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1.
Dig Dis Sci ; 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32524416

RESUMO

BACKGROUND/AIMS: Adherence to medication and maintained virologic response (MVR) are related to the risk of adverse clinical outcomes. This study aimed to compare the efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in relation to the adverse clinical outcomes among chronic hepatitis B (CHB) patients stratified according to adherence to medication and MVR. METHODS: A total of 1794 treatment-naive CHB patients treated with ETV (n = 894) or TDF (n = 900) for > 1 year were identified. RESULTS: Adherence rates were significantly higher in the TDF than in the ETV (93.4% vs. 89.1%, respectively; P < 0.001). The MVR of ETV and TDF were 64.5% and 71.7%, respectively (P = 0.001). The MVR of ETV and TDF in the good adherence group were 72.1% and 76.4%, respectively (P = 0.083); in the poor adherence group, the MVR of ETV and TDF were 63.0% and 54.0%, respectively (P = 0.384) Multivariate analysis showed that the risk of HCC and death or transplantation was similar between groups (HR 0.826, 95% CI 0.522-1.306; P = 0.413 and HR 0.636, 95% CI 0.258-1.569; P = 0.325, respectively) after adjusting for adherence to medication and MVR. In the 589 propensity-matched pairs of patients, risk of HCC and death or transplantation was similar between treatment groups after stratification according to adherence rates and MVR. CONCLUSIONS: After adjustment for adherence and MVR, ETV, and TDF did not differ in terms of the risk of HCC and death or transplantation in all patients and propensity score-matched cohorts.

2.
Korean J Radiol ; 21(7): 812-828, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32524782

RESUMO

OBJECTIVE: To provide an evidence-based guide for the MRI interpretation of complete tumor response after neoadjuvant chemoradiation therapy (CRT) for rectal cancer using visual assessment on T2-weighted imaging (T2) and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: PubMed MEDLINE, EMBASE, and Cochrane Library were searched on November 28, 2019 to identify articles on the following issues: 1) sensitivity and specificity of T2 or DWI for diagnosing pathologic complete response (pCR) and the criteria for MRI diagnosis; 2) MRI alone vs. MRI combined with other test(s) in sensitivity and specificity for pCR; and 3) tests to select patients for the watch-and-wait management. Eligible articles were selected according to meticulous criteria and were synthesized. RESULTS: Of 1615 article candidates, 55 eligible articles (for all three issues combined) were identified. Combined T2 and DWI performed better than T2 alone, with a meta-analytic summary sensitivity of 0.62 (95% confidence interval [CI], 0.43-0.77; I² = 80.60) and summary specificity of 0.89 (95% CI, 0.80-0.94; I² = 92.61) for diagnosing pCR. The criteria for the complete response on T2 in most studies had the commonality of remarkable tumor decrease to the absence of mass-like or nodular intermediate signal, although somewhat varied, as follows: (near) normalization of the wall; regular, thin, hypointense scar in the luminal side with (near) normal-appearance or homogeneous intermediate signal in the underlying wall; and hypointense thickening of the wall. The criteria on DWI were the absence of a hyperintense signal at high b-value (≥ 800 sec/mm²) in most studies. The specific algorithm to combine T2 and DWI was obscure in half of the studies. MRI combined with endoscopy was the most utilized means to select patients for the watch-and-wait management despite a lack of strong evidence to guide and support a multi-test approach. CONCLUSION: This systematic review and meta-analysis provide an evidence-based practical guide for MRI assessment of complete tumor response after CRT for rectal cancer.

3.
Int J Biol Macromol ; 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32599241

RESUMO

Ultraviolet B (UVB) can induce oxidative damage to outermost layers of skin causing suntans, sunburns, and, in severe cases, blisters leading to photoaging. Low molecular weight (MW) fucoidan is renowned for possessing enhanced antioxidant activities. The present study discloses the use of step gradient ethanol precipitation in refining fucoidan fractions (SSQC1-SSQC4) from Sargassum siliquastrum and evaluation of their UVB-protective effects in human HaCaT keratinocytes. Among the fractions, SSQC4 indicated the best bioactive effects. 1H NMR, FTIR, monosaccharide composition by HPAEC-PAD analysis, MW estimation by agarose gel electrophoresis were used to characterize the fractions. SSQC4 was comprising of fucoidan, with an estimated MW distribution of 8-25 kDa. Exposure of UVB increased intracellular ROS, DNA damage, loss of mitochondrial membrane potential, apoptotic body formation causing cell death through the mitochondria-mediated apoptosis pathway. SSQC4 treatment could dose-dependently attenuate the ROS levels and suppress mitochondria-mediated apoptosis in UVB exposed keratinocytes. SSQC4 treatment enhanced cellular antioxidant defense by increasing Nrf2 mediated HO-1 generation, which was identified as the cause of observed bioactivities. The safety and stability of SSQC4 could be further evaluated to promote its use as a bioactive natural ingredient in UV-protective cosmetics.

4.
Exp Neurol ; 331: 113383, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32561413

RESUMO

In the brain, murine double minute-2 (Mdm2), an E3-ubiquitin ligase, modulates neuronal excitability by regulating glutamate receptor and postsynaptic density 95 (PSD95) levels through ubiquitination. Thus, Mdm2 is relevant to epileptic seizures in human patients. Although phosphorylation at serine (S) 166 site by AKT increases Mdm2 activity, phosphatases of Mdm2 have been still elusive. Here, we demonstrate the novel function of pyridoxal-5'-phosphate phosphatase/chronophin (PLPP/CIN) in Mdm2 dephosphorylation that may negatively regulate PSD95 ubiquitination. As compared to wild-type mice, PLPP/CIN knockout (PLPP/CIN-/-) mice showed the brief seizure activity and the higher Mdm2-S166 phosphorylation following kainic acid (KA) injection, independent of AKT activity. In addition, PLPP/CIN-/- mice demonstrated the increases in Mdm2-PSD95 binding and PSD95 ubiquitination, accompanied by the decreases in Mdm2 ubiquitination and PSD95-NR2A (a subunit of N-methyl-d-aspartate receptor) bindings. Human PLPP/CIN over-expressing transgenic (PLPP/CINTg) mice reversed these phenomena. In addition, Mdm2 knockdown abolished PSD95 ubiquitination and increased KA-induced seizure activity in PLPP/CIN-/- mice without affecting AKT activity and protein levels of p53 and neural precursor cell expressed developmentally down-regulated gene 4-like (NEDD4-2). Therefore, we suggest that PLPP/CIN may be a potential therapeutic target for epilepsy and Mdm2-associated neurological diseases.

5.
J Anim Sci Technol ; 62(3): 356-364, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32568269

RESUMO

The reproductive performance of lactating sows was investigated by using different feeding methods including conventional feeding (CF, 3 times/d) or free feeding (FF), and different dietary energy level including low energy (LE: 3,300) or high energy (HE: 3,400 kcal/kg) during the hot season. A total of twenty-eight crossbred (Yorkshire × Landrace) sows were distributed into four treatments as a 2 × 2 factorial arrangement. Sows in the FF group showed lower body weight and backfat loss (p < 0.05) compared with the CF group. Backfat loss during lactation was lower (p < 0.05) in sows fed HE diet than in that fed LE diet. There were no significant differences in litter survival rate and weaning to estrus interval, but the litter weight at weaning was improved (p < 0.05) in FF and HE sows. Hence, it is concluded that using the free-feeding system or increased dietary energy density leads to improved sow performance during hot ambient temperature.

6.
Pestic Biochem Physiol ; 167: 104596, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32527442

RESUMO

Pretreatment with sublethal concentrations (LC10) of three insecticides (chlorfenapyr, dinotefuran, and spinosad) enhanced tolerance to a lethal dose of the respective insecticide in the Western flower thrips, Frankliniella occidentalis. To identify genes responding to sublethal treatment with insecticides, transcriptome analysis was conducted for thrips treated with LC10 of the three insecticides. When based on a fold change >1.5 or < -1.5 as a selection criterion, 199 transcripts were commonly up-regulated, whereas 31 transcripts were commonly down-regulated following all three insecticide treatments. The differential expression levels of representative genes were validated by quantitative PCR. Most over-transcribed transcripts could be categorized as basic biological processes, such as proteolysis and lipid metabolism. Detoxification genes, such as one glutathione S transferase S1, three UDP-glucuronosyltransferases, four CYP450s, and one ABC transporter G family member 20, were commonly overexpressed in all three insecticide-treated groups. Knockdown of the five representative commonly overexpressed genes via ingestion RNA interference increased mortalities to all the three test insecticides, supporting their common role in tolerance induction. In contrast, three C2H2-type zinc finger-containing proteins were significantly down-regulated in all insecticide-treated thrip groups. Since the tested insecticides have distinct structures and modes of action, the roles of commonly expressed genes in tolerance were discussed.


Assuntos
Inseticidas , Tisanópteros , Animais , Flores , Interferência de RNA , Transcriptoma
7.
Abdom Radiol (NY) ; 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32562051

RESUMO

PURPOSE: To investigate the diagnostic efficacy of ZOOMit coronal diffusion-weighted imaging (Z-DWI) and MR texture analysis (MRTA) for differentiating benign from malignant distal bile duct strictures. METHODS: We retrospectively enrolled a total of 71 patients with distal bile duct stricture who underwent magnetic resonance cholangiopancreatography (MRCP). For quantitative analysis, the average apparent diffusion coefficient (ADC) value at suspected stricture sites was assessed on both Z-DWI and conventional DWI (C-DWI). For qualitative analysis, two reviewers independently reviewed two image sets containing different diffusion-weighted images, and receiver operating characteristic (ROC) curve analysis was performed. Several MRTA parameters were extracted from the area of the stricture on the ADC map of the ZOOMit coronal diffusion-weighted images using commercially available software. RESULTS: Among 71 patients, 26 patients were diagnosed with malignant stricture. On quantitative analysis, the average ADC value of the malignant and benign strictures, using Z-DWI, was 1.124 × 10-3 mm2/s and 1.522 × 10-3 mm2/s, respectively (P < 0.001). The average ADC value of the malignant and benign strictures, using C-DWI, was 1.107 × 10-3 mm2/s and 1.519 × 10-3 mm2/s, respectively (P < 0.001). On qualitative analysis, for each reviewer, the area under the ROC curve (AUC) values for differentiating benign from malignant stricture was 0.928 and 0.939, respectively, for the ZOOMit diffusion set and 0.851 and 0.824, respectively, for the conventional diffusion set. Multiple MRTA parameters showed a significantly different distribution for the benign and malignant strictures, including mean, entropy, mean of positive pixels, and kurtosis at spatial filtration values of 0, 5, and 6 mm. CONCLUSION: The addition of Z-DWI to conventional MRCP is helpful in differentiating benign from malignant bile duct strictures, and some MRTA parameters also can be helpful in differentiating benign from malignant distal bile duct strictures.

8.
Int J Mol Sci ; 21(10)2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32456265

RESUMO

Parabens are widely used in personal care products due to their antimicrobial effects. Although the toxicity of parabens has been reported, little information is available on the toxicity of butylparaben (BP) on oocyte maturation. Therefore, we investigated the effects of various concentrations of BP (0 µM, 100 µM, 200 µM, 300 µM, 400 µM, and 500 µM) on the in vitro maturation of porcine oocytes. BP supplementation at a concentration greater than 300 µM significantly reduced the proportion of complete cumulus cell expansion and metaphase II oocytes compared to the control. The 300 µM BP significantly decreased fertilization, cleavage, and blastocyst formation rates with lower total cell numbers and a higher rate of apoptosis in blastocysts compared to the control. The BP-treated oocytes showed significantly higher reactive oxygen species (ROS) levels, and lower glutathione (GSH) levels than the control. BP significantly increased the aberrant mitochondrial distribution and decreased mitochondrial function compared to the control. BP-treated oocytes exhibited significantly higher percentage of γ-H2AX, annexin V-positive oocytes and expression of LC3 than the control. In conclusion, we demonstrated that BP impaired oocyte maturation and subsequent embryonic development, by inducing ROS generation and reducing GSH levels. Furthermore, BP disrupted mitochondrial function and triggered DNA damage, early apoptosis, and autophagy in oocytes.

9.
Parasite Immunol ; 42(6): e12716, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32249951

RESUMO

AIMS: Neuroinflammation can manifest upon infection with the neurotropic parasite Toxoplasma gondii (ME49), which can lead to brain injury and cognitive dysfunction. Rhoptry organelle proteins (ROPs) secreted by T gondii play critical roles in host invasion. METHODS AND RESULTS: In this study, influenza virus-like particles (VLPs) expressing T gondii ROP4 or ROP13 were generated to assess vaccination-induced changes in intracranial pro-inflammatory cytokines and antibody responses upon T gondii challenge infection. Compared to ROP13 VLPs, ROP4VLPs vaccination significantly limited the production of pro-inflammatory cytokines IFN-γ and IL-6 in the brains of mice. Reduced pro-inflammatory cytokine responses by ROP4 VLPs and ROP13 VLPs correlated with significantly increased T gondii-specific IgG and IgA antibody responses in the brain, as well as IgG, IgG1 and IgM antibody responses in the sera. CONCLUSION: We concluded that influenza T gondii VLP vaccination induces antibody responses in sera and brain, which may contribute to the significant reduction of neuroinflammation during T gondii infection.

10.
AJR Am J Roentgenol ; 214(6): 1229-1238, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32208009

RESUMO

OBJECTIVE. The purposes of this study were to assess the performance of a 3D convolutional neural network (CNN) for automatic segmentation of prostates on MR images and to compare the volume estimates from the 3D CNN with those of the ellipsoid formula. MATERIALS AND METHODS. The study included 330 MR image sets that were divided into 260 training sets and 70 test sets for automated segmentation of the entire prostate. Among these, 162 training sets and 50 test sets were used for transition zone segmentation. Assisted by manual segmentation by two radiologists, the following values were obtained: estimates of ground-truth volume (VGT), software-derived volume (VSW), mean of VGT and VSW (VAV), and automatically generated volume from the 3D CNN (VNET). These values were compared with the volume calculated with the ellipsoid formula (VEL). RESULTS. The Dice similarity coefficient for the entire prostate was 87.12% and for the transition zone was 76.48%. There was no significant difference between VNET and VAV (p = 0.689) in the test sets of the entire prostate, whereas a significant difference was found between VEL and VAV (p < 0.001). No significant difference was found among the volume estimates in the test sets of the transition zone. Overall intraclass correlation coefficients between the volume estimates were excellent (0.887-0.995). In the test sets of entire prostate, the mean error between VGT and VNET (2.5) was smaller than that between VGT and VEL (3.3). CONCLUSION. The fully automated network studied provides reliable volume estimates of the entire prostate compared with those obtained with the ellipsoid formula. Fast and accurate volume measurement by use of the 3D CNN may help clinicians evaluate prostate disease.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Imagem por Ressonância Magnética/métodos , Redes Neurais de Computação , Neoplasias da Próstata/diagnóstico por imagem , Humanos , Masculino , Neoplasias da Próstata/patologia , Estudos Retrospectivos
12.
Korean J Gastroenterol ; 75(2): 86-93, 2020 Feb 25.
Artigo em Coreano | MEDLINE | ID: mdl-32098462

RESUMO

CT enterography and magnetic resonance (MR) enterography are widely used imaging modalities used to examine the small bowel. These radiologic tests are distinguished from routine abdominopelvic CT and MRI by the oral ingestion of a large amount of neutral contrast to distend the small bowel before scanning. For achievement of high quality, diagnostic images and proper technique are required. Conducted protocols still vary in patient preparation, enteric contrast, and CT and MRI acquisition sequences, resulting in heterogeneous diagnostic accuracy. The purpose of this article is to review the processes and techniques that optimize CT/MR enterography for patients with suspected Crohn's disease or other small bowel diseases.

13.
Microb Pathog ; 142: 104090, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32097746

RESUMO

Toxoplasmosis is an intracellular parasitic disease caused by the protozoa Toxoplasma gondii, which affects about half of the world's population. In spite of the strenuous endeavors, a T. gondii vaccine for clinical use remains unreported to date. In the present study, we generated virus-like particles (VLPs) containing T. gondii apical membrane antigen 1 (AMA1) and assessed its efficacy in a murine model. VLPs were characterized using western blot and TEM. T. gondii-specific IgG and IgA antibody responses in sera, germinal center B cell responses in spleen, brain cyst counts and their sizes were determined. Elevated T. gondii-specific IgG and IgA antibody responses were observed from the sera of AMA1 VLP-immunized mice. Immunization with AMA1 VLPs enhanced T. gondii-specific antibody-secreting cell responses and germinal center B cell responses upon antigen stimulation. Brain tissue analysis revealed that AMA1 VLP-immunization reduced cyst formation and its size compared to control. Also, VLP-immunized mice were less susceptible to body weight loss and displayed enhanced survival rate compared to the control group. Our results demonstrated that the immune response induced by T. gondii AMA1 VLPs confer partial protection against T. gondii infection and provides important insight into potential T. gondii vaccine design strategy.

14.
Reg Anesth Pain Med ; 45(4): 283-286, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31988268

RESUMO

BACKGROUND: In Korea, anesthesiologists are expected to be mainstream pain medicine (PM) practitioners. However, anesthesiology and pain medicine (APM) residency programs mostly emphasize anesthesia learning, leading to insufficient PM learning. Therefore, this study evaluated the current status of PM training in APM residency programs in 10 Korean university hospitals. METHODS: Overall, 156 residents undergoing APM training participated anonymously in our survey, focusing on PM training. We assessed the aim, satisfaction status, duration, opinion on duration, desired duration, weaknesses of the training programs and plans of residents after graduating. We divided the residents into junior (first and second year) and senior (third and fourth year). Survey data were compared between groups. RESULTS: Senior showed significantly different level of satisfaction grade than did junior (p=0.026). Fifty-seven (81.4%) residents in junior and forty (46.5%) residents in senior underwent PM training for ≤2 months. Most (108; 69.2%) residents felt that the training period was too short for PM learning and 95 (60.9%) residents desired a training period of ≥6 months. The most commonly expressed weakness of the training was low interventional opportunity (29.7%), followed by short duration (26.6%). After residency, 80 (49.1%) residents planned to pursue a fellowship. CONCLUSIONS: Dissatisfaction with PM training was probably due to a structural tendency of the current program towards anesthesia training and insufficient clinical experience, which needs to be rectified, with a change in PM curriculum.

15.
Genes (Basel) ; 11(1)2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963266

RESUMO

The velvet regulator VosA plays a pivotal role in asexual sporulation in the model filamentous fungus Aspergillus nidulans. In the present study, we characterize the roles of VosA in sexual spores (ascospores) in A. nidulans. During ascospore maturation, the deletion of vosA causes a rapid decrease in spore viability. The absence of vosA also results in a lack of trehalose biogenesis and decreased tolerance of ascospores to thermal and oxidative stresses. RNA-seq-based genome-wide expression analysis demonstrated that the loss of vosA leads to elevated expression of sterigmatocystin (ST) biosynthetic genes and a slight increase in ST production in ascospores. Moreover, the deletion of vosA causes upregulation of additional gene clusters associated with the biosynthesis of other secondary metabolites, including asperthecin, microperfuranone, and monodictyphenone. On the other hand, the lack of vosA results in the downregulation of various genes involved in primary metabolism. In addition, vosA deletion alters mRNA levels of genes associated with the cell wall integrity and trehalose biosynthesis. Overall, these results demonstrate that the velvet regulator VosA plays a key role in the maturation and the cellular and metabolic integrity of sexual spores in A. nidulans.

16.
Cancer Res Treat ; 52(1): 51-59, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31096736

RESUMO

PURPOSE: Mutation of the Kirsten Ras (KRAS) oncogene is present in 30%-40% of colorectal cancers and has prognostic significance in rectal cancer. In this study, we examined the ability of radiomics features extracted from T2-weighted magnetic resonance (MR) images to differentiate between tumors with mutant KRAS and wild-type KRAS. Materials and Methods: Sixty patients with primary rectal cancer (25 with mutant KRAS, 35 with wild-type KRAS) were retrospectively enrolled. Texture analysis was performed in all regions of interest on MR images, which were manually segmented by two independent radiologists. We identified potentially useful imaging features using the two-tailed t test and used them to build a discriminant model with a decision tree to estimate whether KRAS mutation had occurred. RESULTS: Three radiomic features were significantly associated with KRASmutational status (p < 0.05). The mean (and standard deviation) skewness with gradient filter value was significantly higher in the mutant KRAS group than in the wild-type group (2.04±0.94 vs. 1.59±0.69). Higher standard deviations for medium texture (SSF3 and SSF4) were able to differentiate mutant KRAS (139.81±44.19 and 267.12±89.75, respectively) and wild-type KRAS (114.55±29.30 and 224.78±62.20). The final decision tree comprised three decision nodes and four terminal nodes, two of which designated KRAS mutation. The sensitivity, specificity, and accuracy of the decision tree was 84%, 80%, and 81.7%, respectively. CONCLUSION: Using MR-based texture analysis, we identified three imaging features that could differentiate mutant from wild-type KRAS. T2-weighted images could be used to predict KRAS mutation status preoperatively in patients with rectal cancer.

17.
Cancer Res Treat ; 52(1): 263-276, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31319641

RESUMO

PURPOSE: The most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 Pan- NETs and PanNECs is difficult in clinical practice. Materials and Methods: Eighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs. RESULTS: Re-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 well-differentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity. CONCLUSION: Histological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.

18.
J Control Release ; 318: 98-108, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31838203

RESUMO

The phosphoinositide 3-kinase (PI3K) and RAS signaling pathways are frequently co-activated and altered during oncogenesis. Owing to their regulatory cross-talk, the early attempts of targeting only one pathway have mostly ended up promoting the development of drug resistance. Here, we propose using small interfering RNA (siRNA) therapeutics to directly target the undruggable KRAS (siKRAS) in combination with the pan-PI3K inhibitor GDC-0941 (GDC) to simultaneously block both PI3K and RAS signaling, thereby exerting synergistic anti-tumor effects on ovarian cancers with PTEN deficiency and KRASG12D mutation. For successful delivery of siKRAS, tGC/psi-nanoparticle formulation of polymerized siRNA and thiol-modified glycol chitosan nanoparticle-was used for KRAS specific inhibition in vitro and in vivo. GDC or siKRAS monotherapy each impede downstream signaling, leading to some delay in cell proliferation and migration. When combined, however, they engender much higher inhibition of PI3K signaling and stimulation of apoptosis in an ovarian allograft model compared to monotherapies. Our results show the feasibility of developing new combination strategies for the management of multiple oncogenic mutations activating PI3K and RAS signaling.

19.
Biol Trace Elem Res ; 194(2): 536-544, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31270730

RESUMO

A study was conducted to determine the effect of dietary selenium (Se) concentration and source for broiler chickens on performance, nutrient digestibility, plasma Se, glutathione peroxidase (GPx) activity, and thiobarbituric acid reactive substances (TBARS). A total of 700 1-day-old broiler chicks were assigned to 7 diets with 20 birds per cage and 5 replicates per treatment. The experimental diets were fed for 32 days in 2 phases (phase 1, day 0 to 14 and phase 2, day 15 to 32). Treatments were as follows: control (without Se supplementation), sodium selenite (SeS; 0.15, 0.30, or 0.45 ppm), and hot-melt extruded sodium selenite (SeHME; 0.15, 0.30, or 0.45 ppm). There were significant linear responses (P < 0.01) for higher plasma Se concentration in SeS and SeHME treatments. Moreover, an increased (P < 0.01) Se concentration of plasma occurred in SeHME treatment compared with that in SeS treatment. The serum GPx analyses revealed that supplemental SeS and SeHME increased significantly the activity of GPx in the plasma in phase 1 (P < 0.05) and phase 2 (P < 0.05). There were significant linear (P < 0.01) responses of SeS and SeHME treatments for the expression of SelW, GPx1, GPx3, and GPx4 in the livers and spleens. In addition, SeHME showed an upregulated expression of GPx-4 in the livers (P < 0.01) and SelW in the spleens (P < 0.05) compared with SeS treatment. SeHME showed a lower TBARS on day 9. Moreover, a decreased (P < 0.01) TBARS occurred in SeS treatment compared with that in control treatment. In conclusion, SeHME can increase antioxidant activity and Se absorption, consequently being a more suitable source of Se than regular sodium selenite.

20.
Neurosurgery ; 86(4): 492-499, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31215629

RESUMO

BACKGROUND: Motor dysfunctions in Parkinson disease (PD) patients are not completely normalized by deep brain stimulation (DBS), and there is an obvious difference in the degree of symptom improvement after DBS for each patient. OBJECTIVE: To test our hypothesis that each patient has their own restoration capacity for motor improvement after DBS, and to investigate whether regional cerebral glucose metabolism in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans is associated with the capacity for off-medication motor improvement (MIoff) after DBS. METHODS: The MIoff (%) was calculated using the Unified Parkinson's Disease Rating Scale part III in 27 PD patients undergoing DBS in the globus pallidus interna. The standardized uptake value ratios (SUVRs) on FDG-PET were quantitatively measured, and the areas where the SUVR correlated with the MIoff (%) were identified. Also, the areas where the SUVR was significantly different between the 2 MIoff groups (≥60% vs <60%) were determined. RESULTS: Ten patients achieved MIoff > 60% at 12 mo after DBS. In general, the MIoff (%) was positively correlated with preoperative SUVR in the temporo-parieto-occipital lobes, while it was inversely correlated with the metabolism in the primary motor cortex. The patients in the MIoff < 60% group showed a significant decrease in SUVR in the parieto-occipital lobes, while parieto-occipital metabolism in those with MIoff ≥ 60% was relatively preserved (Mann-Whitney U test, P = .03). CONCLUSION: Our findings suggest that the parieto-occipital lobes may be implicated more generally in the prognosis of motor improvement after DBS in advanced PD than other regions.

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