RESUMEN

OBJECTIVE: Fetal venous system malformations frequently coincide with cardiac or extracardiac anomalies. This study explores our experience with an integrated fetal echocardiography approach and analyzes the characteristics and outcomes of fetal venous system disorders. MATERIALS AND METHODS: We conducted a retrospective study with 7048 pregnant women (7255 fetuses) who underwent complete two-dimensional (2D) fetal echocardiographic examinations. We primarily employed an integrated 2D approach. Three-/four-dimensional (3D/4D) spatiotemporal image correlation was supplemental. Fetal venous disorders were classified into 3 groups: cardinal (Group 1), umbilical and vitelline (Group 2), and pulmonary (Group 3) systems, based on embryological-anatomical considerations. Maternofetal data were recorded alongside imaging diagnoses. RESULTS: Congenital venous malformations were identified in 98 fetuses, yielding a prevalence of 1.35% (98/7255). Six participants had coexisting venous disorders from different groups. Group 1 included 48 fetuses with persistent left superior vena cava (LSVC) and 3 others (unidentified brachiocephalic vein, left inferior vena cava (IVC), and interrupted IVC with azygous continuation to SVC). Group 2 had 39 fetuses with persistent right umbilical vein and 7 with umbilical-portal-ductus venosus disorders. Group 3 had 7 fetuses with pulmonary venous return disorders. Group 2 showed the most favorable outcomes (alive and without neonatal death), while Group 3 exhibited the poorest. Associated cardiac defects were observed in 43.1% of Group 1, 8.7% of Group 2, and 57.1% of Group 3 (P < 0.001), displaying a broad spectrum of non-specific anomalies. Meanwhile, Group 2 had a greater occurrence of a single venous disorder (93.5%) compared to Group 1 (88.2%) and Group 3 (57.1%) (P = 0.020). CONCLUSION: Our approach offers an integrated strategy for assessing the fetal venous system during fetal echocardiography, providing multiple views to characterize venous anomalies. The presence of a fetal venous disorder may indicate the coexistence of more severe abnormalities, and the prognosis depends on associated anomalies or the venous disorders per se.

Asunto(s)

Ultrasonografía Prenatal , Humanos , Femenino , Embarazo , Estudios Retrospectivos , Ultrasonografía Prenatal/métodos , Adulto , Ecocardiografía/métodos , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/embriología , Venas Umbilicales/diagnóstico por imagen , Venas Umbilicales/anomalías , Venas Umbilicales/embriología , Enfermedades Fetales/diagnóstico por imagen , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/embriología , Relevancia Clínica

RESUMEN

The paracrine actions of adipokine plasminogen activator inhibitor-1 (PAI-1) are implicated in obesity-associated tumorigenesis. Here, we show that PAI-1 mediates extracellular matrix (ECM) signaling via epigenetic repression of DKK1 in endometrial epithelial cells (EECs). While the loss of DKK1 is known to increase ß-catenin accumulation for WNT signaling activation, this epigenetic repression causes ß-catenin release from transmembrane integrins. Furthermore, PAI-1 elicits the disengagement of TIMP2 and SPARC from integrin-ß1 on the cell surface, lifting an integrin-ß1-ECM signaling constraint. The heightened interaction of integrin-ß1 with type 1 collagen (COL1) remodels extracellular fibrillar structures in the ECM. Consequently, the enhanced nanomechanical stiffness of this microenvironment is conducive to EEC motility and neoplastic transformation. The formation of extensively branched COL1 fibrils is also observed in endometrial tumors of patients with obesity. The findings highlight PAI-1 as a contributor to enhanced integrin-COL1 engagement and extensive ECM remodeling during obesity-associated neoplastic development.

Asunto(s)

Matriz Extracelular , Integrina beta1 , Obesidad , Inhibidor 1 de Activador Plasminogénico , beta Catenina , Humanos , Obesidad/metabolismo , Obesidad/patología , Femenino , Inhibidor 1 de Activador Plasminogénico/metabolismo , beta Catenina/metabolismo , Integrina beta1/metabolismo , Matriz Extracelular/metabolismo , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Animales , Osteonectina/metabolismo , Osteonectina/genética , Colágeno/metabolismo , Endometrio/metabolismo , Endometrio/patología , Colágeno Tipo I/metabolismo , Membrana Celular/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Péptidos y Proteínas de Señalización Intercelular

RESUMEN

While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel this engulfment. Here we report that the reverse signaling using CD47 as a receptor additionally enhances a pro-survival function of prostate cancer cells under phagocytic attack. Although low CD47-expressing cancer cells still allow phagocytosis, the reverse signaling delays the process, leading to incomplete digestion of the entrapped cells and subsequent tumor hybrid cell (THC) formation. Viable THCs acquire c-Myc from parental cancer cells to upregulate both M1- and M2-like macrophage polarization genes. Consequently, THCs imitating dual macrophage features can confound immunosurveillance, gaining survival advantage in the host. Furthermore, these cells intrinsically express low levels of androgen receptor and its targets, resembling an adenocarcinoma-immune subtype of metastatic castration-resistant prostate cancer. Therefore, phagocytosis-generated THCs may represent a potential target for treating the disease.

Asunto(s)

Antígeno CD47 , Macrófagos , Metástasis de la Neoplasia , Fagocitosis , Proteínas Proto-Oncogénicas c-myc , Escape del Tumor , Humanos , Masculino , Proteínas Portadoras , Antígeno CD47/metabolismo , Macrófagos/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/inmunología , Transducción de Señal , Escape del Tumor/genética , Escape del Tumor/inmunología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/inmunología , Células Tumorales Cultivadas

RESUMEN

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like" phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.

Asunto(s)

Neoplasias Pulmonares , Macrófagos Asociados a Tumores , Humanos , Animales , Ratones , Células Endoteliales , Transducción de Señal , Diferenciación Celular , Microambiente Tumoral , Línea Celular Tumoral

RESUMEN

OBJECTIVE: Various prophylactic antibiotic regimens are used in the management of preterm premature rupture of membranes. We investigated the efficacy and safety of these regimens in terms of maternal and neonatal outcomes. DATA SOURCES: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 20, 2021. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials involving pregnant women with preterm premature rupture of membranes before 37 weeks of gestation and a comparison of ≥2 of the following 10 antibiotic regimens: control/placebo, erythromycin, clindamycin, clindamycin plus gentamicin, penicillins, cephalosporins, co-amoxiclav, co-amoxiclav plus erythromycin, aminopenicillins plus macrolides, and cephalosporins plus macrolides. METHODS: Two investigators independently extracted published data and assessed the risk of bias with a standard procedure following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Network meta-analysis was conducted using the random-effects model. RESULTS: A total of 23 studies that recruited a total of 7671 pregnant women were included. Only penicillins (odds ratio, 0.46; 95% confidence interval, 0.27-0.77) had significantly superior effectiveness for maternal chorioamnionitis. Clindamycin plus gentamicin reduced the risk of clinical chorioamnionitis, with borderline significance (odds ratio, 0.16; 95% confidence interval, 0.03-1.00). By contrast, clindamycin alone increased the risk of maternal infection. For cesarean delivery, no significant differences were noted among these regimens. CONCLUSION: Penicillins remain the recommended antibiotic regimen for reducing maternal clinical chorioamnionitis. The alternative regimen includes clindamycin plus gentamicin. Clindamycin should not be used alone.

Asunto(s)

Corioamnionitis , Nacimiento Prematuro , Recién Nacido , Embarazo , Femenino , Humanos , Clindamicina/efectos adversos , Corioamnionitis/diagnóstico , Corioamnionitis/epidemiología , Corioamnionitis/prevención & control , Combinación Amoxicilina-Clavulanato de Potasio , Metaanálisis en Red , Antibacterianos/efectos adversos , Nacimiento Prematuro/prevención & control , Eritromicina/efectos adversos , Macrólidos/uso terapéutico , Gentamicinas/efectos adversos , Cefalosporinas

RESUMEN

BACKGROUND: Placenta mesenchymal dysplasia (PMD) is a rare placental anomaly associated with various fetal and maternal complications. Whether close ultrasound surveillance can prevent intrauterine fetal demise (IUFD) in patients with PMD is still under investigation. Amniotic fluid embolism (AFE) is a rare, lethal, and unpredictable maternal complication that has never been described in association with PMD. Here, we report a case of PMD, in which the fetus eventually demised in utero despite weekly color Doppler monitoring, and the mother subsequently encountered AFE during delivery. CASE PRESENTATION: A 43-year-old woman who had received three frozen embryo transfer, was found to have a singleton pregnancy with an enlarged multi-cystic placenta at 8 weeks' gestation. Fetal growth restriction (FGR) was noted since the 21stweek. The fetus eventually demised in-utero at 25 weeks despite weekly color Doppler surveillance. Cesarean section was performed under general anesthesia due to placenta previa totalis and antepartum hemorrhage. During surgery, the patient experienced a sudden blood pressure drop and desaturation followed by profound coagulopathy. AFE was suspected. After administration of inotropic agents and massive blood transfusion, the patient eventually survived AFE. PMD was confirmed after pathological examination of the placenta. CONCLUSIONS: While FGR can be monitored by color Doppler, our case echoed previous reports that IUFD may be unpreventable even under intensive surveillance in PMD cases. Although AFE is usually considered unpredictable, PMD can result in cumulative risk factors contributing to AFE. Whether a specific link exists between the pathophysiology of PMD and AFE requires further investigation.

Asunto(s)

Embolia de Líquido Amniótico , Placenta Previa , Humanos , Femenino , Embarazo , Adulto , Embolia de Líquido Amniótico/diagnóstico por imagen , Embolia de Líquido Amniótico/etiología , Placenta/patología , Cesárea/efectos adversos , Muerte Fetal/etiología , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/etiología , Retardo del Crecimiento Fetal/patología

RESUMEN

The epigenome delineates lineage-specific transcriptional programs and restricts cell plasticity to prevent non-physiological cell fate transitions. Although cell diversification fosters tumor evolution and therapy resistance, upstream mechanisms that regulate the stability and plasticity of the cancer epigenome remain elusive. Here we show that 2-hydroxyglutarate (2HG) not only suppresses DNA repair but also mediates the high-plasticity chromatin landscape. A combination of single-cell epigenomics and multi-omics approaches demonstrates that 2HG disarranges otherwise well-preserved stable nucleosome positioning and promotes cell-to-cell variability. 2HG induces loss of motif accessibility to the luminal-defining transcriptional factors FOXA1, FOXP1, and GATA3 and a shift from luminal to basal-like gene expression. Breast tumors with high 2HG exhibit enhanced heterogeneity with undifferentiated epigenomic signatures linked to adverse prognosis. Further, ascorbate-2-phosphate (A2P) eradicates heterogeneity and impairs growth of high 2HG-producing breast cancer cells. These findings suggest 2HG as a key determinant of cancer plasticity and provide a rational strategy to counteract tumor cell evolution.

Asunto(s)

Cromatina/metabolismo , Glutaratos/metabolismo , Oxidorreductasas de Alcohol/metabolismo , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Reparación del ADN/fisiología , Epigenoma/genética , Factores de Transcripción Forkhead/genética , Expresión Génica/genética , Regulación de la Expresión Génica/genética , Humanos , Isocitrato Deshidrogenasa/genética , Neoplasias/genética , Neoplasias/metabolismo , Nucleosomas/metabolismo , Proteínas Represoras/genética

RESUMEN

Endometriosis is a debilitating gynecologic disorder that affects ∼10% of women of reproductive age. Endometriosis is characterized by growth of endometriosis lesions within the abdominal cavity, generally thought to arise from retrograde menstruation of shed endometrial tissue. While the pathophysiology underlying peritoneal endometriosis lesion formation is still unclear, the interaction between invading endometrial tissue and the peritoneal mesothelial lining is an essential step in lesion formation. In this study, we assessed proteomic differences between eutopic endometrial stromal cells (ESCs) from women with and without endometriosis in response to peritoneal mesothelial cell (PMC) exposure, using single-cell cytometry by time-of-flight (CyTOF). Co-cultured primary eutopic ESCs from women with and without endometriosis with an established PMC line were subjected to immunostaining with a panel of Maxpar CyTOF metal-conjugated antibodies (n = 28) targeting cell junction and mesenchymal markers, which are involved in cell-cell adhesions and epithelial-mesenchymal transition. Exposure of the ESCs to PMCs resulted in a drastic shift in cellular expression profiles in ESCs derived from endometriosis, whereas little effect by PMCs was observed in ESCs from non-endometriosis subjects. The transcription factor SNAI1 was consistently repressed by PMC interactions. ESCs from endometriosis patients are unique in that they respond to PMCs by undergoing changes in adhesive properties and mesenchymal characteristics that would facilitate lesion formation.

Asunto(s)

Biomarcadores/metabolismo , Endometriosis/metabolismo , Endometrio/citología , Epitelio/metabolismo , Uniones Intercelulares/metabolismo , Proteómica/métodos , Células Cultivadas , Técnicas de Cocultivo , Biología Computacional , Endometrio/metabolismo , Endometrio/patología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Humanos , Análisis de la Célula Individual , Células del Estroma/citología , Células del Estroma/metabolismo

RESUMEN

3-n-Butylphthalide (NBP) is a potent drug for the treatment of ischemic stroke. The aim of this study was to develop a simple and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method for the simultaneous determination of NBP and its circulating metabolite 10-hydroxy-NBP in rat plasma using senkyunolide I as the internal standard (IS). The analytes and IS were extracted from the plasma by ethyl acetate-ethyl ether (1:5, v/v) and then separated on an ACQUITY BEH C18 column (2.1 × 50 mm, 1.7 µm). The mobile phase consisted of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid, which was delivered at a flow rate of 0.3 mL/min with gradient elution. MS detection was achieved under selective reaction monitoring mode with precursor-to-product transitions at m/z 191.1 > 145.1 for NBP, m/z 207.1 > 171.1 for 10-hydroxy-NBP and m/z 207.1 > 161.1 for IS, respectively. The assay showed excellent linearity over the concentration range of 0.5-1000 ng/mL for both analytes, with correlation coefficient greater than 0.998. The other validation parameters were all within the required limits. The validated UPLC-MS/MS method has been further applied to the pharmacokinetic study of NBP and 10-hydroxy-NBP in rats after they were orally administered with NBP (30 mg/kg).

Asunto(s)

Benzofuranos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Animales , Benzofuranos/sangre , Benzofuranos/química , Benzofuranos/metabolismo , Benzofuranos/farmacocinética , Límite de Detección , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados

RESUMEN

OBJECTIVE: Microbial contamination of ART culture media is rare but serious. We examined our own experience and conducted a review of the literature with a view to preventing its occurrence and recurrence. CASE REPORT: A total of 12 cases were recorded during January 2006 to March 2019. The contaminations were caused by semen and were shown to be bacteria that were resistant to the prophylactic antibiotics used in the medium. After the procedures were cancelled due to contaminations, nine husbands received antibiotic treatment, while nine couples changed over to the ICSI program. Eventually, eight couples concluded the study with live birth deliveries, and there was no recurrence of contamination. CONCLUSION: ART laboratories should preserve all sperm suspension samples until embryo transfer has been completed for the purpose of checking whether contamination has occurred. In addition to antibiotic treatment, implementation of the ICSI procedure during the next ART cycle has already been proven to be effective. In the future, the zona-removal technique may be considered as another potential option.

Asunto(s)

Medios de Cultivo , Técnicas Reproductivas Asistidas , Preservación de Semen/métodos , Semen/microbiología , Recuperación de la Esperma/efectos adversos , Adulto , Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Femenino , Humanos , Nacimiento Vivo , Masculino , Embarazo , Análisis de Semen , Manejo de Especímenes/métodos , Inyecciones de Esperma Intracitoplasmáticas

RESUMEN

While plasminogen activator inhibitor-1 (PAI-1) is known to potentiate cellular migration via proteolytic regulation, this adipokine is implicated as an oncogenic ligand in the tumor microenvironment. To understand the underlying paracrine mechanism, here, we conduct transcriptomic analysis of 1,898 endometrial epithelial cells (EECs) exposed and unexposed to PAI-1-secreting adipose stromal cells. The PAI-1-dependent action deregulates crosstalk among tumor-promoting and tumor-repressing pathways, including transforming growth factor ß (TGF-ß). When PAI-1 is tethered to lipoprotein receptor-related protein 1 (LRP1), the internalized signaling causes downregulation of SMAD4 at the transcriptional and post-translational levels that attenuates TGF-ß-related transcription programs. Repression of genes encoding the junction and adhesion complex preferentially occurs in SMAD4-underexpressed EECs of persons with obesity. The findings highlight a role of PAI-1 signaling that renders ineffective intercellular communication for the development of adiposity-associated endometrial cancer.

Asunto(s)

Neoplasias Endometriales/metabolismo , Moléculas de Adhesión de Unión/metabolismo , Obesidad/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteína Smad4/metabolismo , Tejido Adiposo/patología , Regulación hacia Abajo/genética , Neoplasias Endometriales/complicaciones , Neoplasias Endometriales/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Obesidad/complicaciones , Unión Proteica , Proteolisis , Proteómica , Proteína Smad4/genética , Células del Estroma/metabolismo , Transcripción Genética , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Ubiquitina/metabolismo

RESUMEN

BACKGROUND: Polyethylene glycol (PEG) is widely used in industry and medicine. Anti-PEG antibodies have been developed for characterizing PEGylated drugs and other applications. However, the underlying mechanism for specific PEG binding has not been elucidated. METHODS: The Fab of two cognate anti-PEG antibodies 3.3 and 2B5 were each crystallized in complex with PEG, and their structures were determined by X-ray diffraction. The PEG-Fab interactions in these two crystals were analyzed and compared with those in a PEG-containing crystal of an unrelated anti-hemagglutinin 32D6-Fab. The PEG-binding stoichiometry was examined by using analytical ultracentrifuge (AUC). RESULTS: A common PEG-binding mode to 3.3 and 2B5 is seen with an S-shaped core PEG fragment bound to two dyad-related Fab molecules. A nearby satellite binding site may accommodate parts of a longer PEG molecule. The core PEG fragment mainly interacts with the heavy-chain residues D31, W33, L102, Y103 and Y104, making extensive contacts with the aromatic side chains. At the center of each half-circle of the S-shaped PEG, a water molecule makes alternating hydrogen bonds to the ether oxygen atoms, in a similar configuration to that of a crown ether-bound lysine. Each satellite fragment is clamped between two arginine residues, R52 from the heavy chain and R29 from the light chain, and also interacts with several aromatic side chains. In contrast, the non-specifically bound PEG fragments in the 32D6-Fab crystal are located in the elbow region or at lattice contacts. The AUC data suggest that 3.3-Fab exists as a monomer in PEG-free solution but forms a dimer in the presence of PEG-550-MME, which is about the size of the S-shaped core PEG fragment. CONCLUSIONS: The differing amino acids in 3.3 and 2B5 are not involved in PEG binding but engaged in dimer formation. In particular, the light-chain residue K53 of 2B5-Fab makes significant contacts with the other Fab in a dimer, whereas the corresponding N53 of 3.3-Fab does not. This difference in the protein-protein interaction between two Fab molecules in a dimer may explain the temperature dependence of 2B5 in PEG binding, as well as its inhibition by crown ether.

Asunto(s)

Anticuerpos Monoclonales de Origen Murino/química , Especificidad de Anticuerpos , Sitios de Unión de Anticuerpos , Fragmentos Fab de Inmunoglobulinas/química , Polietilenglicoles/química , Cristalografía por Rayos X

RESUMEN

High-risk neuroblastoma is associated with low long-term survival rates due to recurrence or metastasis. Retinoids, including 13-cis-retinoic acid (13cRA), are commonly used for the treatment of high-risk neuroblastoma after myeloablative therapy; however, there are significant side effects and resistance rates. In this study, we demonstrated that 13cRA has a better antiproliferative effect in MYCN-amplified neuroblastoma cells than in MYCN-nonamplified neuroblastoma cells. In MYCN-amplified SK-N-DZ cells, 13cRA induced significant upregulation of toll-like receptor 3 (TLR3) and mitochondrial antiviral-signaling protein (MAVS) expression in a time-dependent manner. Furthermore, poly (I:C), a synthetic agonist of TLR3, effectively synergized with 13cRA to enhance antiproliferative effects through upregulation of the innate immune signaling and the mitochondrial stress response, leading to augmentation of the apoptotic response in 13cRA-responsive cancer cells. In addition, the 13cRA/poly (I:C) combination induced neural differentiation through activation of retinoic acid receptors beta (RAR-ß), restoring expression of α-thalassemia/mental retardation syndrome X-linked (ATRX) protein, and inhibiting vessel formation, leading to retarded tumor growth in a mouse xenograft model. These results suggest that the combination of poly (I:C) and RA may provide synergistic therapeutic benefits for treatment of patients with high-risk neuroblastoma.

Asunto(s)

Apoptosis/efectos de los fármacos , Isotretinoína/farmacología , Neuroblastoma/metabolismo , Poli I-C/farmacología , Receptor Toll-Like 3/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Factores Inmunológicos/farmacología , Masculino , Ratones , Ratones SCID , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Social and economic problems related to population aging are becoming increasingly prevalent in many industrialized nations. Moreover, life-related stresses is causing caregivers to become fatigued and exhausted, with some even choosing to end their life due to their overwhelming burdens of care. Evidence demonstrates that failure to cope effectively with the burdens of care greatly increases the risk of personal physical, mental, and family problems for the caregivers. Therefore, caregiver burden is an increasingly important issue and challenge for the long-term care service system. Positive psychology has been studied widely in recent years, and current related research has focused on exploring caregivers' positive coping experiences. Empirical studies indicate that caregivers overcome crisis because they acquire coping strategies and learn to adjust during the caring process. Furthermore, these articles show the successful handling of caring stress to be highly correlated with resilience. This research examined caregiver's burden and resilience. The findings suggest how nurses may identify the potential of caregivers in the caring processing and what kind of support that nurses should provide to caregivers. Further, this study elaborates on how caregivers build resilience. According to the literature, current nursing interventions should enhance caregiver's resilience. In general, this research aimed to offer a new direction for long-term care based on positive energy and caregiver resilience. It is hoped that this introduction provides insights for healthcare professionals in clinical practices.

Asunto(s)

Adaptación Psicológica , Cuidadores/psicología , Resiliencia Psicológica , Estrés Psicológico/psicología , Humanos

RESUMEN

Influenza is a contagious acute respiratory disease caused by the influenza virus infection. Hemagglutinin (HA) is an important target in the therapeutic treatment and diagnostic detection of the influenza virus. Influenza A virus encompasses several different HA subtypes with different strains, which are constantly changing. In this study, we identified a fully human H1N1 neutralizing antibody (32D6) via an Epstein-Barr virus-immortalized B cell-based technology. 32D6 specifically neutralizes the clinically isolated H1N1 strains after the 2009 pandemic but not the earlier strains. The epitope was identified through X-ray crystallographic analysis of the 32D6-Fab/HA1 complex structure, which revealed a unique loop conformation located on the top surface of HA. The major region is composed of two peptide segments (residues 172-177 and 206-213), which form an abreast loop conformation. The residue T262 between the two loops forms a conformational epitope for recognition by 32D6. Three water molecules were observed at the interface of HA and the heavy chain, and they may constitute a stabilizing element for the 32D6-HA association. In addition, each 32D6-Fab is likely capable of blocking one HA trimer. This study provides important information on the strain specificity of 32D6 for the therapeutic treatment and detection of viral infection.

Asunto(s)

Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/virología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/química , Anticuerpos Antivirales/metabolismo , Linfocitos B/metabolismo , Cristalografía por Rayos X , Epítopos/inmunología , Epítopos/metabolismo , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Humanos , Gripe Humana/inmunología , Gripe Humana/metabolismo , Pruebas de Neutralización , Conformación Proteica

RESUMEN

Emerging evidence indicates that adipose stromal cells (ASC) are recruited to enhance cancer development. In this study, we examined the role these adipocyte progenitors play relating to intercellular communication in obesity-associated endometrial cancer. This is particularly relevant given that gap junctions have been implicated in tumor suppression. Examining the effects of ASCs on the transcriptome of endometrial epithelial cells (EEC) in an in vitro coculture system revealed transcriptional repression of GJA1 (encoding the gap junction protein Cx43) and other genes related to intercellular communication. This repression was recapitulated in an obesity mouse model of endometrial cancer. Furthermore, inhibition of plasminogen activator inhibitor 1 (PAI-1), which was the most abundant ASC adipokine, led to reversal of cellular distribution associated with the GJA1 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort (n = 141), DNA hypermethylation of GJA1 and related loci TJP2 and PRKCA was observed in primary endometrial endometrioid tumors and was associated with obesity. Pharmacologic reversal of DNA methylation enhanced gap-junction intercellular communication and cell-cell interactions in vitro. Restoring Cx43 expression in endometrial cancer cells reduced cellular migration; conversely, depletion of Cx43 increased cell migration in immortalized normal EEC. Our data suggest that persistent repression by ASC adipokines leads to promoter hypermethylation of GJA1 and related genes in the endometrium, triggering long-term silencing of these loci in endometrial tumors of obese patients. SIGNIFICANCE: Studies reveal that adipose-derived stem cells in endometrial cancer pathogenesis influence epigenetic repression of gap junction loci, which suggests targeting of gap junction activity as a preventive strategy for obesity-associated endometrial cancer.

Asunto(s)

Adipoquinas/farmacología , Tejido Adiposo/patología , Comunicación Celular , Conexina 43/genética , Neoplasias Endometriales/patología , Represión Epigenética , Obesidad/complicaciones , Tejido Adiposo/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Conexina 43/metabolismo , Dieta Alta en Grasa/efectos adversos , Neoplasias Endometriales/etiología , Neoplasias Endometriales/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Uniones Comunicantes , Humanos , Masculino , Ratones , Ratones Noqueados , Obesidad/fisiopatología , Células del Estroma/metabolismo , Células del Estroma/patología

RESUMEN

The innate immune receptors, such as toll-like receptor 3 (TLR3), melanoma differentiation-associated 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I), have been shown to be differentially expressed in neuroblastoma (NB) and promote dsRNA poly (I:C)-induced NB suppression in vitro and in vivo. However, the role of another important innate immune cytosolic sensor, laboratory of genetics and physiology 2 (LGP2), in the cancer behavior of NB remains unclear. Here, we demonstrated that the expression levels of LGP2 were either low or undetectable in all NB cell lines tested with or without MYCN amplification. LGP2 expression levels were significantly increased only in NB cells without MYCN amplification, including SK-N-AS and SK-N-FI after poly (I:C) treatment in vitro and in mouse xenograft models. Ectopic expression of LGP2 in NB cells significantly enhanced poly (I:C)-induced NB cell death associated with downregulation of MDA5, RIG-I, MAVS and Bcl-2, as well as upregulation of Noxa and tBid. By immunofluorescence analyses, LGP2 localized mainly in the cytoplasm of NB cells after poly (I:C) treatment. In human NB tissue samples, cytoplasmic LGP2 expression was positively correlated with histological differentiation and inversely correlated with MYCN amplification. Positive cytoplasmic LGP2 expression in tumor tissues could predict a favorable outcome in NB patients independent of other prognostic factors. In short, LGP2 was effective in promoting poly (I:C)-induced NB suppression and cytoplasmic LGP2 can serve as an independent favorable prognostic factor in NB patients.

Asunto(s)

Citoplasma/metabolismo , Regulación hacia Abajo , Neuroblastoma/metabolismo , ARN Helicasas/genética , ARN Helicasas/metabolismo , Animales , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Preescolar , Citoplasma/genética , Femenino , Humanos , Inmunidad Innata , Lactante , Masculino , Ratones , Trasplante de Neoplasias , Neuroblastoma/genética , Poli I-C/farmacología , Pronóstico

RESUMEN

Esophageal cancer (EC) is one of the most common cancers in China. The purpose of this study was to investigate the updated incidence rates and risk factors of EC in Nan'ao Island, where the EC incidence rate was chronically the highest in southern China. To calculate the annual incidence rate, data on 338 EC cases from Nan'ao Cancer Registry system diagnosed during 2005-2011 were collected. A case-control study was conducted to explore the EC risk factors. One hundred twenty-five alive EC patients diagnosed during 2005-2011 and 250 controls were enrolled into the case-control study. A pre-test questionnaire on demography, dietary factors, drinking water treatment, and behavioral factors was applied to collect information of all participants. The average EC incidence rates during 2005-2011 were 66.09/105, 94.62/105, 36.83/105 for both genders, males and females, respectively, in Nan'ao Island. The EC incidence rate in males was 2.40- to 4.55-fold higher than that in females in the period from 2006 to 2011 (P < 0.05). Considering the onset age, males tend to be much younger than females and reached peak incidence rate at a younger age (P < 0.05). Drinking water treatment by filter (odds ratio [OR] = 0.28, 95% confidence interval [95% CI] = 0.13-0.58) and fruit consumption (OR = 0.55, 95% CI = 0.32-0.94) reduced the risk for EC. On the contrary, the pickled vegetables consumption (OR = 2.64, 95% CI = 1.46-4.76) and liquor drinking (OR = 2.32, 95% CI = 1.21-4.44) increased the risk for EC. These results may be of importance for future research on EC etiology and prevention strategies.

Asunto(s)

Adenocarcinoma/epidemiología , Consumo de Bebidas Alcohólicas/epidemiología , Carcinoma de Células Escamosas/epidemiología , Dieta/estadística & datos numéricos , Neoplasias Esofágicas/epidemiología , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , China/epidemiología , Agua Potable , Femenino , Conservación de Alimentos , Frutas , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores Protectores , Factores de Riesgo , Distribución por Sexo , Verduras

RESUMEN

Diabetes is a huge problem that has been recognized as an important healthcare issue by most national governments. Diabetes affects patients not only in terms of physical health but also in terms of mental health. Furthermore, the medical costs that are associated with diabetes are considerable. Many countries have developed integrated care models for the treatment of diabetes and pay particular attention to assisting patients that require complicated care. Evidence from empirical studies shows that the integrated care of diabetes reduces complications, increases patients' health literacy, and decreases medical costs. Accordingly, integrated care has been applied to the treatment and care of diabetes patients. In the integrated care model, patients not only receive multidisciplinary care during hospitalization but also receive medical services after their return to the community. There has been a dearth of scholarly discussions in Taiwan related to the integrated care of diabetes. Therefore, we present in this paper the concept of integrated diabetes care and the role of the advanced practice nurse (APN) in the multidisciplinary model. It is hoped that this introduction provides practical insights for healthcare professionals into the essence of integrated care.

Asunto(s)

Prestación Integrada de Atención de Salud , Diabetes Mellitus/terapia , Diabetes Mellitus/enfermería , Humanos , Rol de la Enfermera

RESUMEN

Neuroblastoma (NB) is the deadliest pediatric solid tumor due to its pleomorphic molecular characteristics. In the innate immune system, toll-like receptor 3 (TLR3) recognizes viral double-stranded RNAs to initiate immune signaling. Positive TLR3 expression indicates a favorable prognosis in NB patients, and is associated with MYCN-non-amplified. However, TLR3-mediated innate immune responses remain elusive in NB. In this study, we attempted to dissect the molecular mechanism underlying TLR3-agonist polyinosinic-polycytidylic acid [poly(I:C)] treatment in NB in vivo. We established NB xenograft models in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice with MYCN-amplified SK-N-DZ (DZ) cells or MYCN-non-amplified SK-N-AS (AS) cells. Poly(I:C) treatment led to significant tumor regression in AS xenografts, but not in DZ xenografts. Through immunohistochemical analysis, significant suppression of tumor proliferation, downregulation of c-Myc expression, and upregulation of TLR3 expression were found in the treatment group. Poly(I:C) inducing activation of TLR3/IRF3-mediated innate immunity associated with downregulation of c-Myc can be found in MYCN-non-amplified SK-N-AS cells, but not in MYCN-amplified BE(2)-M17 cells. Knockdown of TLR3 disturbed poly(I:C)-induced suppression of c-Myc and upregulation of p-IRF3 in AS cells. Furthermore, poly(I:C) treatment upregulated active NF-κB, mitochondrial antioxidant manganese superoxide dismutase and 8-hydroxydeoxyguanosine, which works with reactive oxygen species (ROS) generation and DNA damage. Upregulation of active caspase 3 and cleaved poly [ADP-ribose] polymerase 1 were found in poly(I:C)-treated AS xenografts, which indicates the induction of apoptosis. Thus, our results suggest that c-Myc overexpression may increase sensitivity to poly(I:C)-induced tumor growth arrest and ROS-mediated apoptosis in NB. This study demonstrates that c-Myc protein expression has an important role in TLR3-induced innate immune responses, providing future treatment recommendations.

Asunto(s)

Genes myc , Neuroblastoma/genética , Neuroblastoma/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptor Toll-Like 3/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Xenoinjertos , Humanos , Inmunidad Innata , Inmunoterapia , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , FN-kappa B/metabolismo , Neuroblastoma/terapia , Poli I-C/farmacología , Interferencia de ARN , Especies Reactivas de Oxígeno/metabolismo , Receptor Toll-Like 3/agonistas , Receptor Toll-Like 3/genética , Regulación hacia Arriba/efectos de los fármacos