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1.
Int J Biol Sci ; 16(10): 1678-1685, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226285

RESUMO

An ongoing outbreak of pneumonia caused by a novel coronavirus, currently designated as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was reported recently. However, as SARS-CoV-2 is an emerging virus, we know little about it. In this review, we summarize the key events occurred during the early stage of SARS-CoV-2 outbreak, the basic characteristics of the pathogen, the signs and symptoms of the infected patients as well as the possible transmission pathways of the virus. Furthermore, we also review the current knowledge on the origin and evolution of the SARS-CoV-2. We highlight bats as the potential natural reservoir and pangolins as the possible intermediate host of the virus, but their roles are waiting for further investigation. Finally, the advances in the development of chemotherapeutic options are also briefly summarized.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32149637

RESUMO

Bilinear pooling achieves great success in fine-grained visual recognition (FGVC). Recent methods have shown that the matrix power normalization can stabilize the second-order information in bilinear features, but some problems, e.g., redundant information and over-fitting, remain to be resolved. In this paper, we propose an efficient Multi-Objective Matrix Normalization (MOMN) method that can simultaneously normalize a bilinear representation in terms of square-root, low-rank, and sparsity. These three regularizers can not only stabilize the second-order information, but also compact the bilinear features and promote model generalization. In MOMN, a core challenge is how to jointly optimize three non-smooth regularizers of different convex properties. To this end, MOMN first formulates them into an augmented Lagrange formula with approximated regularizer constraints. Then, auxiliary variables are introduced to relax different constraints, which allow each regularizer to be solved alternately. Finally, several updating strategies based on gradient descent are designed to obtain consistent convergence and efficient implementation. Consequently, MOMN is implemented with only matrix multiplication, which is well-compatible with GPU acceleration, and the normalized bilinear features are stabilized and discriminative. Experiments on five public benchmarks for FGVC demonstrate that the proposed MOMN is superior to existing normalization-based methods in terms of both accuracy and efficiency. The code is available: https://github.com/mboboGO/MOMN.

3.
Mol Genet Genomic Med ; : e1217, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32168437

RESUMO

BACKGROUND: The objective of this study was to investigate the genetic causes of two probands diagnosed as Waardenburg syndrome (WS type I and IV) from two unrelated Chinese families. METHODS: PAX3 and SOX10 were the main pathogenic genes for WS type I (WS I) and IV (WS IV), respectively; all coding exons of these genes were sequenced on the two probands and their family members. Luciferase reporter assay and co-immunoprecipitation (CO-IP) were conducted to verify potential functional outcomes of the novel mutations. RESULTS: The first proband is a 9 years old girl diagnosed with WS I. A novel PAX3 heterozygous mutation of c.372-373delGA (p.N125fs) was identified, which results in a frameshift and truncation of PAX3 protein. In family II, a 2 years old girl was diagnosed with WS IV, and Sanger sequencing revealed a de novo SOX10 mutation of c.1114insTGGGGCCCCCACACTACACCGAC (p.Q372fs), a frameshift mutation that extends the amino acid chain of SOX10 protein. Functional studies indicated that the novel mutation of SOX10 had no effects on the interaction of SOX10 and PAX3, but reduced transactivate capacity of melanocyte inducing transcription factor (MITF) promoter. Both PAX3 and SOX10 mutation-induced defects of MITF transcription might contribute to the WS pathogenesis. CONCLUSION: We revealed a novel mutation in PAX3 and a de novo mutation in SOX10, which might account for the underlying pathogenesis of WS. This study expands the database of both PAX10 and PAX3 mutations and improves our understanding of the causes of WS.

4.
Sci Total Environ ; 720: 137610, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32146400

RESUMO

Recently, a high concentration of acetylacetone (AcAc) has been measured in China, and its day-time chemistry with OH reaction has been evaluated. The phenomenon has profound implications in air pollution, human health and climate change. To systematically understand the atmospheric chemistry of AcAc and its role in the atmosphere, the night-time chemistry of AcAc with O3 and NO3 radical were investigated in this work in detail using density functional theory. The results show that for O3- and NO3-initiated atmospheric oxidation reactions of AcAc, the barrier energies of O3/NO3-addition are found to be much lower than those of H-abstraction, suggesting that O3/NO3-addition to AcAc is a major contributing pathway in the atmospheric chemical transformation reactions. The total degradation rate constants were calculated to be 2.36 × 10-17 and 1.92 × 10-17 cm3 molecule-1 s-1 for the O3- and NO3-initiated oxidation of AcAc at 298 K, respectively. The half-life of AcAc+O3 in some polluted areas (such as, Pearl River Delta and Yangtze River Delta) is close to 3 h under typical tropospheric conditions. Due to its short half-life, the ozonolysis of AcAc plays a more significant role in the night-time hours, leading to fast transformations to form primary ozonides (POZs). A prompt, thermal decomposition of POZs occurred to yield methylglyoxal, acetic acid and Criegee intermediates, which mainly contributed to the formation of secondary organic aerosol (SOA). Subsequently, using the high-resolution time-of-flight chemical ionization mass spectrometer (HR-ToF-CIMS), a non-negligible concentration of AcAc was measured in the field observation during the night-time in Nanjing, China. The obtained results reveal that the atmospheric oxidation of AcAc can successively contribute to the formation of SOA under polluted environments regardless of the time (day-time or night-time). This is due to its high reactivity to tropospheric oxidant species (such as, O3 and NO3 radicals at night-time).

5.
G3 (Bethesda) ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161086

RESUMO

Drought stress is an important crop yield limiting factor worldwide. Plant physiological responses to drought stress are driven by changes in gene expression. While drought-responsive genes (DRGs) have been identified in maize, regulation patterns of gene expression during progressive water deficits remain to be elucidated. In this study, we generated time-series transcriptomic data from the maize inbred line B73 under well-watered and drought conditions. Comparisons between the two conditions identified 8,626 DRGs and which the stages (early, middle, and late drought) at which DRGs occurred. Different functional groups of genes were regulated at the three stages. Specifically, early and middle DRGs display higher copy number variation among diverse Zea mays lines, and they exhibited stronger associations with drought tolerance as compared to late DRGs. In addition, correlation of expression between small RNAs (sRNAs) and DRGs from the same samples identified 201 negatively sRNA/DRG correlated pairs, including genes showing high levels of association with drought tolerance, such as two glutamine synthetase genes, gln2 and gln6 The characterization of dynamic gene responses to progressive drought stresses indicates important adaptive roles of early and middle DRGs, as well as roles played by sRNAs in gene expression regulation upon drought stress.

6.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(3): 231-237, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32204759

RESUMO

OBJECTIVE: To identify risk factors for minimally invasive surfactant administration (MISA) failure in the treatment of preterm infants with respiratory distress syndrome (RDS) and the influence of MISA failure on neonatal outcome. METHODS: A retrospective analysis was performed for the clinical data of 148 preterm infants with a gestational age of ≤32 weeks and a clinical diagnosis of RDS, who were admitted to the neonatal intensive care unit of eight tertiary hospitals in Beijing, Tianjin and Hebei Province from July 1, 2017 to December 31, 2018 and were treated with MISA (bovine pulmonary surfactant, PS). According to whether MISA failure (defined as the need for mechanical ventilation within 72 hours after MISA) was observed, the infants were divided into two groups: MISA failure group (n=16) and MISA success (n=132). A logistic regression analysis was used to investigate the risk factors for MISA failure and its influence on neonatal outcome. RESULTS: The MISA failure rate was 10.8% (16/148). The logistic regression analysis showed that a high incidence rate of grade >II RDS before PS administration, low mean arterial pressure and high pulse pressure before administration, a low dose of initial PS administration, and long injection time and operation time were the risk factors for MISA failure (OR=5.983, 1.210, 1.183, 1.055, 1.036, and 1.058 respectively, P<0.05). After the control for the above risk factors, the logistic regression analysis showed that the MISA failure group had a significantly higher incidence rate of bronchopulmonary dysplasia (BPD) (OR=8.537, P<0.05). CONCLUSIONS: A high grade of RDS, a low mean arterial pressure, and a high pulse pressure before administration are independent risk factors for MISA failure, and a low dose of initial PS administration, a long injection time, and a long operation time may increase the risk of MISA failure. MISA failure may increase the incidence rate of BPD in preterm infants.


Assuntos
Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Animais , Displasia Broncopulmonar , Bovinos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , Tensoativos
7.
Drug Des Devel Ther ; 14: 1107-1115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214796

RESUMO

Background: Mitochondria play a critical role as effectors and targets of brain injury in the post-resuscitation period. Although we found previously that the extracellular signal-regulated kinase (ERK)1/2 inhibitor PD98059 (PD) protects the brain against mitochondrial-mediated cell death at 24 h post-resuscitation in rats subjected to cardiac arrest/cardiopulmonary resuscitation (CA/CPR), it is not clear whether PD also exerts mitochondrial protective effect for a lasting time. Therefore, we examined the effect of PD on brain mitochondria at 48 h post-resuscitation to evaluate the time-effect of PD in the current study. Methods: Experimental rats were divided randomly into 5 groups: Sham, CA, dimethylsulfoxide (DMSO), 0.15mg/kg PD and 0.3mg/kg PD. Rats except for sham group were subjected to CA for 6 min followed by CPR. We detected survival rates and neurologic deficit scores, cerebral cortex mitochondrial function by evaluating adenosine triphosphate (ATP) levels, mitochondrial permeability transition pore (MPTP) opening, and the expression of mitofusin2 (Mfn2) and observing the ultrastructure by electron microscopy at 48 h post-resuscitation in a 6-min CA rat model. Results: PD improved survival rates and neurologic deficit scores, alleviated cerebral cortex mitochondrial damage by reducing MPTP opening and increasing Mfn2 production at 48 h post-resuscitation in a 6-min CA rat model. Conclusion: A single dose of PD improved 48 h post-resuscitation outcome and mitochondrial function, indicating the potential of the use of ERK inhibitors for the treatment of brain injury resulting from CA in the future.

8.
Sci Total Environ ; 721: 137700, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32197281

RESUMO

SO2 concentration decreased rapidly in recent years in China due to the implementation of strict control policies by the government. Particulate sulfate (pSO42-) and gaseous H2SO4 (SA) are two major products of SO2 and they play important roles in the haze formation and new particle formation (NPF), respectively. We examined the change in pSO42- and SA concentrations in response to reduced SO2 concentration using long-term measurement data in Beijing. Simulations from the Community Multiscale Air Quality model with a 2-D Volatility Basis Set (CMAQ/2D-VBS) were used for comparison. From 2013 to 2018, SO2 concentration in Beijing decreased by ~81% (from 9.1 ppb to 1.7 ppb). pSO42- concentration in submicrometer particles decreased by ~60% from 2012-2013 (monthly average of ~10 µg·m-3) to 2018-2019 (monthly average of ~4 µg·m-3). Accordingly, the fraction of pSO42- in these particles decreased from 20-30% to <10%. Increased sulfur oxidation ratio was observed both in the measurements and the CMAQ/2D-VBS simulations. Despite the reduction in SO2 concentration, there was no obvious decrease in SA concentration based on data from several measuring periods from 2008 to 2019. This was supported by the increased SA:SO2 ratio with reduced SO2 concentration and condensation sink. NPF frequency in Beijing between 2004 and 2019 remains relatively constant. This constant NPF frequency is consistent with the relatively stable SA concentration in Beijing, while different from some other cities where NPF frequency was reported to decrease with decreased SO2 concentrations.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32196655

RESUMO

OBJECTIVE: To provide clinical management guidelines for novel coronavirus (COVID-19) in pregnancy. METHODS: On February 5, 2020, a multidisciplinary teleconference comprising Chinese physicians and researchers was held and medical management strategies of COVID-19 infection in pregnancy were discussed. RESULTS: Ten key recommendations were provided for the management of COVID-19 infections in pregnancy. CONCLUSION: Currently, there is no clear evidence regarding optimal delivery timing, the safety of vaginal delivery, or whether cesarean delivery prevents vertical transmission at the time of delivery; therefore, route of delivery and delivery timing should be individualized based on obstetrical indications and maternal-fetal status.

10.
Inorg Chem ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32191452

RESUMO

High-capacity germanium-based anode materials are alternative materials for outstanding electrochemical performance lithium-ion batteries (LIBs), but severe volume variation and pulverization problems during charging-discharging processes can seriously affect their electrochemical performance. In addressing this challenge, a simple strategy was used to prepare the self-assembled GeOX/Ti3C2TX composite in which the GeOX nanoparticles can grow directly on Ti3C2TX layers. Nanoscale GeOX uniformly renucleates on the surface and interlayers of Ti3C2TX, forming the stable multiphase structure, which guarantees its excellent electrochemical performance. Electrochemical evaluation has shown that the rate capability and reversibility of GeOX/Ti3C2TX are both greatly improved, which delivers a reversible discharge specific capacity of above 1400 mAh g-1 (at 100 mA g-1) and a reversible specific capacity of 900 mAh g-1 after 50 cycles while it still maintains a stable specific capacity of 725 mAh g-1 at 5000 mA g-1. Furthermore, the composite exhibits an exceptionally superior rate capability, making it a good electrochemical performance anode for LIBs.

11.
Environ Pollut ; 262: 114172, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32155545

RESUMO

Field observations have suggested that particulate nitrate can promote the aging of black carbon (BC), yet the mechanisms of the aging process and its impacts on BC's light absorption are undetermined. Here we performed laboratory simulation of internal mixing of flame-generated BC aggregates with ammonium nitrate. Variations in particle size, mass, coating thickness, effective density, dynamic shape factor, and optical properties were determined online by a suite of instruments. With the development of coatings, the particle size initially decreased until reaching a coating thickness of ∼10 nm and then started increasing, accompanied by an increase in effective density and a decrease in dynamic shape factor, reflecting the transformation of BC particles from highly fractal to near-spherical morphology. This is partially attributable to the restructuring of BC cores to more compact forms. Exposing coated particles to elevated relative humidity (RH) led to additional BC morphology changes, even after drying. Particle light absorption and scattering were also amplified with ammonium nitrate coating, increasing with coating thickness and RH. For BC particles with a 17.8 nm coating, absorption and scattering were increased by 1.5- and 7.9-fold when cycled through 70% RH (5-70-5% RH), respectively. The irreversible restructuring of the BC core caused by condensation of ammonium nitrate and water altered both absorption and scattering, with a magnitude comparable to or even exceeding the effects of increased coating. Results show that ammonium nitrate is among the most efficient coating materials with respect to modifying BC morphology and optical properties compared with other inorganic and organic species investigated previously. Accordingly, mitigation of nitrate aerosols is necessary for the benefits of both air pollution control and reducing the impacts of BC on visibility impairment and radiative forcing on climate change. Our results also pointed out that the effect of BC core restructuring needs to be considered when evaluating BC's light absorption enhancement.

12.
Biomark Med ; 14(4): 259-270, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32134324

RESUMO

Aim: To evaluate the prognostic role of mean corpuscular hemoglobin concentration (MCHC) in hepatocellular carcinoma (HCC) after hepatectomy. Patients & methods: A total of 289 HCC patients were classified into two groups based on the cut-off value of MCHC. Significant prognostic factors were screened by univariate and multivariate analysis. Results: Low MCHC value was significantly associated with tumor diameter (p = 0.004) and vascular invasion (p = 0.038). Besides, Cox regression analysis showed that low MCHC was significantly associated with poor prognostic outcomes with HCC after hepatectomy (overall survival: hazard ratio: 0.372; 95% CI: 0.206-0.672; p = 0.001; recurrence-free survival: hazard ratio: 0.450; 95% confidence interval: 0.317-0.638; p < 0.001). Conclusion: Preoperative MCHC can predict prognosis for patients with HCC, and the lower MCHC value was associated with poor prognosis after hepatectomy.

13.
Zool Res ; 41(2): 188-193, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32135580

RESUMO

A new species of the genus Amolops, Amolops tuanjieensis sp. nov., is described from Yunnan, China. The new species can be distinguished by the following characters: dorsolateral folds present; dorsal and ventral surfaces smooth; top of head and dorsum brown-red with irregular gray and dark spots; flank green; side of head black, from tip of snout, diffusing posteriorly to axilla, continuing as black streak below edge of dorsolateral fold; SVL 39.5-40.4 mm in males, 56.8-60.7 mm in females; tympanum distinct; supratympanic fold indistinct; vomerine teeth in two oblique rows between choanae, closer to each other than choanae; vocal sacs present; nuptial pads present; outer metatarsal tubercle absent, supernumerary tubercles absent; all fingertips expanded into discs; limbs dorsally brown with dark brown bars and irregular dark brown blotches.

14.
Virol J ; 17(1): 38, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183889

RESUMO

BACKGROUND: There are few data on the prevalence of acquired drug resistance mutations (ADRs) in Hunan Province, China, that could affect the effectiveness of antiretroviral therapy (ART). OBJECTIVES: The main objectives of this study were to determine the prevalence of acquired drug resistance (ADR) the epidemic characteristics of HIV-1-resistant strains among ART-failed HIV patients in Hunan Province, China. METHODS: ART-experienced and virus suppression failure subjects in Hunan between 2012 and 2017 were evaluated by genotyping analysis and mutations were scored using the HIVdb.stanford.edu algorithm to infer drug susceptibility. RESULTS: The prevalence of HIV-1 ADR were 2.76, 2.30, 2.98, 2.62, 2.23and 2.17%, respectively, from 2012 to 2017. Overall 2295 sequences were completed from 2932 ART-failure patients, and 914 of these sequences were found to have drug resistance mutation. The most common subtype was AE (64.14%), followed by BC (17.91%) and B (11.50%). Among those 914 patients with drug resistance mutations,93.11% had NNRTI-associated drug resistance mutations, 74.40% had NRTI drug resistance mutations (DRMs) and 6.89% had PI DRMs. Dual-class mutations were observed in 591 (64.66%) cases, and triple-class mutations were observed in 43 (4.70%) cases. M184V (62.04%), K103N (41.90%) and I54L (3.83%) were the most common observed mutations, respectively, in NRTI-, NNRTI- and PI-associated drug resistance. 93.76% subjects who had DRMs received the ART first-line regimens. CD4 count, symptoms in the past 3 months, and ART adherence were found to be associated with HIV-1 DR. CONCLUSIONS: This study showed that although the prevalence of HIV-acquired resistance in Hunan Province is at a low-level, the long-term and continuous surveillance of HIV ADR in antiretroviral drugs (ARVs) patients is necessary.

15.
Mol Biol Rep ; 47(3): 2149-2159, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32072402

RESUMO

Medial degeneration of aorta wall is the principal feature of aortic dissection (AD). Sirtuin 1 (SIRT1) plays essential protective effect on many aortic-associated disease. However, it is still unclear whether SIRT1participates in the process of medial degeneration-mediated AD. The purpose of this study is to explore the association between SIRT1 and AD process. qRT-PCR was used to evaluate the transcriptional level of genes involved in study. Protein levels and acetylation detection were measured by Western blotting. The regulatory relations between AP-1 and decorin was assessed by luciferase reporter gene assay. Acute aortic dissection (AAD) mice model was constructed by feeding with ß-aminopropionitrile monofumarate (BAPN). Haematoxylin and eosin (HE) and Mallory staining were performed for pathological analysis. In clinical aorta tissue of thoracic aortic dissection (TAD), the expression of SIRT1, activator protein 1 (AP-1) and decorin were in accordant trend. AP-1 expression which acts on Decorin promoter region is possibly regulated in a SIRT1-mediated deacetylation dependent manner. Resveratrol or SRT1720-initiated SIRT1 activation ameliorated BAPN-induced AAD symptoms accompanied by the activation of AP-1/decorin signaling and decorin-mediated programmed cell death 4 (PDCD4) expression by inhibiting miR-21 and miR-181b. These data suggest that SIRT1/AP-1/decorin signal cascades possibly play a part role in the process of AD. Our research demonstrate that activation of SIRT1 protects against AAD symptoms by enhancing AP-1-mediated decorin expression and downstream PDCD4 signaling pathway. Possibly, SIRT1 is served as a protective factor of AD and targeting SIRT1 therapy might be an attractive therapeutic approaches for AD treatment.

16.
Sci Rep ; 10(1): 3511, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103135

RESUMO

The reactivation of HIV latency cell will be necessary to curing HIV infection. Although many latency-reversal agents (LRAs) have proven effective to reactivate the latency cell, there is a lack of any systematic analysis of the molecular targets of these LRAs and related pathways in the context of transcriptome. In this study, we performed an integrated analysis of the target profile of bryostatin and transcriptome of the reactivated CD4+ T cells after exposing to bryostatin. The result showed a distinct gene expression profile between latency cells and bryostatin reactivated cells. We found bryostatin can target multiple types of protein other than only protein kinase C. Functional network analysis of the target profile and differential expressed genes suggested that bryostatin may activate a few novel pathways such as pyrimidine metabolism, purine metabolism and p53 signaling pathway, besides commonly known pathways DNA replication, cell cycle and so on. The results suggest that bryostatin may reactivate the HIV-latent cells through up-regulation of pyrimidine and purine metabolism or through starting the cell-cycle arrest and apoptosis induced by up-regulation of p53 signaling pathway. Our study provides some novel insights into the role of bryostatin and its affected pathways in controlling HIV latency and reactivation.

17.
Drug Des Devel Ther ; 14: 175-183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021102

RESUMO

Background: This study was conducted to explore whether the effect of edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol3-one, EDR) can ameliorate renal warm ischemia-reperfusion injury (IRI) by modulating endoplasmic reticulum stress (ERS) and its downstream effector after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in a rat model. Methods: The rats (n=10) experienced anaesthesia and intubation followed by no CA inducement were defined as the Sham group. Transoesophageal alternating current stimulation was employed to establish 8 min of CA followed by conventional CPR for a resuscitation model. The rats with successful restoration of spontaneous circulation (ROSC) randomly received EDR (3 mg/kg, EDR group, n=10) or equal volume normal saline solution (the NS group, n=10). At 24 hr after ROSC, serum creatinine (SCR), blood urea nitrogen (BUN) levels, and cystatin-C (Cys-C) levels were determined and the protein level of glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), extracellular signal-regulated kinase (ERK), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), Bax/Bcl-2, and caspase-3 were detected by Western blot method. Results: At 24 hrs after ROSC, SCR, BUN and Cys-C were obviously increased and the proteins expression, including GRP78, CHOP and p-ERK1/2, cleaved-caspase 3 Bax/Bcl-2 ratio, were significantly upregulated in the NS group compared with the Sham group (p<0.05). The remarkable improvement of these adverse outcomes was observed in the EDR group (p<0.05). Conclusion: In conclusion, we found that EDR ameliorates renal warm IRI by downregulating ERS and its downstream effectors in a rat AKI model evoked by CA/CPR. These data may provide evidence for future therapeutic benefits of EDR against AKI induced by CA/CPR.

18.
Nat Cell Biol ; 22(2): 167-174, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32029896

RESUMO

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32057078

RESUMO

OBJECTIVES: Aortic dissection (AoD) in the presence of an aberrant right subclavian artery (ARSA) is very rare. Clinical experience is limited, and there is no consensus regarding the optimal management strategy. We seek to evaluate the safety and efficacy of the total arch replacement (TAR) and frozen elephant trunk (FET) technique as an approach to AoD in patients with ARSA by retrospectively analysing our single-centre experience. METHODS: From 2009 to 2017, we performed TAR + FET for 22 patients with ARSA sustaining AoD (13 acute, 59.1%). The mean age was 46.0 years [standard deviation (SD) 8.3], and 19 patients were male (86.4%). ARSA orifice was dilated in 15 (68.2%) patients, and a Kommerall diverticulum was diagnosed in 13 (59.1%) patients with a mean diameter of 21.8 mm (SD 7.7; range 15-40). Surgery was performed via femoral and right/left carotid cannulation under hypothermic circulatory arrest at 25°C. The ARSA was reconstructed using a separate branched graft. RESULTS: ARSA was closed proximally by ligation in 16 (72.7%) patients, direct suture in 4 (18.2%) patients and both in 2 (9.1%) patients. Operative mortality was 13.6% (3/22). Type Ib endoleak occurred in 1 (4.5%) patient at 8 days. Follow-up was complete in 100% at mean 4.2 years (SD 2.0), during which 3 late deaths and 1 reintervention for type II endoleak occurred. Survival was 81.8% and 76.4% at 3 and 5 years, respectively. Freedom from reoperation was 89.2% up to 8 years. In competing risks analysis, the incidence was 22.1% for death, 10.8% for reoperation and 67.1% for event-free survival at 5 years. The false lumen, ARSA orifice and Kommerall diverticulum were obliterated in 100%. Grafts were patent in 100%. No patients experienced cerebral ischaemia and upper extremity claudication. Hypothermic circulatory arrest time (min) was sole predictor for death and aortic reintervention (hazard ratio 1.168, 95% confidence interval 1.011-1.348; P = 0.034). CONCLUSIONS: The TAR and FET technique is a safe and efficacious approach to AoD in patients with ARSA. Modifications of routine TAR + FET techniques are essential to successful repair, including femoral and right/left carotid artery cannulation, ligation of ARSA on the right side of the trachea and ARSA reconstruction with a separate graft.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32077675

RESUMO

BACKGROUND: Long-term data are scarce regarding the efficacy of extended repair for acute type A aortic dissection (ATAAD) using frozen elephant trunk and total arch replacement (FET + TAR) technique. We seek to evaluate our single-center experience with the FET + TAR technique in patients with ATAAD, focusing on early and long-term survival and reoperation. METHODS: The early and long-term outcomes of FET + TAR were analyzed for 518 patients with ATAAD operated on between April 2003 and December 2012. Mean age 46.2 ± 10.5 years and 426 were male (82.2%). Malperfusion occurred in 66 (12.7%) and Marfan syndrome (MFS) in 51 (9.8%). Bentall procedure was performed in 153 (29.5%), aortic cusp resuspension in 82 (15.8%), root remodeling (uni- or bi-Yacoub) in 19 (3.7%), ascending aortic replacement in 22 (4.2%) and extra-anatomic bypass in 15 patients (2.9%). The times of cardiopulmonary bypass time (CPB), cross-clamp and selective antegrade cerebral perfusion were 201 ± 50, 112 ± 34, and 26 ± 10 minutes, respectively. RESULTS: Operative mortality rate was 7.5% (39/518). Spinal cord injury occurred in 2.5% (13/518), stroke in 2.9% (15/518), reexploration for bleeding in 2.5% (13/518) and acute kidney injury in 4.6% (24/518). Early reintervention with thoracic endovascular aortic repair (TEVAR) was performed in 3 (0.6%). Follow-up was complete in 98.7% (473/479) at mean 9.0 ± 4.8 years (range 0.2-16.2). Late death occurred in 74, distal dilation in 31 and distal new entry in 9 patients. Late reoperation was performed in 31 patients, including TEVAR in 12, thoracoabdominal aortic replacement in 9, abdominal aortic replacement in 2, anastomotic leak repair in 5. Survival and freedom from distal reoperation were 77.3% (95% confidence interval [CI] 72.9-81.1%) and 69.8% (95% CI 63.4-75.3%), and 92.9% (95% CI 89.9-95.0%) and 92.9% (95% CI 89.9-95.0%) at 10 and 15 years, respectively. Competing risks analysis showed that at 12 years, the incidence was 28.0% for death, 8.5% for distal reoperation, and 63.5% of patients were alive without reoperation. Multivariable analyses found that CPB time (in minutes) (odds ratio [OR], 1.011; 95% CI 1.006-1.017; P < 0.001) and malperfusion syndrome (binary) (OR 2.291; 95% CI 1.283-6.650; P = 0.011) were predictive of operative mortality, while multiple malperfusion predicted late death (hazard ratio, HR 6.815; 95% CI 2.447-18.984; P < 0.001). Risk factors for late death and distal reoperation included MFS (HR, 1.824; 95% CI 1.078-3.087; P = 0.025) and malperfusion (HR, 1.787; 95% CI 1.042-3.064; P = 0.035). CONCLUSIONS: In this large series of ATAAD, the FET + TAR technique has achieved satisfactory early and long-term survival and freedom from reoperation up to 15 years. Marfan syndrome and malperfusion syndrome were risk factors for early and late mortality and distal reoperation. This study adds long-term evidence supporting the use of the FET + TAR technique in patients with ATAAD involving the arch and descending aorta.

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