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1.
Dev Comp Immunol ; 127: 104263, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34563588

RESUMO

Interleukin-17 (IL-17) is a classic pro-inflammatory cytokine that plays an important role in the immune and inflammatory response. In the present study, the sequence feature of CgIL17-5 and its function as a pro-inflammatory factor in inducing the mRNA expressions of downstream immune effectors were investigated in oyster Crassostrea gigas. There were two tightly folded alpha helixes and two pairs of antiparallel beta-pleated sheet in the amino acid sequence of CgIL17-5. The mRNA transcripts of CgIL17-5 were constitutively distributed in all the tested tissues, with the highest level in haemocytes. The mRNA expression level of CgIL17-5 in haemocytes increased significantly at 24 h after Vibrio splendidus stimulation. CgIL17-5 protein was mainly detected in granulocytes which were the main immunocompetent haemocytes in C. gigas. The phosphorylation of mitogen-activated protein kinases (CgJNK, CgERK and CgP38) and nuclear translocation of the transcription factors (CgRel and CgAP-1) in haemocytes were induced after the oysters received an injection of recombinant CgIL17-5 for 2 h. The mRNA expression levels of CgIL-17s, CgTNF-1, Cgdefh1 and Cgdefh2 increased significantly in haemocytes. At the same time, obvious branchial swelling and cilium shedding in gills were observed at 24 h after the oysters received an injection of rCgIL17-5. All the results collectively suggested that CgIL17-5 promoted the activation of CgMAPKs and the nuclear translocation of CgRel and CgAP-1 to promote the mRNA expressions of cytokines and antibacterial peptides.

2.
Appl Environ Microbiol ; : AEM0192121, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34818106

RESUMO

Legionella pneumophila (LP) widely exists in natural and artificial water environments, which facilitates LP to infect people. LP infection causes Legionnaires' disease (LD), which is an important but relatively uncommon respiratory infection. Approximately 90% of LD is caused by L. pneumophila serogroup 1 (Lp1). Meteorological conditions may affect the infectivity and virulence of Lp1, but the exact relationship between them is still unclear. In this study, we evaluated the virulence of Lp1 by screening of total 156 Lp1 strains isolated from cooling tower water in different region of China by detecting their abilities to activate NF-κB signaling pathway in vitro. In addition, we screened the distribution of some selected virulence genes in these strains. The virulence, virulence gene distribution and the meteorological factors were analyzed. We found that both the virulence and the distribution of virulence genes had a certain regional and meteorological correlation. Although loss of several virulence genes showed significant effects on the virulence of Lp1 strains, the distribution of virulence genes had very limited effects on the virulence of Lp1. IMPORTANCE LD is likely to be under-recognized in many countries. Due to the widespread existence of LP in natural and artificial water environments, and to the lack of cross-protection against different strains, LP is a potentially serious threat to human health. Therefore, effective monitoring of the virulence of LP in the water environment is very important to prevent and control the prevalence of LD. Understanding the virulence of LP can not only help us to predict the risk of possible outbreaks in advance, but can also enable more targeted clinical treatment. This study highlights the importance of understanding the epidemiology and ecology of LP isolated from public facilities in terms of public health and biology. Due to the potential for water sources to harbor and disseminate LP, and to the fact that geographical conditions influence the virulence of LP, timely and accurate LP virulence surveillance is urgently needed.

3.
iScience ; 24(12): 103392, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34841231

RESUMO

Myeloid-derived suppressor cells (MDSCs) enhance the proliferation of endothelial cells to stimulate angiogenesis. However, many aggressive malignant tumors do not have endothelial cell-dependent blood vessels in the early stage and instead generate microcirculation by forming vasculogenic mimicry (VM). To date, the relationship between MDSCs and tumor cells remains the focus of ongoing studies. In this work, MDSCs were co-cultured with mouse melanoma cells and can enhance proliferation and VM formation of melanoma cells. For MDSCs targeting, doxycycline (DOX) was found to selectively suppress PMN-MDSCs but has no influence on T cells. In addition, DOX pretreatment substantially reduced the promoting ability of MDSCs for the VM formation of B16-F10 cells. DOX also inhibited tumor growth and enhanced the antitumor activity of PD-1 inhibitors in C57BL6 and BALB/c mice subcutaneously inoculated with B16-F10 and 4T1 cells, respectively. In conclusion, the combination of DOX and PD-1 inhibitor could be an anticancer strategy.

4.
BMJ Open ; 11(11): e053548, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34764177

RESUMO

OBJECTIVES: Identifying high-risk patients in the intensive care unit (ICU) is important given the high mortality rate. However, existing scoring systems lack easily accessible, low-cost and effective inflammatory markers. We aimed to identify inflammatory markers in routine blood tests to predict mortality in ICU patients and evaluate their predictive power. DESIGN: Retrospective case-control study. SETTING: Single secondary care centre. PARTICIPANTS: We analysed data from the Medical Information Mart for Intensive Care III database. A total of 21 822 ICU patients were enrolled and divided into survival and death groups based on in-hospital mortality. PRIMARY AND SECONDARY OUTCOME MEASURES: The predictive values of potential inflammatory markers were evaluated and compared using receiver operating characteristic curve analysis. After identifying the neutrophil-to-lymphocyte ratio (NLR) as having the best predictive ability, patients were redivided into low (≤1), medium (1-6) and high (>6) NLR groups. Univariate and multivariate logistic regression analyses were performed to evaluate the association between the NLR and mortality. The area under the curve (AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to assess whether incorporating the NLR could improve the predictive power of existing scoring systems. RESULTS: The NLR had the best predictive ability (AUC: 0.609; p<0.001). In-hospital mortality rates were significantly higher in the low (OR (OR): 2.09; 95% CI 1.64 to 2.66) and high (OR 1.64; 95% CI 1.50 to 1.80) NLR groups than in the medium NLR group. Adding the NLR to the Simplified Acute Physiology Score II improved the AUC from 0.789 to 0.798, with an NRI and IDI of 16.64% and 0.27%, respectively. CONCLUSIONS: The NLR predicted mortality in ICU patients well. Both low and high NLRs were associated with elevated mortality rates, including the NLR may improve the predictive power of the Simplified Acute Physiology Score II.

5.
Fish Shellfish Immunol ; 119: 145-153, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34600117

RESUMO

Caspase-8 has been reported to be involved not only in apoptosis, but also in many other important immune response processes, such as inflammation and autophagy. In the present study, the open reading frame of CgCaspase-8-2 was cloned from the Pacific oyster Crassostrea gigas, which was of 2160 bp encoding 737 amino acids. There were two death effector domains (DEDs) and a cysteine aspartase cysteine structural (CASc) domain in the deduced amino acid sequences of CgCaspase-8-2. The mRNA expressions of CgCaspase-8-2 in haemocytes and gills all increased significantly after Vibrio splendidus stimulation at 3 h, 6 h, and 24 h. The cleaved CgCaspase-8-2 protein was observed in haemocytes at 3 h after V. splendidus stimulation and the expression of CgCaspase-8-2 protein was relatively higher in granulocytes, compared with that in agranulocytes. In CgCaspase-8-2-RNAi oysters, the mRNA expressions of CgIL17s (CgIL17-1, -2, -3, -4, -6), CgTNF, CgIFNLP and CgBigDef1 all decreased significantly at 12 h after V. splendidus stimulation. Meanwhile, the mRNA expressions of CgATG5 and CgBeclin1 decreased significantly at 12 h after V. splendidus stimulation, while CgBcl2 increased significantly. These results indicated that CgCaspase-8-2 was involved in not only the regulation of cytokine and antibacterial peptide production, but also autophagy-related gene expressions.

6.
J Biol Chem ; 297(6): 101352, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34715129

RESUMO

The ancient origin of the lectin pathway of the complement system can be traced back to protochordates (such as amphioxus and tunicates) by the presence of components such as ficolin, glucose-binding lectin, mannose-binding lectin-associated serine protease (MASP), and C3. Evidence for a more primitive origin is offered in the present study on the Pacific oyster Crassostrea gigas. C3 protein in C. gigas (CgC3) was found to be cleaved after stimulation with the bacteria Vibrio splendidus. In addition, we identified a novel C-type lectin (defined as CgCLec) with a complement control protein (CCP) domain, which recognized various pathogen-associated molecular patterns (PAMPs) and bacteria. This protein was involved in the activation of the complement system by binding CgMASPL-1 to promote cleavage of CgC3. The production of cytokines and antibacterial peptides, as well as the phagocytotic ratio of haemocytes in CgCLec-CCP-, CgMASPL-1-, or CgC3-knockdown oysters, decreased significantly after V. splendidus stimulation. Moreover, this activated CgC3 participated in perforation of bacterial envelopes and inhibiting survival of the infecting bacteria. These results collectively suggest that there existed an ancient lectin pathway in molluscs, which was activated by a complement cascade to regulate the production of immune effectors, phagocytosis, and bacterial lysis.

7.
BMC Infect Dis ; 21(1): 1030, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598707

RESUMO

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is the common cause of community-acquired pneumonia (CAP) and is also found in the upper respiratory tract of healthy people. Hence, the study aimed to compare the serotypes, virulence/pili genes, and antibiotic susceptibility of S. pneumoniae from healthy asymptomatic participants and CAP patients. METHODS: Streptococcus pneumoniae were retrospectively collected from health asymptomatic participants and CAP patients in Sichuan, China. The serotypes were tested by multiplex polymerase chain reaction (PCR) or Quellung reaction. Antibiotic susceptibility testing was performed using the broth microdilution method. The molecular epidemiology of S. pneumoniae was analyzed by multilocus sequence typing (MLST). Additionally, the presence of virulence/pili genes were detected using PCR. RESULTS: A total of 83 pneumococcal isolates were collected in the current study. Of these, 52 and 31 isolates were from healthy asymptomatic participants and CAP patients, respectively. Most of S. pneumoniae were resistant to erythromycin (ERY), clindamycin (CLI), tetracycline (TET) and trimethoprim-sulfamethoxazole (SXT). 90.4% isolates were classified as multidrug resistant (MDR). The predominant serotypes were 3, 19F and 19A in the CAP carriers, whereas 3, 6 and 19F were the main serotypes among the asymptomatic carriers. The overall coverage rates of pneumococcal conjugate vaccine (PCV) 10 and PCV13 serotypes were 34.9% and 66.3%, respectively. The predominant sequence types (STs) were ST271, ST320, and ST3397. There were significant differences in some resistance and virulence characteristics between CAP patients and asymptomatic carriers. Additionally, clonal complex (CC) 271 strains had higher percentage in resistance to cefuroxime (CXM) and cefotaxime (CEF), meropenem (MER) and cefepime (CFP), which mainly carried the rlrA and sipA genes. CONCLUSIONS: High coverage rate of PCV13 and high prevalence of MDR indicated the necessity to expand immunization with PCV13 and rationally use the antibiotics in Sichuan, China. Importantly, long-term surveillance should be conducted to assess effectiveness brought by vaccines. Our findings may supply new guidance for developing new pneumococcal vaccines.


Assuntos
Infecções Pneumocócicas , Pneumonia , Humanos , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Estudos Retrospectivos , Streptococcus pneumoniae/genética
8.
J Hepatocell Carcinoma ; 8: 1233-1240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34676181

RESUMO

Background: Lenvatinib (LEN) combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). We assessed the safety and clinical efficacy of triple therapy [LEN+PD-1+transcatheter arterial chemoembolization (TACE)] in uHCC. Methods: uHCC patients with an ECOG PS score of 0-1 and Child-Pugh class A who underwent triple therapy were included. The primary endpoint was objective response rate (ORR) based on mRECIST. Secondary endpoints were conversion rate to liver resection and treatment-related adverse events. Results: Between November 2018 and December 2020, 62 uHCC patients who underwent triple therapy at four major cancer centers in China were analyzed, including 35 in BCLC-C, 21 in BCLC-B, and 6 in BCLC-A. With a median follow-up of 12.2 months (range, 7.6-33.3 months), the investigator and blinded independent central review-assessed ORR were 80.6% and 77.4%, respectively. A total of 33 patients (53.2%) reached the standard of conversion to resectable HCC and 29 patients underwent resection. The median interval between start of triple therapy and resection was 123 days (range, 55-372 days). Pathological complete response and major pathological response were observed in 16 and 24 patients, respectively. Median overall survival and progression-free survival were not reached. Treatment-related adverse events occurred in 74.2% of the patients (grade ≥3, 14.5%; grade ≥4, 4.8%). Conclusion: Combination of LEN, PD-1 and TACE showed a high rate of tumor response and convert resection in uHCC patients, with manageable toxicity.

9.
Front Cell Dev Biol ; 9: 736540, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631713

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and has strong immunogenicity. A systematically investigation of the tumor microenvironment (TME) in ccRCC could contribute to help clinicians develop personalized treatment and facilitate clinical decision-making. In this study, we analyzed the immune-related subtype of ccRCC on the basis of immune-related gene expression data in The Cancer Genome Atlas (TCGA, N = 512) and E-MTAB-1980 (N = 101) dataset, respectively. As a result, two subtypes (C1 and C2) were identified by performing non-negative matrix factorization clustering. Subtype C1 was characterized by increased advance ccRCC cases and immune-related pathways. A higher immune score, stromal score, TMB value, Tumor Immune Dysfunction and Exclusion (TIDE) prediction score, and immune checkpoint genes expression level were also observed in C1. In addition, the C1 subtype might benefit from chemotherapy and immunotherapy. The patients in subtype C2 had more metabolism-related pathways, higher tumor purity, and a better prognosis. Moreover, some small molecular compounds for the treatment of ccRCC were identified between the two subtypes by using the Connectivity Map (CMap) database. Finally, we constructed and validated an immune-related (IR) score to evaluate immune modification individually. A high IR score corresponded to a favorable prognosis compared to a low IR score, while more advanced tumor stage and grade cases were enriched in the low IR score group. The two IR score groups also showed a distinct divergence among immune status, TME, and chemotherapy. The external validation dataset (E-MTAB-1980) and another immunotherapy cohort (IMvigor 210) demonstrated that patients in the high IR score group had a significantly prolonged survival time and clinical benefits compared to the low IR score group. Together, characterization of molecular heterogeneity and IR signature may help develop new insights into the TME of ccRCC and provide new strategies for personalized treatment.

10.
ACS Omega ; 6(39): 25749-25761, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34632231

RESUMO

Ethanol is usually combined with gasoline to manufacture ethanol-gasoline with excellent combustion characteristics. However, extracting water from hydrous ethanol to manufacture anhydrous ethanol consumed much energy, which increases the production cost of ethanol-gasoline. Many researchers have studied the combustion and emissions of hydrous ethanol-gasoline to explore the application of hydrous ethanol-gasoline as the fuel for spark-ignition engines. Most previous studies changed the hydrous ethanol ratio with fixed purity in hydrous ethanol-gasoline to study the effects of hydrous ethanol. Different from previous studies, this paper studied the effects of water ratio (Wr) in hydrous ethanol on the combustion and emissions of a hydrous ethanol/gasoline combined injection engine under different excess air ratio (λ) values. The ratios of ethanol and gasoline keep constant, while the purity of hydrous ethanol changes during the research. The experiment adopted the combined injection mode with hydrous ethanol direct injection plus gasoline port injection; the direct injection ratio was 20%. The experiment set three λ (0.9, 1, and 1.2) and five Wrs (0, 5, 10, 15, and 20%). The test engine's speed was 1500 rpm, and the intake manifold absolute pressure was 48 kPa. Results showed that water inhibited combustion, prolonged CA 0-10 and CA 10-90, reduced P max and T max, and delayed APmax; larger λ made the deterioration on combustion more obvious, and the smaller λ had a larger tolerance to water. Water could increase torque and improve emissions, but different parameters corresponded to different optimal Wrs. For torque, the optimal Wr was 5%. For HC emissions, the optimal Wr was 0%; for CO emissions, the optimal value was 5%; and for NO x emissions, the best value was 20%. The best Wr was 10% for particle number (PN) emissions. Under the optimal Wr condition, when λ values were 0.9, 1, and 1.2, compared with pure gasoline, the torque increased by 7.5, 5.54, and 5.31%; HC emissions decreased by 21.37, 23.43, and 26.58%; NO x emissions decreased by 4.26, 11.47, and 12.55%; CO emissions decreased by 17.51, 34.56, -50%; and the total PN emissions decreased by 87.64, 89.64, and 76.07%.

11.
MicroPubl Biol ; 20212021.
Artigo em Inglês | MEDLINE | ID: mdl-34549172

RESUMO

Terminal selector-type transcription factors are key regulators of neuronal identity and function (Hobert and Kratsios, 2019; Kratsios and Hobert, 2018). Mechanistically, terminal selectors are thought to act directly through binding at the cis-regulatory region of genes (termed "terminal identity genes") that encode, among others, neurotransmitter [NT] synthesis proteins, ion channels, neuropeptides, and cell adhesion molecules (Hobert and Kratsios, 2019; Kratsios and Hobert, 2018). Although dozens of terminal selectors have been described thus far for individual neuron types of the nematode C. elegans (Hobert, 2016), the identification of their target genes has primarily relied on candidate approaches and availability of markers for neuronal terminal identity. Hence, unbiased methods are needed to identify the full spectrum of terminal selector target genes in individual neuron types. This study focuses on the phylogenetically conserved terminal selector UNC-3/Ebf (member of the Collier/Olf/Ebf family), which controls cholinergic motor neuron (MN) identity in the ventral nerve cord of the nematode C. elegans. To identify novel UNC-3 target genes, we took advantage of the genome-wide binding map of UNC-3 from our previous Chromatin Immunoprecipitation followed by Sequencing (ChIP-Seq) analysis (Li et al., 2020). We generated transgenic reporter lines for ten putative terminal identity genes (pxd-1, cal-2, lgc-4, ldb-1, nep-21, D2007.2, dmsr-2, ncs-2, npr-29, drn-1), whose expression patterns were largely unknown in C. elegans. Six of these reporter lines showed expression in ventral nerve cord MNs (nep-21, D2007.2, dmsr-2, ncs-2, npr-29, drn-1), whereas the remaining four (pxd-1, cal-2, lgc-4, ldb-1) showed expression in head and tail neurons, as well as some non-neuronal cells. Importantly, the number of ventral nerve cord MNs showing expression of the nep-21, D2007.2, and dmsr-2 reporters was significantly reduced in unc-3 null mutant animals, thereby expanding the repertoire of known UNC-3 target genes in these cells. Altogether, this study demonstrates that transgenic reporter analysis guided by ChIP-Seq results is a relatively efficient approach for the identification and validation of transcription factor target genes.

12.
Front Med (Lausanne) ; 8: 655042, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381792

RESUMO

Background: The aim of this systematic review and meta-analysis was to investigate the efficacy and safety of remimazolam in clinical endoscopic procedure sedation. Methods: The authors searched the databases of PubMed, Embase, and Cochrane Library for studies published until January 2, 2021, that reported remimazolam sedation for endoscopic procedures. The sedative efficiency and the incidence of adverse events were assessed as outcomes. Cochrane Review Manager Software 5.3 was used to perform the statistical analyses. Results: Seven relevant studies involving a total of 1,996 patients were identified. We conducted a meta-analysis of the different controls used in the studies, that is, the placebo, midazolam, and propofol. The results demonstrated that remimazolam had a strong sedative effect, and its sedative efficiency was significantly higher than that of placebo [OR = 0.01, 95% CI: (0.00, 0.10), I 2 = 30%, p <0.00001]. The sedative efficiency of remimazolam was significantly higher than that of midazolam [OR = 0.12, 95% CI: (0.08, 0.21), I 2 = 0%, p < 0.00001] but lesser than that of propofol [OR = 12.22, 95% CI: (1.58, 94.47), I 2 = 0%, p = 0.02]. Regarding the adverse events, remimazolam is associated with a lower incidence of hypotension than placebo and midazolam. Similarly, remimazolam was associated with a lower incidence of hypotension and hypoxemia than propofol. Conclusions: Remimazolam is a safe and effective sedative for patients undergoing endoscopic procedures. The sedative efficiency of remimazolam was significantly higher than that of midazolam but slightly lower than that of propofol. However, the respiration and circulation inhibitory effects of remimazolam were weaker than those of midazolam and propofol.

13.
Chem Res Toxicol ; 34(8): 1866-1878, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34296853

RESUMO

The relationship between human papillomavirus (HPV) and esophageal cancer (EC) has been controversial, which may be caused by the difference in geographic regions of sample origin. Thus, we conducted a case-control study to find that HPV increased the risk of esophageal cancer, and the HPV18 detection rate is the highest (24.2%) among patients with EC, suggesting that HPV18 could be the most risk subtype of HPV infected. We then identified high-risk HPV18 and N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) to establish a model on the viral etiology cooperating with environmental carcinogens. Het-1A cells containing HPV18 were continuously exposed to MNNG or not; then the morphological phenotype and function assays were performed in 25th passage cells. MNNG promoted the proliferation and invasion abilities and inhibited apoptosis both in Het-1A-HPV18 and control group. However, the Het-1A-HPV18 had a stronger change in phenotypic features and formed more transformed foci in soft agar. Further, Western blot found p53 and p21 were down-regulated, and expression of c-Myc, MMP-2, and MMP-9 and Bcl-2/Bax ratio were up-regulated. Our results revealed that MNNG was easier to induce malignant transformation of Het-1A cells transfected with HPV18. It is good evidence for the close relationship between HPV and the etiology of EC, providing foundation for further study in molecular mechanism and specific intervention targets.

14.
Front Pediatr ; 9: 566195, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307242

RESUMO

Background: Acute kidney injury (AKI) after cardiac surgery contributes to adverse outcomes. We aimed to assess the incidence and identify the predictors for persistent AKI after total cavopulmonary connection (TCPC) surgery. Methods: A retrospective study, including 465 children undergoing TCPC surgery from 2010 to 2019, was conducted. We used pRIFLE criteria to define AKI and defined persistent AKI as AKIs occurring between post-operative day1 (POD1) and POD3 and sustaining at least on POD7. Univariate and multivariate logistic regressions were applied to analyze the predictors for persistent AKI. Results: A total of 35.3% patients developed AKI between POD1 to POD3 and 15.5% patents had persistent AKI after TCPC. Patients with persistent AKI had prolonged mechanical ventilation and ICU stay, and had higher rates of renal replacement treatment and reintubation, which was associated with higher hospitalization costs and in-hospital mortality. The independent predictors for persistent AKI were peripheral oxygen saturation (SpO2) upon admission, intraoperative fluid balance, POD0 maximal lactic acid, renal perfusion pressure (RPP), POD0 estimated glomerular filtration rate and POD0 total bilirubin. The areas under receiver operating characteristic curve (AUC) in the total cohort and the subgroup undergoing TCPC surgery after 2017 were 0.75 (95% CI, 0.66-0.82) and 0.87 (95% CI, 0.77-0.97), respectively. The acceptable AUCs (nearly 0.7) were achieved in other 5 subgroups and good calibration ability (p ≥ 0.05) were achieved in the total cohort and all six subgroups. Conclusions: Persistent AKI after TCPC was common and strongly associated with poorer in-hospital outcomes in Chinese pediatric patients. Six perioperative variables, including SpO2, intraoperative fluid balance, POD0 maximal lactic acid, RPP, POD0 moderate-to-severe kidney injury and POD0 total bilirubin, were identified as independent predictors for persistent AKI. Our findings may help to perform an early risk stratification for these vulnerable patients and improve their outcomes.

15.
Nat Commun ; 12(1): 4404, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285225

RESUMO

Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-ß (TGFß) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFß induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFß on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFß-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFß signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.


Assuntos
Autofagia/genética , Epigênese Genética , Histona Acetiltransferases/metabolismo , Escleroderma Sistêmico/patologia , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Biópsia , Estudos de Casos e Controles , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Fibroblastos , Fibrose , Técnicas de Inativação de Genes , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Células NIH 3T3 , Cultura Primária de Células , Receptores de Fatores de Crescimento Transformadores beta , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Proteína Smad3/metabolismo , Adulto Jovem
16.
BMC Cancer ; 21(1): 842, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34284736

RESUMO

BACKGROUND: Patients with lung cancer (LC) have a poor quality of life (QoL) and easily suffer from psychological diseases. Previous studies focused less on the relationship between genetic factors and QoL, depression, and anxiety status in LC patients. The current study is intended to explore the relationship between SNPs and haplotypes of ERCC1 and ERCC2 and the QoL, depression and anxiety status of patients with LC. METHODS: QoL, depression and anxiety status were assessed in 291 LC patients using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), SDS and SAS. Nine tag SNPs of ERCC1 and ERCC2 were detected using an improved multiplex ligation detection reaction (iMLDR) technique. Haplotype analysis was conducted using the software Haploview 4.2. The association between SNPs or haplotypes and QoL or depression or anxiety in LC patients was analyzed by regression analysis. RESULTS: ERCC1 rs11615 was associated with emotional functioning (P = 0.027), and ERCC1 rs3212986 was associated with anxiety scores (P = 0.018). ERCC1 rs762562-rs3212986 haplotype was associated with cognitive function (P = 0.029), somatic function (P = 0.014) and dysphagia (OR = 3.32, P = 0.044). Patients with ERCC1 rs3212986-rs11615 AG haplotype had worse cognitive function (adjusted Beta = - 5.42) and somatic function (adjusted Beta = - 6.55) and had severer symptoms of loss of appetite (adjusted OR = 1.67) and dysphagia (adjusted OR = 4.43) (All adjusted P < 0.05). ERCC2 rs13181-rs3916874-rs238416 haplotype was associated with emotional functioning (P = 0.035), pain at other sites (OR 1.88, P = 0.014), chest pain (OR 0.42, P = 0.02), dysphagia (OR 2.82, P = 0.048), and anxiety status (OR 0.23, P = 0.009). CONCLUSION: After adjustment for environmental factors, SNPs and haplotypes of ERCC1 and ERCC2 were associated with different domains of QoL, depression and anxiety in LC patients.


Assuntos
Ansiedade/genética , Proteínas de Ligação a DNA/genética , Depressão/genética , Endonucleases/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/psicologia , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Qualidade de Vida , Adulto Jovem
17.
J Mol Diagn ; 23(10): 1334-1342, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34325059

RESUMO

High-risk human papillomavirus (HR-HPV) infection is a major risk factor of head and neck cancers (HNCs). Despite the rising prevalence of HPV-driven HNC (HPV-HNC), biomarkers for detection, prognostication, and disease monitoring are lacking. To evaluate the capacity of salivary HR-HPV DNA as a biomarker of HPV-HNC, the salivary HR-HPV statuses of 491 and 10 patients with primary and recurrent HNC, respectively, were determined at diagnosis, using quantitative real-time PCR and MassARRAY. Tumor cyclin-dependent kinase inhibitor 2A (p16) expression was determined by IHC analysis. Patients with oropharyngeal cancer (OPC) (n = 215) were followed up for ≤5 years. Survival characteristics were evaluated in terms of event-free and cause-specific survival. Of the primary-HNC cohort, 43.2% were positive for salivary HR-HPV DNA, with most having OPC. Salivary HR-HPV DNA was detected in 81.4% of tumor p16-positive OPC patients at diagnosis. Prognosis in salivary HR-HPV-positive OPC patients was favorable compared with that in salivary HR-HPV-negative patients (event-free survival, hazard ratio = 0.42 [95% CI, 0.21-0.81, P = 0.010]; cause-specific survival, hazard ratio = 0.39 [95% CI, 0.18-0.86, P = 0.019]). In the recurrent-HNC cohort, salivary HR-HPV DNA was detected in 83.3% of those who previously had tumor p16-positive HNC. These findings indicate that this liquid biopsy-based, noninvasive biomarker can play an essential role in the detection and management of HPV-HNC.

18.
iScience ; 24(6): 102513, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34142029

RESUMO

Carbon neutrality by 2060 is the recent expression of China's international commitment to reduce its carbon dioxide emissions. Energy and chemical sectors, the two main contributors for carbon dioxide emissions in China, are the biggest bottlenecks for reaching the objective of carbon neutrality. Moreover, coal-to-ammonia production and coal-to-methanol production are the major CO2 emission process contributors in China's coal chemical sector. Herein, a possible route to the carbon neutral target based on energy-chemical nexus for electricity generation as well as methanol and ammonia production is proposed in this study. The most cost-effective solution for meeting the commitment is identified by considering regional variations in renewable and non-renewable resources and adopting an optimized regional cooperation. According to the roadmap presented in this study, an optimized combination of fossil fuels and renewable energies forming "blue energy economy" is feasible and promising.

19.
Fish Shellfish Immunol ; 114: 161-170, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957267

RESUMO

The family of fibrinogen-related proteins (FREPs) is a group of proteins with fibrinogen-like (FBG) domains, which play important roles as pattern recognition receptors (PRRs) in the innate immune responses. In the present study, a fibrinogen-like protein was identified from the oyster Crassostrea gigas (defined as CgFREP1). The open reading frame of CgFREP1 was of 966 bp that encoded a predicted polypeptide of 321 amino acids comprising a signal peptide and a fibrinogen-like domain. The mRNA expression of CgFREP1 was detected in all the examined tissues. The recombinant CgFREP1 (rCgFREP1) displayed binding activities to lipopolysaccharide (LPS), mannose (MAN), as well as Gram-positive bacteria (Micrococcus luteus and Staphylococcus aureus) and Gram-negative bacteria (Vibrio splendidus and Escherichia coli). The rCgFREP1 displayed the agglutinating activity towards M. luteus, V. splendidus and E. coli in the presence of Ca2+. rCgFREP1 was able to enhance the phagocytic activity of haemocytes towards V. splendidus, and exhibited binding activity to the CUB domain of CgMASPL-1. These results suggest that CgFREP1 not only serves as a PRR to recognize and agglutinate different bacteria but also mediates the haemocytes phagocytosis towards V. splendidus.


Assuntos
Crassostrea/microbiologia , Hemócitos/fisiologia , Fagocitose/fisiologia , Proteínas/metabolismo , Vibrio/fisiologia , Animais , Crassostrea/imunologia , Crassostrea/metabolismo , Interações Hospedeiro-Patógeno , Micrococcus luteus/fisiologia , Proteínas/imunologia , Staphylococcus aureus/fisiologia
20.
J Am Heart Assoc ; 10(11): e019098, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33998242

RESUMO

Background Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Absolute lymphocyte count (ALC) is a low-cost and easy-to-obtain inflammatory indicator; however, its association with the prognosis of patients with TOF remains unknown. This study aimed to determine the prognostic value of preoperative ALC in children with TOF. Methods and Results This retrospective study included 707 patients aged <6 years who underwent corrective operations for TOF between January 2016 and December 2018 in Fuwai Hospital, China. The end points were mortality, extracorporeal membrane oxygenation placement, postoperative hospital stay >30 days, and severe postoperative complications; patients were grouped on the basis of prognosis: poor prognosis (n=76) and good prognosis (n=631). Univariable and multivariable logistic regression analyses were performed to identify the independent risk factors for poor prognosis, on which a risk scoring system was based. The receiver operating characteristic curve was used to assess model performance. Using another model without ALC, the effect of the addition of ALC was assessed. Results suggested that ALC was an independent factor with a cutoff point of 4.36×109/L. The addition of ALC improved the area under the curve from 0.771 to 0.781 (P<0.001). To avoid reverse causality and further control for confounding factors, the patients were further divided on the basis of ALC level, and a propensity score matching was performed; 117 paired patients were identified for further analysis. Low ALC levels had an odds ratio of 3.500 (95% CI, 1.413-8.672). Conclusions Low preoperative ALC represents an independent predictor of poor prognosis in children with TOF.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Contagem de Linfócitos/métodos , Tetralogia de Fallot/diagnóstico , Pequim/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Período Pré-Operatório , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Tetralogia de Fallot/epidemiologia , Tetralogia de Fallot/cirurgia
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