Identification of Alternatively-Activated Pathways between Primary Breast Cancer and Liver Metastatic Cancer Using Microarray Data

Alternatively-activated pathways have been observed in biological experiments in cancer studies, but the concept had not been fully explored in computational cancer system biology. Therefore, an alternatively-activated pathway identification method was proposed and applied to primary breast cancer and breast cancer liver metastasis research using microarray data. Interestingly, the results show that cytokine-cytokine receptor interaction and calcium signaling were significantly enriched under both conditions. TGF beta signaling was found to be the hub in network topology analysis. In total, three types of alternatively-activated pathways were recognized. In the cytokine-cytokine receptor interaction pathway, four active alteration patterns in gene pairs were noticed. Thirteen cytokine-cytokine receptor pairs with inverse activity changes of both genes were verified by the literature. The second type was that some sub-pathways were active under only one condition. For the third type, nodes were significantly active in both conditions, but with different active genes. In the calcium signaling and TGF beta signaling pathways, node E2F5 and E2F4 were significantly active in primary breast cancer and metastasis, respectively. Overall, our study demonstrated the first time using microarray data to identify alternatively-activated pathways in breast cancer liver metastasis. The results showed that the proposed method was valid and effective, which could be helpful for future research for understanding the mechanism of breast cancer metastasis

P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim

Erythropoietin (EPO) stimulates erythropoiesis and is commonly used to treat anemia. Here Hu et al. find that P38α/JNK signaling restrains erythropoiesis independently of EPO by regulating epigenetic silencing of the proapoptotic protein Bim, and thus identify putative targets for the treatment of anemic disorders resistant to EPO

P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim

While erythropoietin (EPO) constitutes the major treatment for anemia, a range of anemic disorders remain resistant to EPO treatment. The need for alternative therapeutic strategies requires the identification of mechanisms that physiologically restrain erythropoiesis. Here we show that P38α restrains erythropoiesis in mouse and human erythroblasts independently of EPO by integrating apoptotic signals during recovery from anemia. P38α deficiency promotes JNK activation through increased expression of Map3k4 via a negative feedback mechanism. JNK prevents Cdk1-mediated phosphorylation and subsequent degradation by Smurf2 of the epigenetic silencer Ezh2. Stabilized Ezh2 silences Bim expression and protects erythroblasts from apoptosis. Thus, we identify P38α/JNK signaling as a molecular brake modulating erythropoiesis through epigenetic silencing of Bim. We propose that inhibition of P38α, by enhancing erythropoiesis in an EPO-independent fashion, may provide an alternative strategy for the treatment of anemia

Untargeted Metabolomics and Body Mass in Adolescents: A Cross-Sectional and Longitudinal Analysis

Obesity in children and adolescents has increased globally. Increased body mass index (BMI) during adolescence carries significant long-term adverse health outcomes, including chronic diseases such as cardiovascular disease, stroke, diabetes, and cancer. Little is known about the metabolic consequences of changes in BMI in adolescents outside of typical clinical parameters. Here, we used untargeted metabolomics to assess changing BMI in male adolescents. Untargeted metabolomic profiling was performed on urine samples from 360 adolescents using UPLC–QTOF-MS. The study includes a baseline of 235 subjects in a discovery set and 125 subjects in a validation set. Of them, a follow-up of 81 subjects (1 year later) as a replication set was studied. Linear regression analysis models were used to estimate the associations of metabolic features with BMI z-score in the discovery and validation sets, after adjusting for age, race, and total energy intake (kcal) at false-discovery-rate correction (FDR) ≤ 0.1. We identified 221 and 16 significant metabolic features in the discovery and in the validation set, respectively. The metabolites associated with BMI z-score in validation sets are glycylproline, citrulline, 4-vinylsyringol, 3′-sialyllactose, estrone sulfate, carnosine, formiminoglutamic acid, 4-hydroxyproline, hydroxyprolyl-asparagine, 2-hexenoylcarnitine, L-glutamine, inosine, N-(2-Hydroxyphenyl) acetamide glucuronide, and galactosylhydroxylysine. Of those 16 features, 9 significant metabolic features were associated with a positive change in BMI in the replication set 1 year later. Histidine and arginine metabolism were the most affected metabolic pathways. Our findings suggest that obesity and its metabolic outcomes in the urine metabolome of children are linked to altered amino acids, lipid, and carbohydrate metabolism. These identified metabolites may serve as biomarkers and aid in the investigation of obesity’s underlying pathological mechanisms. Whether these features are associated with the development of obesity, or a consequence of changing BMI, requires further study

The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress

International audienceLung cancer is the leading cause of cancer death worldwide, with poor prognosis and a high rate of recurrence despite early surgical removal. Hypoxic regions within tumors represent sources of aggressiveness and resistance to therapy. Although long non-coding RNAs (lncRNAs) are increasingly recognized as major gene expression regulators, their regulation and function following hypoxic stress are still largely unexplored. Combining profiling studies on early-stage lung adenocarcinoma (LUAD) biopsies and on A549 LUAD cell lines cultured in normoxic or hypoxic conditions, we identified a subset of lncRNAs that are both correlated with the hypoxic status of tumors and regulated by hypoxia in vitro. We focused on a new transcript, NLUCAT1, which is strongly upregulated by hypoxia in vitro and correlated with hypoxic markers and poor prognosis in LUADs. Full molecular characterization showed that NLUCAT1 is a large nuclear transcript composed of six exons and mainly regulated by NF-κB and NRF2 transcription factors. CRISPR-Cas9-mediated invalidation of NLUCAT1 revealed a decrease in proliferative and invasive properties, an increase in oxidative stress and a higher sensitivity to cisplatin-induced apoptosis. Transcriptome analysis of NLUCAT1-deficient cells showed repressed genes within the antioxidant and/or cisplatin-response networks. We demonstrated that the concomitant knockdown of four of these genes products, GPX2, GLRX, ALDH3A1, and PDK4, significantly increased ROS-dependent caspase activation, thus partially mimicking the consequences of NLUCAT1 inactivation in LUAD cells. Overall, we demonstrate that NLUCAT1 contributes to an aggressive phenotype in early-stage hypoxic tumors, suggesting it may represent a new potential therapeutic target in LUADs

Transplantation of mouse HSCs genetically modified to express a CD4-restricted TCR results in long-term immunity that destroys tumors and initiates spontaneous autoimmunity

The development of effective cancer immunotherapies has been consistently hampered by several factors, including an inability to instigate long-term effective functional antitumor immunity. This is particularly true for immunotherapies that focus on the adoptive transfer of activated or genetically modified mature CD8+ T cells. In this study, we sought to alter and enhance long-term host immunity by genetically modifying, then transplanting, mouse HSCs. We first cloned a previously identified tumor-reactive HLA-DR4–restricted CD4+ TCR specific for the melanocyte differentiation antigen tyrosinase-related protein 1 (Tyrp1), then constructed both a high-expression lentivirus vector and a TCR-transgenic mouse expressing the genes encoding this TCR. Using these tools, we demonstrated that both mouse and human HSCs established durable, high-efficiency TCR gene transfer following long-term transplantation into lethally irradiated mice transgenic for HLA-DR4. Recipients of genetically modified mouse HSCs developed spontaneous autoimmune vitiligo that was associated with the presence of a Th1-polarized memory effector CD4+ T cell population that expressed the Tyrp1-specific TCR. Most importantly, large numbers of CD4+ T cells expressing the Tyrp1-specific TCR were detected in secondary HLA-DR4–transgenic transplant recipients, and these mice were able to destroy subcutaneously administered melanoma cells without the aid of vaccination, immune modulation, or cytokine administration. These results demonstrate the creation of what we believe to be a novel translational model of durable lentiviral gene transfer that results in long-term effective immunity

Interactions between the microbiota and the immune system

The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health