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1.
Mol Ecol Resour ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33000522

RESUMO

Whole-genome duplication (WGD), contributing to evolutionary diversity and environmental adaptability, has been observed across a wide variety of eukaryotic groups, but not in mollusks. Mollusks are the second largest animal phylum in species numbers, and among the organisms that have successfully adapted to the nonmarine realm through aquatic-terrestrial (A-T) transition. We assembled a chromosome-level reference genome for Achatina immaculata, a global invasive species, and compared the genomes of two giant African snails (A. immaculata and Achatina fulica) to the other available mollusk genomes. The macrosynteny, colinearity blocks, Ks peak and Hox gene clusters collectively suggested the WGD event in the two snails. The estimated WGD timing (~70 MYA) was close to the speciation age of the Sigmurethra-Orthurethra (within Stylommatophora) lineage and the Cretaceous-Tertiary (K-T) mass extinction, indicating that the WGD may have been a common event shared by all Sigmurethra-Orthurethra species and conferred ecological adaptability allowing the K-T extinction survival. Further, the adaptive mechanism of WGD in terrestrial ecosystems was confirmed by the gene families related to the respiration, aestivation and immune defense. Several mucus-related gene families expanded early in the Stylommatophora lineage, and the hemocyanins, phosphoenolpyruvate carboxykinase families were doubled during WGD, and zinc metalloproteinase genes were highly tandemly duplicated after WGD. Theses evidence suggests that although the WGD may not have been the direct driver of the A-T transition, it provided an important legacy for the terrestrial adaptation of the giant African snails.

2.
Anal Bioanal Chem ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001243

RESUMO

A simple but efficient colorimetric assay was developed for the detection and quantification of acid phosphatase (ACP) using a smartphone. This strategy is based on target-controlled iodine-mediated etching of gold nanorods (AuNRs). Due to effective hydrolysis of the substrate pyrophosphate (PPi) by ACP, chelated Cu2+ with PPi was released, which promoted the redox reaction with an iodide ion (I-), leading to the formation of I3-. As the etching agent of AuNRs, I3- caused a blueshift of the localized surface plasmon resonance peak and, more importantly, an observable color change. The vivid colors were recorded with a smartphone camera and directly analyzed using an image-processing app. On the basis of the direct correlation between ACP concentration and the etching degree of AuNRs as well as color change, this smartphone nanocolorimetry technique showed a good linear response toward ACP over the range of 0-15.0 U/L, with a detection limit of 0.97 U/L. Using the standard addition method, the practical applicability of the proposed smartphone-based assay was successfully demonstrated by determining ACP in human serum samples, with results consistent with those obtained by UV-Vis spectrophotometry.

3.
J Thorac Imaging ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003106

RESUMO

PURPOSE: We evaluated the prevalence of coronary stenosis on coronary computed tomography angiography (CCTA) in patients aged 18 to 30 years, who presented to the emergency department with chest pain. We also examined the risk factors potentially associated with abnormal coronary findings on CCTA in this age group. MATERIALS AND METHODS: A total of 884 patients were retrospectively evaluated. Indication for CCTA was guided by our hospital's chest pain protocol based on ACC/AHA guidelines. These were performed using the standard technique and interpreted based on CAD-RADS guidelines. Scans were identified as abnormal if atherosclerotic coronary artery disease (CAD), myocardial bridging (MB), or any anatomic coronary artery anomaly were present. RESULTS: Twenty-two percent of patients had a coronary abnormality on CCTA. The most common abnormality was MB (17.3%), followed by CAD (4.4%) and coronary anomalies (1.5%). A small minority had stenosis (2.8%), most commonly caused by CAD. Most cases with stenosis were minimal to mild (72%) with 0.8% having coronary stenosis ≥50%. Age and male sex were risk factors for both coronary artery stenosis (odds ratio: 1.32 and 4.50, 95% confidence interval: 1.03-1.69, and 1.23-16.46, P=0.028 and 0.023, respectively) and CAD (odds ratio: 1.52 and 3.67, 95% confidence interval: 1.14-2.04, and 1.26-10.66, P=0.005 and 0.017, respectively). CONCLUSIONS: Epicardial coronary stenosis is rarely the cause of chest pain among young adult patients presenting to the emergency department. Age and male sex were both risk factors for coronary artery stenosis/disease in this age group.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33001810

RESUMO

Stroke is an acute cerebral vascular disease that is likely to cause long-term disabilities and death. Immediate emergency care with accurate diagnosis of computed tomographic (CT) images is crucial for dealing with a hemorrhagic stroke. However, due to the high variability of a stroke's location, contrast, and shape, it is challenging and time-consuming even for experienced radiologists to locate them. In this paper, we propose a U-net based deep learning framework to automatically detect and segment hemorrhage strokes in CT brain images. The input of the network is built by concatenating the flipped image with the original CT slice which introduces symmetry constraints of the brain images into the proposed model. This enhances the contrast between hemorrhagic areas and normal brain tissue. Various Deep Learning topologies are compared by varying the layers, batch normalization, dilation rates, and pre-train models. This could increase the respective filed and preserves more information on lesion characteristics. Besides, the adversarial training is also adopted in the proposed network to improve the accuracy of the segmentation. The proposed model is trained and evaluated on two different datasets, which achieve the competitive performance with human experts with the highest location accuracy 0.9859 for detection, 0.8033 Dice score, and 0.6919 IoU for segmentation. The results demonstrate the effectiveness, robustness, and advantages of the proposed deep learning model in automatically hemorrhage lesion diagnosis, which make it possible to be a clinical decision support tool in stroke diagnosis.

6.
Shock ; 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026218

RESUMO

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a devastating and incurable disease characterized by pulmonary vascular remodeling, resulting to right heart failure and even death. Accumulated evidence has confirmed long coding RNAs (lncRNAs) are involved in hypoxia induced pulmonary vascular remodeling in HPH. The exact mechanism of lncRNA in hypoxic pulmonary hypertension remains unclear. METHODS: Microarray analysis was applied to investigate the profiles of lncRNA expression in pulmonary artery smooth muscle cells (PASMCs) cultured under hypoxia and normoxia condition. qRT-PCR was performed for the expression of lncRNAs, miRNA and mRNAs, western blot analysis was employed for detection the expression of proteins. CCK-8 and transwell chamber assay were applied for assessment of PASMC proliferation and migration, respectively. Besides, flow cytometry was performed for assessments of cell cycle progression. The binding between AC068039.4 and miR-26a-5p, miR-26a-5p and TRPC6 3'UTR were detected by dual luciferase reporter assay. RESULTS: A total of 1211 lncRNAs (698 up-regulated and 513 down-regulated) were differently expressed in hypoxia induced PASMCs. Consistent with microarray analysis, quantitative PCR verified that AC068039.4 was obviously up-regulated in hypoxia induced PASMCs. Knocking down AC068039.4 alleviated proliferation and migration of PASMCs and regulated cell cycle progression through inhibiting cells entering the G0/G1 cell cycle phase. Further experiment indicated AC068039.4 promoted hypoxic PASMCs proliferation via sponging miR-26-5p. In addition, transient receptor potential canonical 6 (TRPC6) was confirmed to be a target gene of miR-26a-5p. CONCLUSION: In conclusion, downregulation of lncRNA AC068039.4 inhibited pulmonary vascular remodeling through AC068039.4/miR-26a-5p/TRPC6 axis, providing new therapeutic insights for the treatment of HPH.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33045325

RESUMO

This study sought to characterize sirtuin 2 (sirt2), sirtuin 3 (sirt3), and sirtuin 5 (sirt5) in Megalobrama amblycephala (M. amblycephala) by cloning the open reading frame (ORF) of sirt2, sirt3, and sirt5. The full-lengths of the resulting M. amblycephala sirt2, sirt3, and sirt5 cDNA sequences were 1845, 1534, and 1920 bp, respectively, with 92%, 98%, and 91% similarities to Danio rerio sequences. Based on our bioinformatic analyses and predictions, the sirt2 and sirt3 genes of M. amblycephala were classified within the Sir2 I family, whereas sirt5 belonged to the Sir2 III family. Furthermore, sirt2, sirt3, and sirt5 were widely distributed in different M. amblycephala tissues. Particularly, sirt2 and sirt5 were highly expressed in gills, intestines, and liver (P < 0.05), whereas sirt3 was highly expressed in gills, kidney, liver, and spleen (P < 0.05). A 2 × 2 factorial experiment was also conducted to analyze sirt2, sirt3, and sirt5 expression patterns in response to acute temperature (25 and 32 °C) and ammonia nitrogen (0 and 20 mg/L) stress. Notably, these two stressors were found to interactively affect sirt2, sirt3, and sirt5 expression patterns in M. amblycephala liver. At the higher water temperature (32 °C) and ammonia nitrogen concentration (20 mg/L) tested herein, sirt2, sirt3, and sirt5 had similar expression levels and exhibited a down-regulation trend at 6 and 48 h post-stress but became up-regulated thereafter to counteract the stressors at 96 h post-stress.

8.
Strahlenther Onkol ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33047151

RESUMO

BACKGROUND/PURPOSE: Frameless stereotactic radiosurgery (SRS) requires dedicated systems to monitor patient motion in order to avoid inaccurate radiation delivery due to involuntary shifts. The purpose of this study is to assess the accuracy and sensitivity of two distinct motion monitoring systems used for frameless SRS. METHODS: A surface image-guided system known as optical surface monitoring system (OSMS), and a fiducial marker-based system known as high definition motion management (HDMM) as part of the latest Gamma Knife Icon® were compared. A 3D printer-based cranial motion phantom was developed to evaluate the accuracy and sensitivity of these two systems in terms of: (1) the capability to recognize predefined shifts up to 3 cm, and (2) the capability to recognize predefined speeds up to 3 cm/s. The performance of OSMS, in terms of different reference surfaces, was also evaluated. RESULTS: Translational motion could be accurately detected by both systems, with an accuracy of 0.3 mm for displacement up to 1 cm, and 0.5 mm for larger displacements. The reference surface selection had an impact on OSMS performance, with flat surface resulting in less accuracy. HDMM was in general more sensitive when compared with OSMS in capturing the motion, due to its faster frame rate, but a delay in response was observed with faster speeds. Both systems were less sensitive in detection of superior-inferior motion when compared to lateral or vertical displacement directions. CONCLUSION: Translational motion can be accurately and sensitively detected by OSMS and HDMM real-time monitoring systems. However, performance variations were observed along different motion directions, as well as amongst the selection of reference images. Caution is needed when using real-time monitoring systems for frameless SRS treatment.

9.
Arch Microbiol ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33047173

RESUMO

A Gram-stain-negative, rod-shaped, facultatively anaerobic, motile and spore-forming strain designated FJAT-44921T was isolated from red mud collected from Chiping County, Shandong Province, China. The 16S rRNA gene sequence result showed that strain FJAT-44921T shared a low sequence identity (96.6%) with the members of the genus Bacillus. Growth was observed at pH 8.0-10.0 (optimum pH 9.0), 10-40 °C (optimum 20-25 °C) with 0-8% (v/w %) NaCl (optimum 4-6 v/w %). FJAT-44921T consists of MK-7 as the isoprenoid quinone and meso-2,6-diaminopimelic acid as the cell-wall diamino acid. The predominant fatty acids were anteiso-C15:0, iso-C15:0, C16:0, and anteiso-C17:0. The polar lipids were diphosphatidylglycerol, phosphatidyl glycerol, phosphatidylmethylethanolamine, unidentified phospholipid, and unidentified aminophospholipid. The genomic DNA G + C content was 37.3 mol%. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between FJAT-44921T and other closely related Bacillus members were lower than the recognized threshold values of ANI (95-96%) and dDDH (70%) recommended as the criterion for interspecies identity. The type strain is FJAT-44921T (=CCTCC AB 2016196T =DSM 104630T).

10.
Updates Surg ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048340

RESUMO

Laparoscopic cholecystectomy and percutaneous transhepatic gallbladder drainage (PTGBD) are common treatments for patients with acute cholecystitis. However, the safety and efficacy of emergency laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC) after PTGBD in patients with acute cholecystitis remain unclear. The PubMed, EMBASE, and Cochrane Library databases were searched through October 2019. The quality of the included nonrandomized studies was assessed using the Methodological Index for Nonrandomized Studies (MINORS). The meta-analysis was performed using STATA version 14.2. A random-effects model was used to calculate the outcomes. A total of fifteen studies involving 1780 patients with acute cholecystitis were included in the meta-analysis. DLC after PTGBD was associated with a shorter operative time (SMD - 0.51; 95% CI - 0.89 to - 0.13; P = 0.008), a lower conversion rate (RR 0.43; 95% CI 0.26 to 0.69; P = 0.001), less intraoperative blood loss (SMD - 0.59; 95% CI - 0.96 to - 0.22; P = 0.002) and longer time of total hospital stay compared to ELC (SMD 0.91; 95% CI 0.57-1.24; P < 0.001). There was no difference in the postoperative complications (RR 0.68; 95% CI 0.48-0.97; P = 0.035), biliary leakage (RR 0.65; 95% CI 0.34-1.22; P = 0.175) or mortality (RR 1.04; 95% CI 0.39-2.80; P = 0.933). Compared to ELC, DLC after PTGBD had the advantages of a shorter operative time, a lower conversion rate and less intraoperative blood loss.

11.
BMC Musculoskelet Disord ; 21(1): 661, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032581

RESUMO

BACKGROUND: Neglected long-term unreduced hip joint dislocation with secondary osteoarthritis and pseudoarthrosis poses a great challenge to hip surgeons. However, as this is an uncommon injury, few studies have systematically investigated these patients. METHODS: We retrospectively reviewed 16 patients from 2010 to 2017. The diagnostic values of three different types of common radiological examinations were evaluated. We evaluated the bone conditions of the original acetabulum and classified the patients into three types (four subtypes). The surgical procedures and prognosis of the patients were also investigated. RESULTS: With the combined application of X-ray, CT scans and 3D reconstruction, 93.8% of these patients (sensitivity = 93.8%, Youden's index = 0.93, intraclass correlation coefficient = 0.95) could be diagnosed correctly. There were 6/16 (37.5%) type A patients, 4/16 (25.0%) type B1 patients, 5/16 (31.3%) type B2 patients and 1/16 (6.3%) type C patient. For patients with type A injury, the surgical procedures for total hip arthroplasty were similar to "standard" total hip arthroplasty. For patients with type B injury, due to atrophy or partial bone deficiency of the original acetabulum, the surgical procedure for total hip arthroplasty was probably similar to those for patients with developmental dysplasia of the hip. For patients with type C injury, the situation was similar to that of revision surgery. The average Harris hip score postoperatively was 89.94 ± 5.78 points (range: 79-98 points). CONCLUSIONS: The new classification system could help surgeons estimate potential difficulties during total hip arthroplasty. The prognosis of most patients after total hip arthroplasty is expected to be excellent or good.

12.
Bioresour Technol ; 319: 124155, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-33035862

RESUMO

In this work, agricultural wastes were treated by composting in an ectopic fermentation bed system (EFBS) with a continuous nitrogen addition technique. With decreasing of NH4+-N concentration and increasing of NO3--N concentration were observed, and activities of protease, urease and nitrate reductase changed significantly during the fermentation process. To elucidate the key microbes and their function in nitrogen-transforming, microbial diversity and clusters of orthologous groups (COGs) in composting materials were evaluated using metagenomic technology. Comparing with ammonification, the COGs involved in nitrification and denitrification were predominant in the composts. The correlation heatmap revealed that Streptomyces predominant in ammonification was significantly affected by contents of N, NH4+-N and NO3--N. Meanwhile, ammonia-oxidizing archaea (AOA) had a positive relationship with moisture. The most abundant genera in denitrification had positive relationships with N and NO3--N. The results indicated that EFBS had functionally diverse microbes and COGs for NH3 removal.

13.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120313584, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33054391

RESUMO

Macrophages have key functional role in the pathogenesis are various cardiovascular diseases, such as atherosclerosis and aortic aneurysm. Their accumulation within the vessel wall leads to sustained local inflammatory responses characterized by secretion of chemokines, cytokines, and matrix protein degrading enzymes. Here, we summarize recent findings on macrophage contribution to cardiovascular disease published in ATVB. In this issue, we focus on the origin, survival/death, and phenotypic switching of macrophages within vessel walls.

14.
J Biomater Sci Polym Ed ; : 1-16, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054642

RESUMO

The fabrication of novel and intelligent delivery systems that can effectively deliver therapeutics to the targeted site and release payload in enhanced/controlled manner is highly desired to overcome the multiple challenges in chemotherapy. The present article demonstrates the potential application of dual stimuli responsive nanogels as tumor microenvironment targeted drug delivery carrier. Disulfide cross-linked pH and redox responsive PEG-PDMAEMA nanogels were synthesized by atom transfer radical polymerization (ATRP). The nanogels were characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The PEG-PDMAEMA nanogels exhibited dual stimuli-responsive release of the encapsulated model anticancer drug (doxorubicin, DOX) due to the acidic pH-response of dimethyl amine group in PDMAEMA and reductive cleavage of the disulfide linkages. A relatively higher release of DOX was observed from the nanogels at pH 5.0 than at pH 7.4. DOX release was further accelerated in tumor simulated environment of pH 5.0 and 10 mM glutathione (GSH). Confocal microscopy images revealed that DOX-loaded PEG-PDMAEMA nanogels can rapidly internalize and effectively deliver the drug into the cells. The nanogels exhibited higher cytotoxicity in GSH-OEt pretreated HeLa cells than untreated cells. The dual stimuli responsive nanogels synthesized in this study exhibited many favorable traits, such as pH and redox dependent controlled release of drug, biodegradability, biocompatibility, and enhanced cytotoxicity, which endow them as a promising candidate for anticancer drug delivery.

15.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1061-1067, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051419

RESUMO

OBJECTIVES: To evaluate the expression of myeloid ecotropic viral integration site 1 (Meis1) and vascular endothelial growth factor receptor 2 (VEGFR-2) in early-stage kidney cancers and the clinical significance. METHODS: The cancer tissues and the matched adjacent normal tissues in patients with kidney cancer, who received surgical treatment from April 2005 to September 2018 in the Haikou Hospital Affiliated to Xiangya School of Medicine, Central South University, were collected. The samples included 80 pairs of paraffin specimen, 15 pairs of fresh cancer and the matched adjacent normal tissues from these patients. Real-time PCR and immunohistochemical method were used to detect the expression levels of Meis1 and VEGFR-2 mRNA and protein in kidney tissues and adjacent normal tissues, and the correlation of clinical pathology parameters and the prognosis were analyzed in the patients. RESULTS: The expression levels of Meis1 and VEGFR-2 mRNA and protein in the renal carcinoma tissues were lower than those in the matched adjacent normal tissues (both P<0.01), and the expression levels of Meis1 were positively correlated with that of VEGFR-2 (r=0.681, P<0.01). The analysis of relevant clinical-pathological parameters in the patients showed that: the expression positive rate of Meis1 was significantly related with the pathological type of renal cancer (P<0.01), while the positive rate of Meis1 and VEGFR-2 expression was not related with the gender, age, T stage of patients (all P>0.05), but it was significantly related with the prognosis in the patients (P<0.05). Cox regression analysis showed that: Meis1 was an independent factor for the prognosis of patients (P<0.05). CONCLUSIONS: The mRNA and protein expression levels of Meis1 and VEGFR-2 in the early-stage kidney cancer tissues are significantly decreased compared with those in the adjacent normal tissues. Meis1 may be served as a tumor suppressor to affect the occurrence and development of kidney cancer. Therefore, Meis1 may be used as a biomarker to predict the prognosis of patients with kidney cancer.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteína Meis1 , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Neoplasias Renais/genética , Proteína Meis1/metabolismo , Prognóstico , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
16.
Mol Med Rep ; 22(5): 4135-4142, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33000217

RESUMO

Vitamin D and the vitamin D receptor (VDR) complex have been reported to inhibit the growth of several types of tumor; however, their function in papillary thyroid cancer (PCT) remains unknown. In addition, the Wnt/ß­catenin signaling pathway was discovered to serve a critical role in the pathology of PCT. Therefore, the present study aimed to determine the role of the VDR and its association with Wnt/ß­catenin signaling in vitamin D­treated PTC cells. VDR expression was detected in human PTC cells (including MDA­T120, MDA­T85, SNU­790 and IHH4 cells) and thyroid follicular cells (Nthy­ori 3­1 cells). SNU­790 and IHH4 cells were infected with KD­VDR or negative control (KD­NC) lentiviruses, treated with 1,25(OH)2D3 (the active form of vitamin D), and subsequently referred to as the KD­VDR&vitD and KD­NC&vitD groups, respectively. Additionally, PTC cells infected with KD­NC and not treated with 1,25(OH)2D3 were used as the normal control and referred to as the KD­NC group. VDR mRNA and protein expression levels were increased in MDA­T120, SNU­790 and MDA­T85 cells compared to Nthy­ori 3­1 cells, whereas in IHH4 cells, VDR mRNA and protein expression levels were similar to Nthy­ori 3­1 cells. In SNU­790 and IHH4 cells, cell proliferation and invasion were decreased in the KD­NC&vitD group compared with the KD­NC group, but increased in the KD­VDR&vitD group compared with the KD­NC&vitD group. Cell apoptosis was increased in the KD­NC&vitD group compared with the KD­NC group, and decreased in the KD­VDR&vitD group compared with the KD­NC&vitD group. Furthermore, the expression levels of Wnt family member 3 and catenin ß1 were decreased in the KD­NC&vitD group compared with the KD­NC group, but increased in the KD­VDR&vitD group compared with the KD­NC&vitD group. In conclusion, the present study revealed that VDR­KD attenuated the antiproliferative, pro­apoptotic and anti­invasive effects of vitamin D in PTC by activating the Wnt/ß­catenin signaling pathway.

17.
J Clin Invest ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33031100

RESUMO

Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3' splice sites (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33031557

RESUMO

CONTEXT: Impaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR). OBJECTIVE: In a secondary analysis of a randomized controlled trial, we compared the effects of intermittent fasting (IF) and CR on markers of lipid metabolism in muscle. DESIGN: Seventy-six women (BMI 25-40 kg/m2) were randomized to one of three diets for eight weeks and provided with foods at 70% (CR70 and IF70) or 100% (IF100) of energy requirements. IF groups ate breakfast, prior to a 24-hour fast on 3 non-consecutive days per week. On non-fasting days, IF70 ate at 100% and IF100 ate at 145% of energy requirements to achieve the prescribed target. Weight, body composition, insulin sensitivity by clamp, non-esterified fatty acids (NEFA), ß-hydroxybutyrate, and markers of lipid metabolism and oxidative stress in muscle by qPCR were measured at baseline and week 8 following a 12-hour overnight fast (all groups) and 24-hour fast (IF groups). RESULTS: IF70 resulted in greater weight and fat losses and reduced NEFA versus CR70 and IF100 after an overnight fast. IF70 and IF100 induced a greater reduction only in mRNA levels of antioxidant enzymes  GPX1, SOD1 and SOD2 versus CR70. Fasting for 24-hours increased NEFA and ß-hydroxybutyrate in IF groups, but impaired insulin sensitivity and increased PLIN5 mRNA levels. CONCLUSIONS: In comparison to CR, IF did not increase markers of lipid metabolism in muscle, but reduced expression of antioxidant enzymes. However, fasting-induced insulin resistance was detected, alongside increased PLIN5 expression, potentially reflecting transient lipid storage.

19.
Clin Appl Thromb Hemost ; 26: 1076029620944492, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33032448

RESUMO

Contrast-induced acute kidney injury (CI-AKI) is a serious complication of percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). Early identification of high-risk patients has an essential role in preventing CI-AKI. This study was designed to evaluate the predictive value of d-dimer, a marker of thrombosis and hypercoagulable state, for CI-AKI and prognosis in patients with STEMI. We included 400 patients with STEMI who underwent PCI. The patients were subdivided into 4 groups according to d-dimer level using the 4-quantile method. Contrast-induced acute kidney injury occurred in 66 (16.5%) patients. The incidence of CI-AKI in the highest quartile of the d-dimer groups (29.0%) was higher than that in the other 3 groups. Multivariable logistic regression showed that a low d-dimer level was significantly associated with a decreased risk of CI-AKI independent of confounding factors, with an odds ratio (OR) of 0.487 (95% CI: 0.178-0.931, P = 0.041) for those in the first quartile compared with those in the highest quartile. Age (OR: 1.047, 95% CI: 1.003-1.092), diabetes mellitus (OR: 5.896, 95% CI: 2.496-13.927), anemia (OR: 3.488, 95% CI: 1.308-9.306), and total bilirubin (OR: 0.946, 95% CI: 0.904-0.992) were independent predictors of CI-AKI. The incidence of major adverse cardiovascular and cerebral events and all-cause mortality within 30 days, 6 months, and 1 year after PCI in the highest quartile of the d-dimer groups were higher than those in the other 3 groups. In conclusion, increasing d-dimer levels were independently associated with the incidence of CI-AKI and adverse outcomes in patients with STEMI after PCI.

20.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120314913, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33028100

RESUMO

OBJECTIVE: Abdominal aortic aneurysm is characterized by the progressive loss of aortic integrity and accumulation of inflammatory cells primarily macrophages. We previously reported that global deletion of matricellular protein TSP1 (thrombospondin-1) protects mice from aneurysm formation. The objective of the current study is to investigate the cellular and molecular mechanisms underlying TSP1's action in aneurysm. Approach and Results: Using RNA fluorescent in situ hybridization, we identified macrophages being the major source of TSP1 in human and mouse aneurysmal tissues, accounting for over 70% of cells that actively expressed Thbs1 mRNA. Lack of TSP1 in macrophages decreased solution-based gelatinase activities by elevating TIMP1 (tissue inhibitor of metalloproteinases-1) without affecting the major MMPs (matrix metalloproteinases). Knocking down Timp1 restored the ability of Thbs1-/- macrophages to invade matrix. Finally, we generated Thbs1 flox/flox mice and crossed them with Lyz2-cre mice. In the CaCl2-induced model of abdominal aortic aneurysm, lacking TSP1 in myeloid cells was sufficient to protect mice from aneurysm by reducing macrophage accumulation and preserving aortic integrity. CONCLUSIONS: TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.

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