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1.
Revista Digital de Postgrado ; 10(1): 275, abr. 2021. tab
Artículo en Español | LILACS, LIVECS | ID: biblio-1147596

RESUMEN

El hígado graso del embarazo es una patología poco frecuente en la especialidad obstétrica, cuyo diagnóstico se realiza basado en los criterios de Swansea, muchas veces es un diagnóstico que se realiza por exclusión; usualmente se presenta entre las semanas 30 y 35 del embarazo, y la cura definitiva se realiza con la interrupción expedita del mismo; con una tasa de recuperación casi del 100% si se realiza la interrupción oportuna y una tasa de mortalidad materno fetal actual del 10%. Es importante estar atentos a la ganancia ponderal de la embarazada durante el control prenatal, la epigastralgia, y los signos clínicos asociados a hipoglicemia(AU)


Fatty liver of pregnancy is a rare pathology in obstetrics, whose diagnosis is made based on the Swansea criteria, many times it is a diagnosis that is made by exclusion; It usually occurs between weeks 30 and 35, and the definitive cure is carried out with the expeditious interruption of pregnancy; with a recovery rate of almost 100% if timely interruption is made and a current maternal-fetal mortality rate of 10%. It is important to be attentive to the weight gain of the pregnant woman during prenatal control, epigastric pain, and clinical signs associated with hypoglycemia


Asunto(s)
Humanos , Femenino , Embarazo , Síndrome HELLP , Aborto , Hígado Graso/patología , Hipoglucemia , Mortalidad Materna , Mortalidad Fetal , Técnicas de Diagnóstico Obstétrico y Ginecológico
2.
Rev. venez. oncol ; 33(1): 46-59, mar. 2021. tab
Artículo en Español | LILACS, LIVECS | ID: biblio-1147479

RESUMEN

El cáncer de mama Triple Negativo es un subtipo molecular que se caracteriza por ausencia de expresión de receptores de estrógeno, progesterona y proteína HER2. Representa el 10 % a 15 % de todos los subtipos de cáncer de mama con impacto en el pronóstico y en las líneas de tratamiento; siendo negativo para receptores hormonales y HER2, la terapéutica hormonal y anti-HER2 no cuentan para su manejo. Aún no se dispone de productos dirigidos a blancos específicos para esta categoría.(AU)


The Triple Negative breast cancer is a molecular subtype characterized by no expression of the estrogen, the progesterone and the HER2 protein receptors. They represents 10 % to 15 % of all the breast cancer subtypes with an impact on the prognosis and in the treatment lines; is negative for the hormone receptors and for the HER2, hormonal and the anti-HER2 therapeutics do not count for the management of them. The products targeting specific to this category are not yet available(AU)


Asunto(s)
Humanos , Femenino , Biomarcadores de Tumor , Antraciclinas/uso terapéutico , Taxoides/uso terapéutico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/epidemiología , Mamografía , Quimioterapia , Oncología Médica
3.
BMC Surg ; 21(1): 68, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33522915

RESUMEN

BACKGROUND: The role of laparoscopic adrenalectomy (LA) in a large adrenal tumor is controversial due to the risk of malignancy and technical difficulty. In this study, we compared the perioperative outcomes and complications of LA on large (≥ 6 cm) and (< 6 cm) adrenal tumors. METHODS: We retrospectively reviewed all clinical data of patients who underwent unilateral transperitoneal LA in our institution between April 2000 and June 2019. Patients were classified by tumor size into 2 groups. Patients in group 1 had tumor size < 6 cm (n = 408) and patient in group 2 had tumor size ≥ 6 cm (n = 48). Demographic data, perioperative outcomes, complications, and pathologic reports were compared between groups. RESULTS: Patients in group 2 were significant older (p = 0.04), thinner (p = 0.001) and had lower incident of hypertension (p = 0.001), with a significantly higher median operative time (75 vs 120 min), estimated blood loss (20 vs 100 ml), transfusion rate (0 vs 20.8%), conversion rate (0.25 vs 14.6%) and length of postoperative stays ( 4 vs 5.5 days) than in group 2 (all p < 0.001). Group 2 patients also had significantly higher frequency of intraoperative complication (4.7 vs 31.3%; adjust Odds Ratio [OR] = 9.67 (95% CI 4.22-22.17), p-value < 0.001) and postoperative complication (5.4 vs 31.3%; adjust OR = 5.67 (95% CI 2.48-12.97), p-value < 0.001). Only eight (1.8%) major complications occurred in this study. The most common pathology in group 2 patient was pheochromocytoma and metastasis. CONCLUSIONS: Laparoscopic transperitoneal adrenalectomy in large adrenal tumor ≥ 6 cm is feasible but associated with significantly worse intraoperative complications, postoperative complications, and recovery. However, most of the complications were minor and could be managed conservatively. Careful patient selection with the expert surgeon in adrenal surgery is the key factor for successful laparoscopic surgery in a large adrenal tumor. TRIAL REGISTRATION: This study was retrospectively registered in the Thai Clinical Trials Registry on 02/03/2020. The registration number was TCTR20200312004.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Adrenalectomía , Laparoscopía , Carga Tumoral , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía/efectos adversos , Adrenalectomía/métodos , Adulto , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
4.
JAMA ; 325(7): 669-685, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33591350

RESUMEN

Importance: Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850 000 deaths annually. Of new colorectal cancer diagnoses, 20% of patients have metastatic disease at presentation and another 25% who present with localized disease will later develop metastases. Observations: Colorectal cancer is the third most common cause of cancer mortality for men and women in the United States, with 53 200 deaths projected in 2020. Among people diagnosed with metastatic colorectal cancer, approximately 70% to 75% of patients survive beyond 1 year, 30% to 35% beyond 3 years, and fewer than 20% beyond 5 years from diagnosis. The primary treatment for unresectable metastatic CRC is systemic therapy (cytotoxic chemotherapy, biologic therapy such as antibodies to cellular growth factors, immunotherapy, and their combinations.) Clinical trials completed in the past 5 years have demonstrated that tailoring treatment to the molecular and pathologic features of the tumor improves overall survival. Genomic profiling to detect somatic variants is important because it identifies the treatments that may be effective. For the 50% of patients with metastatic CRC with KRAS/NRAS/BRAF wild-type tumors, cetuximab and panitumumab (monoclonal antibodies to the epithelial growth factor receptor [EGFR]), in combination with chemotherapy, can extend median survival by 2 to 4 months compared with chemotherapy alone. However, for the 35% to 40% of patients with KRAS or NRAS sequence variations (formerly termed mutations), effective targeted therapies are not yet available. For the 5% to 10% with BRAF V600E sequence variations, targeted combination therapy with BRAF and EGFR inhibitors extended overall survival to 9.3 months, compared to 5.9 months for those receiving standard chemotherapy. For the 5% with microsatellite instability (the presence of numerous insertions or deletions at repetitive DNA units) or mismatch repair deficiency, immunotherapy may be used in the first or subsequent line and has improved treatment outcomes with a median overall survival of 31.4 months in previously treated patients. Conclusions and Relevance: Advances in molecular profiling of metastatic CRC facilitate the ability to direct treatments to the biologic features of the tumor for specific patient subsets. Although cures remain uncommon, more patients can anticipate extended survival. Genomic profiling allows treatment selection so that more patients derive benefit and fewer are exposed to toxicity from ineffective therapies.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/secundario , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Perfil Genético , Humanos , Quimioterapia de Mantención , Masculino , Técnicas de Diagnóstico Molecular , Pronóstico , Tasa de Supervivencia
5.
Nat Commun ; 12(1): 1064, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594056

RESUMEN

Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment.


Asunto(s)
Síndrome del Ovario Poliquístico/patología , Adiposidad , Animales , Animales Recién Nacidos , Peso Corporal , Análisis Discriminante , Modelos Animales de Enfermedad , Dislipidemias/patología , Sistema Endocrino/patología , Ciclo Estral , Femenino , Prueba de Tolerancia a la Glucosa , Gonadotropinas/farmacología , Hormonas/sangre , Humanos , Secreción de Insulina , Análisis de los Mínimos Cuadrados , Lípidos/química , Masculino , Intercambio Materno-Fetal , Análisis Multivariante , Ovario/patología , Ovario/fisiopatología , Fenotipo , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/fisiopatología , Embarazo , Ratas Wistar , Reproducción , Maduración Sexual
6.
Nat Commun ; 12(1): 1055, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594058

RESUMEN

mTORC1, a central controller of cell proliferation in response to growth factors and nutrients, is dysregulated in cancer. Whereas arginine activates mTORC1, it is overridden by high expression of cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Because cancer cells often encounter low levels of nutrients, an alternative mechanism might exist to regulate CASTOR1 expression. Here we show K29-linked polyubiquitination and degradation of CASTOR1 by E3 ubiquitin ligase RNF167. Furthermore, AKT phosphorylates CASTOR1 at S14, significantly increasing its binding to RNF167, and hence its ubiquitination and degradation, while simultaneously decreasing its affinity to MIOS, leading to mTORC1 activation. Therefore, AKT activates mTORC1 through both TSC2- and CASTOR1-dependent pathways. Several cell types with high CASTOR1 expression are insensitive to arginine regulation. Significantly, AKT and RNF167-mediated CASTOR1 degradation activates mTORC1 independent of arginine and promotes breast cancer progression. These results illustrate a mTORC1 regulating mechanism and identify RNF167 as a therapeutic target for mTORC1-dysregulated diseases.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Animales , Arginina/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Péptidos y Proteínas de Señalización Intercelular/farmacología , Cinética , Lisina/metabolismo , Ratones Desnudos , Fosforilación/efectos de los fármacos , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitinación/efectos de los fármacos
7.
Nat Commun ; 12(1): 1072, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594057

RESUMEN

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.


Asunto(s)
Desmetilación del ADN , Nucleosomas/metabolismo , Iniciación de la Transcripción Genética , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Cromatina/química , Cromatina/metabolismo , Células HEK293 , Proteína HMGA2/metabolismo , Histonas/metabolismo , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Ratones , Fosforilación , Fosfoserina/metabolismo , ARN Polimerasa II/metabolismo , Sitio de Iniciación de la Transcripción , Activación Transcripcional/genética , Factor de Crecimiento Transformador beta1/metabolismo
8.
Nat Commun ; 12(1): 1065, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594067

RESUMEN

The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-ß receptor (LTßR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTßR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTßR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTßR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTßR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.


Asunto(s)
Diferenciación Celular , Autorrenovación de las Células , Células Madre Hematopoyéticas/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Receptor beta de Linfotoxina/metabolismo , Células Madre Neoplásicas/patología , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Animales , Antígenos CD34/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/genética , Daño del ADN , Fluorouracilo/farmacología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos
9.
Nat Commun ; 12(1): 1066, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594071

RESUMEN

Pelvic radiograph (PXR) is essential for detecting proximal femur and pelvis injuries in trauma patients, which is also the key component for trauma survey. None of the currently available algorithms can accurately detect all kinds of trauma-related radiographic findings on PXRs. Here, we show a universal algorithm can detect most types of trauma-related radiographic findings on PXRs. We develop a multiscale deep learning algorithm called PelviXNet trained with 5204 PXRs with weakly supervised point annotation. PelviXNet yields an area under the receiver operating characteristic curve (AUROC) of 0.973 (95% CI, 0.960-0.983) and an area under the precision-recall curve (AUPRC) of 0.963 (95% CI, 0.948-0.974) in the clinical population test set of 1888 PXRs. The accuracy, sensitivity, and specificity at the cutoff value are 0.924 (95% CI, 0.912-0.936), 0.908 (95% CI, 0.885-0.908), and 0.932 (95% CI, 0.919-0.946), respectively. PelviXNet demonstrates comparable performance with radiologists and orthopedics in detecting pelvic and hip fractures.


Asunto(s)
Algoritmos , Aprendizaje Profundo , Pelvis/diagnóstico por imagen , Médicos , Heridas y Traumatismos/diagnóstico por imagen , Adulto , Anciano , Femenino , Fracturas de Cadera/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Pelvis/patología , Curva ROC
10.
Nat Commun ; 12(1): 1047, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594075

RESUMEN

Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRß sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.


Asunto(s)
Epítopos/inmunología , Terapia Neoadyuvante , Receptores OX40/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Biopsia , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Células Clonales , Supervivencia sin Enfermedad , Papillomavirus Humano 16/fisiología , Humanos , Estimación de Kaplan-Meier , Activación de Linfocitos/inmunología , Subgrupos Linfocitarios/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Terapia Neoadyuvante/efectos adversos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores OX40/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células del Estroma/metabolismo
11.
Nat Commun ; 12(1): 1045, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594072

RESUMEN

Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-'reading' bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.


Asunto(s)
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Co-Represoras/química , Proteínas Co-Represoras/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Leucemia Mieloide Aguda/patología , Lisina Acetiltransferasa 5/metabolismo , Acetilación , Animales , Carcinogénesis , Diferenciación Celular , Proliferación Celular , Transformación Celular Neoplásica , Modelos Animales de Enfermedad , Elementos de Facilitación Genéticos/genética , Regulación Leucémica de la Expresión Génica , Genoma Humano , Células HEK293 , Células Madre Hematopoyéticas/metabolismo , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Ratones Endogámicos BALB C , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas de Fusión Oncogénica/metabolismo , Unión Proteica , Dominios Proteicos , Factores de Transcripción/metabolismo
12.
Nat Commun ; 12(1): 1067, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594081

RESUMEN

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.


Asunto(s)
Inflamación/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Glicoproteínas de Membrana/metabolismo , Células Acinares/metabolismo , Células Acinares/patología , Animales , Colitis/metabolismo , Colitis/patología , Citocinas/metabolismo , Sulfato de Dextran , Escherichia coli/efectos de los fármacos , Escherichia coli/fisiología , Heces , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inmunoglobulina A/metabolismo , Mucosa Intestinal/microbiología , Ratones Endogámicos C57BL , Páncreas/patología , Proteínas Recombinantes/farmacología , Factores de Transcripción/metabolismo , Regulación hacia Arriba/genética
15.
BMC Infect Dis ; 21(1): 192, 2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602128

RESUMEN

BACKGROUND: Coronavirus disease 2019 (COVID-19) has caused a global pandemic that has raised worldwide concern. This study aims to investigate the correlation between the extent of lung infection and relevant clinical laboratory testing indicators in COVID-19 and to analyse its underlying mechanism. METHODS: Chest high-resolution computer tomography (CT) images and laboratory examination data of 31 patients with COVID-19 were extracted, and the lesion areas in CT images were quantitatively segmented and calculated using a deep learning (DL) system. A cross-sectional study method was carried out to explore the differences among the proportions of lung lobe infection and to correlate the percentage of infection (POI) of the whole lung in all patients with clinical laboratory examination values. RESULTS: No significant difference in the proportion of infection was noted among various lung lobes (P > 0.05). The POI of total lung was negatively correlated with the peripheral blood lymphocyte percentage (L%) (r = - 0.633, P < 0.001) and lymphocyte (LY) count (r = - 0.555, P = 0.001) but positively correlated with the neutrophil percentage (N%) (r = 0.565, P = 0.001). Otherwise, the POI was not significantly correlated with the peripheral blood white blood cell (WBC) count, monocyte percentage (M%) or haemoglobin (HGB) content. In some patients, as the infection progressed, the L% and LY count decreased progressively accompanied by a continuous increase in the N%. CONCLUSIONS: Lung lesions in COVID-19 patients are significantly correlated with the peripheral blood lymphocyte and neutrophil levels, both of which could serve as prognostic indicators that provide warning implications, and contribute to clinical interventions in patients.


Asunto(s)
/diagnóstico por imagen , Pulmón/patología , Aprendizaje Automático , Adulto , Técnicas de Laboratorio Clínico , Estudios Transversales , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/virología , Recuento de Linfocitos , Linfocitos/citología , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Pandemias , Pronóstico , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X
16.
Int J Nanomedicine ; 16: 515-538, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33519199

RESUMEN

Background: Several studies have demonstrated various molecular mechanisms involved in the biogenesis and release of exosomes. However, how external stimuli, such as platinum nanoparticles (PtNPs), induces the biogenesis and release of exosomes remains unclear. To address this, PtNPs were synthesized using lutein to examine their effect on the biogenesis and release of exosomes in human lung epithelial adenocarcinoma cancer cells (A549). Methods: The size and concentration of isolated exosomes were characterized by dynamic light scattering (DLS) and nanoparticle tracking analysis system (NTA). Morphology and structure of exosomes were examined using scanning electron microscopy and transmission electron microscopy (TEM), respectively. Quantification of exosomes were analyzed by EXOCETTM assay and fluorescence polarization (FP). The expression of typical markers of exosomes were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Results: A549 cells cultured with PtNPs enhance exosome secretion by altering various physiological processes. Interestingly, A549 cells treated with PtNPs increases total protein concentration, biogenesis and release of exosomes associated with PtNPs-induced oxidative stress. GW4869 inhibits PtNPs induced biogenesis and release of exosomes and also acetylcholinesterase (AChE), neutral sphingomyelinase activity (n-SMase), and exosome counts. A549 cells pre-treated with N-acetylcysteine (NAC) significantly inhibited PtNPs induced exosome biogenesis and release. These findings confirmed that PtNPs-induced exosome release was due to the induction of oxidative stress and the ceramide pathway. These factors enhanced exosome biogenesis and release and may be useful in understanding the mechanism of exosome formation, release, and function. Conclusion: PtNPs provide a promising agent to increase exosome production in A549 cells. These findings offer novel strategies for enhancing exosome release, which can be applied in the treatment and prevention of cancer. Importantly, this is the first study, to our knowledge, showing that PtNPs stimulate exosome biogenesis by inducing oxidative stress and the ceramide pathway.


Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Ceramidas/metabolismo , Exosomas/metabolismo , Neoplasias Pulmonares/metabolismo , Nanopartículas del Metal/química , Estrés Oxidativo , Platino (Metal)/farmacología , Células A549 , Acetilcolinesterasa/metabolismo , Acetilcisteína/farmacología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Compuestos de Anilina/farmacología , Compuestos de Bencilideno/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Exosomas/ultraestructura , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Luteína/farmacología , Nanopartículas del Metal/ultraestructura , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , ARN Mensajero/genética , ARN Mensajero/metabolismo , Suero , Esfingomielina Fosfodiesterasa/metabolismo , Electricidad Estática
17.
Biol Res ; 54(1): 3, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33546773

RESUMEN

BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake-via AMP-activated protein kinase (AMPK)-after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Glucosa/metabolismo , Miocitos Cardíacos , Receptores Androgénicos/metabolismo , Testosterona/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Células Cultivadas , Hipertrofia , Masculino , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Transducción de Señal
18.
Nat Commun ; 12(1): 863, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558489

RESUMEN

A concept of polyclonal metastasis has recently been proposed, wherein tumor cell clusters break off from the primary site and are disseminated. However, the involvement of driver mutations in such polyclonal mechanism is not fully understood. Here, we show that non-metastatic AP cells metastasize to the liver with metastatic AKTP cells after co-transplantation to the spleen. Furthermore, AKTP cell depletion after the development of metastases results in the continuous proliferation of the remaining AP cells, indicating a role of AKTP cells in the early step of polyclonal metastasis. Importantly, AKTP cells, but not AP cells, induce fibrotic niche generation when arrested in the sinusoid, and such fibrotic microenvironment promotes the colonization of AP cells. These results indicate that non-metastatic cells can metastasize via the polyclonal metastasis mechanism using the fibrotic niche induced by malignant cells. Thus, targeting the fibrotic niche is an effective strategy for halting polyclonal metastasis.


Asunto(s)
Metástasis de la Neoplasia/patología , Neoplasias/genética , Neoplasias/patología , Animales , Agregación Celular , Proliferación Celular , Células Clonales , Fibrosis , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Hígado/irrigación sanguínea , Hígado/patología , Ratones Endogámicos NOD , Organoides/patología , Fenotipo , Bazo/trasplante , Factor de Crecimiento Transformador beta/farmacología
19.
Nat Commun ; 12(1): 847, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558503

RESUMEN

A large G4C2-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders.


Asunto(s)
Proteína C9orf72/genética , Expansión de las Repeticiones de ADN/genética , Mutación/genética , Oligonucleótidos/química , Oligonucleótidos/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Proteína C9orf72/química , Exones/genética , Glutamatos/toxicidad , Intrones/genética , Ratones , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/patología , Empalme del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estereoisomerismo
20.
Nat Commun ; 12(1): 868, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558511

RESUMEN

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.


Asunto(s)
Alelos , Antígeno de Maduración de Linfocitos B/genética , Resistencia a Antineoplásicos , Inmunoterapia Adoptiva , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Médula Ósea/patología , Humanos , Mieloma Múltiple/inmunología , Microambiente Tumoral
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