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1.
Environ Pollut ; 292(Pt B): 118381, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34673156

RESUMO

Colon microenvironment and microbiota dysbiosis are closely related to various human metabolic diseases. In this study, a total of 72 healthy female mice were exposed to fluoride (F) (0, 25, 50 and 100 mg/L F-) in drinking water for 70 days. The effect of F on intestinal barrier and the diversity and composition in colon microbiota have been evaluated. Meanwhile, the relationship among F-induced colon microbiota alterations and antimicrobial peptides (AMPs) expression and short-chain fatty acids (SCFAs) level also been assessed. The results suggested that F decreased the goblet cells number and glycoprotein expression in colon. And further high-throughput 16S rRNA gene sequencing result demonstrated that F exposure induced the diversity and community composition of colonic microbiota significantly changes. Linear Discriminant Analysis Effect Size (LEfSe) analysis identified 11 predominantly characteristic taxa which may be the biomarker in response to F exposure. F-induced intestinal microbiota perturbations lead to the significantly decreased SCFAs levels in colon. Immunofluorescence results showed that F increased the protein expression of interleukin-17A (IL-17A) and IL-22 (P < 0.01) and disturbed the expression of interleukin-17 receptor A (IL-17RA) and IL-22R (P < 0.05 or P < 0.01). In addition, the increased expression of IL-17A and IL-22 cooperatively enhanced the mRNA expression of AMPs which response to F-induced microbiota perturbations. Collectively, destroyed microenvironment and disturbed AMPs are the primary reason of microbiota dysbiosis in colon after F exposure. Colonic homoeostasis imbalance would be helpful for finding the source of F-induced chronic systemic diseases.

2.
J Virol ; : JVI0171321, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34787453

RESUMO

Rift Valley fever virus (RVFV) belongs to the order Bunyavirales and is the type species of genus Phlebovirus, which accounts for over 50% of family Phenuiviridae species. RVFV is mosquito-borne and causes severe diseases in both humans and livestock, and consists of three segments (S, M, L) in the genome. The L segment encodes an RNA-dependent RNA polymerase (RdRp, L protein) that is responsible for facilitating the replication and transcription of the virus. It is essential for the virus and has multiple drug targets. Here, we established an expression system and purification procedures for full-length L protein, which is composed of an endonuclease domain, RdRp domain, and cap-binding domain. A cryo-EM L protein structure was reported at 3.6 Å resolution. In this first L protein structure of genus Phlebovirus, the priming loop of RVFV L protein is distinctly different from those of other L proteins and undergoes large movements related to its replication role. Structural and biochemical analyses indicate that a single template can induce initiation of RNA synthesis, which is notably enhanced by 5' viral RNA. These findings help advance our understanding of the mechanism of RNA synthesis and provide an important basis for developing antiviral inhibitors. Importance The zoonosis RVF virus (RVFV) is one of the most serious arbovirus threats to both human and animal health. RNA-dependent RNA polymerase (RdRp) is a multifunctional enzyme catalyzing genome replication as well as viral transcription, so the RdRp is essential for studying the virus and has multiple drug targets. In our study, we report the structure of RVFV L protein at 3.6 Å resolution by cryo-EM. This is the first L protein structure of genus Phlebovirus. Strikingly, a single template can initiate RNA replication. The structure and assays provide a comprehensive and in-depth understanding of the catalytic and substrate recognition mechanism of RdRp.

3.
Mol Med ; 27(1): 147, 2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34773993

RESUMO

BACKGROUND: Patients with salt-sensitive hypertension are often accompanied with severe renal damage and accelerate to end-stage renal disease, which currently lacks effective treatment. Fibroblast growth factor 21 (FGF21) has been shown to suppress nephropathy in both type 1 and type 2 diabetes mice. Here, we aimed to investigate the therapeutic effect of FGF21 in salt-sensitive hypertension-induced nephropathy. METHODS: Changes of FGF21 expression in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mice were detected. The influence of FGF21 knockout in mice on DOCA-salt-induced nephropathy were determined. Recombinant human FGF21 (rhFGF21) was intraperitoneally injected into DOCA-salt-induced nephropathy mice, and then the inflammatory factors, oxidative stress levels and kidney injury-related indicators were observed. In vitro, human renal tubular epithelial cells (HK-2) were challenged by palmitate acid (PA) with or without FGF21, and then changes in inflammation and oxidative stress indicators were tested. RESULTS: We observed significant elevation in circulating levels and renal expression of FGF21 in DOCA-salt-induced hypertensive mice. We found that deletion of FGF21 in mice aggravated DOCA-salt-induced nephropathy. Supplementation with rhFGF21 reversed DOCA-salt-induced kidney injury. Mechanically, rhFGF21 induced AMPK activation in DOCA-salt-treated mice and PA-stimulated HK-2 cells, which inhibited NF-κB-regulated inflammation and Nrf2-mediated oxidative stress and thus, is important for rhFGF21 protection against DOCA-salt-induced nephropathy. CONCLUSION: These findings indicated that rhFGF21 could be a promising pharmacological strategy for the treatment of salt-sensitive hypertension-induced nephropathy.

4.
Nat Commun ; 12(1): 6204, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34707099

RESUMO

Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-ß-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts.

5.
Nat Genet ; 53(10): 1493-1503, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594040

RESUMO

How two subgenomes in allo-tetraploids adapt to coexistence and coordinate through structure and expression evolution requires extensive studies. In the present study, we report an improved genome assembly of allo-tetraploid common carp, an updated genome annotation of allo-tetraploid goldfish and the chromosome-scale assemblies of a progenitor-like diploid Puntius tetrazona and an outgroup diploid Paracanthobrama guichenoti. Parallel subgenome structure evolution in the allo-tetraploids was featured with equivalent chromosome components, higher protein identities, similar transposon divergence and contents, homoeologous exchanges, better synteny level, strong sequence compensation and symmetric purifying selection. Furthermore, we observed subgenome expression divergence processes in the allo-tetraploids, including inter-/intrasubgenome trans-splicing events, expression dominance, decreased expression levels, dosage compensation, stronger expression correlation, dynamic functionalization and balancing of differential expression. The potential disorders introduced by different progenitors in the allo-tetraploids were hypothesized to be alleviated by increasing structural homogeneity and performing versatile expression processes. Resequencing three common carp strains revealed two major ecotypes and uncovered candidate genes relevant to growth and survival rate.


Assuntos
Carpas/genética , Evolução Molecular , Regulação da Expressão Gênica , Genoma , Carpa Dourada/genética , Tetraploidia , Processamento Alternativo/genética , Animais , Sequência de Bases , Variação Genética , Cariótipo , Funções Verossimilhança , Anotação de Sequência Molecular , Filogenia , Seleção Genética , Especificidade da Espécie , Sintenia/genética
6.
ACS Nano ; 15(10): 16562-16571, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34569229

RESUMO

Cryo-electron microscopy (cryo-EM) has emerged as a vital tool to reveal the native structure of beam-sensitive biomolecules and materials. Yet high-resolution cryo-EM analysis is still limited by the poorly controlled specimen preparation and urgently demands a robust supporting film material to prepare desirable samples. Here, we developed a bilayer Janus graphene membrane with the top-layer graphene being functionalized to interact with target molecules on the surface, while the bottom layer being kept intact to reinforce its mechanical steadiness. The ultraclean and atomically thin bilayer Janus membrane prepared by our protocol on one hand generates almost no extra noise and on the other hand reduces the specimen motion during cryo-EM imaging, thus allowing the atomic-resolution characterization of surface functional groups. Using such Janus membranes in cryo-EM specimen preparation, we were able to directly image the lithium dendrite and reconstruct macromolecules at near-atomic resolution. Our results demonstrate the bilayer Janus design as a promising supporting material for high-resolution cryo-EM and EM imaging.


Assuntos
Grafite , Microscopia Crioeletrônica , Substâncias Macromoleculares , Movimento (Física) , Manejo de Espécimes
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1011-1018, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362476

RESUMO

OBJECTIVE: To the clinical characteristics and prognostic value of the patients with complete deletion of TET_JBP domain (ΔJBP) in TET2 acute myeloid leukemia (AML). METHODS: Next Generation Sequencing technology was used to determine the mutations of 34 AML-related genes (including TET2 gene). The I-TASSER tool was used to predict the tertiary structure of the full-length TET2 protein and TET_JBP structure deletion. RESULTS: Among 38 AML patients with TET2 mutations, 22(57.9%) showed truncation mutations, of which 16 (72.7%) produced TET2ΔJBP truncation mutants. Protein structure prediction showed that the deletion of TET_JBP domain lead to the significant changes of tertiary structure in TET2 protein. Compared with the patients in non-ΔJBP group, the age of patients in ΔJBP group were older (63 vs 54 years old, P=0.047), and the occurrence rate of CEBPA double mutation (CEBPAdm) were more frequency (31.3% vs 0, P=0.009), the complete remission (CR) rate after induction chemotherapy(37.5% vs 81.8%, P=0.008) were lower, the median EFS (5 vs 19 months, P=0.000) and median OS (16 vs 22 months, P=0.041) were shorter. Univariate analysis showed that platelets <50×109/L (P=0.004) and CEBPAdm (P=0.001) were related to the shorter OS of the patients. Further COX multivariate analysis showed that CEBPAdm is an independent prognostic factors of OS in TET2ΔJBP patients (P=0.010). In addition, ΔJBP patients with CEBPAdm showed lower hemoglobin levels (62 vs 75g/L, P=0.030) and lower median OS (9 months vs 18 months, P=0.000) than the patients without CEBPAdm. CONCLUSION: AML patients with TET2ΔJBP truncation mutant shows lower CR rate, shorter EFS and OS after induction chemotherapy, which may be related to the poor prognosis, and co-mutation with CEBPAdm, which is the independent prognostic factors of OS in AML patients with TET2ΔJBP.


Assuntos
Leucemia Mieloide Aguda , Proteínas de Ligação a DNA/genética , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas/genética , Indução de Remissão
8.
Build Environ ; 205: 108231, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34393324

RESUMO

The COVID-19 pandemic provides an opportunity to study the effects of urban lockdown policies on the variation in pollutant concentrations and to characterize the recovery patterns of urban air pollution under the interruption of COVID-19 lockdown policies. In this paper, interruption-recovery models and regression discontinuity design were developed to characterize air pollution interruption-recovery patterns and analyze environmental impacts of the COVID-19 lockdown, using air pollution data from four Chinese metropolises (i.e., Shanghai, Wuhan, Tianjin, and Guangzhou). The results revealed the air pollutant interruption-recovery curve represented by the three lockdown response periods (Level I, Level II and Level III) during COVID-19. The curve decreased during Level I (A 25.3%-48.8% drop in the concentration of NO2 has been observed in the four metropolises compared with the same period in 2018-2019.), then recovered around reopening, but decreased again during Level III. Moreover, the interruption-recovery curve of the year-on-year air pollution difference suggests a process of first decreasing during Level I and gradually recovering to a new equilibrium during Level III (e.g., the unit cumulative difference of NO2 mass concentrations in Shanghai was 21.7, 22.5, 11.3 (µg/m3) during Level I, II, and III and other metropolises shared similar results). Our findings reveal general trends in the air quality externality of different lockdown policies, hence could provide valuable insights into air pollutant interruption-recovery patterns and clear scientific guides for policymakers to estimate the effect of different lockdown policies on urban air quality.

9.
BMC Surg ; 21(1): 327, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399728

RESUMO

BACKGROUND: Local treatment remains the best option for recurrent colorectal liver metastasis (CRLM). The current study aimed to investigate predictive factors of survival outcomes and select candidates for local treatment for CRLM at first recurrence. METHODS: Data were collected retrospectively from CRLM patients who underwent hepatic resection and developed first recurrence between 2000 and 2019 at our institution.A nomogram predicting overall survival was established based on a multivariable Cox model of clinicopathologic factors. The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index and calibration curve. RESULTS: Among 867 patients who underwent curative hepatic resection, 549 patients developed recurrence. Three hundred patients were evaluated and had resectable and liver-limited disease. Among them, repeat liver resection and percutaneous radiofrequency ablation were performed in 88 and 85 patients, respectively. The other 127 patients received only systemic chemotherapy. Multivariable analysis identified primary lymph node positivity, tumor size > 3 cm, early recurrence, RAS gene mutation and no local treatment as independent risk factors for survival outcomes. Integrating these five variables, the nomogram presented a good concordance index of 0.707. Compared with patients who received only systemic chemotherapy, radical local treatment did not significantly improve survival outcomes (median OS: 21 vs. 15 months, p = 0.126) in the high-risk group (total score ≥ 13). CONCLUSION: Radical local treatment improved the survival of recurrent CRLM patients. The proposed model facilitates personalized assessments of prognosis for patients who develop first recurrence in the liver.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Colorretais/cirurgia , Hepatectomia , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos
10.
Biol Trace Elem Res ; 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34392477

RESUMO

Estrogen exerts essential role in liver metabolism, and its deficiency is frequently accompanied by a series of metabolic disorder diseases. To investigate the role of estrogen deficiency in fluorine ions (F-) induced liver injury, the ovariectomy (OVX) rat models were performed by surgically removing the ovaries, and the rats from OVX and non-OVX models were exposed to differential dose of F- (0, 25, 50 and 100 mg/L) in drinking water for 90 days. The liver morphological structure was evaluated by hematoxylin-eosin staining. Proliferation ability of hepatocytes was evaluated by 5-bromo-2-deoxyuridine (BrdU) assay. And distribution of lipid droplets in liver tissue was observed via oil red O staining. In addition, the liver function and lipid metabolism parameters in serum were detected by commercial kits. Results showed that F- induced hepatocytes morphological damage and inhibited the proliferation ability of hepatocytes; estrogen deficiency exacerbated these changes. The deposition of lipid droplets in the liver tissue was multiplicative with increased F- dose, especially after estrogen deficiency. In addition, F- exposure increased (P < 0.05 or P < 0.01) serum aminotransferase (ALT), aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transpeptidase (γ-GT) activities and total bilirubin (T-bil) level; meanwhile, serum triglyceride (TG) and cholesterol (TC) levels were also elevated (P < 0.05 or P < 0.01). F--induced liver function and lipid metabolism indexes were further increased (P < 0.05 or P < 0.01) in the state of estrogen deficiency. In conclusion, estrogen deficiency aggravated F--induced liver damage and lipid metabolism disorder.

11.
Inorg Chem ; 60(14): 10808-10818, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34210127

RESUMO

Six isostructural three-dimensional (3D) Ln(III)-organic frameworks, {[Ln2(HMIDC)2(µ4-C2O4)(H2O)3]·4H2O}n [LnIII = GdIII (1), EuIII (2), SmIII (3), NdIII (4), PrIII (5), and CeIII (6)], have been fabricated by using a multifunctional ligand of 2-methyl-1H-imidazole-4,5-dicarboxylic acid (H3MIDC). Ln-metal-organic frameworks (MOFs) 1-6 present 3D structures and possess abundant H-bonded networks between imidazole-N atoms and coordinated and free water molecules. All the six Ln-MOFs demonstrate humidity- and temperature-dependent proton conductivity (σ) having the optimal values of 2.01 × 10-3, 1.40 × 10-3, 0.93 × 10-3, 2.25 × 10-4, 1.11 × 10-4, and 0.96 × 10-4 S·cm-1 for 1-6, respectively, at 100 °C/98% relative humidity, in the order of CeIII (6) < PrIII (5) < NdIII (4) < SmIII (3) < EuIII (2) < GdIII (1). In particular, the σ for 1 is 1 order of magnitude higher than that for 6, and it enhances systematically according to the decreasing order of the ionic radius, indicating that the lanthanide-contraction tactics can effectively regulate the proton conductivity while retaining the proton conduction routes. This will offer valuable guidance for the acquisition of new proton-conducting materials. In addition, the outstanding water stability and electrochemical stability of such Ln-MOFs will afford a solid material basis for future applications.

12.
Animals (Basel) ; 11(6)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203588

RESUMO

Fatty acid desaturase 2 (fads2) is one of the rate-limiting enzymes in PUFAs biosynthesis. Compared with the diploid fish encoding one fads2, the allo-tetraploid common carp, one most important food fish, encodes two fads2 genes (fads2a and fads2b). The associations between the contents of different PUFAs and the polymorphisms of fads2a and fads2b have not been studied. The contents of 12 PUFAs in common carp individuals were measured, and the polymorphisms in the coding sequences of fads2a and fads2b were screened. We identified five coding single nucleotide polymorphisms (cSNPs) in fads2a and eleven cSNPs in fads2b. Using the mixed linear model and analysis of variance, a synonymous fads2a cSNP was significantly associated with the content of C20:3n-6. One non-synonymous fads2b cSNP (fads2b.751) and one synonymous fads2b cSNP (fads2b.1197) were associated with the contents of seven PUFAs and the contents of six PUFAs, respectively. The heterozygous genotypes in both loci were associated with higher contents than the homozygous genotypes. The fads2b.751 genotype explained more phenotype variation than the fads2b.1197 genotype. These two SNPs were distributed in one haplotype block and associated with the contents of five common PUFAs. These results suggested that fads2b might be the major gene responding to common carp PUFA contents and that fads.751 might be the main effect SNP. These cSNPs would be potential markers for future selection to improve the PUFA contents in common carp.

13.
Bone Joint Res ; 10(7): 411-424, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34259564

RESUMO

AIMS: The use of 3D-printed titanium implant (DT) can effectively guide bone regeneration. DT triggers a continuous host immune reaction, including macrophage type 1 polarization, that resists osseointegration. Interleukin 4 (IL4) is a specific cytokine modulating osteogenic capability that switches macrophage polarization type 1 to type 2, and this switch favours bone regeneration. METHODS: IL4 at concentrations of 0, 30, and 100 ng/ml was used at day 3 to create a biomimetic environment for bone marrow mesenchymal stromal cell (BMMSC) osteogenesis and macrophage polarization on the DT. The osteogenic and immune responses of BMMSCs and macrophages were evaluated respectively. RESULTS: DT plus 30 ng/ml of IL4 (DT + 30 IL4) from day 3 to day 7 significantly (p < 0.01) enhanced macrophage type 2 polarization and BMMSC osteogenesis compared with the other groups. Local injection of IL4 enhanced new bone formation surrounding the DT. CONCLUSION: DT + 30 IL4 may switch macrophage polarization at the appropriate timepoints to promote bone regeneration. Cite this article: Bone Joint Res 2021;10(7):411-424.

14.
Prog Cardiovasc Dis ; 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34245777

RESUMO

BACKGROUND: Coronary artery disease (CAD) patients undergoing revascularization procedures often experience ongoing, diminished functional capacity, high rates of depression and markedly low quality of life (QoL). In CAD patients, studies have demonstrated that high-intensity interval training (HIIT) is superior to traditional moderate-to-vigorous intensity continuous training (MICT) for improving functional capacity, whereas no differences between Nordic walking (NW) and MICT have been observed. Mental health is equally as important as physical health, yet few studies have examined the impact of HIIT and NW on depression and QoL. The purpose of this randomized controlled trial (RCT) was to compare the effects of 12 weeks of HIIT, NW and MICT on functional capacity in CAD patients. The effects on depression severity, brain-derived neurotrophic factor (BDNF) and QoL were also examined. METHODS: CAD patients who underwent coronary revascularization procedures were randomly assigned to: (1) HIIT (4 × 4-min of high-intensity work periods at 85%-95% peak heart rate [HR]), (2) NW (resting HR [RHR] + 20-40 bpm), or (3) MICT (RHR + 20-40 bpm) twice weekly for 12 weeks. Functional capacity (six-min walk test [6MWT]), depression (Beck Depression Inventory-II [BDI-II]), BDNF (from a blood sample), and general (Short-Form 36 [SF-36]) and disease-specific (HeartQoL) QoL were measured at baseline and follow-up. Linear mixed-effects models for repeated measures were used to test the effects of time, group and time × group interactions. RESULTS: N = 135 CAD patients (aged 61 ± 7 years; male: 85%) participated. A significant time × group interaction (p = 0.042) showed greater increases in 6MWT distance (m) for NW (77.2 ± 60.9) than HIIT (51.4 ± 47.8) and MICT (48.3 ± 47.3). BDI-II significantly improved (HIIT: -1.4 ± 3.7, NW: -1.6 ± 4.0, MICT: -2.3 ± 6.0 points, main effect of time: p < 0.001) whereas BDNF concentrations did not change (HIIT: -2.5 ± 9.6, NW: -0.4 ± 7.7, MICT: -1.2 ± 6.4 ng/mL, main effect of time: p > 0.05). Significant improvements in SF-36 and HeartQoL values were observed (main effects of time: p < 0.05). HIIT, NW and MICT participants attended 17.7 ± 7.5, 18.3 ± 8.0 and 16.1 ± 7.3 of the 24 exercise sessions, respectively (p = 0.387). CONCLUSIONS: All exercise programmes (HIIT, NW, MICT) were well attended, safe and beneficial in improving physical and mental health for CAD patients. NW was, however, statistically and clinically superior in increasing functional capacity, a predictor of future cardiovascular events.

15.
J Transl Med ; 19(1): 313, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281583

RESUMO

BACKGROUND: The exploration of genomic alterations in Chinese colorectal liver metastasis (CRLM) is limited, and corresponding genetic biomarkers for patient's perioperative management are still lacking. This study aims to understand genome diversification and complexity that developed in CRLM. METHODS: A custom-designed IDT capture panel including 620 genes was performed in the Chinese CRLM cohort, which included 396 tumor samples from metastatic liver lesions together with 133 available paired primary tumors. RESULTS: In this Chinese CRLM cohort, the top-ranked recurrent mutated genes were TP53 (324/396, 82%), APC (302/396, 76%), KRAS (166/396, 42%), SMAD4 (54/396, 14%), FLG (52/396, 13%) and FBXW7 (43/396, 11%). A comparison of CRLM samples derived from left- and right-sided primary lesions confirmed that the difference in survival for patients with different primary tumor sites could be driven by variations in the transforming growth factor ß (TGF-ß), phosphatidylinositol 3-kinase (PI3K) and RAS signaling pathways. Certain genes had a higher variant rate in samples with metachronous CRLM than in samples with simultaneous metastasis. Overall, the metastasis and primary tumor samples displayed highly consistent genomic alterations, but there were some differences between individually paired metastases and primary tumors, which were mainly caused by copy number variations. CONCLUSION: We provide a comprehensive depiction of the genomic alterations in Chinese patients with CRLM, providing a fundamental basis for further personalized therapy applications.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , China , Neoplasias Colorretais/genética , Variações do Número de Cópias de DNA/genética , Genômica , Humanos , Neoplasias Hepáticas/genética , Mutação/genética , Fosfatidilinositol 3-Quinases
16.
Cell Discov ; 7(1): 53, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285195

RESUMO

Coronavirus disease 2019 (COVID-19), a pandemic disease caused by the newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 3.8 million deaths to date. Neutralizing antibodies are effective therapeutic measures. However, many naturally occurring mutations at the receptor-binding domain (RBD) have emerged, and some of them can evade existing neutralizing antibodies. Here, we utilized RenMab, a novel mouse carrying the entire human antibody variable region, for neutralizing antibody discovery. We obtained several potent RBD-blocking antibodies and categorized them into four distinct groups by epitope mapping. We determined the involved residues of the epitope of three representative antibodies by cryo-electron microscopy (Cryo-EM) studies. Moreover, we performed neutralizing experiments with 50 variant strains with single or combined mutations and found that the mixing of three epitope-distinct antibodies almost eliminated the mutant escape. Our study provides a sound basis for the rational design of fully human antibody cocktails against SARS-CoV-2 and pre-emergent coronaviral threats.

17.
Vet Parasitol ; 296: 109477, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34087564

RESUMO

An anticoccidial model of chicken infected with Eimeria tenella was established to investigate the effect of toltrazuril (Tol) combined with the Radix Sophorae Flavescentis (RSF) on coccidiosis. The anticoccidial index (ACI) was evaluated, and the cecal developmental parameters (i.e., villus height, [VH], crypt depth, [CD], and VH/CD) were determined. The distributions of glycoproteins and goblet cells in the cecal tissue were determined through the Periodic Acid-Schiff (PAS) and Alcian blue PAS staining methods, respectively. The mRNA expression levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, and IL-17 of the cecal tissue were determined through quantitative real-time PCR. The moderate ACI was obtained using the combination of Tol and RSF. Compared with the normal control (NC) group, the infected control (IC) group showed remarkably lower VH and VH/CD at five and seven days postinfection. Compared with the IC group, the IC + RSF and IC + TolRSF groups showed remarkably higher VH and VH/CD at five and seven days postinfection. Compared with the NC group, the IC group contained fewer glycoproteins and goblet cells, but the Tol and RSF treatment promoted more glycoproteins and goblet cells at five and seven days postinfection. The mRNA expression levels of IL-1ß, IL-2, IL-4, IL-6, IL-10, and IL-17 in the IC group were upregulated (P < 0.01) compared with those in the NC group. The IC + RSF and IC + TolRSF groups had downregulated mRNA expression levels of IL-1ß, IL-6, and IL-17 cytokines (P < 0.01), and upregulated mRNA expression levels of IL-2 and IL-4 cytokines (P < 0.01) compared with the IC group. Results showed that the combination of Tol and RSF exerts anticoccidial effect by reducing inflammation and promoting intestinal mucosal immunity.


Assuntos
Imunidade nas Mucosas , Extratos Vegetais , Ranunculaceae , Triazinas , Animais , Galinhas , Coccidiose/tratamento farmacológico , Coccidiose/veterinária , Coccidiostáticos/farmacologia , Coccidiostáticos/uso terapêutico , Eimeria tenella , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Inflamação/veterinária , Interleucinas/genética , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Doenças das Aves Domésticas/tratamento farmacológico , Ranunculaceae/química , Triazinas/farmacologia , Triazinas/uso terapêutico
18.
BMC Surg ; 21(1): 302, 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187443

RESUMO

BACKGROUND: En bloc right hemicolectomy with pancreatoduodenectomy (RHCPD) is the optimum treatment to achieve the adequate margin of resection (R0) for locally advanced right-sided colon cancer with duodenal invasion. Information regarding the indications and outcomes of this procedure is limited. METHOD: In this retrospective study, 2269 patients with right colon cancer underwent radical right colectomy between October 2010 and May 2019, in which 19 patients underwent RHCPD for LARCC were identified. The overall survival (OS), disease-free survival (DFS), operative mortality, postsurgical complications, gene mutational analysis, and prognostic factors were evaluated. Survival was estimated using Kaplan-Meir method. RESULTS: Of these 19 patients who underwent LARCC, the OS was 88%, 66%, and 58% at 1, 3, and 5 years. The DFS was 72%, 56%, and 56% at 1, 3, and 5 years. The median operative time was 320 min (range: 222-410 min), and the median operative blood loss was 268 mL (range: 100-600 mL). The OS was significantly better among patients with well-differentiated tumor, N0 stage, and high microsatellite instability (MSI) and in patients who received adjuvant chemotherapy. The major postoperative complications occurred in 8 patients (42%), with pancreatic fistula (PF) being the most common. On the basis of the univariate analysis, poorly differentiated tumor, regional lymph node dissemination, MSI status, and no perioperative chemotherapy were the significant predictors of poor survival (P < 0.05). CONCLUSIONS: This study suggests that RHCPD is feasible and can achieve complete tumor clearance with favorable outcome, particularly in patients with lymph node-negative status.


Assuntos
Neoplasias do Colo , Pancreaticoduodenectomia , Colectomia , Neoplasias do Colo/cirurgia , Duodeno/cirurgia , Humanos , Estudos Retrospectivos
19.
J Surg Oncol ; 124(4): 619-626, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34081792

RESUMO

BACKGROUND: Surgical margin status remains a controversial factor in predicting the outcome of colorectal liver metastases (CRLM) resection. Our study aims to evaluate the effects of surgical margins on oncologic outcomes with regard to the genetic and morphological evaluation (GAME) score. METHODS: R1 resection was defined as having a less than 1 mm margin width. Patients who underwent surgery for CRLM from January 2005 to December 2018 were recruited. The patients were divided into two risk subgroups, namely, the low or medium risk (GAME 0-3) and high-risk (GAME score 4 or more) groups. The effects of margin status on overall survival (OS) and recurrence-free survival rate (RFS) were examined. RESULTS: In total, 661 patients were recruited, among which 159 (24.1%) had R1 resection. Before hepatectomy, 514 patients showed a low or medium risk (R1 resection: n = 124), while 147 patients demonstrated a high risk (R1 resection: n = 35). In the whole cohort, multivariable analysis did show that R1 resection was associated with worse RFS and OS. While further research only found that in the low or medium risk group, R1 resection was related to poor OS and RFS. Meanwhile, in the high risk group, no significant difference was found in the median OS and RFS among patients with R0 or R1 resection. CONCLUSION: The prognostic role of margin status varied according to the GAME score. Margin clearance only improved survival rates in patients with low or medium GAME score. In contrast, R1 resection demonstrated similar oncologic outcomes with R0 resection in patients with high GAME score.


Assuntos
Neoplasias Colorretais/patologia , Hepatectomia/mortalidade , Neoplasias Hepáticas/secundário , Margens de Excisão , Recidiva Local de Neoplasia/patologia , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
20.
Front Oncol ; 11: 643413, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34109111

RESUMO

We report on a case of metastatic urothelial bladder carcinoma (mUBC) treated with anlotinib combined with sintilimab. A 69-year-old male was diagnosed with non-muscle invasive bladder cancer (NMIBC). He received transurethral resection of bladder tumor (TURBT) and intravesical gemcitabine chemotherapy. After the patients' cancer progressed to mUBC, cisplatin-based chemotherapy (gemcitabine combined with cisplatin, GC) was performed to this patient as first line therapy for four cycles. However, the disease progressed again within 6 months. Local radiotherapy was performed on the metastatic lesions, and after radiotherapy, the patient received anti-PD-1 antibody (sintilimab 200 mg, q3w)combined with Albumin-bound (Nab)-paclitaxel (100 mg, qw) as the second-line therapy, but the patient's cancer was still observed to be progressing. Molecular characterization confirmed the presence of FGFR3 mutations in the patient. Anlotinib was recommended to this patient. After the patient was fully informed and he was aware of off-label use of the drug, then, Nab-paclitaxel was replaced by anlotinib (10 mg D1-14, q3w) and sintilimab infusions were maintained for every 3 weeks. Partial response (PR) was observed through imaging examinations and stable disease (SD) was observed for more than 11 months; the patient's quality of life also improved. This case suggested that anlotinib combined with sintilimab may be a safe and effective choice in the treatment of mUBC in patients with FGFR3 mutations.

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