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1.
JAMA Oncol ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34762093

RESUMO

Importance: All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL. Objective: To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively. Design, Setting, and Participants: The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/µL) and high-risk APL (white blood cell count ≥10 000/µL) cohorts. Interventions: All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered. Main Outcomes and Measures: Event-free survival (EFS) at 2 years after diagnosis. Results: Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL). Conclusions and Relevance: In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized. Trial Registration: ClinicalTrials.gov Identifier: NCT02339740.

2.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502300

RESUMO

Folate depletion causes chromosomal instability by increasing DNA strand breakage, uracil misincorporation, and defective repair. Folate mediated one-carbon metabolism has been suggested to play a key role in the carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. Methylenetetrahydrofolate reductase (MTHFR) is the enzyme catalyzing the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate that can control folate cofactor distributions and modulate the partitioning of intracellular one-carbon moieties. The association between MTHFR polymorphisms and HCC risk is inconsistent and remains controversial in populational studies. We aimed to establish an in vitro cell model of liver origin to elucidate the interactions between MTHFR function, folate status, and chromosome stability. In the present study, we (1) examined MTHFR expression in HCC patients; (2) established cell models of liver origin with stabilized inhibition of MTHFR using small hairpin RNA delivered by a lentiviral vector, and (3) investigated the impacts of reduced MTHFR and folate status on cell cycle, methyl group homeostasis, nucleotide biosynthesis, and DNA stability, all of which are pathways involved in DNA integrity and repair and are critical in human tumorigenesis. By analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that HCC cancer patients with higher MTHFR had a worse survival rate. The shRNA of MTHFR (shMTHFR) resulted in decreased MTHFR gene expression, MTHFR protein, and enzymatic activity in human hepatoma cell HepG2. shMTHFR tended to decrease intracellular S-adenosylmethionine (SAM) contents but folate depletion similarly decreased SAM in wildtype (WT), negative control (Neg), and shMTHFR cells, indicating that in cells of liver origin, shMTHFR does not exacerbate the methyl group supply in folate depletion. shMTHFR caused cell accumulations in the G2/M, and cell population in the G2/M was inversely correlated with MTHFR gene level (r = -0.81, p < 0.0001), MTHFR protein expression (r = -0.8; p = 0.01), and MTHFR enzyme activity (r = -0.842; p = 0.005). Folate depletion resulted in G2/M cell cycle arrest in WT and Neg but not in shMTHFR cells, indicating that shMTHFR does not exacerbate folate depletion-induced G2/M cell cycle arrest. In addition, shMTHFR promoted the expression and translocation of nuclei thymidine synthetic enzyme complex SHMT1/DHFR/TYMS and assisted folate-dependent de novo nucleotide biosynthesis under folate restriction. Finally, shMTHFR promoted nuclear MLH1/p53 expression under folate deficiency and further reduced micronuclei formation and DNA uracil misincorporation under folate deficiency. In conclusion, shMTHFR in HepG2 induces cell cycle arrest in G2/M that may promote nucleotide supply and assist cell defense against folate depletion-induced chromosome segregation and uracil misincorporation in the DNA. This study provided insight into the significant impact of MTHFR function on chromosome stability of hepatic tissues. Data from the present study may shed light on the potential regulatory mechanism by which MTHFR modulates the risk for hepatic malignancies.


Assuntos
Carcinoma Hepatocelular/patologia , Segregação de Cromossomos , DNA de Neoplasias/genética , Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Uracila/metabolismo , Apoptose , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Instabilidade Cromossômica , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo Genético , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
3.
Reproduction ; 162(6): 397-410, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34554110

RESUMO

The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.

4.
Reprod Sci ; 28(11): 3094-3108, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34460091

RESUMO

Many functional activities of endometrium epithelium are energy consuming which are very important for maintaining intrauterine environment needed by early embryonic development and establishment of implantation window. Glucose is a main energy supplier and one of the main components of intrauterine fluid. Obviously, glucose transports in endometrium epithelium involve in for these activities but their functions have not been elucidated. In this research, we observed a spatiotemporal pattern of sodium glucose transporter 1 (SGLT1) expression in the mouse endometrium. We also determined that progesterone can promote the expression of SGLT1 in the mouse endometrial epithelium in response to the action of oestrogen. Treatment with the SGLT1 inhibitor phlorizin or small interfering RNA specific for SGLT1 (SGLT1-siRNA) altered glucose uptake in primary cultured endometrial epithelial cells, which exhibited reduced ATP levels and AMPK activation. The injection of phlorizin or SGLT1-siRNA into one uterine horn of each mouse on day 2 of pregnancy led to an increased glucose concentration in the uterine fluid and decreased number of harvested normal blastocysts and decreased expression of integrin αVß3 in endometrial epithelium and increased expression of mucin 1 and lactoferrin in endometrial epithelium and the uterine homogenates exhibited activated AMPK, a decreased ATP level on day 4, and a decreased number of implantation sites on day 5. In embryo transfer experiments, pre-treatment of the uterine horn with phlorizin or SGLT1-siRNA during the implantation window led to a decreased embryo implantation rate on day 5 of pregnancy, even when embryos from normal donor mice were used. In conclusion, SGLT1, which participates in glucose transport in the mouse endometrial epithelium, inhibition and/or reduced expression of SGLT1 affects early embryo development by altering the glucose concentration in the uterine fluid. Inhibition and/or reduced expression of SGLT1 also affects embryo implantation by influencing energy metabolism in epithelial cells, which consequently influences implantation-related functional activities.

5.
Front Physiol ; 12: 674924, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248664

RESUMO

GLUT4 is involved in rapid glucose uptake among various kinds of cells to contribute to glucose homeostasis. Prior data have reported that aberrant glucose metabolism by GLUT4 dysfunction in the uterus could be responsible for infertility and increased miscarriage. However, the expression and precise functions of GLUT4 in the endometrium under physiological conditions remain unknown or controversial. In this study, we observed that GLUT4 exhibits a spatiotemporal expression in mouse uterus on pregnant days 1-4; its expression especially increased on pregnant day 4 during the window of implantation. We also determined that estrogen, in conjunction with progesterone, promotes the expression of GLUT4 in the endometrial epithelium in vivo or in vitro. GLUT4 is an important transporter that mediates glucose transport in endometrial epithelial cells (EECs) in vitro or in vivo. In vitro, glucose uptake decreased in mouse EECs when the cells were treated with GLUT4 small interfering RNA (siRNA). In vivo, the injection of GLUT4-siRNA into one side of the mouse uterine horns resulted in an increased glucose concentration in the uterine fluid on pregnant day 4, although it was still lower than in blood, and impaired endometrial receptivity by inhibiting pinopode formation and the expressions of leukemia inhibitory factor (LIF) and integrin ανß3, finally affecting embryonic development and implantation. Overall, the obtained results indicate that GLUT4 in the endometrial epithelium affects embryo development by altering glucose concentration in the uterine fluid. It can also affect implantation by impairing endometrial receptivity due to dysfunction of GLUT4.

6.
Blood ; 138(13): 1137-1147, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33951732

RESUMO

Biallelic CEBPA mutations are associated with favorable outcomes in acute myeloid leukemia (AML). We evaluated the clinical and biologic implications of CEBPA-basic leucine zipper (CEBPA-bZip) mutations in children and young adults with newly diagnosed AML. CEBPA-bZip mutation status was determined in 2958 patients with AML enrolled on Children's Oncology Group trials (NCT00003790, NCT0007174, NCT00372593, NCT01379181). Next-generation sequencing (NGS) was performed in 1863 patients (107 with CEBPA mutations) to characterize the co-occurring mutations. CEBPA mutational status was correlated with disease characteristics and clinical outcomes. CEBPA-bZip mutations were identified in 160 (5.4%) of 2958 patients, with 132 (82.5%) harboring a second CEBPA mutation (CEBPA-double-mutated [CEBPA-dm]) and 28 (17.5%) had a single CEBPA-bZip only mutation. The clinical and laboratory features of the 2 CEBPA cohorts were very similar. Patients with CEBPA-dm and CEBPA-bZip experienced identical event-free survival (EFS) of 64% and similar overall survival (OS) of 81% and 89%, respectively (P = .259); this compared favorably to EFS of 46% and OS of 61% in patients with CEBPA-wild-type (CEBPA-WT) (both P < .001). Transcriptome analysis demonstrated similar expression profiles for patients with CEBPA-bZip and CEBPA-dm. Comprehensive NGS of patients with CEBPA mutations identified co-occurring CSF3R mutations in 13.1% of patients and GATA2 mutations in 21.5% of patients. Patients with dual CEBPA and CSF3R mutations had an EFS of 17% vs 63% for patients with CEBPA-mutant or CSF3R-WT (P < .001) with a corresponding relapse rate (RR) of 83% vs 22%, respectively (P < .001); GATA2 co-occurrence did not have an impact on outcome. CEBPA-bZip domain mutations are associated with favorable clinical outcomes, regardless of monoallelic or biallelic status. Co-occurring CSF3R and CEBPA mutations are associated with a high RR that nullifies the favorable prognostic impact of CEBPA mutations.

7.
Stud Health Technol Inform ; 281: 498-499, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34042619

RESUMO

Tumor-associated autoantibodies can be used as biomarkers for detecting different types of cancers. Our objective was to use machine learning techniques to predict high-risk cases of oral squamous cell carcinoma (OSCC) with salivary autoantibodies. The optimal model was using eXtreme Gradient Boosting (XGBoost) with the area under the receiver operating characteristic curve (AUC) of 0.765 (p < 0.01). Thus, applying machine learning model to early detect high-risk cases of OSCC could assist the clinic treatment and prognosis.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Aprendizado de Máquina , Carcinoma de Células Escamosas de Cabeça e Pescoço
8.
Cell Death Dis ; 12(4): 362, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824276

RESUMO

Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1-/-) model. The results show that Adgra1-/- male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and ß3-adrenergic receptor (ß3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus-pituitary-thyroid axis. Finally, Adgra1-/- male mice present abnormal activation of PI3K/AKT/GSK3ß and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1-/- female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus-pituitary-thyroid axis by regulating PI3K/AKT/GSK3ß and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.


Assuntos
Tecido Adiposo Branco/metabolismo , Hipotálamo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Termogênese/fisiologia , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo Energético/fisiologia , Masculino , Camundongos , Obesidade/metabolismo , Transdução de Sinais/fisiologia , Sistema Nervoso Simpático/metabolismo , Glândula Tireoide/metabolismo
9.
Zhongguo Zhong Yao Za Zhi ; 46(3): 678-684, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33645035

RESUMO

The purpose of this study was to understand the pharmacodynamic effect of Valeriana jatamansi extract in diarrhea predominant irritable bowel syndrome(IBS-D) rat model induced by maternal separation combined with three kinds of stress, and observe the changes of endogenous metabolites in feces after intervention to find potential biomarkers and related metabolic pathways. The animal model of IBS-D was established by maternal separation combined with restraint, ice swimming and tail clamping. The therapeutic effect of each dose group of V. jatamansi extract was evaluated in terms of abdominal withdrawal reflex pressure threshold, fecal water content and immobility time of forced swimming test. In addition, rat feces were collected for detection of metabolic profiles of small molecular metabolites with UPLC-LTQ-Orbitrap MS platform, so as to find the biomarkers of differential metabolism with multivariate statistical analysis methods such as principal component analysis(PCA) and orthogon partial least squares discrimination analysis(OPLS-DA). The results showed that as compared with the normal group, the threshold of abdominal withdrawal reflex pressure was decreased, the fecal water content was increased, and the immobility time of forced swimming test was prolonged in the model group. The results of fecal metabonomics showed that the levels of 39 metabolites were down-regulated and those of 37 metabolites were up-re-gulated. Further analysis showed that these metabolites were related to bile acid metabolism, unsaturated fatty acid metabolism, amino acid metabolism, ceramide metabolism and other metabolic pathways. This study proved that the extract of V. jatamansi had definite pharmacodynamic effect on IBS-D model rats, and the mechanism was discussed from the perspective of fecal metabonomics.


Assuntos
Síndrome do Intestino Irritável , Valeriana , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Diarreia , Fezes , Síndrome do Intestino Irritável/tratamento farmacológico , Privação Materna , Metabolômica , Ratos , Espectrometria de Massas em Tandem
10.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572934

RESUMO

(1) Background: Antifolate methotrexate (MTX) is the most common disease-modifying antirheumatic drug (DMARD) for treating human rheumatoid arthritis (RA). The mitochondrial-produced formate is essential for folate-mediated one carbon (1C) metabolism. The impacts of MTX on formate homeostasis in unknown, and rigorously controlled kinetic studies can greatly help in this regard. (2) Methods: Combining animal model (8-week old female C57BL/6JNarl mice, n = 18), cell models, stable isotopic tracer studies with gas chromatography/mass spectrometry (GC/MS) platforms, we systematically investigated how MTX interferes with the partitioning of mitochondrial and cytosolic formate metabolism. (3) Results: MTX significantly reduced de novo deoxythymidylate (dTMP) and methionine biosyntheses from mitochondrial-derived formate in cells, mouse liver, and bone marrow, supporting our postulation that MTX depletes mitochondrial 1C supply. Furthermore, MTX inhibited formate generation from mitochondria glycine cleavage system (GCS) both in vitro and in vivo. Folinate selectively rescued 1C metabolic pathways in a tissue-, cellular compartment-, and pathway-specific manner: folinate effectively reversed the inhibition of mitochondrial formate-dependent 1C metabolism in mouse bone marrow (dTMP, methionine, and GCS) and cells (dTMP and GCS) but not methionine synthesis in liver/liver-derived cells. Folinate failed to fully recover hepatic mitochondrial-formate utilization for methionine synthesis, suggesting that the efficacy of clinical folinate rescue in MTX therapy on hepatic methionine metabolism is poor. (4) Conclusion: Conducting studies in mouse and cell models, we demonstrate novel findings that MTX specifically depletes mitochondrial 1C supply that can be ameliorated by folinate supplementation except for hepatic transmethylation. These results imply that clinical use of low-dose MTX may particularly impede 1C metabolism via depletion of mitochondrial formate. The MTX induced systematic and tissue-specific formate depletion needs to be addressed more carefully, and the efficacy of folinate with respect to protecting against such depletion deserves to be evaluated in medical practice.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Formiatos/metabolismo , Leucovorina/uso terapêutico , Metotrexato/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Animais , Antirreumáticos/farmacologia , Artrite Reumatoide/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Leucovorina/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metotrexato/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Complexo Vitamínico B/farmacologia
11.
Chin Med J (Engl) ; 134(4): 415-424, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33617184

RESUMO

BACKGROUND: The current deep learning diagnosis of breast masses is mainly reflected by the diagnosis of benign and malignant lesions. In China, breast masses are divided into four categories according to the treatment method: inflammatory masses, adenosis, benign tumors, and malignant tumors. These categorizations are important for guiding clinical treatment. In this study, we aimed to develop a convolutional neural network (CNN) for classification of these four breast mass types using ultrasound (US) images. METHODS: Taking breast biopsy or pathological examinations as the reference standard, CNNs were used to establish models for the four-way classification of 3623 breast cancer patients from 13 centers. The patients were randomly divided into training and test groups (n = 1810 vs. n = 1813). Separate models were created for two-dimensional (2D) images only, 2D and color Doppler flow imaging (2D-CDFI), and 2D-CDFI and pulsed wave Doppler (2D-CDFI-PW) images. The performance of these three models was compared using sensitivity, specificity, area under receiver operating characteristic curve (AUC), positive (PPV) and negative predictive values (NPV), positive (LR+) and negative likelihood ratios (LR-), and the performance of the 2D model was further compared between masses of different sizes with above statistical indicators, between images from different hospitals with AUC, and with the performance of 37 radiologists. RESULTS: The accuracies of the 2D, 2D-CDFI, and 2D-CDFI-PW models on the test set were 87.9%, 89.2%, and 88.7%, respectively. The AUCs for classification of benign tumors, malignant tumors, inflammatory masses, and adenosis were 0.90, 0.91, 0.90, and 0.89, respectively (95% confidence intervals [CIs], 0.87-0.91, 0.89-0.92, 0.87-0.91, and 0.86-0.90). The 2D-CDFI model showed better accuracy (89.2%) on the test set than the 2D (87.9%) and 2D-CDFI-PW (88.7%) models. The 2D model showed accuracy of 81.7% on breast masses ≤1 cm and 82.3% on breast masses >1 cm; there was a significant difference between the two groups (P < 0.001). The accuracy of the CNN classifications for the test set (89.2%) was significantly higher than that of all the radiologists (30%). CONCLUSIONS: The CNN may have high accuracy for classification of US images of breast masses and perform significantly better than human radiologists. TRIAL REGISTRATION: Chictr.org, ChiCTR1900021375; http://www.chictr.org.cn/showproj.aspx?proj=33139.


Assuntos
Neoplasias da Mama , Aprendizado Profundo , Área Sob a Curva , Mama/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , China , Humanos , Curva ROC , Sensibilidade e Especificidade
12.
Reprod Sci ; 28(3): 703-714, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33151524

RESUMO

Type 2 diabetes mellitus (T2DM) is a disease characterized by hyperglycemia resulting from insulin resistance. In recent years, the incidence of T2DM has been increasing. Women with T2DM often suffer from infertility and early miscarriage; however, the underlying mechanisms remain unclear. Insulin is the most important regulatory hormone of glycogen metabolism. In addition, 5' adenosine monophosphate-activated protein kinase (AMPK) is an important regulator of glycogen metabolism. Patients with T2DM have inhibited AMPK expression in the liver, which leads to impaired glucose metabolism. However, the role of AMPK in endometrial glycogen metabolism has not been reported. In this study, a mouse model of T2DM was established to investigate whether altered endometrial glucose metabolism affects early embryo implantation. Metformin and insulin were used for therapy; the resulting changes to glycogen metabolism and embryo implantation were examined. The results indicate that the concentrations of glycogen decreased significantly in T2DM mice, resulting in insufficient energy supplies for proper endometrial function, and thereby impeding embryonic implantation. Interestingly, endometrial AMPK was not found to be overactivated. Insulin treatment was found to partially resolve the embryo implantation defects in T2DM mice. Metformin improved blood glucose but did not have a significant effect on local endometrial glucose metabolism. This study explored the changes in endometrial glucose metabolism in T2DM mouse, and the effects of these changes on embryo implantation. We found that insulin, but not metformin, significantly resolved embryo implantation problems. These findings will help to increase our understanding of the pathomechanisms of infertility and early miscarriage in women with T2DM.

13.
Blood Adv ; 4(23): 6000-6008, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33284945

RESUMO

Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98-NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.


Assuntos
Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Idoso , Criança , Humanos , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Complexo de Proteínas Formadoras de Poros Nucleares
14.
Adv Funct Mater ; 30(28): 2001763, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32684908

RESUMO

Cellulose-based triboelectric nanogenerators (TENGs) have gained increasing attention. In this study, a novel method is demonstrated to synthesize cellulose-based aerogels and such aerogels are used to fabricate TENGs that can serve as mechanical energy harvesters and self-powered sensors. The cellulose II aerogel is fabricated via a dissolution-regeneration process in a green inorganic molten salt hydrate solvent (lithium bromide trihydrate), where. The as-fabricated cellulose II aerogel exhibits an interconnected open-pore 3D network structure, higher degree of flexibility, high porosity, and a high surface area of 221.3 m2 g-1. Given its architectural merits, the cellulose II aerogel-based TENG presents an excellent mechanical response sensitivity and high electrical output performance. By blending with other natural polysaccharides, i.e., chitosan and alginic acid, electron-donating and electron-withdrawing groups are introduced into the composite cellulose II aerogels, which significantly improves the triboelectric performance of the TENG. The cellulose II aerogel-based TENG is demonstrated to light up light-emitting diodes, charge commercial capacitors, power a calculator, and monitor human motions. This study demonstrates the facile fabrication of cellulose II aerogel and its application in TENG, which leads to a high-performance and eco-friendly energy harvesting and self-powered system.

15.
J Clin Med ; 9(4)2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32290366

RESUMO

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) and the outcome of lumboperitoneal shunt treatment remains to be systematically explored. Here, we aim to evaluate whether the severity of dopaminergic degeneration and white matter small vessel disease could be predictors of outcome for iNPH patients subjected to lumboperitoneal shunt treatment. This is a single center retrospective study with 39 patients with probable iNPH undergoing programmable surgical lumboperitoneal shunt from June 2016 to March 2018 at Hualien Tzu Chi Hospital. In all patients, dopaminergic degeneration was determined with 99mTc- TRODAT-1 SPECT scan, while white matter small vessel disease (Fazekas scale) was assessed with Brain MRI. The iNPH grading scale (iNPHGS) score and Karnofsky Performance Score (KPS) pre- and post-operation (6-month follow-up) were available for all patients. Linear regression was used to correlate the severities of dopaminergic degeneration and small vessel disease with lumboperitoneal shunt treatment outcomes. Their iNPHGS score improved significantly after surgery (pre-operatively, 7.8 ± 2.6; post-operatively, 5.7 ± 2.6 (26.9% improvement) (p < 0.05)). Moreover, the KPS was also improved significantly after surgery, by a mean of 24.6% from the baseline score (p < 0.05). A significant correlation was observed between the severity of dopaminergic degeneration and a poorer improvement of iNPHGS score (p = 0.03). However, improvement of the iNPHGS score was not correlated with white matter small vessel disease. Dopaminergic degeneration comorbidity neutralized the degree of improvement after surgery. Although white matter small vessel disease was correlated with iNPH incidence, it may not be a prognostic factor for shunt operation. These findings have implications for the use of dopaminergic imaging, as they might help predict the surgical outcome of patients with iNPH, while vascular mechanisms seem to be involved in iNPH pathophysiology.

16.
ACS Nano ; 14(4): 4585-4594, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32181639

RESUMO

Triboelectric nanogenerators (TENGs) have demonstrated their promising potential in biomotion energy harvesting. A combination of the TENG and textile materials presents an effective approach toward smart fabric. However, most traditional fabric TENGs with an alternating current (AC) have to use a stiff, uncomfortable, and unfriendly rectifier bridge to obtain direct current (DC) to store and supply power for electronic devices. Here, a DC fabric TENG (DC F-TENG) with the most common plain structure is designed to harvest biomotion energy by tactfully taking advantage of the harmful and annoying electrostatic breakdown phenomenon of clothes. A small DC F-TENG (1.5 cm × 3.5 cm) can easily light up 416 serially connected light-emitting diodes. Furthermore, some yarn supercapacitors are fabricated and woven into the DC F-TENG to harvest and store energy and to power electronic devices, such as a hygrothermograph or a calculator, which shows great convenience and high efficiency in practice. This low-cost and efficient DC F-TENG which can directly generate DC energy without using the rectifier bridge by harvesting energy from unhealthy electrostatic breakdown has great potential as a lightweight, flexible, wearable, and comfortable energy-harvesting device in the future.

18.
Reprod Sci ; 27(9): 1752-1757, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32086756

RESUMO

The incidence of diabetes in women of childbearing age has been increasing recently and implantation failure and early abortion are important reasons for infertility in diabetic women. Glycogen synthesis and decomposition are the cores of glucose homeostasis in endometrium and AMPK is activated when cellular energy consumption increases. Embryo implantation is a complex process required huge energy. Yet the changes of glucose metabolism in endometrium and its impact on embryo implantation in diabetic women are still unclear. In this research, we established diabetic pregnancy mice model by intraperitoneal injecting streptozotocin on pregnant day 1. We first tested the changes of endometrial glucose homeostasis and embryo implantation. Next, we demonstrated abnormal activation of AMPK in the endometrium of diabetic mice and its affecting endometrial glucose homeostasis. Finally, we compared the endometrial glucose homeostasis and embryo implantation outcome in diabetic pregnant mice treated with insulin or insulin combined with metformin. The results indicated that there was disturbed glucose homeostasis associated with excessive activation of AMPK in endometrium of diabetic pregnant mice. AMPK inhibitor improved the over-activation of AMPK pathway in the endometrium, meanwhile, partially corrected the abnormal glycogen metabolism and improved the implantation. Insulin improved the disorder of endometrial glucose homeostasis and implantation of diabetic mice. Our research explores the causes of high abortion and infertility rate in diabetic women which is to provide a therapeutic reference for patients with diabetes complicated with infertility and early abortion.


Assuntos
Adenilato Quinase/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Implantação do Embrião/fisiologia , Endométrio/metabolismo , Glucose/metabolismo , Homeostase/fisiologia , Animais , Glicemia/metabolismo , Implantação do Embrião/efeitos dos fármacos , Feminino , Glicogênio/metabolismo , Hipoglicemiantes/administração & dosagem , Infertilidade Feminina/metabolismo , Insulina/administração & dosagem , Metformina/administração & dosagem , Gravidez
19.
J Int Med Res ; 48(4): 300060519870407, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31891278

RESUMO

OBJECTIVE: To investigate the relationships among serum resistin, adiponectin, and leptin and microvascular complications in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 120 patients with T2DM were divided into non-microangiopathy and microangiopathy groups. Sixty age- and sex-matched healthy subjects were used as a normal control (NC) group. Body height, body mass, waist circumference, and blood pressure were determined, and waist/hip ratio (WHR), body mass index, blood glucose, lipids, resistin, leptin, adiponectin, free fatty acids (FFA), high-sensitivity C-reactive protein (hs-CRP), fasting insulin, hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR) were compared among the three groups. RESULTS: Serum levels of resistin, leptin, FFA, and hs-CRP were significantly higher and levels of adiponectin were significantly lower in patients in the non-microangiopathy (n = 60) and microangiopathy groups (n = 60) compared with the NC group (n = 60). Serum resistin and leptin levels in patients with T2DM were positively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but negatively correlated with high-density lipoprotein-cholesterol (HDL-C). Serum adiponectin levels in patients with T2DM were negatively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but positively correlated with HDL-C. CONCLUSION: Serum resistin, adiponectin, and leptin levels correlate with the occurrence of T2DM and microvascular complications.


Assuntos
Adiponectina/sangue , Diabetes Mellitus Tipo 2/complicações , Leptina/sangue , Resistina/sangue , Doenças Vasculares/complicações , Glicemia , Índice de Massa Corporal , Humanos , Resistência à Insulina
20.
Anal Chim Acta ; 1100: 57-65, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987153

RESUMO

This work describes an electrochemical-assisted desorption method that has been developed for solid-phase extraction of metal ions (Pb2+), based on a well-ordered conducting sorbent: an array-like polyaniline nanofiber synthesized on the surface of graphene oxide (PANI-GO). Combining the advantages of the allowable mechanical deformation of GO with the reduced ionic-diffusion path of vertical PANI nanofibers, this method's synergistic effect lends the prepared sorbent an enhanced stability and high analyte-desorption effectiveness. In terms of the adsorption and electrochemical-assisted desorption behavior of PANI-GO, the paper reports that the adsorption/desorption process is accompanied by the changes of the as-prepared sorbent in cyclic voltammetry, and that the prepared PANI-GO exhibits good anti-interference properties across various interference ions. Given optimal pH values, the limit of detection of the proposed method is 0.04 µg L-1; the repeatability relative standard deviation (RSD) and reproducibility RSD are 1.97% and 2.51%, respectively; and the method shows good recovery capability in the case of real beverage samples spiked with Pb2+.


Assuntos
Técnicas Eletroquímicas , Análise de Alimentos , Contaminação de Alimentos/análise , Chumbo/isolamento & purificação , Extração em Fase Sólida , Adsorção , Compostos de Anilina/química , Bebidas/análise , Condutividade Elétrica , Grafite/química , Íons/química , Íons/isolamento & purificação , Chumbo/química , Tamanho da Partícula , Propriedades de Superfície , Poluentes Químicos da Água/química
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