Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 706
Filtrar
1.
Genet Res (Camb) ; 102: e2, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32234109

RESUMO

The X chromosome is known to play an important role in many sex-specific diseases. However, only a few single-nucleotide polymorphisms on the X chromosome have been found to be associated with diseases. Compared to the autosomes, conducting association tests on the X chromosome is more intractable due to the difference in the number of X chromosomes between females and males. On the other hand, X-chromosome inactivation takes place in female mammals, which is a phenomenon in which the expression of one copy of two X chromosomes in females is silenced in order to achieve the same gene expression level as that in males. In addition, imprinting effects may be related to certain diseases. Currently, there are some existing approaches taking X-chromosome inactivation into account when testing for associations on the X chromosome. However, none of them allows for imprinting effects. Therefore, in this paper, we propose a robust test, ZXCII, which accounts for both X-chromosome inactivation and imprinting effects without requiring specifying the genetic models in advance. Simulation studies are conducted in order to investigate the validity and performance of ZXCII under various scenarios of different parameter values. The simulation results show that ZXCII controls the type I error rate well when there is no association. Furthermore, with regards to power, ZXCII is robust in all of the situations considered and generally outperforms most of the existing methods in the presence of imprinting effects, especially under complete imprinting effects.

3.
Am J Surg ; 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32145919

RESUMO

BACKGROUND: The role of surgery in breast cancer liver metastases (BCLM) remains elusive, and current application is limited. Our aim is to investigate whether hepatic resection (HR) of BCLM improves survival compared with non-hepatic resection (NHR) treatment. METHODS: Three hundred and eighty-four patients with BCLM from 2008 to 2018 were divided into two groups. Propensity score matching (PSM) analysis was used to compare the clinical outcomes. RESULTS: After PSM the mean overall survival (OS) and the 1, 3, and 5-year OS rates in HR group were 61.8 months, 92.6%, 54.7% and 54.7%, respectively; while for NHR group these values were 38.6 months, 79.2%, 45.6% and 21.9%, respectively (p < 0.007). Multivariate analysis indicated hormonal receptor status (p = 0.039) and hepatic resection (p = 0.032) were independent prognostic factors. CONCLUSION: Our study revealed that hepatectomy yields a survival benefit safely compared with medical treatments, especially for patients with positive hormonal receptors.

4.
Microbiol Immunol ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221997

RESUMO

HIV replication can be inhibited by CXCR5+ CD8 T cells (TFC) which transfer into B cell follicles where latent HIV locate. As for how cytokines affect TFC are not yet clear. To understanding which cytokines show the ability to affect TFC could be a key strategy to HIV curing. Similar mechanisms could be used for the growth and transferring of TFC and TFH; we supposed that cytokines IL-6, IL-21, and TGF-ß, which are necessary for the differentiation of TFH, could also dedicate the development of TFC. In our research, LNMCs and PBMCs from HIV infected individuals were co-cultured with IL-6, IL-21, and TGF-ß. We then conducted TCR repertoire analysis to compare the differences of CXCR5- and CXCR5+ CD8 T cells. Our founding showed that the percentage and function of TFC can be enhanced by the stimulation of TGF-ß. Besides, TGF-ß stimulation enhanced the diversity of TCR and CDR3 sequences. HIV DNA showed negative correlationship with TFC. The usage of TGF-ß to promote CXCR5+ CD8 T cells expression could become a new treatment approach for HIV curing. This article is protected by copyright. All rights reserved.

5.
Cell Mol Immunol ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210395

RESUMO

The viral reservoir is the major hurdle in developing and establishing an HIV cure. Understanding factors affecting the size and decay of this reservoir is crucial for the development of therapeutic strategies. Recent work highlighted that CD8+ T cells are involved in the control of viral replication in ART-treated HIV-1-infected individuals, but how CD8+ T cells sense and restrict the HIV reservoir are not fully understood. Here, we demonstrate that a population of unconventional CD45RA+, PanKIR+, and/or NKG2A+ virtual memory CD8+ T cells (TVM cells), which confer rapid and robust protective immunity against pathogens, plays an important role in restraining the HIV DNA reservoir in HIV-1-infected patients with effective ART. In patients undergoing ART, TVM cells negatively correlate with HIV DNA and positively correlate with circulating IFN-α2 and IL-15. Moreover, TVM cells constitutively express high levels of cytotoxic granule components, including granzyme B, perforin and granulysin, and demonstrate the capability to control HIV replication through both cytolytic and noncytolytic mechanisms. Furthermore, by using an ex vivo system, we showed that HIV reactivation is effectively suppressed by TVM cells through KIR-mediated recognition. This study suggests that TVM cells are a promising target to predict posttreatment virological control and to design immune-based interventions to reduce the reservoir size in ART-treated HIV-1-infected individuals.

6.
Int J Surg ; 75: 116-127, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32014597

RESUMO

BACKGROUND & OBJECTIVES: Irritable bowel syndrome (IBS) is a functional bowel disorder that may involve disturbance of the gastrointestinal microbiota. We performed a systematic review and meta-analysis of the efficacy and safety of probiotics in patients with IBS. METHODS: We searched the Cochrane Library, PubMed, EMBASE and Web of Science databases up to 1 April, 2019. Randomized controlled trials (RCTs) involving adults with IBS that compared probiotics to placebo or no therapy were eligible for the analysis. Dichotomous symptom data were pooled to calculate the relative risk (RR) with a 95% confidence interval (CI) of remaining symptoms after therapy. Continuous data were pooled using a standardized mean difference (SMD) with the 95% CI. Two reviewers assessed trial quality and extracted data independently. RESULTS: Thirty-five RCTs involving 3,452 patients were included in the analysis. Compared with placebo, patients using probiotics had a lower incidence of persistence of symptoms (RR 0.79, 95% CI 0.70 to 0.89, P < 0.0001). Also, probiotics exerted a beneficial effect on global symptoms and the abdominal pain score (SMD -0.25, 95% CI -0.36 to -0.14, P < 0.00001), bloating score (SMD -0.15, 95% CI -0.27 to -0.03, P = 0.01), and flatulence score (SMD -0.20, 95% CI -0.35 to -0.05, P = 0.01). However, patients treated with probiotics had a higher incidence of any adverse event (RR 1.21; 95% CI 1.02 to 1.44). CONCLUSIONS: Supplementation with multi-strain probiotics can improve IBS symptoms. Further research is required if probiotics are to be adopted as a treatment for IBS.

7.
J Org Chem ; 85(5): 3963-3972, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32037828

RESUMO

A novel visible-light photoredox catalysis protocol for the effective and efficient synthesis of 3-substituted chroman-4-ones and 2,3-dihydroquinolin-4(1H)-ones via tandem radical addition/cyclization of alkenyl aldehydes has been described. This reaction features a broad substrate scope, mild reaction conditions, and good functional group tolerance character.

8.
Cancer Sci ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32030850

RESUMO

Estrogen-related receptor-α (ERRα) is a nuclear receptor of transcription factor that binds to estrogen responsive elements and estrogen-related responsive elements. Estrogen-related receptor-α is involved in metabolic processes and implicated in the progression and growth of several human malignancies. However, the biologic role and clinical significance of ERRα in gallbladder cancer (GBC) remains to be clarified. Here, we reported that ERRα protein expression was notably higher in GBC tissues than in cholecystitis tissues, and that the aberrantly higher ERRα expression was positively correlated with advanced TNM stage and indicated dismal prognosis of GBC (P < .01). In GBC cell lines NOZ and OCUG, the targeted depletion of ERRα retarded the growth and suppressed the migration and invasive capabilities of GBC cells, and inhibited epithelial-mesenchymal transition by decreasing the expression of mesenchymal markers and elevating the expression of epithelial markers. Moreover, ERRα knockdown inhibited tumor growth in nude mice and led to decreased expression levels of Nectin-4, p-PI3K p85α, and p-AKT. Overexpression of ERRα in the GBC-SD cell line showed exactly the opposite effect. The targeted inhibition of Nectin-4 antagonized GBC cell proliferation and invasion, which were induced by ERRα upregulation. Moreover, Nectin-4 depletion inhibited the ERRα-induced activation of the PI3K/AKT pathway. Chromatin immunoprecipitation analysis and dual-luciferase reporter gene assays showed that ERRα enhanced the transcription of Nectin-4 by binding to the promoter of Nectin-4. In conclusion, our data indicated that ERRα could be a potential target for the genetic treatment of GBC.

9.
Org Lett ; 22(5): 1903-1907, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32065751

RESUMO

An efficient and straightforward Lewis-acid-mediated stereoselective (4 + 3)-cyclization of indole-substituted alkylidene malonates and donor-acceptor cyclopropanes has been developed involving the Friedel-Crafts/Michael addition cyclization cascade. This reaction provides a mild and effective method for the construction of synthetically and structurally interesting functionalized cycloheptannelated indoles.

10.
Nature ; 578(7793): 122-128, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025013

RESUMO

Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

11.
Cancer Cell ; 37(3): 371-386.e12, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32109374

RESUMO

Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.

12.
Int J Biol Macromol ; 152: 199-206, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32088231

RESUMO

Hyaluronic acid (HA) is a major glycosaminoglycan, a family of structurally complex, linear, anionic hetero-co-polysaccharides. HA is important in various anatomical structures including the eyes, joints, heart and myriad intricate tissues, and is currently widely used in the therapeutics and cosmetics areas. The synthesis of HA of well-defined and uniform chain lengths is of major interest for the development of safer and more reliable drugs and to gain a better understanding of its structure-activity relationships. However, HA has received less attention from the synthetic carbohydrate community compared with other members of the glycosaminoglycan family. In this review, we examine the remarkable progress that has been made in the chemical and chemoenzymatic synthesis of HA, providing a broad spectrum of options to access HA of well controlled chain lengths.

13.
Biostatistics ; 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061093

RESUMO

A basket trial in oncology encompasses multiple "baskets" that simultaneously assess one treatment in multiple cancer types or subtypes. It is well-recognized that hierarchical modeling methods, which adaptively borrow strength across baskets, can improve over simple pooling and stratification. We propose a novel Bayesian method, RoBoT (Robust Bayesian Hypothesis Testing), for the data analysis and decision-making in phase II basket trials. In contrast to most existing methods that use posterior credible intervals to determine the efficacy of the new treatment, RoBoT builds upon a formal Bayesian hypothesis testing framework that leads to interpretable and robust inference. Specifically, we assume that the baskets belong to several latent subgroups, and within each subgroup, the treatment has similar probabilities of being more efficacious than controls, historical, or concurrent. The number of latent subgroups and subgroup memberships are inferred by the data through a Dirichlet process mixture model. Such model specification helps avoid type I error inflation caused by excessive shrinkage under typical hierarchical models. The operating characteristics of RoBoT are assessed through computer simulations and are compared with existing methods. Finally, we apply RoBoT to data from two recent phase II basket trials of imatinib and vemurafenib, respectively.

14.
Aliment Pharmacol Ther ; 51(4): 469-478, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943297

RESUMO

BACKGROUND: To date, 14 single-nucleotide polymorphisms (SNPs) have been identified as susceptibility loci for chronic hepatitis B (CHB). AIM: To investigate if these SNPs are associated with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. METHODS: We performed a retrospective analysis of 1623 Han Chinese HBeAg-positive CHB patients (782 patients treated with pegylated interferon alpha [PegIFNα] for 48 weeks plus 24 weeks follow-up, and 841 patients treated with nucleos(t)ide analogues [NUCs] for 104 weeks) included in four phase-IV multicentre randomised controlled trials. All 14 SNPs were genotyped for each CHB patient. A polygenic score (PGS) was used to evaluate the cumulative effect of multiple SNPs. The associations of SNPs or PGS with combined response (CR) and hepatitis B s antigen (HBsAg) loss were assessed. RESULTS: We found that rs12614, a missense variant of complement factor B (CFB), was significantly associated with CR in PegIFNα-treated patients, and the CR rate in patients with the rs12614 TT/CT genotype was less than one-third of that in patients with the CC genotype (7.4% vs 22.6%, P = 0.009). Moreover, a PGS integrating CFB rs12614 and STAT4 rs7574865 (previously reported to be associated with response to PegIFNα) was significantly associated with both CR (P-trend = 4.000 × 10-4 ) and HBsAg loss (P-trend = 0.010) in PegIFNα-treated patients. However, none of the SNPs were associated with treatment response in NUCs-treated patients. CONCLUSIONS: CFB rs12614 is an independent predictor of response to PegIFNα therapy in Chinese HBeAg-positive CHB patients. A PGS integrating CFB rs12614 with STAT4 rs7574865 can effectively discriminate responders to PegIFNα from nonresponders.

15.
Chem Commun (Camb) ; 56(11): 1693-1696, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31939945

RESUMO

Asymmetric conjugate addition of PhMe2SiBPin to a wide range of N-heteroaryl alkenes proceeded in the presence of a copper catalyst coordinated with an easily accessible chiral phosphoramidite ligand to afford useful ß-silyl N-heteroarenes in high yields (up to 96%) and excellent enantioselectivities (up to 97% ee).

16.
AIDS ; 34(2): 189-195, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634199

RESUMO

OBJECTIVE: CD4CD19 conjugates play an important role in regulating antibody responses and follicular helper T cells development in animal models. However, little is known regarding the characteristic of CD4CD19 conjugates in humans with chronic HIV-1 infection. METHODS: The numbers of CD4CD19 conjugates were counted in 86 HIV-1-infected patients, including 66 typical progressors and 20 complete responders. CD4CD19 conjugates were sorted by flow cytometry and dissociated into CD4 T singlets and CD19 B singlets. The phenotypes of these cells were analyzed in both typical progressors and complete responders, and the levels of HIV-1 DNA in CD4CD19 conjugates were measured in 10 complete responders. RESULTS: We identified CD4CD19 cells as one type of T-B conjugate in peripheral blood, and the numbers and percentages of CD4CD19 conjugates decreased with HIV-1 disease progression. Phenotypic analysis showed CD4CD19 conjugates expressed higher levels of surface CD32. mRNA analysis found that the mRNA levels for CD32b were significantly higher compared with CD32a in CD4CD19 conjugates. Further analysis found that CD4CD19 conjugates expressed higher levels of CCR7 and CXCR5 than CD4 T and CD19 B singlets. A virus infectivity assay showed that CD4CD19 conjugates expressed higher levels of HIV-1-p24 than CD4CD19 cells. CD4CD19 conjugates in lymph node from typical progressors expressed higher levels of HIV-1-p24 than CD4CD19 conjugates in respective peripheral blood. Importantly, CD4CD19 conjugates from complete responders contained higher levels of HIV-1 DNA than total CD4 T cells. CONCLUSION: Our study indicates that CD4CD19 conjugates actively participate in HIV-1 infection and latency, and may serve as a new cellular target to eliminate latency.

17.
ACS Appl Mater Interfaces ; 12(2): 2049-2058, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31799832

RESUMO

Graphene materials have attracted special attention because of their electrical conductivity, mechanical properties, and favorable biocompatibility. Although various methods have been developed for fabricating micro/nano conductive fibrous scaffolds, it is still challenging to fabricate the three-dimensional (3D) graphene fibrous scaffolds. Herein, we developed a new method, termed as microfluidic 3D printing technology (M3DP), to fabricate 3D graphene oxide (GO) microfibrous scaffolds with an adjustable fiber length, fiber diameter, and scaffold structure by integrating the microfluidic spinning technology with a programmable 3D printing system. GO microfibrous scaffolds were then transformed into conductive reduced graphene oxide (rGO) microfibrous scaffolds by hydrothermal reduction. Our results demonstrated that the fabricated 3D fibrous graphene scaffolds exhibited tunable structures, maneuverable mechanical properties, and good electrical conductivity and biocompatibility, as reflected by the adhesion and proliferation of SH-SY5Y cells on the graphene microfibrous scaffolds in an obviously oriented manner. The developed M3DP would be a powerful tool for fabricating 3D graphene microfibrous scaffolds for electroactive tissue regeneration and drug-screening applications.

18.
Prostate ; 80(2): 173-185, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31763714

RESUMO

BACKGROUND: Carcinoma-associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub-populations of human prostate CAF can be identified and functionally characterized. METHODS: Single-cell RNA-seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non-tumorigenic, initiated prostate epithelial BPH-1 cells. Resultant grafts were assessed for inflammatory cell recruitment. RESULTS: Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub-renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine-related genes of individual clusters. Migration of THP-1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF-derived chemokine CCL2 may be responsible for CAF-stimulated migration of THP-1 cells, since neutralization of this chemokine abrogates migration capacity. CONCLUSIONS: CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued.

19.
Clin Gastroenterol Hepatol ; 18(1): 196-204.e8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31042581

RESUMO

BACKGROUND & AIMS: Variants in STAT4 (rs7574865) have been associated with seroconversion to hepatitis B e antigen (HBeAg) and reduction in levels of hepatitis B virus (HBV) DNA in patients with chronic infection treated with interferon alpha (IFNA). We evaluated the associations among rs7574865, loss of HB surface antigen (HBsAg, a marker of functional cure of HBV infection), and response to treatment with pegylated IFNA (PegIFN) or nucleos(t)ide analogues (NUCs) in HBeAg-positive patients with chronic HBV infection. METHODS: We performed a retrospective analysis of 1823 HBeAg-positive patients with chronic HBV infection (954 patients treated with PegIFN and 869 patients treated with NUCs) included in 4 phase-4 multicenter randomized controlled trials. The Cochran-Armitage trend test was used to evaluate the association of rs7574865 genotype with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <2000 IU/mL) and loss of HBsAg at week 72, for patients given PegIFN, or week 104, for patients given NUCs. RESULTS: We found a significant association between rs7574865 genotype and CR (P = .004) and loss of HBsAg (P = .037) in patients treated with PegIFN. In patients with HBV genotype B infection, 43.6% of those with rs7574865 TT achieved a CR, compared to patients with rs7574865 GG (20.5%), and 7.7% had loss of HBsAg, compared to 1.9% of patients with rs7574865 GG. However, in patients treated with NUCs, we found no association of rs7574865 genotype with CR (P = .811) or loss of HBsAg (P=.439). CONCLUSIONS: In a retrospective analysis of data from 4 clinical trials, we found rs7574865 in STAT4 to be associated with functional cure of chronic HBV infection by PegIFN treatment, but not NUCs treatment, in HBeAg-positive patients with HBV genotype B infection.

20.
J Biopharm Stat ; 30(2): 294-304, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31304864

RESUMO

The traditional rule-based design, 3 + 3, has been shown to be less likely to achieve the objectives of dose-finding trials when compared with model-based designs. We propose a new rule-based design called i3 + 3, which is based on simple but more advanced rules that account for the variabilities in the observed data. We compare the operating characteristics for the proposed i3 + 3 design with other popular phase I designs by simulation. The i3 + 3 design is far superior than the 3 + 3 design in trial safety and the ability to identify the true MTD. Compared with model-based phase I designs, i3 + 3 also demonstrates comparable performances.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA