YD383、YD439对JAK-STAT6信号传导通路作用的特异性研究

目的:探讨化合物YD383和YD439对STAT6信号传导通路的作用是否具有特异性.方法:通过瞬时转染的方法将分别依赖于STAT1和STAT6活性的带有荧光素酶报告基因的质粒转染至HeLa细胞株,两种细胞株在各自相应的细胞因子(IFN-γ或IL-4)刺激下激活JAK-STAT1或JAK-STAT6信号传导通路.通过测定荧光素酶的活性来评价细胞株在化合物存在的情况下报告基因的表达.结果:YD383和YD439均能降低相应细胞因子刺激引起的报告基因的表达,并且具有剂量依赖性.随着化合物剂量的增加,报告基因的表达降低(P＜0.05).但化合物引起的两种转染细胞报告基因表达降低的差异比较无统计学意义(P＞0.05).结论:两种化合物对JAK-STAT1和JAK-STAT6信号传导通路均有抑制作用,对JAK-STAT6通路的抑制不具有特异性.     

Effects of an Amino Acid-Based Formula Supplemented with Two Human Milk Oligosaccharides on Growth,Tolerability, Safety,and Gut Microbiome in Infants with Cow’s Milk Protein Allergy

This open-label, non-randomized, multicenter trial (Registration: {"type":"clinical-trial","attrs":{"text":"NCT 03661736","term_id":"NCT03661736"}}NCT 03661736) aimed to assess if an amino acid-based formula (AAF) supplemented with two human milk oligosaccharides (HMO) supports normal growth and is well tolerated in infants with a cow’s milk protein allergy (CMPA). Term infants aged 1–8 months with moderate-to-severe CMPA were enrolled. The study formula was an AAF supplemented with 2′-fucosyllactose (2′-FL) and lacto-N-neotetraose (LNnT). Infants were fed the study formula for 4 months and were offered to remain on the formula until 12 months of age. Tolerance and safety were assessed throughout the trial. Out of 32 infants (mean age 18.6 weeks; 20 (62.5%) male), 29 completed the trial. During the 4-month principal study period, the mean weight-for-age Z score (WAZ) increased from –0.31 at the baseline to +0.28 at the 4-months’ follow-up. Linear and head growth also progressed along the WHO child growth reference, with a similar small upward trend. The formula was well tolerated and had an excellent safety profile. When comparing the microbiome at the baseline to the subsequent visits, there was a significant on-treatment enrichment in HMO-utilizing bifidobacteria, which was associated with a significant increase in fecal short-chain fatty acids. In addition, we observed a significant reduction in the abundance of fecal Proteobacteria, suggesting that the HMO-supplemented study formula partially corrected the gut microbial dysbiosis in infants with CMPA.     

Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy

Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). Methods: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. Results: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal. Conclusion: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.     

Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer

Background To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.Methods Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.Results Two patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete ‘punctate’ areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high ‘punctate’ IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.Conclusions These results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.Subject terms: Prognostic markers, Colorectal cancer     

microRNA调控NK细胞KIR3DL1表达初探

目的初步探寻人外周血自然杀伤细胞（Nature Killer,NK）杀伤细胞免疫球蛋白样受体（Killer Cell Immnoglobulin-Like Receptor,KIR3DL1）表达可能存在的microRNA（miR）调控机制。方法利用生物信息学方法,从miR信息库中筛选出可能与KIR3DL1相关的miRs,构建含KIR3DL1 3’非翻译区（UTR）的PGL3质粒,分别将含相应miR的PcDNA3.0质粒与前者共转染293T细胞,通过荧光素酶报告实验及之后的突变实验筛选出可能调控KIR3DL1的miR。结果通过TARGET SCAN信息库筛选了miR-146b等10个miR;转染miR-146b后,荧光素酶活性下降最多（61.3%）,突变其KIR3DL1 3’UTR靶位点后荧光素酶活性恢复（91.4%）。结论 miR-146b可与KIR3DL1’UTR在靶位点特异结合,很可能参与KIR3DL1表达的调控。     

Important Considerations for Recruiting Women to Cancer Genetics Studies in Puerto Rico

A goal of the Minority Institution/Cancer Center Partnership between the Ponce School of Medicine in Puerto Rico and the H. Lee Moffitt Cancer Center & Research Institute in Florida is to provide cross-cultural training in cancer research. This is achieved through a collaborative summer exchange program, which provides US students with an opportunity to conduct research in Puerto Rico. As part of this program, students recruited participants and collected data for a study to enhance the understanding of sociocultural factors among Puerto Rican women regarding genetic testing for hereditary breast/ovarian cancer. Limited studies have examined cancer genetics issues among Latinos, particularly those specific to the various Latino subgroups, such as Puerto Ricans. As a result of the student training experience, culturally appropriate strategies for the recruitment of women in Puerto Rico have been identified. These recommendations can inform the design of cancer research projects and interventions targeting the Puerto Rican population.     

The Utility of a Composite Biological Endpoint in HIV/STI Prevention Trials

A human immunodeficiency virus (HIV) as a biological endpoint in HIV prevention trials may not be feasible, so investigators have used surrogate biological outcomes. In a multisite trial, the epidemiology of STIs may be different across sites and preclude using one STI as the outcome. This study explored using a composite STI outcome to address that problem. The combined biological endpoint was the incidence of any of six new STIs (chlamydia, gonorrhea, trichomonas (women only), syphilis, herpes simplex virus type 2 infection and HIV) during a 24-month follow up period. We investigated how a composite STI outcome would perform compared to single and dual STI outcomes under various conditions. We simulated outcomes for four populations that represented a wide range of sex and age distributions, and STI prevalences. The simulations demonstrated that a combined biologic outcome was superior to single and dual STI outcomes in assessing intervention effects in 82 % of the cases. A composite biological outcome was effective in detecting intervention effects and might allow more investigations to incorporate multiple biological outcomes in the assessment of behavioral intervention trials for HIV prevention.