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1.
Eur J Surg Oncol ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33934940

RESUMO

BACKGROUND & AIMS: Postoperative morbidity following hepatectomy for hepatocellular carcinoma (HCC) is common and its impact on long-term oncological outcome remains unclear. This study aimed to investigate if postoperative morbidity impacts long-term survival and recurrence following hepatectomy for HCC. METHODS: The data from a multicenter Chinese database of curative-intent hepatectomy for HCC were analyzed, and independent risks of postoperative 30-day morbidity were identified. After excluding patients with postoperative early deaths (≤90 days), early (≤2 years) and late (>2 years) recurrence rates, overall survival (OS), and time-to-recurrence (TTR) were compared between patients with and without postoperative morbidity. RESULTS: Among 2,161 patients eligible for the study, 758 (35.1%) had postoperative 30-day morbidity. Multivariable logistic regression analysis showed that diabetes mellitus, obesity, Child-Pugh grade B, cirrhosis, and intraoperative blood transfusion were independent risks of postoperative morbidity. The rates of early and late recurrence among patients with postoperative morbidity were higher than those without (50.7% vs. 38.8%, P < 0.001; and 41.7% vs. 34.1%, P = 0.017). Postoperative morbidity was associated with decreased OS (median: 48.1 vs. 91.6 months, P < 0.001) and TTR (median: 19.8 vs. 46.1 months; P < 0.001). After adjustment of confounding factors, multivariable Cox-regression analyses revealed that postoperative morbidity was associated with a 27.8% and 18.7% greater likelihood of mortality (hazard ratio 1.278; 95% confidence interval: 1.126-1.451; P < 0.001) and recurrence (1.187; 1.058-1.331; P = 0.004). CONCLUSION: This large multicenter study provides strong evidence that postoperative morbidity adversely impacts long-term oncologic prognosis after hepatectomy for HCC. The prevention and management of postoperative morbidity may be oncologically important.

2.
ACS Nano ; 15(4): 7649-7658, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33871962

RESUMO

Accurate and rapid blood typing plays a vital role in a variety of biomedical and forensic scenarios, but recognizing weak agglutination remains challenging. Herein, we demonstrated a flipping identification with a prompt error-discrimination (FLIPPED) platform for automatic blood group readouts. Bromocresol green dye was exploited as a characteristic chromatography indicator for the differentiation of plasma from whole blood by presenting a teal color against a brown color. After integrating these color changes into a quick-response (QR) code, prompt typing of ABO and Rhesus groups was automatically achieved and data could be uploaded wirelessly within 30 s using a commercially available smartphone to facilitate blood cross-matching. We further designed a color correction model and algorithm to remove potential errors from scanning angles and ambient light intensities, by which weak agglutination could be accurately recognized. With comparable accuracy and repeatability to classical column assay in grouping 450 blood samples, the proposed approach further demonstrates to be a versatile sample-to-result platform for clinical diagnostics, food safety, and environmental monitoring.

3.
J Org Chem ; 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881865

RESUMO

Hypermonins A-D (1-4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A-D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1-7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.

4.
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 35(4): 371-374;379, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33794641

RESUMO

Children with microtia are often associated with maxillofacial dysostosis, such as Treacher Collins syndrome, Goldenhar syndrome, and Nager syndrome, and they are prone to suffer from obstructive sleep apnea(OSA). Obstruction widely occurred in the upper airway is the main mechanism of OSA in these children, and dysplasia of the pharynx and neurodevelopmental abnormalities may also participate. Early diagnosis requires symptom screening and polysomnography. Imaging techniques and endoscopy can be adopted to fully assess the upper airway status to guide further treatment. According to the child's condition and the main obstruction site, treatment methods include maxillofacial deformity correction, continuous positive pressure ventilation and tracheotomy. OSA in microtia children with maxillofacial dysostosis needs to be identified and treated in time to reduce the adverse effects on the growth and development of children.


Assuntos
Microtia Congênita , Disostose Craniofacial , Anormalidades Maxilofaciais , Apneia Obstrutiva do Sono , Criança , Anormalidades do Olho , Humanos , Distúrbios da Fala
5.
Org Lett ; 23(8): 3125-3129, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33818113

RESUMO

Hymoins A-D (1-4), two pairs of light-induced transformative polyprenylated acylphloroglucinols with an unprecedented pentacyclic skeleton, were isolated from the flowers of Hypericum monogynum. The first decarbonylative ring contraction of complex natural products was investigated by light irradiation. Their structures were elucidated by nuclear magnetic resonance analysis, X-ray crystallography, and electronic circular dichroism calculations. In addition, compound 3 showed moderate inhibition efficacy of the platelet-activating-factor-induced aggregation of rabbit platelets.

6.
Sci Adv ; 7(14)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33789902

RESUMO

Cancer cell-intrinsic programmed cell death protein-1 (PD-1) has emerged as a tumor regulator in an immunity-independent manner, but its precise role in modulating tumor behaviors is complex, and how PD-1 is regulated in cancer cells is largely unknown. Here, we identified PD-1 as a direct target of tumor suppressor p53. Notably, p53 acetylation at K120/164 played a critical role in p53-mediated PD-1 transcription. Acetylated p53 preferentially recruited acetyltransferase cofactors onto PD-1 promoter, selectively facilitating PD-1 transcription by enhancing local chromatin acetylation. Reexpression of PD-1 in cancer cells inhibited tumor growth, whereas depletion of cancer cell-intrinsic PD-1 compromised p53-dependent tumor suppression. Moreover, histone deacetylase inhibitor (HDACi) activated PD-1 in an acetylated p53-dependent manner, supporting a synergistic effect by HDACi and p53 on tumor suppression via stimulating cancer cell-intrinsic PD-1. Our study reveals a mechanism for activating cancer cell-intrinsic PD-1 and indicates that p53-mediated PD-1 activation is critically involved in tumor suppression in an immunity-independent manner.

7.
Cardiovasc Res ; 2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33839767

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of February 8th, 2020 and causing more than 2.3 million deaths according the World Health Organization. Not only affecting the lungs and provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts and the added value of artificial intelligence to achieve reliable advances.

8.
Transl Oncol ; 14(7): 101091, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33848808

RESUMO

The potential therapeutic effects of oncolytic measles virotherapy have been verified against plenty of malignancies. However, the oncolytic effects and underlying mechanisms of the recombinant Chinese measles virus vaccine strain Hu191 (rMV-Hu191) against human colorectal cancer (CRC) remain elusive. In this study, the antitumor effects of rMV-Hu191 were evaluated in CRC both in vitro and in vivo. From our data, rMV-Hu191 induced remarkably caspase-dependent apoptosis and complete autophagy in vitro. In mice bearing CRC xenografts, tumor volume was remarkably suppressed and median survival was prolonged significantly with intratumoral treatment of rMV-Hu191. To gain further insight into the relationship of rMV-Hu191-induced apoptosis and autophagy, we utilized Rapa and shATG7 to regulate autophagy. Our data suggested that autophagy was served as a protective role in rMV-Hu191-induced apoptosis in CRC. PI3K/AKT signaling pathway as one of the common upstream pathways of apoptosis and autophagy was activated in CRC after treatment with rMV-Hu191. And inhibition of PI3K/AKT pathway using LY294002 was accompanied by enhanced apoptosis and decreased autophagy which suggested that PI3K/AKT pathway promoted rMV-Hu191-induced autophagy and inhibited rMV-Hu191-induced apoptosis. This is the first study to demonstrate that rMV-Hu191 could be used as a potentially effective therapeutic agent in CRC treatment. As part of the underlying cellular mechanisms, apoptosis and autophagy were involved in the oncolytic effects generated by rMV-Hu191. And the cross-talk between these two processes and the PI3K/AKT signaling pathway was well identified.

9.
Plant Physiol ; 185(3): 985-1001, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33793873

RESUMO

Endoplasmic reticulum (ER) type I signal peptidases (ER SPases I) are vital proteases that cleave signal peptides from secreted proteins. However, the specific function of ER SPase I in plants has not been genetically characterized, and the substrate is largely unknown. Here, we report the identification of a maize (Zea mays) miniature seed6 (mn6) mutant. The loss-of-function mn6 mutant exhibited severely reduced endosperm size. Map-based cloning and molecular characterization indicated that Mn6 is an S26-family ER SPase I, with Gly102 (box E) in Mn6 critical for protein function during processing. Mass spectrometric and immunoprecipitation analyses revealed that Mn6 is predominantly involved in processing carbohydrate synthesis-related proteins, including the cell wall invertase miniature seed1 (Mn1), which is specifically expressed in the basal endosperm transfer layer. RNA and protein expression levels of Mn1 were both significantly downregulated in the mn6 mutant. Due to the significant reduction in cell wall invertase activity in the transfer cell layer, mutation of Mn6 caused dramatic defects in endosperm development. These results suggest that proper maturation of Mn1 by Mn6 may be a crucial step for proper seed filling and maize development.

10.
Phytomedicine ; 86: 153558, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33866197

RESUMO

BACKGROUND: Curcumae Rhizoma (CR) has a clinical efficacy in activating blood circulation to dissipate blood stasis and has been used for the clinical treatment of qi stagnation and blood stasis (QSBS) primary dysmenorrhea for many years. However, its molecular mechanism is unknown. OBJECTIVE: The present study aimed to demonstrate the multicomponent, multitarget and multipathway regulatory molecular mechanisms of CR in the treatment of QSBS primary dysmenorrhea. METHODS: Observations of pathological changes in uterine tissues and biochemical assays were used to confirm that a rat model was successfully established and that CR was effective in the treatment of QSBS primary dysmenorrhea. The main active components of CR in rat plasma were identified and screened by ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS). The component-target-disease network and protein-protein interaction (PPI) network of CR were constructed by a network pharmacology approach. Then, we performed Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was adopted to verify the interactions between the core components and targets of CR to confirm the accuracy of the network pharmacology prediction results. Furthermore, we evaluated the bioactive constituents of CR and molecular mechanism of by which CR promote blood circulation and remove blood stasis via platelet tests in vivo and in vitro and Western blot analysis. RESULTS: The results of HE staining and biochemical assays of PGF2α, TXB2 and Ca2+ showed that CR was effective in the treatment of QSBS primary dysmenorrhea. A total of 36 active components were identified in CR, and 329 common targets were obtained and used to construct the networks. Of these, 14 core components and 10 core targets of CR in the treatment of primary dysmenorrhea were identified. The GO and KEGG enrichment analyses revealed that the common targets were involved in multiple signaling pathways, including the calcium, cAMP, MAPK, and PI3K-Akt signaling pathways, as well as platelet activation, which is closely related to platelet aggregation. The molecular docking results showed that the 14 core components and 10 core targets could bind spontaneously. Two core targets (MAPK1 and CCR5) and 7 core components (Isoprocurcumenol, Curcumadione, Epiprocurcumenol, (+)-Curdione, Neocurdione, Procurcumenol, and 13-Hydroxygermacrone) were closely related to CR in the treatment of primary dysmenorrhea. Furthermore, the in vivo platelet test showed that CR clearly inhibited platelet aggregation. Five core components ((+)-Curdione, Neocurdione, Isoprocurcumenol, Curcumadione and Procurcumenol) obviously inhibited platelet aggregation in vitro. In addition, based on the relationships among the signaling pathways, we confirmed that CR can effectively inhibit the expression of MAPK and PI3K-Akt signaling pathway-related proteins and decrease the protein expression levels of ERK, JNK, MAPK, PI3K, AKT and CCR5, thereby inhibiting platelet aggregation. CONCLUSION: This study demonstrated the bioactive constituents and mechanisms of CR in promoting blood circulation and removing blood stasis and its multicomponent, multitarget and multipathway treatment characteristics in primary dysmenorrhea. The results provide theoretical evidence for the development and utilization of CR.

11.
Aging (Albany NY) ; 13(8): 11629-11645, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879631

RESUMO

Emerging evidence has demonstrated that circular RNAs (circRNAs) are abnormally expressed in non-small cell lung carcinoma (NSCLC). However, the contributions of circRNAs to the tumorigenesis of lung adenocarcinoma (LUAD), one of the subtypes of NSCLC, remain unclear. Based on a microarray assay, we found that hsa_circ_0072309 was significantly upregulated in NSCLC compared with matched normal samples. Moreover, functional experiments demonstrated that hsa_circ_0072309 promotes the proliferation, migration, and invasion of NSCLC cells. In vitro precipitation of circRNAs, luciferase reporter assays, and biotin-coupled microRNA capture assays were carried out to investigate the mechanisms by which hsa_circ_0072309 regulates NSCLC. Through the above work, we found that hsa_circ_0072309 interacted with miR-607 via its miRNA response element to upregulate the expression of FTO, an m6A demethylase and downstream target of miR-607, thus promoting tumorigenesis of NSCLC. In total, our findings indicated the oncogenic role of hsa_circ_0072309 in NSCLC and provide a potential target for treatment.

12.
Brain ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33876820

RESUMO

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), that is highly expressed in the brain-predominantly in the cerebral cortex-and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of UNC13B mutation in human disease is not known. In this study we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed favorable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant, and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database. Computational modeling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favorable outcome under antiepileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

13.
Biotechnol Bioeng ; 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33811654

RESUMO

The integration of a bile drainage structure into engineered liver tissues is an important issue in the advancement of liver regenerative medicine. Primary biliary cells, which play a vital role in bile metabolite accumulation, are challenging to obtain in vitro because of their low density in the liver. In contrast, large amounts of purified hepatocytes can be easily acquired from rodents. The in vitro chemically induced liver progenitors (CLiPs) from primary mature hepatocytes offer a platform to produce biliary cells abundantly. Here, we generated a functional CLiP-derived tubular bile duct-like structure using the chemical conversion technology. We obtained an integrated tubule-hepatocyte tissue via the direct coculture of hepatocytes on the established tubular biliary-duct-like structure. This integrated tubule-hepatocyte tissue was able to transport the bile, as quantified by the cholyl-lysyl-fluorescein assay, which was not observed in the un-cocultured structure or in the biliary cell monolayer. Furthermore, this in vitro integrated tubule-hepatocyte tissue exhibited an upregulation of hepatic marker genes. Together, these findings demonstrated the efficiency of the CLiP-derived tubular biliary-duct-like structures regarding the accumulation and transport of bile.

14.
Br J Ophthalmol ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785508

RESUMO

AIM: To explore and evaluate an appropriate deep learning system (DLS) for the detection of 12 major fundus diseases using colour fundus photography. METHODS: Diagnostic performance of a DLS was tested on the detection of normal fundus and 12 major fundus diseases including referable diabetic retinopathy, pathologic myopic retinal degeneration, retinal vein occlusion, retinitis pigmentosa, retinal detachment, wet and dry age-related macular degeneration, epiretinal membrane, macula hole, possible glaucomatous optic neuropathy, papilledema and optic nerve atrophy. The DLS was developed with 56 738 images and tested with 8176 images from one internal test set and two external test sets. The comparison with human doctors was also conducted. RESULTS: The area under the receiver operating characteristic curves of the DLS on the internal test set and the two external test sets were 0.950 (95% CI 0.942 to 0.957) to 0.996 (95% CI 0.994 to 0.998), 0.931 (95% CI 0.923 to 0.939) to 1.000 (95% CI 0.999 to 1.000) and 0.934 (95% CI 0.929 to 0.938) to 1.000 (95% CI 0.999 to 1.000), with sensitivities of 80.4% (95% CI 79.1% to 81.6%) to 97.3% (95% CI 96.7% to 97.8%), 64.6% (95% CI 63.0% to 66.1%) to 100% (95% CI 100% to 100%) and 68.0% (95% CI 67.1% to 68.9%) to 100% (95% CI 100% to 100%), respectively, and specificities of 89.7% (95% CI 88.8% to 90.7%) to 98.1% (95%CI 97.7% to 98.6%), 78.7% (95% CI 77.4% to 80.0%) to 99.6% (95% CI 99.4% to 99.8%) and 88.1% (95% CI 87.4% to 88.7%) to 98.7% (95% CI 98.5% to 99.0%), respectively. When compared with human doctors, the DLS obtained a higher diagnostic sensitivity but lower specificity. CONCLUSION: The proposed DLS is effective in diagnosing normal fundus and 12 major fundus diseases, and thus has much potential for fundus diseases screening in the real world.

15.
Semin Cancer Biol ; 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33785447

RESUMO

Although the classic activities of p53 including induction of cell-cycle arrest, senescence, and apoptosis are well accepted as critical barriers to cancer development, accumulating evidence suggests that loss of these classic activities is not sufficient to abrogate the tumor suppression activity of p53. Numerous studies suggest that metabolic regulation contributes to tumor suppression, but the mechanisms by which it does so are not completely understood. Cancer cells rewire cellular metabolism to meet the energetic and substrate demands of tumor development. It is well established that p53 suppresses glycolysis and promotes mitochondrial oxidative phosphorylation through a number of downstream targets against the Warburg effect. The role of p53-mediated metabolic regulation in tumor suppression is complexed by its function to promote both cell survival and cell death under different physiological settings. Indeed, p53 can regulate both pro-oxidant and antioxidant target genes for complete opposite effects. In this review, we will summarize the roles of p53 in the regulation of glucose, lipid, amino acid, nucleotide, iron metabolism, and ROS production. We will highlight the mechanisms underlying p53-mediated ferroptosis, AKT/mTOR signaling as well as autophagy and discuss the complexity of p53-metabolic regulation in tumor development.

16.
Endocrine ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33786714

RESUMO

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effects of SARS-CoV-2 on normal pituitary glands function or pituitary neuroendocrine tumors (PitNETs) have not yet been elucidated. Thus, the present study aimed to investigate the potential risks of SARS-CoV-2 infection on the impairment of pituitary glands and the development of PitNETs. METHODS: PitNETs tissues were obtained from 114 patients, and normal pituitary gland tissues were obtained from the autopsy. The mRNA levels of ACE2 and angiotensin II receptor type 1 (AGTR1) were examined by quantitative real-time PCR. Immunohistochemical staining was performed for ACE2 in 69 PitNETs and 3 normal pituitary glands. The primary tumor cells and pituitary cell lines (MMQ, GH3 and AtT-20/D16v-F2) were treated with diminazene aceturate (DIZE), an ACE2 agonist, with various dose regimens. The pituitary hormones between 43 patients with SARS-CoV-2 infection were compared with 45 healthy controls. RESULTS: Pituitary glands and the majority of PitNET tissues showed low/negative ACE2 expression at both the mRNA and protein levels, while AGTR1 showed high expression in normal pituitary and corticotroph adenomas. ACE2 agonist increased the secretion of ACTH in AtT-20/D16v-F2 cells through downregulating AGTR1. The level of serum adrenocorticotropic hormone (ACTH) was significantly increased in COVID-19 patients compared to normal controls (p < 0.001), but was dramatically decreased in critical cases compared to non-critical patients (p = 0.003). CONCLUSIONS: This study revealed a potential impact of SARS-CoV-2 infection on corticotroph cells and adenomas.

17.
Genes Dev ; 35(7-8): 528-541, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737385

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide and evolves often to lung metastasis. P53R175H (homologous to Trp53 R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC remains to be investigated. To investigate p53R175H-mediated molecular mechanisms, we used a carcinogen-induced approach in Trp53R172H/- mice to model ESCC. In the primary Trp53R172H/- tumor cell lines, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We identified the YAP-BIRC5 axis as a potential mediator of Trp53 R172H -mediated metastasis. We demonstrate that expression of Survivin, an antiapoptotic protein encoded by BIRC5, increases in the presence of Trp53R172H Furthermore, depletion of Survivin specifically decreases Trp53R172H-driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce Survivin expression. Furthermore, Survivin high expression level is associated with increased metastasis in several GI cancers. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.

18.
Health Qual Life Outcomes ; 19(1): 103, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33752686

RESUMO

BACKGROUND: More than 210,000 medical workers have fought against the outbreak of Coronavirus Disease 2019 (COVID-19) in Hubei in China since December 2019. However, the prevalence of mental health problems in frontline medical staff after fighting COVID-19 is still unknown. METHODS: Medical workers in Wuhan and other cities in Hubei Province were invited to participate a cross-sectional and convenience sampling online survey, which assessed the prevalence of anxiety, insomnia, depression, and post-traumatic stress disorder (PTSD). RESULTS: A total of 1,091 responses (33% male and 67% female) were valid for statistical analysis. The prevalence was anxiety 53%, insomnia 79%, depression 56%, and PTSD 11%. Healthcare workers in Wuhan were more likely to face risks of anxiety (56% vs. 52%, P = 0.03) and PTSD (15% vs. 9%, P = 0.03) than those in other cities of Hubei. In terms of educational attainment, those with doctoral and masters' (D/M) degrees may experience more anxiety (median of 7.0, [interquartile range (IQR) 2.0-8.5] vs. median 5.0 [IQR 5.0-8.0], P = 0.02) and PTSD (median 26.0 [IQR 19.5-33.0] vs. median 23.0 [IQR 19.0-31.0], P = 0.04) than those with lower educational degrees. CONCLUSIONS: The mental problems were an important issue for the healthcare workers after COVID-19. Thus, an early intervention on such mental problems is necessary for healthcare workers.


Assuntos
Transtorno Depressivo/epidemiologia , Surtos de Doenças , Pessoal de Saúde/psicologia , Doenças Profissionais/epidemiologia , Adulto , China/epidemiologia , Estudos Transversais , Transtorno Depressivo/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/psicologia , Prevalência , Psicometria , Qualidade de Vida , Inquéritos e Questionários , Adulto Jovem
19.
CNS Neurosci Ther ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33650297

RESUMO

AIMS: To evaluate the antidepressant-like effect of compound GW117 in rodents using in vitro binding and uptake assays as well in vivo behavioral tests. METHODS: We investigated the target profile of GW117 using [35 S]-GTPγS and [3 H]PIP binding. Using the forced swimming test and chronic unpredictable stress in rats, tail suspension test in mice and rats, and learned helplessness model in mice, we further revealed the antidepressant-like and anxiolytic-like effects of GW117. RESULTS: The current study suggests that GW117 displays serotonin 2C (5-HT2C ) receptor antagonist and melatonin type 1 and 2 (MT1 /MT2 ) receptor agonist properties, as well as evident antidepressant and anxiolytic effects. CONCLUSION: These data suggest that GW117 is probably a potent antidepressant.

20.
Sci Rep ; 11(1): 5154, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664368

RESUMO

USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of > 200 T-ALL transcriptomes linked USP7 haploinsufficiency with decreased activities of E-proteins. E-proteins are also negatively regulated by TAL1, leading to concerted down-regulation of E-protein target genes involved in T-cell development. In T-ALL cell lines, we showed the physical interaction of USP7 with E-proteins and TAL1 by mass spectrometry and ChIP-seq. Haploinsufficient but not complete CRISPR knock-out of USP7 showed accelerated cell growth and validated transcriptional down-regulation of E-protein targets. Our study unveiled the synergistic effect of USP7 haploinsufficiency with aberrant TAL1 activation on T-ALL, implicating USP7 as a haploinsufficient tumor suppressor in T-ALL. Our findings caution against a universal oncogene designation for USP7 while emphasizing the dosage-dependent consequences of USP7 inhibitors currently under development as potential cancer therapeutics.

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