-resolution time courses of the natural progression of asthma symptoms through childhood and adolescence. METHODS: We used the asthma diary symptom code as a measure of daily disease severity. Annual records of Tanner stage were used to determine the influence of puberty on severity. A data alignment technique was used to derive 13-year time courses of mean symptoms and mean Tanner stage. MEASUREMENTS AND MAIN RESULTS: Data analyses showed three age- and sex-related phases of asthma symptom progression: Phase 1 (ages 5 and 6 yr)-greater severity in boys; Phase 2 (ages 7 to 9 yr)-no sex difference in severity; and Phase 3 (age 10-17 yr)-greater severity in girls. The continuous decline of symptoms in both sexes stops abruptly at the onset of puberty. CONCLUSIONS: The severity of asthma symptoms varies through childhood and adolescence, and patterns differ by sex. Puberty has a strong influence on symptom progression in both sexes. Progression of symptoms is a distinct aspect of asthma epidemiology.
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Asma/epidemiología , Pubertad , Adolescente , Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Morbilidad/tendencias , Factores de Riesgo , Factores Sexuales , Maduración Sexual , Estados Unidos/epidemiologíaRESUMEN
We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-ß1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-ß1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-ß1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-ß1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony.
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Asma/metabolismo , Células Epiteliales/metabolismo , Mitosis , Factor de Crecimiento Transformador beta1/metabolismo , Afidicolina/administración & dosificación , Bronquios/metabolismo , Bronquios/patología , Células Cultivadas , Medios de Cultivo Condicionados/química , Dexametasona/administración & dosificación , Epitelio/metabolismo , Fibrosis , Humanos , Inflamación , Mucosa Respiratoria/metabolismo , Simvastatina/administración & dosificación , Factores de TiempoRESUMEN
Both Duchenne and golden retriever muscular dystrophy (GRMD) are caused by dystrophin deficiency. The Duchenne muscular dystrophy sartorius muscle and orthologous GRMD cranial sartorius (CS) are relatively spared/hypertrophied. We completed hierarchical clustering studies to define molecular mechanisms contributing to this differential involvement and their role in the GRMD phenotype. GRMD dogs with larger CS muscles had more severe deficits, suggesting that selective hypertrophy could be detrimental. Serial biopsies from the hypertrophied CS and other atrophied muscles were studied in a subset of these dogs. Myostatin showed an age-dependent decrease and an inverse correlation with the degree of GRMD CS hypertrophy. Regulators of myostatin at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) levels were altered in GRMD CS, consistent with down-regulation of myostatin signaling, CS hypertrophy, and functional rescue of this muscle. mRNA and proteomic profiling was used to identify additional candidate genes associated with CS hypertrophy. The top-ranked network included α-dystroglycan and like-acetylglucosaminyltransferase. Proteomics demonstrated increases in myotrophin and spectrin that could promote hypertrophy and cytoskeletal stability, respectively. Our results suggest that multiple pathways, including decreased myostatin and up-regulated miRNAs, α-dystroglycan/like-acetylglucosaminyltransferase, spectrin, and myotrophin, contribute to hypertrophy and functional sparing of the CS. These data also underscore the muscle-specific responses to dystrophin deficiency and the potential deleterious effects of differential muscle involvement.
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Distrofina/deficiencia , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular Animal/patología , Transducción de Señal , Animales , Análisis por Conglomerados , Perros , Distroglicanos/metabolismo , Distrofina/metabolismo , Técnica del Anticuerpo Fluorescente , Glicosilación , Hipertrofia , Péptidos y Proteínas de Señalización Intercelular/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Distrofia Muscular Animal/genética , Miostatina/metabolismo , Tamaño de los Órganos , Fenotipo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Espectrina/metabolismo , Regulación hacia Arriba/genética , Utrofina/metabolismoRESUMEN
OBJECTIVE: This study sought to examine implantation and implantation kinetics in double umbilical cord blood transplantation (DUCBT). METHODS: Twenty-nine patients who underwent a two-unit unrelated donor cord blood transplantation were included in this study. After transplantation, hematopoietic chimerism of the peripheral blood was evaluated based on the results of short tandem repeat polymerase chain reaction. Using these results, we were able to judge whether the transplanted cells implanted, determine which donor's cells implanted, and further examine the kinetics of implantation in DUCBT. The numbers of total nucleated cells (TNCs), CD34(+) cells, colony forming units (CFUs), colony forming unit-granulocytes and macrophages (CFU-GMs), and CD3(+) cells were compared between the dominant units and the non-dominant units in an attempt to understand the discipline and implantation kinetics of DUCBT. RESULTS: Neither the TNC counts nor the counts of CD34(+) cells, CFU, CFU-GM, or CD3(+) cells were significantly different between the dominant units and the non-dominant units (P values of 0.584, 0.322, 0.842, 0.534, and 0.082, respectively). CONCLUSIONS: We were able to determine the engraftment status at 14 days after DUCBT, although the implantation kinetics of DUCBT remain uncharacterized and require further research.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Enfermedades Hematológicas/cirugía , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Quimera por Trasplante , Donante no Emparentado , Adulto JovenRESUMEN
OBJECTIVE: To retrospectively analyze the curative efficacy of umbilical cord blood transplantation (UCBT) with improved myeloablative conditioning regimen (total body irradiation (TBI)/cytosine arabinoside (Ara-c)/cyclophosphamide (CY) without antithymocyte globulin (ATG)) in adult patients with hematological malignancies. METHODS: Forty consecutive adult patients with hematological malignancies received improved myeloablative unrelated CBT at a single center from September 2006 to May 2011. Their average age was (23 ± 6) years and the average weight (58 ± 9) kg. Thirty-five (87.5%) patients were high-risk and 15 (37.5%) at the advanced disease status at pre-transplantation. They received 1 (n = 23) or 2 (n = 17) cord blood units. Seventy-five percent of them were transplanted with 1/2-human leukocyte antigen mismatched unit. The conditioning regimen consisted of 12 Gy TBI, granulocyte colony-stimulating factor (G-CSF) plus Ara-c and CY without ATG. All patients received a combination of cyclosporine (CsA) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD). RESULTS: For the entire group of patients, the average cell doses infused were (4.1 ± 1.1)×107 total nucleated cells/kg and (2.4 ± 1.0)×105 CD34(+) cells/kg. All patients acquired engraftment with an implantation rate of 100%. The average time of absolute neutrophil count (ANC) ≥ 0.5×109/L was (20 ± 5) days and the average time of platelet ≥ 20×109/L was(38 ± 12) days. Acute GVHD occurred in 23 patients (57.5%) and 4 (10.0%) were of grade III-IV. Chronic GVHD occurred in 22.9% (8/35) evaluable patients. Relapse occurred in 12.5% (5/40) patients. During a median follow-up period of 19.8 (range 4.6 - 55.0) months, the transplantation-related mortality was 15.0% (6/40) within 100 days and 35.0% (14/40) within 1 year. The main causes of mortality were pneumonia and severe acute GVHD. Two-year overall survival (OS) or disease-free survival was 58.8% and 58.8%, respectively. Two-year OS for patients with advanced or complete remission disease was 48.6% and 63.8%, respectively. CONCLUSIONS: The TBI/Ara-c/CY myeloablative conditioning regimen is well-tolerated and capable of establishing sustained donor cell engraftment and decreasing the risks of transplant-related death in adults with hematologic malignancies. For the high-risk and advanced patients, it may reduce the occurrences of relapse and chronic GVHD.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Neoplasias Hematológicas/cirugía , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia/cirugía , Masculino , Irradiación Corporal Total , Adulto JovenRESUMEN
Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids--drugs able to retain or improve efficacy associated with transrepression [nuclear factor-κB (NF-κB) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a Δ-9,11 modification as a dissociative steroid. The Δ-9,11 analog showed potent inhibition of tumor necrosis factor-α-induced NF-κB signaling in cell reporter assays, and this transrepression activity was blocked by 17ß-hydroxy-11ß-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The Δ-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GR-luciferase constructs as well as mRNA profiles of treated cells. The Δ-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the Δ-9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a Δ-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, Δ-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.
Asunto(s)
Dronabinol/análogos & derivados , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , FN-kappa B/antagonistas & inhibidores , Elementos de Respuesta/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Dronabinol/química , Dronabinol/farmacología , Femenino , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Ratones Noqueados , FN-kappa B/metabolismo , Elementos de Respuesta/fisiología , Bazo/efectos de los fármacos , Bazo/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVE: In recent years, many studies have revealed the prognosis in patients with non-small cell lung cancer (NSCLC). In general, some clinic-pathological parameters have been related with prognosis. The aim of this study is to detect the relationship among lymphatic vessel density (LVD), microvessel density (MVD), expression of carcinoembryonic antigen (CEA) mRNA, metastasis suppressor genes (KAI1 and Kiss-1), and the prognosis of NSCLC patients. METHODS: Blood samples were collected from 57 cases of NSCLC. The transcription of CEA mRNA was detected via nested reverse transcriptase-polymerase chain reaction and micro-fluid chip. Immunohistochemistry was performed to detect the expression of LVD, MVD, KAI1 and Kiss-1 in the patients. All follow-up data were collected and analyzed. RESULTS: The overall five-year survival rate was 18%, and the median survival was 34 months. TNM stage, lymph node metastasis, and expression of MVD, LVD, CEA mRNA and Kiss-1 were factors to survival, as determined via single survival analysis. Multivariate analysis demonstrated that TNM stage, lymph node metastasis, and expression of CEA mRNA were independent prognostic factors for NSCLC patients. CONCLUSIONS: The expression of MVD, LVD, Kiss-1 and CEA mRNA is related to the prognosis of NSCLC.