Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 930
Filtrar
Más filtros

Tipo del documento
Intervalo de año de publicación
1.
Cell ; 184(10): 2649-2664.e18, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33848463

RESUMEN

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling.


Asunto(s)
Condensados Biomoleculares/metabolismo , Gránulos Citoplasmáticos/metabolismo , Neoplasias/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proteínas ras/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Activación Enzimática , Proteína Adaptadora GRB2/genética , Proteína Adaptadora GRB2/metabolismo , Células HEK293 , Humanos , Proteína SOS1/metabolismo , Transducción de Señal
2.
Cell ; 150(3): 549-62, 2012 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-22863008

RESUMEN

Heat-Shock Factor 1 (HSF1), master regulator of the heat-shock response, facilitates malignant transformation, cancer cell survival, and proliferation in model systems. The common assumption is that these effects are mediated through regulation of heat-shock protein (HSP) expression. However, the transcriptional network that HSF1 coordinates directly in malignancy and its relationship to the heat-shock response have never been defined. By comparing cells with high and low malignant potential alongside their nontransformed counterparts, we identify an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock. Cancer-specific genes in this program support oncogenic processes: cell-cycle regulation, signaling, metabolism, adhesion and translation. HSP genes are integral to this program, however, many are uniquely regulated in malignancy. This HSF1 cancer program is active in breast, colon and lung tumors isolated directly from human patients and is strongly associated with metastasis and death. Thus, HSF1 rewires the transcriptome in tumorigenesis, with prognostic and therapeutic implications.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Células Cultivadas , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Genoma Humano , Factores de Transcripción del Choque Térmico , Humanos , Neoplasias/patología , Factores de Transcripción/análisis , Factores de Transcripción/genética
3.
Immunity ; 47(3): 498-509.e6, 2017 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-28916264

RESUMEN

Double-stranded RNA (dsRNA) is a common by-product of viral infections and acts as a potent trigger of antiviral immunity. In the nematode C. elegans, sid-1 encodes a dsRNA transporter that is highly conserved throughout animal evolution, but the physiological role of SID-1 and its orthologs remains unclear. Here, we show that the mammalian SID-1 ortholog, SIDT2, is required to transport internalized extracellular dsRNA from endocytic compartments into the cytoplasm for immune activation. Sidt2-deficient mice exposed to extracellular dsRNA, encephalomyocarditis virus (EMCV), and herpes simplex virus 1 (HSV-1) show impaired production of antiviral cytokines and-in the case of EMCV and HSV-1-reduced survival. Thus, SIDT2 has retained the dsRNA transport activity of its C. elegans ortholog, and this transport is important for antiviral immunity.


Asunto(s)
Inmunidad Innata , Proteínas de la Membrana/metabolismo , Transporte de ARN , ARN Bicatenario/inmunología , ARN Bicatenario/metabolismo , Animales , Infecciones por Cardiovirus/genética , Infecciones por Cardiovirus/inmunología , Línea Celular , Citoplasma , Proteína 58 DEAD Box/metabolismo , Modelos Animales de Enfermedad , Virus de la Encefalomiocarditis/genética , Virus de la Encefalomiocarditis/inmunología , Endosomas/metabolismo , Femenino , Expresión Génica , Técnicas de Inactivación de Genes , Herpes Simple/genética , Herpes Simple/inmunología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/inmunología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Lisosomas/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Proteínas de Transporte de Nucleótidos , Unión Proteica , Transporte de Proteínas , ARN Viral/genética , ARN Viral/metabolismo , Transducción de Señal , Receptor Toll-Like 3/metabolismo
4.
EMBO Rep ; 25(10): 4542-4569, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39271776

RESUMEN

High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the malignant transformation of FTECs. HPV prevents FTECs from natural replicative and YAP1-induced senescence, thereby promoting YAP1-induced malignant transformation of FTECs. HPV also stimulates proliferation and drives metastasis of YAP1-transformed FTECs. YAP1, in turn, stimulates the expression of the putative HPV receptors and suppresses the innate immune system to facilitate HPV acquisition. These findings provide critical clues for developing new strategies to prevent and treat HGSOC.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Transformación Celular Neoplásica , Células Epiteliales , Trompas Uterinas , Factores de Transcripción , Proteínas Señalizadoras YAP , Humanos , Femenino , Proteínas Señalizadoras YAP/metabolismo , Células Epiteliales/virología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Transformación Celular Neoplásica/genética , Trompas Uterinas/patología , Trompas Uterinas/virología , Trompas Uterinas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Papillomaviridae/genética , Proliferación Celular , Animales , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/complicaciones , Neoplasias Ováricas/patología , Neoplasias Ováricas/virología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Ratones , Inmunidad Innata
5.
Breast Cancer Res ; 26(1): 132, 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39272208

RESUMEN

BACKGROUND: Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures. METHODS: We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan-Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering. RESULTS: The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences-expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival. CONCLUSIONS: The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Receptores Androgénicos , Receptores de Calcitriol , Receptores de Estrógenos , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Pronóstico , Receptores de Estrógenos/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Estimación de Kaplan-Meier , Transcriptoma
6.
Genes Dev ; 30(7): 870, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-27036968

RESUMEN

In the above-mentioned article, it has come to the authors' attention that, during the preparation of Figure 5C and Supplemental Figure S2C for the final version of this article, the authors unintentionally assembled incorrect tubulin immunoblots due to similarities in the markings or names, such as FLT3 versus FT, between two similar experiments. The amended versions of these figures are shown below. Neither the quantitative determinations nor the conclusions of this article are altered. The authors apologize for these errors.

7.
Zhonghua Yu Fang Yi Xue Za Zhi ; 58(6): 875-882, 2024 Jun 06.
Artículo en Zh | MEDLINE | ID: mdl-38955736

RESUMEN

Objective: To explore the relationship between serum 1, 5-dehydratoglucitol (1, 5-AG) level and insulin resistance, microvascular complications in patients with type 2 diabetes mellitus (T2DM). Methods: The clinical data of 836 patients with T2DM admitted to the Changsha Central Hospital Affiliated to University of South China from May to December 2023 were retrospectively and cross-sectionally analyzed. Serum 1, 5-AG levels were detected by pyranose oxidase method. According to the microvascular complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy), the patients were divided into simple group (no microvascular complications, n=490), complication group 1 (1 microvascular complications, n=217), and complication group 2 (2 or more microvascular complications, n=129). The relationship between serum 1, 5-AG level and the related indicators of insulin resistance in T2DM patients were explored by Spearman correlation analysis, and the influencing factors of microvascular complications in T2DM patients were explored by multiple ordered logistic regression analysis. Results: The levels of FBG(fasting blood glucose) [(7.37±0.56) mmol/L], FINS(fasting insulin) [(11.34±1.86) mU/L] and HOMA-IR(homeostatic model assessment of insulin resistance) (0.96±0.31) in simple group were lower than those in complication group 1 [(8.37±1.02) mmol/L, (16.26±2.32) mU/L, (1.32±0.41)], complication group 2 [(10.25±2.13) mmol/L, (18.53±2.67) mU/L, (1.54±0.44)], and FBG, FINS and HOMA-IR in complication group 1 were lower than those in complication group 2, and the differences were statistically significant (F=537.470, 791.690, 136.340, P<0.001). Serum 1, 5-AG level in simple group [77.16 (16.30, 128.07) µg/ml] was higher than that in complication group 1 [51.05 (14.67, 63.18) µg/ml] and complication group 2 [30.42 (12.53, 47.26) µg/ml], and the serum level of 1, 5-AG in complication group 1 was higher than that in complication group 2, and the difference was statistically significant (H=210.020, P<0.001). The results of Spearman correlation analysis showed that serum 1, 5-AG level was negatively correlated with FBG, FINS and HOMA-IR in T2DM patients (r=-0.431, -0.372, -0.546, P<0.001). The results of multiple ordered logistic regression analysis showed that Longer duration of diabetes (OR=2.261, 95%CI: 1.564-3.269), increased HbA1c (OR=2.040, 95%CI: 1.456-2.858), and increased HOMA-IR (OR=2.158, 95%CI: 1.484-3.137) and decreased 1, 5-AG (OR=2.512, 95%CI: 1.691-3.732) were independent risk factors for microvascular complications in T2DM patients (P<0.05). The results of ROC curve analysis showed that the area under the curve of serum 1, 5-AG in the identification of one microvascular complication was 0.763 (95%CI: 0.731-0.795), and the area under the curve of serum 1, 5-AG in the identification of two or more microvascular complications was 0.730 (95%CI: 0.692-0.767). Conclusion: Serum 1, 5-AG level is negatively correlated with insulin resistance in T2DM patients. Low serum 1, 5-AG level may be an independent risk factor for microvascular complications in T2DM patients.


Asunto(s)
Desoxiglucosa , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Estudios Transversales , Estudios Retrospectivos , Desoxiglucosa/sangre , Desoxiglucosa/análogos & derivados , Glucemia , Masculino , Femenino , Insulina/sangre , Persona de Mediana Edad , Angiopatías Diabéticas/sangre
8.
Med J Malaysia ; 79(Suppl 1): 197-202, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38555905

RESUMEN

INTRODUCTION: The ankles and feet of footballers are the most commonly affected areas by acute and chronic injuries, especially sprains. The durability of changes in motor control for the sprained injury strongly suggests that central motor commands have been reorganized and restructured involving the sensorimotor system. Indirectly, providing strength training improves muscular strength and benefits cardiometabolic health, coordination, sensorimotor, and motor performance. Thus, this study aimed to identify the effects of strengthening exercises on motor control among footballers with sprained ankles. MATERIALS AND METHODS: This scoping review selected studies published from January 2002 to November 2022. The articles were searched through PubMed Central, BMJ Journal, Science Direct, and Scopus using "motor control", "ankle sprain" and "strengthening exercise" as the keywords. After finding the articles, the information extracted included author, year of publication, country, objective, type of study, and motor control analysis summary. The literature search strategy used Preferred Reporting Items for Systematic Review and a meta-analysis (PRISMA) where studies that are related to strengthening exercise and motor control were selected. RESULTS: From the initial search, 50 articles were found. After processing, only ten articles were further reviewed. The findings demonstrated strengthening exercises provide changes in neurophysiological parameters with motor performance, improved motor control, strength, balance, pain, and functional movement in footballers with sprained ankles. CONCLUSION: This review suggests the application of strengthening exercise interventions not only improves motor control, but strength, balance, pain, and functional performance among footballers with sprained ankles.


Asunto(s)
Traumatismos del Tobillo , Fútbol , Esguinces y Distensiones , Humanos , Traumatismos del Tobillo/prevención & control , Ejercicio Físico , Terapia por Ejercicio , Dolor
9.
Cell ; 133(6): 994-1005, 2008 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-18555776

RESUMEN

The effects of primary tumors on the host systemic environment and resulting contributions of the host to tumor growth are poorly understood. Here, we find that human breast carcinomas instigate the growth of otherwise-indolent tumor cells, micrometastases, and human tumor surgical specimens located at distant anatomical sites. This systemic instigation is accompanied by incorporation of bone-marrow cells (BMCs) into the stroma of the distant, once-indolent tumors. We find that BMCs of hosts bearing instigating tumors are functionally activated prior to their mobilization; hence, when coinjected with indolent cells, these activated BMCs mimic the systemic effects imparted by instigating tumors. Secretion of osteopontin by instigating tumors is necessary for BMC activation and the subsequent outgrowth of the distant otherwise-indolent tumors. These results reveal that outgrowth of indolent tumors can be governed on a systemic level by endocrine factors released by certain instigating tumors, and hold important experimental and therapeutic implications.


Asunto(s)
Adenocarcinoma/metabolismo , Células de la Médula Ósea/citología , Neoplasias de la Mama/metabolismo , Metástasis de la Neoplasia , Osteopontina/metabolismo , Animales , Células de la Médula Ósea/metabolismo , División Celular , Línea Celular Tumoral , Movimiento Celular , Neoplasias del Colon/metabolismo , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante Heterólogo
10.
Cell ; 134(1): 62-73, 2008 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-18614011

RESUMEN

The p53 tumor suppressor is a key mediator of cellular responses to various stresses. Here, we show that under conditions of basal physiologic and cell-culture stress, p53 inhibits expression of the CD44 cell-surface molecule via binding to a noncanonical p53-binding sequence in the CD44 promoter. This interaction enables an untransformed cell to respond to stress-induced, p53-dependent cytostatic and apoptotic signals that would otherwise be blocked by the actions of CD44. In the absence of p53 function, the resulting derepressed CD44 expression is essential for the growth and tumor-initiating ability of highly tumorigenic mammary epithelial cells. In both tumorigenic and nontumorigenic cells, CD44's expression is positively regulated by p63, a paralogue of p53. Our data indicate that CD44 is a key tumor-promoting agent in transformed tumor cells lacking p53 function. They also suggest that the derepression of CD44 resulting from inactivation of p53 can potentially aid the survival of immortalized, premalignant cells.


Asunto(s)
Receptores de Hialuranos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Células Epiteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Proteína p53 Supresora de Tumor/genética
11.
Int J Mol Sci ; 24(9)2023 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-37175547

RESUMEN

Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair cells. The survival of supporting cells with regenerative potential after cochlear trauma in adults is promising for promoting hair cell regeneration through therapeutic approaches. Targeting these cells by manipulating key signaling pathways that control mammalian cochlear development and non-mammalian hair cell regeneration could lead to regeneration of hair cells in the mammalian cochlea. This review discusses the pathways involved in the development of the cochlea and the impact that trauma has on the regenerative capacity of the endogenous progenitor cells. Furthermore, it discusses the effects of manipulating key signaling pathways targeting supporting cells with progenitor potential to promote hair cell regeneration and translates these findings to the human situation. To improve hearing recovery after hearing loss in adults, we propose a combined approach targeting (1) the endogenous progenitor cells by manipulating signaling pathways (Wnt, Notch, Shh, FGF and BMP/TGFß signaling pathways), (2) by manipulating epigenetic control, and (3) by applying neurotrophic treatments to promote reinnervation.


Asunto(s)
Cóclea , Células Ciliadas Auditivas , Recién Nacido , Adulto , Humanos , Células Ciliadas Auditivas/metabolismo , Cóclea/metabolismo , Transducción de Señal , Ganglio Espiral de la Cóclea , Neurogénesis
12.
Ann Oncol ; 33(1): 99-106, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34687894

RESUMEN

BACKGROUND: We have previously shown that 75% of patients treated with programmed cell death protein 1 (PD-1) with or without CTLA4 who have not progressed by 1 year have complete metabolic response (CMR), including two-thirds of patients with partial response (PR). We now report 5-year outcomes. PATIENTS AND METHODS: Retrospective analysis of 104 patients with baseline and 1-year positron emission tomography (PET) and computed tomography (CT). The 1-year response was determined using RECIST for CT and European Organisation for Research and Treatment of Cancer (EORTC) criteria for PET. Progression-free survival (PFS) and overall survival (OS) were determined from the 1-year landmark. RESULTS: At the median follow-up of 61 months (range 58-64 months) from 1-year PET, 94% remained alive and all but one had discontinued treatment after a median treatment duration of 23 months (range 1-59 months). Disease progression occurred in 19 patients (18%): 10 (53%) while on treatment and 12 (63%) in solitary sites for which 8 (67%) received local treatment. RECIST PFS rate at 5 years after PET was higher in complete response (CR) compared with PR/stable disease (SD) (93% versus 76%, respectively) and CMR compared with non-CMR (90% versus 54%, respectively). In patients with PR, 5-year PFS rate was superior in CMR (88% and 59%). A total of 35 (34%) patients (14/29 in CR, 31/78 in CMR) discontinued treatment within 12 months, largely due to toxicity, with no impact on PFS rate compared with those that continued (84% versus 78%). Despite progression events, OS rate at 5 years was excellent and similar in patients with CR and PR/SD (100% versus 91%, respectively) as well as in those with CMR and non-CMR (96% versus 87%, respectively). CONCLUSIONS: Five years after the 1-year PET, sustained responses are observed in the majority of patients, particularly in those with CMR. PET continues to predict progression better than CT, particularly in those with residual disease on CT. In the minority that progress, often in solitary sites and managed locally, OS rate remains excellent. PET is effective in evaluating residual lesions on CT and can predict long-term benefit.


Asunto(s)
Fluorodesoxiglucosa F18 , Melanoma , Humanos , Melanoma/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Radiofármacos , Estudios Retrospectivos , Resultado del Tratamiento
13.
Osteoporos Int ; 33(9): 1871-1893, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35426508

RESUMEN

To elucidate the association of coffee and bone health would help fracture risk reduction via dietary intervention. Although those who had higher coffee consumption were less likely to have osteoporosis, the associations between coffee consumption and fracture risk need further investigations with better study designs. INTRODUCTION: The associations between coffee consumption and the risk of osteoporosis and fracture remain inconclusive. We aimed to better quantify these associations by conducting meta-analyses of observational studies. METHODS: Relevant studies were systematically searched on PubMed, Web of Science, Cochrane library, and Embase Database up to November 25, 2021. The odds ratio (OR) or relative risk (RR) with 95% confidence intervals (CI) was pooled and a dose-response analysis was performed. RESULTS: Four studies with 7114 participants for osteoporosis and thirteen studies with 391,956 participants for fracture incidence were included in the meta-analyses. High versus low coffee consumption was associated with a lower risk of osteoporosis [pooled OR (95% CI): 0.79 (0.65-0.92)], while it was non-significantly associated with fracture incidence [pooled OR (95% CI): 0.86 (0.67-1.05) at hip and 0.89 (0.42-1.36) at non-hip]. A non-linear association between the level of coffee consumption and hip fracture incidence was shown (P = 0.004). The pooled RR (95% CI) of hip fracture risk in those who consumed 1, 2-3, 4, and ≥ 9 cups of coffee per day was 0.92 (0.87-0.97), 0.89 (0.83-0.95), 0.91 (0.85-0.98), and 1.10 (0.76-1.59), respectively. The significance in the association between coffee consumption and the hip fracture incidence decreased in those studies that had larger sample size, higher quality, and more adjustments. CONCLUSIONS: A dose-dependent relationship may exist between coffee consumption and hip fracture incidence. The effect of high versus low coffee consumption was influenced by study designs. Further studies with dedicated designs are needed to confirm the independent effects of coffee consumption on bone health.


Asunto(s)
Fracturas de Cadera , Osteoporosis , Café/efectos adversos , Fracturas de Cadera/epidemiología , Fracturas de Cadera/etiología , Fracturas de Cadera/prevención & control , Humanos , Incidencia , Osteoporosis/complicaciones , Osteoporosis/etiología , Factores de Riesgo
14.
FASEB J ; 35(3): e21389, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33583081

RESUMEN

The glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein that is highly expressed in astrocytes, neural stem cells, and in gliomas. Gliomas are a heterogeneous group of primary brain tumors that arise from glia cells or neural stem cells and rely on accurate diagnosis for prognosis and treatment strategies. GFAP is differentially expressed between glioma subtypes and, therefore, often used as a diagnostic marker. However, GFAP is highly regulated by the process of alternative splicing; many different isoforms have been identified. Differential expression of GFAP isoforms between glioma subtypes suggests that GFAP isoform-specific analyses could benefit diagnostics. In this study we report on the differential expression of a new GFAP isoform between glioma subtypes, GFAPµ. A short GFAP transcript resulting from GFAP exon 2 skipping was detected by RNA sequencing of human glioma. We show that GFAPµ mRNA is expressed in healthy brain tissue, glioma cell lines, and primary glioma cells and that it translates into a ~21 kDa GFAP protein. 21 kDa GFAP protein was detected in the IF protein fraction isolated from human spinal cord as well. We further show that induced GFAPµ expression disrupts the GFAP IF network. The characterization of this new GFAP isoform adds on to the numerous previously identified GFAP splice isoforms. It emphasizes the importance of studying the contribution of IF splice variants to specialized functions of the IF network and to glioma research.


Asunto(s)
Empalme Alternativo , Neoplasias Encefálicas/metabolismo , Proteína Ácida Fibrilar de la Glía/biosíntesis , Glioma/metabolismo , Encéfalo/metabolismo , Línea Celular Tumoral , Proteína Ácida Fibrilar de la Glía/química , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Biosíntesis de Proteínas , Isoformas de Proteínas , Vimentina/química
15.
BJOG ; 129(6): 845-854, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34839565

RESUMEN

BACKGROUND: Pharmacological pain management options can relieve women's pain during labour and birth. Trials of these interventions have used a wide variety of outcomes, complicating meaningful comparisons of their effects. To facilitate better assessment of the effectiveness of labour pain management in trials and meta-analyses, consensus about key outcomes and the development of a core outcome set is essential. OBJECTIVE: To identify all outcomes used in studies of pharmacological pain management interventions during labour and birth. DESIGN: A review of systematic reviews and their included randomised controlled trials was undertaken. SEARCH STRATEGY: Cochrane CENTRAL was searched to identify all Cochrane systematic reviews describing pharmacological pain management options for labour and birth. Search terms included 'pain management', 'labour' and variants, with no limits on year of publication or language. SELECTION CRITERIA: Cochrane reviews and randomised controlled trials contained within these reviews were included, provided they compared a pharmacological intervention with other pain management options, placebo or no treatment. DATA COLLECTION AND ANALYSIS: All outcomes reported by reviews or trials were extracted and tabulated, with frequencies of individual outcomes reported. MAIN RESULTS: Nine Cochrane reviews and 227 unique trials were included. In total, 146 unique outcomes were identified and categorised into maternal, fetal, neonatal, child, health service, provider's perspective or economic outcome domains. CONCLUSIONS: Outcomes of pharmacological pain management interventions during labour and birth vary widely between trials. The standardisation of trial outcomes would permit the assessment of meta-analyses for best clinical practice. TWEETABLE ABSTRACT: Outcomes to measure pharmacological pain management options during labour are highly variable and require standardisation.


Asunto(s)
Dolor de Parto , Trabajo de Parto , Femenino , Humanos , Recién Nacido , Dolor de Parto/tratamiento farmacológico , Manejo del Dolor , Parto , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Revisiones Sistemáticas como Asunto
16.
Anaesthesia ; 77 Suppl 1: 59-68, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35001387

RESUMEN

Stroke is a leading cause of death and disability, and is associated with a huge societal and economic burden. Interventions for the immediate treatment of ischaemic stroke due to large vessel occlusion are dependent on recanalisation of the occluded vessel. Trials have provided evidence supporting the efficacy of mechanical thrombectomy in ischaemic stroke due to large vessel occlusion. This has resulted in changes in management and organisation of stroke care worldwide. Major determinants of effectiveness of thrombectomy include: time between stroke onset and reperfusion; location of occlusion and local collateral perfusion; adequacy of reperfusion; patient age; and stroke severity. The role of anaesthetic technique on outcome remains controversial with published research showing conflicting results. As a result, choice of conscious sedation or general anaesthesia for mechanical thrombectomy is often dependent on individual operator choice or institutional preference. More recent randomised controlled trials have suggested that protocol-driven general anaesthesia is no worse than conscious sedation and may even be associated with better outcomes. These and other studies have highlighted the importance of optimal blood pressure management as a major determinant of patient outcome. Anaesthetic management should be tailored to the individual patient and circumstances. Acute ischaemic stroke is a neurological emergency; clinicians should focus on minimising door-to-groin puncture time and the provision of high-quality periprocedural care with a particular emphasis on the maintenance of an adequate blood pressure.


Asunto(s)
Anestesia General/métodos , Anestesia Local/métodos , Sedación Consciente/métodos , Complicaciones Intraoperatorias/prevención & control , Trombectomía/métodos , Anestesia General/normas , Anestesia Local/efectos adversos , Anestesia Local/normas , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/cirugía , Sedación Consciente/efectos adversos , Sedación Consciente/normas , Humanos , Complicaciones Intraoperatorias/inducido químicamente , Complicaciones Intraoperatorias/diagnóstico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/cirugía , Trombectomía/efectos adversos , Trombectomía/normas
17.
Blood ; 133(16): 1729-1741, 2019 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-30755422

RESUMEN

Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and ß receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis.


Asunto(s)
Células Madre Hematopoyéticas/citología , Proteínas de Homeodominio/metabolismo , Leucemia/etiología , Proteínas Represoras/fisiología , Animales , Carcinogénesis , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Noqueados , Receptores de Interferón , Proteínas Represoras/genética , Proteínas Supresoras de Tumor
18.
J Immunol ; 202(12): 3483-3492, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-31061008

RESUMEN

dsRNA is a common by-product of viral replication and acts as a potent trigger of antiviral immunity. SIDT1 and SIDT2 are closely related members of the SID-1 transmembrane family. SIDT2 functions as a dsRNA transporter and is required to traffic internalized dsRNA from endocytic compartments into the cytosol for innate immune activation, but the role of SIDT1 in dsRNA transport and in the innate immune response to viral infection is unclear. In this study, we show that Sidt1 expression is upregulated in response to dsRNA and type I IFN exposure and that SIDT1 interacts with SIDT2. Moreover, similar to SIDT2, SIDT1 localizes to the endolysosomal compartment, interacts with the long dsRNA analog poly(I:C), and, when overexpressed, enhances endosomal escape of poly(I:C) in vitro. To elucidate the role of SIDT1 in vivo, we generated SIDT1-deficient mice. Similar to Sidt2-/- mice, SIDT1-deficient mice produced significantly less type I IFN following infection with HSV type 1. In contrast to Sidt2-/- mice, however, SIDT1-deficient animals showed no impairment in survival postinfection with either HSV type 1 or encephalomyocarditis virus. Consistent with this, we observed that, unlike SIDT2, tissue expression of SIDT1 was relatively restricted, suggesting that, whereas SIDT1 can transport extracellular dsRNA into the cytoplasm following endocytosis in vitro, the transport activity of SIDT2 is likely to be functionally dominant in vivo.


Asunto(s)
Infecciones por Cardiovirus/inmunología , Citoplasma/metabolismo , Virus de la Encefalomiocarditis/fisiología , Endosomas/metabolismo , Herpes Simple/inmunología , Herpesvirus Humano 1/fisiología , Lisosomas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Nucleótidos/metabolismo , Animales , Células Cultivadas , ADN/inmunología , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Transporte de Nucleótidos/genética , Poli I-C/inmunología , Transporte de ARN/genética
19.
Clin Radiol ; 76(1): 81.e1-81.e10, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32958223

RESUMEN

AIM: To assess whether magnetic resonance imaging (MRI)-based measurements of T2, fat fraction, diffusion tensor imaging, and muscle volume can detect differences between the muscles of myositis patients and healthy controls, and to identify how they compare with semi-quantitative MRI diagnosis. MATERIALS AND METHODS: Sixteen myositis patients and 16 age- and gender-matched healthy controls underwent MRI of their thigh. Quantitative MRI measurements and radiologists' semi-quantitative scores were assessed. Strength was assessed using an isokinetic dynamometer. RESULTS: Fat fraction and T2 values were higher in myositis patients whereas muscle volume was lower compared to healthy controls. There was no difference in diffusion. Muscle strength was lower in myositis patients compared to healthy controls. In a subgroup of eight patients, scored as unaffected by radiologists, T2 values were still significantly higher in myositis patients. CONCLUSIONS: Quantitative MRI measurements can detect differences between myositis patients and healthy controls. Changes in the muscles of myositis patients, undetected by visual, semi-quantitative scoring, can be detected using quantitative T2 measurements. This suggests that MRI T2 values may be useful for the management of myositis patients.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Miositis/diagnóstico por imagen , Estudios de Casos y Controles , Imagen de Difusión Tensora , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad
20.
Clin Exp Dermatol ; 46(7): 1181-1188, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33811771

RESUMEN

The ectoparasite Pthirus pubis (PtP), commonly known as the crab or pubic louse, has plagued primates from prehistoric apes to Homo sapiens. We combed the literature from antiquity to the present day, reviewing the pubic louse's origins, its evolution with mankind, and its presentation and management. MEDLINE and EMBASE provided the greatest yield of literature compared with other databases. Estimates for PtP incidence range from 0.3% to 4.6% and for prevalence around 2% in adults. War, disasters and overcrowding support lice transmission, but modern pubic hair grooming has reduced the incidence of PtP in recent years. PtP, is usually found on pubic hair, but may infest scalp and body hair, eyebrows and eyelashes. Reports suggest the possibility of PtP as a vector for Bartonella spp. and Acinetobacter spp., which require further study. Transmission of PtP is via close contact, so sexual abuse and concomitant sexually transmitted infections should be considered. Symptoms and signs of infestation include pruritus, red papules and rust/brown deposits from feeding or faecal matter. Visualization of live lice confirms the diagnosis. Traditional treatments include hand-picking and combing, but in modern times pediculicidal products may generate faster resolution. Permethrin or pyrethrins are the first-line recommendations. Resistance to pediculicides is common with head lice and is presumed likely with PtP, although data are lacking. Pseudoresistance occurs as a result of poor compliance, incorrect or ineffective dosing, and reinfestation. In true resistance, a different pediculicide class should be used, e.g. second-line agents such as phenothrin, malathion or ivermectin. Lice have existed long before humans and given their adaptability, despite habitat challenges from fashion trends in body hair removal, are likely to continue to survive.


Asunto(s)
Insecticidas/uso terapéutico , Infestaciones por Piojos , Phthirus , Animales , Historia del Siglo XVI , Historia del Siglo XX , Historia Antigua , Humanos , Resistencia a los Insecticidas , Insecticidas/historia , Ivermectina/uso terapéutico , Infestaciones por Piojos/tratamiento farmacológico , Infestaciones por Piojos/epidemiología , Infestaciones por Piojos/historia , Infestaciones por Piojos/terapia , Permetrina/uso terapéutico , Piretrinas/uso terapéutico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA