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1.
Environ Res ; : 111085, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33812874

RESUMEN

BACKGROUND: To evaluate the impact of ambient air pollutant exposures on semen quality parameters during COVID-19 outbreak in China, and to identify susceptible windows for associations between air pollution and semen quality. METHODS: A case study was carried out, including 781 sperm donor candidates (1991 semen samples) collected between November 23, 2019 and July 23, 2020 (a period covering COVID-19 lock-down in China) in University-affiliated Sichuan provincial Human Sperm Bank. RESULT(S): Our results suggested that sperm motility is susceptible to ambient pollution exposure. Exposure to particulate matters (PM2.5 and PM10), O3 and NO2 during late stage of spermatogenesis appeared to have weak but positive association with semen quality. Exposure to CO late in sperm development appeared to have inverse relationship with sperm movement parameters. Exposure to SO2 appeared to influence semen quality throughout spermatogenesis. Collinearity did not appear to be a major issue in our analysis based on correlationship analysis; we conducted robustness test of the regression results with additional analysis on a subset of our study population to affirm our results. CONCLUSION(S): Male exposure to different air pollutants have different correlations with semen quality parameters during different exposure windows of spermatogenesis. Findings from current study help to further elucidate the importance of sensitive periods during spermatogenesis and could provide evidence for future intervention in male fertility.

2.
Metabolites ; 11(3)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33803928

RESUMEN

The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment.

3.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33672962

RESUMEN

Sepsis results in lethal organ malfunction due to dysregulated host response to infection, which is a condition with increasing prevalence worldwide. Transglutaminase 2 (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. TG2 plays important roles in diverse cellular processes, including extracellular matrix stabilization, cytoskeletal function, cell motility, adhesion, signal transduction, apoptosis, and cell survival. We have shown that the co-culture of Candida albicans and hepatocytes activates and induces the translocation of TG2 into the nucleus. In addition, the expression and activation of TG2 in liver macrophages was dramatically induced in the lipopolysaccharide-injected and cecal ligation puncture-operated mouse models of sepsis. Based on these findings and recently published research, we have reviewed the current understanding of the relationship between TG2 and sepsis. Following the genetic and pharmacological inhibition of TG2, we also assessed the evidence regarding the use of TG2 as a potential marker and therapeutic target in inflammation and sepsis.

4.
Radiology ; : 203496, 2020 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-33289614

RESUMEN

Background Singapore saw an escalation of coronavirus disease 2019 (COVID-19) cases from under 4,000 in April 2020 to over 40,000 in June 2020 largely attributed to spread within shared facilities housing foreign workers. Appropriate triage and escalation of clinical care are critical for this patient group managed in community care facilities (CCFs). Purpose To evaluate the imaging guideline recommendations for COVID-19 from the Fleischner Society and analyze the clinical utility of chest radiograph screening for asymptomatic or minimally symptomatic patients with COVID-19. Materials and Methods In this retrospective study, patients with COVID-19 confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) who were admitted to Singapore Expo, a designated CCF, for continuation of their management during May 3-31, 2020 were identified. Upon admission, patients aged 36 and older without any baseline chest imaging received a chest radiograph. All chest radiographs and clinical outcomes of patients including those who were subsequently transferred to acute hospitals for escalation of care were reviewed. Key proportions of patients with findings of pulmonary infection and those requiring further inpatient treatment were calculated, and 95% binomial proportion confidence intervals obtained using the Clopper-Pearson method. Results The study included 5,621 patients: all men 100% (5,621/5,621), mean age 37 ± 8 years (range 17-60). A total of 1,964 chest radiographs were performed of which normal accounted for 98.0% (1,925/1,964) and findings of pulmonary infection represented 2.0% (39/1,964). Only 0.2% (4/1,964) with chest radiograph findings of pulmonary infection (all of whom were symptomatic) required supplemental oxygenation and inpatient treatment. None of the asymptomatic patients with findings of pulmonary infection required supplemental oxygenation, and they received only symptomatic treatment. Conclusion In accordance with Fleischner Society recommendations, chest radiograph screening for patients with COVID-19 aged 17-60 with mild or no symptoms is not indicated unless there is risk of clinical deterioration. See also the editorial by Schaefer-Prokop and Prokop.

5.
Ying Yong Sheng Tai Xue Bao ; 31(9): 3067-3074, 2020 Sep 15.
Artículo en Chino | MEDLINE | ID: mdl-33345508

RESUMEN

Long-term herbicide application may facilitate the adaptive evolution of weed populations. With Echinochloa crus-galli var. crus-galli population A from a rice field used for the experiment of effectiveness of herbicide in Nanling County, Anhui Province, we conducted common garden experi-ments with seeds of population A and three control populations collected from normal rice fields. Compared with the three control populations, population A had significantly lower seed production for individual plant, but higher 1000-seed weight. Population A had faster in seedling growth, higher in number of reproductive tillers, shorter life span, lower in height and biomass of individual plant, as well as lower in sensitivity to herbicide penoxsulam. Individuals from population A survived from 2× label dose (60 g·hm-2) of penoxsulam treatment at the three- to four-leaf stage showed significantly reduction in plant height, biomass, and mature seed production (1066 seeds per plant), but no difference in heading period, number of reproductive tillers, number of seeds per raceme and 1000-seed weight. The short lifespan, heavy seeds, dwarf architecture, more reproductive tillers and penoxsulam resistance made E. crus-galli var. crus-galli population A extremely adapting to rice planting systems, which should be prevented to spread to normal rice fields.


Asunto(s)
Echinochloa , Herbicidas , Rasgos de la Historia de Vida , Oryza , Herbicidas/farmacología , Humanos , Semillas
7.
Int J Mol Sci ; 21(15)2020 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-32756504

RESUMEN

Stress in early life has been linked with the development of late-life neurological disorders. Early developmental age is potentially sensitive to several environmental chemicals such as alcohol, drugs, food contaminants, or air pollutants. The recent advances using three-dimensional neural sphere cultures derived from pluripotent stem cells have provided insights into the etiology of neurological diseases and new therapeutic strategies for assessing chemical safety. In this study, we investigated the neurodevelopmental effects of exposure to thalidomide (TMD); 2,2',4,4'-tetrabromodiphenyl ether; bisphenol A; and 4-hydroxy-2,2',3,4',5,5',6-heptachlorobiphenyl using a human embryonic stem cell (hESC)-derived sphere model. We exposed each chemical to the spheres and conducted a combinational analysis of global gene expression profiling using microarray at the early stage and morphological examination of neural differentiation at the later stage to understand the molecular events underlying the development of hESC-derived spheres. Among the four chemicals, TMD exposure especially influenced the differentiation of spheres into neuronal cells. Transcriptomic analysis and functional annotation identified specific genes that are TMD-induced and associated with ERK and synaptic signaling pathways. Computational network analysis predicted that TMD induced the expression of DNA-binding protein inhibitor ID2, which plays an important role in neuronal development. These findings provide direct evidence that early transcriptomic changes during differentiation of hESCs upon exposure to TMD influence neuronal development in the later stages.

8.
Nat Immunol ; 21(10): 1205-1218, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32839608

RESUMEN

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.

9.
Nat Rev Immunol ; 20(12): 739-755, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32728220

RESUMEN

The ATP-adenosine pathway functions as a key modulator of innate and adaptive immunity within the tumour microenvironment. Consequently, multiple clinical strategies are being explored to target this pathway for the treatment of cancer; in particular, recent clinical data with CD73 antagonists and inhibitors of A2A receptors have demonstrated the therapeutic potential of modulating this pathway. Now, inhibitors of the ectonucleotidase CD39, the rate-limiting enzyme in the conversion of ATP to immunomodulatory adenosine, are entering clinical trials. Consequently, there is currently a focus on understanding the impact of CD39 enzymatic function on innate and adaptive immunity and how therapeutic modulation of this pathway alters their functional potential within the tumour microenvironment. Recent findings reveal multipronged mechanisms of action of CD39 antagonism that rely not only on preventing the accumulation of adenosine but also on the stabilization of pro-inflammatory extracellular ATP to restore antitumour immunity. Here, we review the impact of CD39 expression and ectonucleotidase activity on immunity with a focus on the setting of oncology. Additionally, we discuss the implications for immunotherapy strategies targeting CD39, including their inclusion in rational combination therapies.

10.
Clin Cancer Res ; 26(20): 5520-5533, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32591463

RESUMEN

PURPOSE: Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell-mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell-mediated tumor reactivity. EXPERIMENTAL DESIGN: We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell-mediated cytotoxicity in vitro and in two mouse models. RESULTS: NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT- NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155+ MHC class I-deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell-mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade. CONCLUSIONS: Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell-mediated destruction of MHC class I-deficient melanoma, which are refractory to CD8+ T-cell-mediated immunity.See related commentary by Pietra et al., p. 5274.

11.
Preprint | medRxiv | ID: ppmedrxiv-20096073

RESUMEN

Artificial intelligence can potentially provide a substantial role in streamlining chest computed tomography (CT) diagnosis of COVID-19 patients. However, several critical hurdles have impeded the development of robust AI model, which include deficiency, isolation, and heterogeneity of CT data generated from diverse institutions. These bring about lack of generalization of AI model and therefore prevent it from applications in clinical practices. To overcome this, we proposed a federated learning-based Unified CT-COVID AI Diagnostic Initiative (UCADI, http://www.ai-ct-covid.team/), a decentralized architecture where the AI model is distributed to and executed at each host institution with the data sources or client ends for training and inferencing without sharing individual patient data. Specifically, we firstly developed an initial AI CT model based on data collected from three Tongji hospitals in Wuhan. After model evaluation, we found that the initial model can identify COVID from Tongji CT test data at near radiologist-level (97.5% sensitivity) but performed worse when it was tested on COVID cases from Wuhan Union Hospital (72% sensitivity), indicating a lack of model generalization. Next, we used the publicly available UCADI framework to build a federated model which integrated COVID CT cases from the Tongji hospitals and Wuhan Union hospital (WU) without transferring the WU data. The federated model not only performed similarly on Tongji test data but improved the detection sensitivity (98%) on WU test cases. The UCADI framework will allow participants worldwide to use and contribute to the model, to deliver a real-world, globally built and validated clinic CT-COVID AI tool. This effort directly supports the United Nations Sustainable Development Goals number 3, Good Health and Well-Being, and allows sharing and transferring of knowledge to fight this devastating disease around the world.

12.
Clin Cancer Res ; 26(14): 3671-3681, 2020 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-32345648

RESUMEN

PURPOSE: Resistance to anti-PD1-based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB. EXPERIMENTAL DESIGN: Pretreatment tumor specimens, from 155 patients with metastatic melanoma treated with ICB and from 50 patients treated with BRAF/MEK-directed targeted therapy, were assessed for CD155 expression by IHC. Intratumor T-cell features were analyzed using multiplex-immunohistofluorescence for CD8, PD1, and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA sequencing results, as well as clinical RECIST response and progression-free survival. RESULTS: High pretreatment CD155 tumor levels correlated with high parenchymal PD1+CD8+/CD8+ T-cell ratios (PD1tR) and poor response to anti-PD1 therapy. In PDL1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/CTLA4 therapy. CONCLUSIONS: Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1+CD8+ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for patients with metastatic melanoma.

13.
Medicine (Baltimore) ; 99(15): e19589, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32282708

RESUMEN

With development of tumor treatment, survival time of patients with cancer is significantly prolonged. Therefore, the current emphasis is not only the survival, but also the quality of life, especially, it is crucial for young male cancer patients who are unmarried and maintaining fertility. However, the awareness of fertility preservation for these patients is currently insufficient.To give physician and cancer patients more clear understanding of the importance and safety of sperm cryopreservation, so that achieve patient fertility benefits.First, the knowledge level and attitudes about fertility preservation were investigated by surveying 332 cancer patients and 103 medical staff with questionnaires. Second, 30 male cancer patients (experimental group) and 30 normal donors (control group) were selected and their sperm samples were cryopreserved. The sperm quality was compared between cancer patients and normal donors, before and after antitumor treatment in the cancer patients, and before and after sperm cryopreservation in both groups.In the questionnaire survey, we found that there were 70% to 80% of medical staffs and cancer patients lacked knowledge of fertility preservation, and 27.7% of patients worried that tumor and sperm cryopreservation might affect their offspring. In the sperm preservative experiment, we found that sperm quality in cancer patients was further damaged after radiotherapy/chemotherapy in addition to tumor itself had a negative effect. However, sperm deoxyribonucleic acid fragments were not affected by sperm cryopreservation although there were significant differences in sperm quality before and after sperm preservation in both groups.Radiotherapy/chemotherapy would further damage sperm quality of young male cancer patients. Medical staff should be aware of importance of sperm cryopreservation for fertility preservation for these patients. It is also necessary that medical staff should inform the patient about the safety of sperm freezing and guide the patient to participate in sperm cryopreservation.


Asunto(s)
Criopreservación , Preservación de la Fertilidad , Conocimientos, Actitudes y Práctica en Salud , Neoplasias , Espermatozoides , Adulto , Estudios de Casos y Controles , Humanos , Masculino , Encuestas y Cuestionarios
14.
J Exp Med ; 217(6)2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32289156

RESUMEN

Current immunotherapies involving CD8+ T cell responses show remarkable promise, but their efficacy in many solid tumors is limited, in part due to the low frequency of tumor-specific T cells in the tumor microenvironment (TME). Here, we identified a role for host atypical chemokine receptor 4 (ACKR4) in controlling intratumor T cell accumulation and activation. In the absence of ACKR4, an increase in intratumor CD8+ T cells inhibited tumor growth, and nonhematopoietic ACKR4 expression was critical. We show that ACKR4 inhibited CD103+ dendritic cell retention in tumors through regulation of the intratumor abundance of CCL21. In addition, preclinical studies indicate that ACKR4 and CCL21 are potential therapeutic targets to enhance responsiveness to immune checkpoint blockade or T cell costimulation.

15.
Anal Biochem ; 597: 113654, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32142762

RESUMEN

Sepsis is the leading cause of death in hospitalized patients and is characterized by a dysregulated inflammatory response to infection and multiple organ failure, including the liver. Transglutaminase 2 (TG2) is a multifunctional enzyme that exhibits transamidase, GTPase, and integrin-binding activities and has opposing roles in the regulation of cell growth, differentiation, and apoptosis. TG2 plays both pathogenic and protective roles in liver diseases, revealing the need to examine the activities of TG2. Here, we introduced an ex vivo imaging approach to examine the in vivo transamidase activity of TG2 based on the combination of intraperitoneal injection of 5-biotinamidopentylamine (5BAPA), a biotinylated substrate for TG2, and fluorescent streptavidin staining in frozen liver sections. Increased 5BAPA signals was observed in the livers of lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-induced sepsis mice. Pharmacological inhibition of TG2 activity ameliorated LPS-induced liver injury. 5BAPA signals were observed in TG2-expressing and F4/80-positive midzonal macrophages, providing direct evidence that activated macrophages are the major cellular source of active TG2 in the livers of sepsis mice. Further studies focusing on the activation of 5BAPA-stained midzonal macrophages may improve understanding of the molecular pathophysiology and the development of therapeutic strategies for sepsis.

16.
Exp Ther Med ; 19(2): 1522-1527, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32010333

RESUMEN

Garlic and its sulfur constituents have numerous biological functions, such as antioxidant, anti-inflammatory, anti-microbial, anticancer, antidiabetic and cardioprotective effects. Fatty liver diseases, such as non-alcoholic steatohepatitis, which is characterized by the accumulation of lipids and oxidative stress in hepatocytes and continual liver damage, has attracted much attention, and it is believed that it will become the leading etiology of liver cancer. We have previously reported that the growth-suppressive effects of arachidonic acid (AA), an unsaturated fatty acid known to be a pro-inflammatory precursor, is accompanied by the production of reactive oxygen species followed by the nuclear accumulation and activation of the protein crosslinking enzyme, transglutaminase (TG)2. In this study, we examined the potential role of garlic extracts in preventing the growth-suppressive effects of AA on human hepatic cells. We also aimed to provide a mechanistic insight regarding the association between the hepatoprotective effects of garlic extract and the inhibition of the TG-related crosslinking of nuclear proteins, which is not associated with hepatic lipid partitioning mediated by stearoyl-CoA desaturase-1. Given the critical roles of unsaturated fatty acids in the regulation of cancer cell stemness and immune surveillance in the context of chronic injury, we propose that garlic extracts may serve as a therapeutic option for the prevention of chronic liver injury and inflammation, as well as for the prevention of the carcinogenesis of fatty livers.

17.
Materials (Basel) ; 13(1)2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31906365

RESUMEN

Chloride-induced corrosion is the main threat to the service life of concrete structures. In order to better investigate chloride distribution in offshore concrete, this study proposed a new prediction model based on statistical analysis as well as a large body of experimental results collected from various sources. A detailed discussion found that the key influential parameters, such as diffusion coefficient ( D ), surface chloride concentration ( C S ) and penetration depth ( x ) are all highly time-dependent. The exposure zone, water-cement ratio and service time were also considered as relevant factors. The proposed model is then validated by two alternative tests and the results suggest that it is feasible in predicting the chloride content and penetration depth of concrete structures in a marine environment under chloride attack.

18.
Cancer Immunol Res ; 8(3): 356-367, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31992567

RESUMEN

Natural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK cell effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including NK cells, converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits the mouse ectoenzyme CD39 suppressed experimental and spontaneous metastases in a number of different tumor models and displayed superior antimetastatic activity compared with the CD39 inhibitor POM1 and inhibitors and mAbs that block other members of the adenosinergic family (e.g., A2AR and CD73). The antimetastatic activity of anti-CD39 was NK cell and IFNγ dependent, and anti-CD39 enhanced the percentage and quantity of IFNγ produced and CD107a expression in lung-infiltrating NK cells following tumor challenge and anti-CD39 therapy. Using conditional Cd39 gene-targeted mouse strains and adoptive NK cell transfers, we showed that CD39 expressed on bone marrow-derived myeloid cells was essential for anti-CD39's antimetastatic activity, but NK cell expression of CD39 was not critical. The eATP receptor P2X7 and the NALP3 inflammasome, including downstream IL18, were critical in the mechanism of action of anti-CD39, and the frequency of P2X7 and CD39 coexpressing lung alveolar macrophages was specifically reduced 1 day after anti-CD39 therapy. The data provide a mechanism of action involving NK cells and myeloid cells, and anti-CD39 combined with anti-PD-1, NK cell-activating cytokines IL15 or IL2, or an inhibitor of A2AR to effectively suppress tumor metastases.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antígenos CD/inmunología , Apirasa/inmunología , Neoplasias Renales/inmunología , Células Asesinas Naturales/inmunología , Neoplasias Pulmonares/inmunología , Melanoma Experimental/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Apirasa/antagonistas & inhibidores , Tolerancia Inmunológica , Inflamasomas/inmunología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/terapia , Células Asesinas Naturales/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Células Tumorales Cultivadas
19.
Cell Death Dis ; 11(1): 66, 2020 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-31988297

RESUMEN

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide due to its high rate of recurrence, in part because of cancer stem cell (CSC)-dependent "field cancerization". Recently, we identified that the oncogene v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) marked CSC-like subpopulations in heterogeneous HCC and served as a therapeutic target and prognostic marker for HCC. In this study, we explored the molecular basis of upregulated MYCN gene expression in HCC cells. Liquid chromatograph time-of-flight mass spectrometry-based metabolome analysis demonstrated that the content of unsaturated fatty acids was increased in MYCN high expression (MYCNhigh) CSC-like HCC cells. Inhibition of lipid desaturation using either the chemical inhibitor or siRNA/shRNA against stearoyl-CoA desaturase-1 (SCD1) suppressed cell proliferation as well as MYCN gene expression in MYCNhigh HCC cells, grown as both monolayer and spheres. Further mechanistic study using RNA-seq based transcriptome analysis revealed that endoplasmic reticulum (ER) stress related signaling networks such as endocannabinoid cancer inhibition pathway were under the control of SCD1 in MYCNhigh HCC cells. Furthermore, the expression of ER stress-inducible transcription suppressor cyclic AMP-dependent transcription factor (ATF3) was downregulated in MYCNhigh CSC-like HCC cells and CSC-rich spheroids, which was upregulated by inhibition of lipid desaturation or treatment with acyclic retinoid (ACR). Lipid profiling using NMR spectroscopy revealed that the ACR dramatically reduced the content of unsaturated fatty acids in HCC cells. The chemical inducer of ER stress inhibited MYCN gene expression, while the chemical inhibitor of ER stress or knockdown of ATF3 gene expression partially rescued the suppression of MYCN gene expression by ACR in MYCNhigh HCC cells. These data suggested that lipid desaturation-mediated ER stress signaling regulates MYCN gene expression in HCC cells and serves as a promising therapeutic target for the treatment and prevention of HCC.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Estrés del Retículo Endoplásmico/genética , Ácidos Grasos Insaturados/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína Proto-Oncogénica N-Myc/metabolismo , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cromatografía Liquida , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácidos Grasos Insaturados/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Hepáticas/genética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Metaboloma , Proteína Proto-Oncogénica N-Myc/genética , Células Madre Neoplásicas/metabolismo , Organoides/efectos de los fármacos , Organoides/metabolismo , ARN Interferente Pequeño , RNA-Seq , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Tretinoina/análogos & derivados , Tretinoina/metabolismo , Tretinoina/farmacología
20.
J Stroke Cerebrovasc Dis ; 29(3): 104602, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31924485

RESUMEN

BACKGROUND: Dysphagia is a common symptom seen in stroke patients, it not only affects patients' nutrition supply, but also causes aspiration pneumonia. To solve the problem of nutritional support for patients with dysphagia after stroke, nasogastric tubes are routinely indwelling to provide nutrition in China. However, this feeding method sometimes causes food reflux, aspiration, pneumonia, and often affects the patients' comfort and self-image acceptance. AIM: The aim of this study was to determine whether a new feeding method called intermittent oroesophageal (IOE) tube feeding compared with continuous nasogastric tube feeding as a practical and beneficial mean of decreasing the rate of stroke associated pneumonia (SAP), and improving patients' swallowing function, comfort, psychological status. DESIGN: This was an assessor-blinded, single-center, randomized controlled trial. METHODS: Ninety-seven hospitalized stroke patients with dysphagia in the rehabilitation department from January to December 2018 were randomized to a control group and an intervention group. Patients in both groups received routine nursing, rehabilitation treatment and swallowing therapy. Patients in the intervention group were given IOE tube feeding, while those in the control group were fed by indwelling nasogastric tube. Outcomes were assessed at admission, discharge or the end of the tube feeding. RESULTS: The incidence of SAP in the intervention group was 16.33% lower than that (31.25%) in the control group; the comfort score (2.08 ± .64), anxiety score (10.98 ± 2.28), depression score (7.39 ± 2.16) were lower than those (3.02 ± .70), (12.10 ± 2.18), (8.42 ± 2.34) in the control group. The improvement rate of swallowing function in the intervention group was 83.67% higher than that (66.67%) in the control group (all P < .05). CONCLUSIONS: The IOE tube feeding compared with continuous tube feeding may reduce the incidence of SAP, and improve patients' swallowing function, comfort, psychological status in patients with dysphagia after stroke.


Asunto(s)
Trastornos de Deglución/terapia , Deglución , Nutrición Enteral/métodos , Estado Nutricional , Neumonía por Aspiración/prevención & control , Rehabilitación de Accidente Cerebrovascular/métodos , Accidente Cerebrovascular/terapia , Anciano , China , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Nutrición Enteral/efectos adversos , Femenino , Estado de Salud , Humanos , Masculino , Salud Mental , Persona de Mediana Edad , Neumonía por Aspiración/diagnóstico , Neumonía por Aspiración/etiología , Neumonía por Aspiración/fisiopatología , Recuperación de la Función , Factores de Riesgo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/fisiopatología , Rehabilitación de Accidente Cerebrovascular/efectos adversos , Factores de Tiempo , Resultado del Tratamiento
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