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1.
Breast Cancer Res ; 26(1): 108, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38951862

RESUMEN

BACKGROUND: Metastasis, the spread, and growth of malignant cells at secondary sites within a patient's body, accounts for over 90% of cancer-related mortality. Breast cancer is the most common tumor type diagnosed and the leading cause of cancer lethality in women in the United States. It is estimated that 10-16% breast cancer patients will have brain metastasis. Current therapies to treat patients with breast cancer brain metastasis (BCBM) remain palliative. This is largely due to our limited understanding of the fundamental molecular and cellular mechanisms through which BCBM progresses, which represents a critical barrier for the development of efficient therapies for affected breast cancer patients. METHODS: Previous research in BCBM relied on co-culture assays of tumor cells with rodent neural cells or rodent brain slice ex vivo. Given the need to overcome the obstacle for human-relevant host to study cell-cell communication in BCBM, we generated human embryonic stem cell-derived cerebral organoids to co-culture with human breast cancer cell lines. We used MDA-MB-231 and its brain metastatic derivate MDA-MB-231 Br-EGFP, other cell lines of MCF-7, HCC-1806, and SUM159PT. We leveraged this novel 3D co-culture platform to investigate the crosstalk of human breast cancer cells with neural cells in cerebral organoid. RESULTS: We found that MDA-MB-231 and SUM159PT breast cancer cells formed tumor colonies in human cerebral organoids. Moreover, MDA-MB-231 Br-EGFP cells showed increased capacity to invade and expand in human cerebral organoids. CONCLUSIONS: Our co-culture model has demonstrated a remarkable capacity to discern the brain metastatic ability of human breast cancer cells in cerebral organoids. The generation of BCBM-like structures in organoid will facilitate the study of human tumor microenvironment in culture.


Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Técnicas de Cocultivo , Organoides , Humanos , Organoides/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/patología , Femenino , Neoplasias de la Mama/patología , Línea Celular Tumoral , Encéfalo/patología , Comunicación Celular
2.
PLoS Med ; 21(2): e1004340, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38386617

RESUMEN

BACKGROUND: Screening reduces colorectal cancer (CRC) burden by allowing early resection of precancerous and cancerous lesions. An adequate selection of high-risk individuals and a high uptake rate for colonoscopy screening are critical to identifying people more likely to benefit from screening and allocating healthcare resources properly. We evaluated whether combining a questionnaire-based interview for risk factors with fecal immunochemical test (FIT) outcomes for high-risk assessment is more efficient and economical than a questionnaire-based interview-only strategy. METHODS AND FINDINGS: In this multicenter, population-based, prospective cohort study, we enrolled community residents aged 40 to 74 years in 29 provinces across China. From 2016 to 2020, a total of 1,526,824 eligible participants were consecutively enrolled in the Cancer Screening Program in Urban China (CanSPUC) cohort, and 940,605 were enrolled in the Whole Life Cycle of Cancer Screening Program (WHOLE) cohort, with follow-up to December 31, 2022. The mean ages were 56.89 and 58.61 years in CanSPUC and WHOLE, respectively. In the WHOLE cohort, high-risk individuals were identified by combining questionnaire-based interviews to collect data on risk factors (demographics, diet history, family history of CRC, etc.) with FIT outcomes (RF-FIT strategy), whereas in the CanSPUC cohort, high-risk individuals were identified using only interview-based data on risk factors (RF strategy). The primary outcomes were participation rate and yield (detection rate of advanced neoplasm, early-stage detection rate of CRCs [stage I/II], screening yield per 10,000 invitees), which were reported for the entire population and for different gender and age groups. The secondary outcome was the cost per case detected. In total, 71,967 (7.65%) and 281,985 (18.47%) individuals were identified as high-risk and were invited to undergo colonoscopy in the RF-FIT group and RF group, respectively. The colonoscopy participation rate in the RF-FIT group was 26.50% (19,071 of 71,967) and in the RF group was 19.54% (55,106 of 281,985; chi-squared test, p < 0.001). A total of 102 (0.53%) CRCs and 2,074 (10.88%) advanced adenomas were detected by the RF-FIT, versus 90 (0.16%) and 3,593 (6.52%) by the RF strategy (chi-squared test, both p < 0.001). The early-stage detection rate using the RF-FIT strategy was significantly higher than that by the RF strategy (67.05% versus 47.95%, Fisher's exact test, p = 0.016). The cost per CRC detected was $24,849 by the RF-FIT strategy versus $55,846 by the RF strategy. A limitation of the study was lack of balance between groups with regard to family history of CRC (3.5% versus 0.7%). CONCLUSIONS: Colonoscopy participation and screening yield were better with the RF-FIT strategy. The association with CRC incidence and mortality reduction should be evaluated after long-term follow-up.


Asunto(s)
Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Persona de Mediana Edad , Estudios de Cohortes , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Detección Precoz del Cáncer/métodos , Selección de Paciente , Estudios Prospectivos , Medición de Riesgo , Encuestas y Cuestionarios , Adulto , Anciano
3.
Drug Resist Updat ; 69: 100975, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37207473

RESUMEN

AIMS: Vessel co-option is responsible for tumor resistance to antiangiogenic therapies (AATs) in patients with colorectal cancer liver metastasis (CRCLM). However, the mechanisms underlying vessel co-option remain largely unknown. Herein, we investigated the roles of a novel lncRNA SYTL5-OT4 and Alanine-Serine-Cysteine Transporter 2 (ASCT2) in vessel co-option-mediated AAT resistance. METHODS: SYTL5-OT4 was identified by RNA-sequencing and verified by RT-qPCR and RNA fluorescence in situ hybridization assays. The effects of SYTL5-OT4 and ASCT2 on tumor cells were investigated by gain- and loss-of-function experiments, and those of SYTL5-OT4 on ASCT2 expression were analyzed by RNA immunoprecipitation and co-immunoprecipitation assays. The roles of SYTL5-OT4 and ASCT2 in vessel co-option were detected by histological, immunohistochemical, and immunofluorescence analyses. RESULTS: The expression of SYTL5-OT4 and ASCT2 was higher in patients with AAT-resistant CRCLM. SYTL5-OT4 enhanced the expression of ASCT2 by inhibiting its autophagic degradation. SYTL5-OT4 and ASCT2 promoted vessel co-option by increasing the proliferation and epithelial-mesenchymal transition of tumor cells. Combination therapy of ASCT2 inhibitor and antiangiogenic agents overcame vessel co-option-mediated AAT resistance in CRCLM. CONCLUSION: This study highlights the crucial roles of lncRNA and glutamine metabolism in vessel co-option and provides a potential therapeutic strategy for patients with AAT-resistant CRCLM.


Asunto(s)
Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Alanina , Proteínas Portadoras , Línea Celular Tumoral , Cisteína , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Proteínas de la Membrana , Proteínas de Transporte de Membrana , ARN Largo no Codificante/genética , Serina
4.
Genes Dev ; 30(7): 856-69, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-27013233

RESUMEN

Autophagy is an evolutionarily conserved cellular process controlled through a set of essential autophagy genes (Atgs). However, there is increasing evidence that most, if not all, Atgs also possess functions independent of their requirement in canonical autophagy, making it difficult to distinguish the contributions of autophagy-dependent or -independent functions of a particular Atg to various biological processes. To distinguish these functions for FIP200 (FAK family-interacting protein of 200 kDa), an Atg in autophagy induction, we examined FIP200 interaction with its autophagy partner, Atg13. We found that residues 582-585 (LQFL) in FIP200 are required for interaction with Atg13, and mutation of these residues to AAAA (designated the FIP200-4A mutant) abolished its canonical autophagy function in vitro. Furthermore, we created a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo, providing direct support for the essential role of the ULK1/Atg13/FIP200/Atg101 complex in the process beyond previous studies relying on the complete knockout of individual components. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth. These studies provide the first genetic evidence linking an Atg's autophagy and nonautophagic functions to different biological processes in vivo.


Asunto(s)
Autofagia/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Relacionadas con la Autofagia , Proliferación Celular/genética , Modelos Animales de Enfermedad , Desarrollo Embrionario/genética , Femenino , Técnicas de Sustitución del Gen , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Mutación , Análisis de Supervivencia , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/metabolismo
5.
Neurobiol Dis ; 179: 106066, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36889483

RESUMEN

Although both are myeloid cells located surrounding cerebral vasculature, vessel-associated microglia (VAM) and perivascular macrophages (PVMs) can be distinguished by their distinct morphologies, signatures and microscopic location. As key component of neuro-glia-vascular unit (NGVU), they play prominent roles in neurovasculature development and pathological process of various central nervous system (CNS) diseases, including phagocytosis, angiogenesis, vessel damage/protection and blood flow regulation, therefore serving as potential targets for therapeutics of a broad array of CNS diseases. Herein, we will provide a comprehensive overview of heterogeneity of VAM/PVMs, highlight limitations of current understanding in this field, and discuss possible directions of future investigations.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Microglía , Humanos , Microglía/fisiología , Encéfalo/patología , Macrófagos , Fagocitosis , Enfermedades del Sistema Nervioso Central/patología
6.
Cancer ; 129(18): 2871-2886, 2023 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-37221876

RESUMEN

BACKGROUND: There were limited studies on the quantification of the modifiable and nonmodifiable lung cancer burden over time in China. Furthermore, the potential effect of risk factor reduction for lung cancer on gains in life expectancy (LE) remains unknown. METHODS: This study explored temporal trends in lung cancer deaths and disability-adjusted life years (DALY) attributable to modifiable risk factors from 1990 to 2019, based on the 2019 Global Burden of Disease Study. The abridged period life table method was used to quantify the effect of risk factors on LE. The authors used the decomposition approach to estimate contributions of aging metrics to change in the lung cancer burden. RESULTS: Nationally, the majority of lung cancer deaths and DALYs were attributable to behavioral and environmental risk clusters. Potential gains in life expectancy (PGLE) at birth would be 0.78 years for males and 0.35 years for females if the exposure to risk factors was mitigated to the theoretical minimum level. Tobacco use had the most robust impact on LE for both sexes (PGLE: 0.71 years for males and 0.19 years for females). From 1990 to 2019, risk-attributable age-standardized death and DALY rates of lung cancer showed an increasing trend in both sexes; adult population growth imposed 245.9 thousand deaths and 6.2 million DALYs for lung cancer. CONCLUSIONS: The modifiable risk-attributable lung cancer burden remains high in China. Effective tobacco control is the critical step toward addressing the lung cancer burden. Adult population growth was the foremost driver of transition in the age-related lung cancer burden. PLAIN LANGUAGE SUMMARY: We estimate the lung cancer burden attributable to modifiable and nonmodifiable contributors and the effect of risk factor reduction for lung cancer on the life expectancy in China. The findings suggest that the majority of lung cancer deaths and disability-adjusted life years were attributable to behavioral risk clusters, and the risk-attributable lung cancer burden increased nationally from 1990 to 2019. The average gains in life expectancy would be 0.78 years for males and 0.35 years for females if the exposure to risk factors for lung cancer was reduced to the theoretical minimum risk exposure level. Adult population growth was identified as the foremost driver of variation in the aging lung cancer burden.


Asunto(s)
Esperanza de Vida , Neoplasias Pulmonares , Adulto , Masculino , Recién Nacido , Femenino , Humanos , Años de Vida Ajustados por Calidad de Vida , Factores de Riesgo , Neoplasias Pulmonares/epidemiología , Envejecimiento , China/epidemiología
7.
Neurochem Res ; 48(9): 2857-2869, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37195378

RESUMEN

Microglia are the residential immune cells of central nervous system and they are crucial for brain development and homeostasis, as well as the progression of inflammatory brain diseases. To study microglia's physiological and pathological functions, one of the most widely used models is primary microglia culture from neonatal rodents. However, primary microglia culture is time consuming and needs a great number of animals. In our microglia culture, we found a strain of spontaneously immortalized microglia that continued to divide without any known genetic intervention. We confirmed the immortalization of these cells for uninterrupted thirty passages and we named them as immortalized microglia like-1 cells (iMG-1). The iMG-1 cells kept their microglia morphology, and they expressed macrophage/microglia-specific proteins of CD11b, CD68, P2RY12, and IBA1 in vitro. iMG-1 cells were responsive to inflammatory stimulations with lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (pIpC), triggering increased mRNA/protein levels of IL1-ß, IL-6, TNF-α, and interferons. LPS and pIpC treated iMG-1 cells also significantly increased their accumulation of lipid droplets (LDs). We also generated a 3D spheroid model using immortalized neural progenitor cells and iMG-1 cells with defined percentages to study neuroinflammation. The iMG-1 cells distributed evenly in spheroids, and they regulated the basal mRNA levels of cytokines of neural progenitors in 3D spheroid. iMG-1 cells were responsive to LPS by increased expression of IL-6 and IL1-ß in spheroids. Together, this study indicated the reliability of iMG-1 which could be readily available to study the physiological and pathological functions of microglia.


Asunto(s)
Lipopolisacáridos , Microglía , Ratones , Animales , Microglía/metabolismo , Lipopolisacáridos/farmacología , Interleucina-6/metabolismo , Reproducibilidad de los Resultados , Línea Celular , ARN Mensajero/metabolismo
8.
BMC Pregnancy Childbirth ; 23(1): 451, 2023 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-37330495

RESUMEN

BACKGROUND: Implementation of Kangaroo Mother Care (KMC) in resource-limited areas of China may face unique barriers, such as a lack of resources, geographic location and more traditional culture among others. This qualitative study analyses the facilitators and barriers to implementing KMC in county-level health facilities in resource-limited areas of China for the promotion of KMC on a larger scale. METHODS: Participants from 4 of the 18 pilot counties where early essential newborn care was implemented through the Safe Neonatal Project and 4 control counties not enrolled in Safe Neonatal Project were selected using purposive sampling. A total of 155 participants were interviewed, including stakeholders of the Safe Neonatal Project such as national maternal health experts, relevant government officials and medical staff. Thematic analysis was used to process and analyse the interview content in order to summarise the facilitators and barriers to implementing KMC. RESULTS: KMC was accepted in the pilot areas but still faced certain challenges due to institutional regulation, resource provision and the perceptions of health staff, postpartum mothers and their families as well as COVID-19 prevention and control regulations. The facilitators identified were government officials and medical staff acceptance and the incorporation of KMC into routine clinical care. The barriers identified were a lack of dedicated funding and other resources, the present scope of health insurance and KMC cost-sharing mechanism, providers' knowledge and practical abilities, parental awareness, postpartum discomfort, fathers' inadequate involvement, and the impact from COVID-19. CONCLUSION: The Safe Neonatal Project pilot experience indicated the feasibility of implementing KMC in more areas of China. Optimising institutional regulations, providing necessary supporting resources and enhancing education and training may help to refine the implementation and scale-up of KMC practice in China.


Asunto(s)
Método Madre-Canguro , Madres , Niño , Femenino , Humanos , Recién Nacido , China , COVID-19 , Recien Nacido Prematuro , Proyectos Piloto , Actitud del Personal de Salud , Conocimientos, Actitudes y Práctica en Salud , Madres/psicología
9.
Cell Mol Life Sci ; 79(8): 439, 2022 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-35864266

RESUMEN

Previous studies suggested that anti-inflammatory microglia/macrophages (Mi/MΦ) play a role in "normal phagocytosis," which promoted the rapid clearance of necrotic substances and apoptotic cells. More recently, a few studies have found that Mi/MΦ also play a role in "pathological phagocytosis" in the form of excessive or reduced phagocytosis, thereby worsening damage induced by CNS diseases. However, the underlying mechanisms and the Mi/MΦ subtypes related to this pathological phagocytosis are still unknown. Salt-inducible kinase 3 (SIK3), a member of the 5' adenosine monophosphate-activated protein kinase (AMPK) family, has been shown to regulate inflammation in several peripheral diseases. Whether SIK3 also regulates the inflammatory response in CNS diseases is currently unknown. Therefore, in this study, we created a transgenic tamoxifen-induced Mi/MΦ-specific SIK3 conditional knockout (SIK3-cKO) mouse to examine SIK3's role in phagocytotic function induced by transient focal cerebral ischemia (tFCI). By single-cell RNA-seq, we found the pro-inflammatory Mi/MΦ phenotype performed an excessive phagocytotic function, but the anti-inflammatory Mi/MΦ phenotype performed a normal phagocytotic function. We found that SIK3-cKO caused Mi/MΦ heterogenization from the transitional phenotype to the anti-inflammatory phenotype after tFCI. This phenotypic shift corresponded with enhanced phagocytosis of both apoptotic and live neurons. Interestingly, SIK3-cKO enhanced normal phagocytosis of myelin debris but attenuating excessive phagocytosis of non-damaged myelin sheath, thereby protecting white matter integrity after tFCI. CD16, a pro-inflammation marker, was decreased significantly by SIK3-cKO and correlated with "excessive phagocytosis." SIK3-cKO promoted long-term recovery of white matter function and neurological function as assessed with electrophysiological compound action potential (CAPs) and behavioral analysis. This study is the first to show a role of SIK3 in Mi/MΦ phagocytosis in CNS diseases, and reveals that promoting Mi/MΦ anti-inflammatory heterogenization inhibits "excessive phagocytosis" of live cells and facilitates "normal phagocytosis" of apoptotic cells. Therefore, inhibition of SIK3 in Mi/MΦ may be a potential therapeutic target in stroke and other CNS diseases with accompanying white matter destruction. In the acute stage of tFCI, Mi/MΦ polarized into different phenotypes. The pro-inflammatory Mi/MΦ phenotype performed an excessive phagocytotic function. In contrast, the anti-inflammatory Mi/MΦ phenotype performed a normal phagocytotic function. After tFCI, SIK3-cKO promoted anti-inflammatory phenotypic heterogenization of Mi/MΦ. SIK3-cKO promoted Mi/MΦ phagocytosis of apoptotic (normal phagocytosis) and living neuronal cell bodies (excessive phagocytosis) in gray matter. Interestingly, SIK3-cKO specifically increased normal phagocytosis of myelin debris concurrent with an attenuation of excessive phagocytosis of myelin sheath in white matter. These changes induced by SIK3-cKO were associated with protection of white matter integrity and long-term neurofunctional recovery after tFCI.


Asunto(s)
Isquemia Encefálica , Enfermedades del Sistema Nervioso Central , Animales , Isquemia Encefálica/metabolismo , Enfermedades del Sistema Nervioso Central/patología , Inflamación/patología , Macrófagos/metabolismo , Ratones , Microglía/metabolismo , Fagocitosis , Proteínas Serina-Treonina Quinasas/genética
10.
Drug Resist Updat ; 64: 100849, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35842983

RESUMEN

Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival benefits to many cancer patients, resistance to antiangiogenic drugs frequently occurs during clinical treatment, leading to poor outcomes and treatment failure. Cumulative evidence has demonstrated that the intricate interplay among tumor cells, bone marrow-derived cells, and local stromal cells critically allows for tumor escape from antiangiogenic therapy. Currently, drug resistance has become the main challenge that hinders the therapeutic efficacies of antiangiogenic therapy. In this review, we describe and summarize the cellular and molecular mechanisms conferring tumor drug resistance to antiangiogenic therapy, which was predominantly associated with redundancy in angiogenic signaling molecules (e.g., VEGFs, GM-CSF, G-CSF, and IL17), alterations in biological processes of tumor cells (e.g., tumor invasiveness and metastasis, stemness, autophagy, metabolic reprogramming, vessel co-option, and vasculogenic mimicry), increased recruitment of bone marrow-derived cells (e.g., myeloid-derived suppressive cells, tumor-associated macrophages, and tumor-associated neutrophils), and changes in the biological functions and features of local stromal cells (e.g., pericytes, cancer-associated fibroblasts, and endothelial cells). We also review potential biomarkers to predict the response to antiangiogenic therapy in cancer patients, which mainly consist of imaging biomarkers, cellular and extracellular proteins, a certain type of bone marrow-derived cells, local stromal cell content (e.g., pericyte coverage) as well as serum or plasma biomarkers (e.g., non-coding RNAs). Finally, we highlight the recent advances in combination strategies with the aim of enhancing the response to antiangiogenic therapy in cancer patients and mouse models. This review introduces a comprehensive understanding of the mechanisms and biomarkers associated with the evasion of antiangiogenic therapy in cancer, providing an outlook for developing more effective approaches to promote the therapeutic efficacy of antiangiogenic therapy.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos , Neoplasias , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Bevacizumab/uso terapéutico , Células Endoteliales/metabolismo , Células Endoteliales/patología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Sorafenib/uso terapéutico
11.
Environ Monit Assess ; 195(12): 1488, 2023 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-37975891

RESUMEN

This study aimed to investigate the distribution and migration characteristics of lead (Pb) and zinc (Zn) in paddy soils in Hunan Province, China. A total of 343 soil samples from 63 profiles were collected from typical regions. The concentration, spatial distribution, and migration behaviors of Pb and Zn in the paddy soils were examined. The results showed that (1) the concentration ranges of Pb and Zn in the surface layer were 17.62-114.07 mg/kg and 44.98-146.84 mg/kg, respectively. (2) The content was higher in the middle and lower reaches of the Xiangjiang River basin horizontally and exhibited shallow enrichment characteristics vertically. (3) Pb migration was weaker than Zn migration, and the parent material had the most significant influence on Pb and Zn content in the bottom soil layer. The research results will clarify the characteristics of Pb and Zn contents in paddy soils in Hunan Province, further understand the horizontal distribution and vertical migration and transformation characteristics of Pb and Zn contents in paddy soils, and provide basic data for scientific rice cultivation and safe food production.


Asunto(s)
Metales Pesados , Oryza , Contaminantes del Suelo , Zinc/análisis , Suelo , Plomo , Contaminantes del Suelo/análisis , Monitoreo del Ambiente , China , Metales Pesados/análisis
12.
BMC Bioinformatics ; 23(1): 368, 2022 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-36076158

RESUMEN

Protein ligand docking is an indispensable tool for computational prediction of protein functions and screening drug candidates. Despite significant progress over the past two decades, it is still a challenging problem, characterized by the still limited understanding of the energetics between proteins and ligands, and the vast conformational space that has to be searched to find a satisfactory solution. In this project, we developed a novel reinforcement learning (RL) approach, the asynchronous advantage actor-critic model (A3C), to address the protein ligand docking problem. The overall framework consists of two models. During the search process, the agent takes an action selected by the actor model based on the current location. The critic model then evaluates this action and predict the distance between the current location and true binding site. Experimental results showed that in both single- and multi-atom cases, our model improves binding site prediction substantially compared to a naïve model. For the single-atom ligand, copper ion (Cu2+), the model predicted binding sites have a median root-mean-square-deviation (RMSD) of 2.39 Å to the true binding sites when starting from random starting locations. For the multi-atom ligand, sulfate ion (SO42-), the predicted binding sites have a median RMSD of 3.82 Å to the true binding sites. The ligand-specific models built in this study can be used in solvent mapping studies and the RL framework can be readily scaled up to larger and more diverse sets of ligands.


Asunto(s)
Diseño de Fármacos , Proteínas , Sitios de Unión , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica , Proteínas/química
13.
BMC Anesthesiol ; 22(1): 19, 2022 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-35021986

RESUMEN

BACKGROUND: Delta-opioid receptor is widely expressed in human and rodent hearts, and has been proved to protect cardiomyocytes against ischemia/reperfusion and heart failure. The antagonist of delta-opioid receptor could block the rescue effect of lipid emulsion against local anesthetic cardiotoxicity. However, no evidence is available for the direct effect of delta-opioid-receptor agonists on the cardiotoxicity of local anesthetics. METHODS: Anesthetized Sprague Dawley rats were divided into five groups. Group NS received 2 ml·kg-1·min-1 normal saline, group LE received 2 ml·kg-1·min-1 30% lipid emulsion and group BW received 0.1, 1.0, or 5.0 mg/kg BW373U86, a delta-opioid-receptor agonist, for 5 min. Then 0.5% bupivacaine was infused intravenously at a rate of 3.0 mg·kg-1·min-1 until asystole. The time of arrhythmia, 50% mean arterial pressure-, 50% heart rate-reduction and asystole were recorded, and the dose of bupivacaine at each time point was calculated. RESULTS: All three different doses of BW373U86 did not affect the arrhythmia, 50% mean arterial pressure-reduction, 50% heart rate-reduction and asystole dose of bupivacaine compared with group NS. 30% LE significantly increased the bupivacaine threshold of 50% mean arterial pressure-reduction (17.9 [15.4-20.7] versus 7.2 [5.9-8.7], p = 0.018), 50% heart rate-reduction (18.7 ± 4.2 versus 8.8 ± 1.7, p < 0.001) and asystole (26.5 [21.0-29.1] versus 11.3 [10.7-13.4], p = 0.008) compared with group NS. There was no difference between group LE and group NS in the arrhythmia dose of bupivacaine (9.9 [8.9-11.7] versus 5.6 [4.5-7.0], p = 0.060). CONCLUSIONS: Our data show that BW373U86 does not affect the cardiotoxicity of bupivacaine compared with NS control in rats. 30% LE pretreatment protects the myocardium against bupivacaine-induced cardiotoxicity.


Asunto(s)
Anestésicos Locales/efectos adversos , Benzamidas/farmacología , Bupivacaína/efectos adversos , Cardiotoxicidad/prevención & control , Piperazinas/farmacología , Receptores Opioides/agonistas , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ratas , Ratas Sprague-Dawley
14.
BMC Health Serv Res ; 22(1): 1185, 2022 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-36131341

RESUMEN

BACKGROUND: Neonatal survival is a public health concern globally. However, the regional disparity in neonatal mortality between rural counties of western China and urban areas of eastern provinces remains high. Early essential newborn care (EENC), recommended by World Health Organization, refers to a set of cost-effective interventions to improve neonatal health and development outcomes. In this study, we aimed to explore the effectiveness of EENC implementation in four counties of western China. METHODS: Pre- and post-intervention investigations were conducted in four selected EENC intervention counties and four control counties of four western provinces of China, from June to August 2017 and from December 2020 to April 2021 respectively. A mixed quantitative and qualitative approach was used for data collection and analysis. Data on the coverage of EENC practices were collected via a post-intervention face-to-face questionnaire survey with postpartum mothers before hospital discharge. Hospital-reported data on neonatal health indicators were obtained through mail surveys in both investigations. We also performed semi-structured interviews with policymakers, health staff and postpartum mothers to understand their perceptions about the usefulness of EENC implementation. RESULTS: Overall, 599 mother-newborn pairs in the intervention group and 699 pairs in the control group participated in the post-intervention survey. Controlling for the confounding factor of province, the proportion of newborns receiving EENC interventions was higher in the intervention group than in the control group (P < 0.05). Intervention groups in four provinces had higher coverage of: any skin-to-skin contact (99.50% vs. 49.07%); early breastfeeding initiation (within 60 min of birth) (90.84% vs. 80.35%); no medicine applied to the umbilical cord (98.50% vs. 9.73%); routine eye care (93.16% vs. 8.73%); and vitamin K1 administration (98.33% vs. 88.98%). EENC implementation was associated with decreased risk of neonatal diarrhea (OR: 0.326, 95% CI: 0.123, 0.865) and eye infection (OR: 0.147, 95% CI: 0.045, 0.483). Policymakers, health staff and postpartum mothers expressed satisfaction with the EENC interventions, noting a willingness among staff and policymakers to implement and sustain these interventions; the promotion of these interventions within hospital policy; the positive emotions experienced by postpartum mothers; perceived improvements in health; and improvements in support for health workers. CONCLUSION: EENC-recommended core practices (except kangaroo mother care) have been successfully introduced in pilot hospitals. The efficacy of EENC implementation should be highly recognized to accelerate the progress towards its national roll out.


Asunto(s)
Método Madre-Canguro , Lactancia Materna , Niño , China , Femenino , Humanos , Madres , Parto , Embarazo , Vitamina K
15.
Genes Dev ; 28(11): 1204-16, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24888590

RESUMEN

Autophagy is crucial for cellular homeostasis and plays important roles in tumorigenesis. FIP200 (FAK family-interacting protein of 200 kDa) is an essential autophagy gene required for autophagy induction, functioning in the ULK1-ATG13-FIP200 complex. Our previous studies showed that conditional knockout of FIP200 significantly suppressed mammary tumorigenesis, which was accompanied by accumulation of p62 in tumor cells. However, it is not clear whether FIP200 is also required for maintaining tumor growth and how the increased p62 level affects the growth in autophagy-deficient FIP200-null tumors in vivo. Here, we describe a new system to delete FIP200 in transformed mouse embryonic fibroblasts as well as mammary tumor cells following their transplantation and show that ablation of FIP200 significantly reduced growth of established tumors in vivo. Using similar strategies, we further showed that either p62 knockdown or p62 deficiency in established FIP200-null tumors dramatically impaired tumor growth. The stimulation of tumor growth by p62 accumulation in FIP200-null tumors is associated with the up-regulated activation of the NF-κB pathway by p62. Last, we showed that overexpression of the autophagy master regulator TFEB(S142A) increased the growth of established tumors, which correlated with the increased autophagy of the tumor cells. Together, our studies demonstrate that p62 and autophagy synergize to promote tumor growth, suggesting that inhibition of both pathways could be more effective than targeting either alone for cancer therapy.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autofagia/fisiología , Neoplasias de la Mama/fisiopatología , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Animales , Autofagia/genética , Proteínas Relacionadas con la Autofagia , Neoplasias de la Mama/genética , Línea Celular , Línea Celular Tumoral , Femenino , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Transgénicos , Proteína Sequestosoma-1
16.
Br J Cancer ; 124(10): 1711-1723, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33723393

RESUMEN

BACKGROUND: Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied. METHODS: Using glioma patient database and human glioma cells, we assessed the mechanisms and function of selective autophagy to sustain mTORC1 hyper-activation in glioma. RESULTS: We revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with prognosis of glioma patients. Our results indicated that autophagy-mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibitors in combination with 2-Deoxy-D-glucose (2DG) decreased energy production and survival of glioma cells in vitro. Consistently, inhibition of autophagy or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with hyper-activated mTORC1. CONCLUSIONS: This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.


Asunto(s)
Autofagia/fisiología , Neoplasias Encefálicas/metabolismo , Metabolismo Energético/fisiología , Glioma/metabolismo , Metabolismo de los Lípidos , Animales , Apoptosis/genética , Autofagia/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Metabolismo Energético/genética , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/patología , Células HEK293 , Humanos , Metabolismo de los Lípidos/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Desnudos , Transducción de Señal/genética
17.
BMC Pulm Med ; 21(1): 189, 2021 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-34090386

RESUMEN

BACKGROUND: Different from current cognition, our study demonstrated that adrenergic receptors agonist phenylephrine significantly relaxed isolated pulmonary artery but constricted pulmonary veins. Through comparing differences in the effects of commonly used vasoactive drugs on pulmonary artery and veins, the study aimed to improve efficiency and accuracy of isolated pulmonary vascular experiments, and to provide experimental basis for clinical drug use. METHODS: The contractile responses of pulmonary arteries and veins from twelve-week-old Male Sprague-Dawley rats to phenylephrine, arginine vasopressin (AVP), U46619, endothelin-1, and potassium chloride (KCl) were recorded, as well as the relaxation in response to phenylephrine, AVP, acetylcholine. To further explore the mechanism, some vessels was also pre-incubated with adrenergic receptors antagonists propranolol, prazosin and nitric oxide synthesis inhibitor N[gamma]-nitro-L-arginine methyl ester (L-NAME) before addition of the experimental drugs. RESULTS: Phenylephrine constricted pulmonary veins directly, but constricted pulmonary artery only after incubation with propranolol or/and L-NAME. The pulmonary artery exhibited significant relaxation to AVP with or without L-NAME incubation. AVP more clearly constricted the veins after incubation with L-NAME. Changes in vascular tension also varied from pulmonary artery to veins for KCl stimulation. Different from phenomena presented in veins, acetylcholine did not relax pulmonary artery preconstricted by KCl, U46619, and endothelin-1. CONCLUSIONS: According to the results, phenylephrine, KCl, AVP, and acetylcholine could be used to distinguish pulmonary arteries and pulmonary veins in vitro. This also suggested that the pulmonary arteries and pulmonary veins have great differences in physiology and drug reactivity.


Asunto(s)
Fenilefrina/farmacología , Arteria Pulmonar/efectos de los fármacos , Venas Pulmonares/efectos de los fármacos , Vasoconstrictores/farmacología , Acetilcolina/farmacología , Animales , Arginina Vasopresina/farmacología , Masculino , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley
18.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33923449

RESUMEN

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in TSC1 (hamartin) or TSC2 (tuberin), crucial negative regulators of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. TSC affects multiple organs including the brain. The neurologic manifestation is characterized by cortical tubers, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA) in brain. SEGAs may result in hydrocephalus in TSC patients and mTORC1 inhibitors are the current recommended therapy for SEGA. Nevertheless, a major limitation in the research for SEGA is the lack of cell lines or animal models for mechanistic investigations and development of novel therapy. In this study, we generated TSC1-deficient neural cells from spontaneously immortalized mouse astrocytes in an attempt to mimic human SEGA. The TSC1-deficient cells exhibit mTORC1 hyperactivation and characteristics of transition from astrocytes to neural stem/progenitor cell phenotypes. Rapamycin efficiently decreased mTORC1 activity of these TSC1-deficient cells in vitro. In vivo, TSC1-deficient cells could form SEGA-like tumors and Rapamycin treatment decreased tumor growth. Collectively, our study generates a novel SEGA-like cell line that is invaluable for studying mTORC1-driven molecular and pathological alterations in neurologic tissue. These SEGA-like cells also provide opportunities for the development of novel therapeutic strategy for TSC patients with SEGA.


Asunto(s)
Astrocitoma/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Antibióticos Antineoplásicos/farmacología , Astrocitos/metabolismo , Astrocitos/patología , Astrocitoma/genética , Astrocitoma/patología , Células Cultivadas , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Ratones , Ratones Desnudos , Cultivo Primario de Células/métodos , Sirolimus/farmacología , Proteína 1 del Complejo de la Esclerosis Tuberosa/deficiencia , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética
19.
Proteins ; 88(7): 819-829, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31867753

RESUMEN

Designing protein sequences that fold to a given three-dimensional (3D) structure has long been a challenging problem in computational structural biology with significant theoretical and practical implications. In this study, we first formulated this problem as predicting the residue type given the 3D structural environment around the C α atom of a residue, which is repeated for each residue of a protein. We designed a nine-layer 3D deep convolutional neural network (CNN) that takes as input a gridded box with the atomic coordinates and types around a residue. Several CNN layers were designed to capture structure information at different scales, such as bond lengths, bond angles, torsion angles, and secondary structures. Trained on a very large number of protein structures, the method, called ProDCoNN (protein design with CNN), achieved state-of-the-art performance when tested on large numbers of test proteins and benchmark datasets.


Asunto(s)
Redes Neurales de la Computación , Ingeniería de Proteínas/estadística & datos numéricos , Proteínas/química , Programas Informáticos , Secuencia de Aminoácidos , Benchmarking , Bases de Datos de Proteínas , Conjuntos de Datos como Asunto , Ingeniería de Proteínas/métodos , Estructura Secundaria de Proteína , Alineación de Secuencia
20.
Br J Cancer ; 122(12): 1791-1802, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32336756

RESUMEN

BACKGOUND: The mechanistic target of rapamycin complex 1 (mTORC1) is important in the development and progression of many cancers. Targeted cancer therapy using mTORC1 inhibitors is used for treatment of cancers; however, their clinical efficacies are still limited. METHODS: We recently created a new mouse model for human lymphangiosarcoma by deleting Tsc1 in endothelial cells and consequent hyper-activation of mTORC1. Using Tsc1iΔEC tumour cells from this mouse model, we assessed the efficacies of histone deacetylase (HDAC) inhibitors as anti-tumour agents for mTORC1-driven tumours. RESULTS: Unlike the cytostatic effect of mTORC1 inhibitors, HDAC inhibitors induced Tsc1iΔEC tumour cell death in vitro and their growth in vivo. Analysis of several HDAC inhibitors suggested stronger anti-tumour activity of class I HDAC inhibitor than class IIa or class IIb inhibitors, but these or pan HDAC inhibitor SAHA did not affect mTORC1 activation in these cells. Moreover, HDAC inhibitor-induced cell death required elevated autophagy, but was not affected by disrupting caspase-dependent apoptosis pathways. We also observed increased reactive oxygen species and endoplasmic reticulum stress in SAHA-treated tumour cells, suggesting their contribution to autophagic cell death, which were dependent on mTORC1 hyper-activation. CONCLUSION: These studies suggest a potential new treatment strategy for mTORC1-driven cancers like lymphangiosarcoma through an alternative mechanism.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Linfangiosarcoma/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Terapia Molecular Dirigida/métodos , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones , Neoplasias Experimentales/patología
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