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\"Lucky thinks he's an ordinary Human boy. But one night, he dreams that the stars are singing - and wakes to find an uncontrollable power rising inside him. Now he's on the run, racing through space, searching for answers. In a galaxy at war, where Humans and Aliens are deadly enemies, the only people who can help him are an Alien starship crew - and an Alien warrior girl, with neon needles in her hair. Together, they must find a way to save the galaxy. For Lucky is not the only one in danger. His destiny and the fate of the universe are connected in the most explosive way\"--Publisher information.

Key Points Increased levels of circulating nucleic acids (DNA, mRNA and microRNA (miRNA)) in the blood reflect pathological processes, including malignant and benign lesions, inflammatory diseases, stroke, trauma and sepsis. During these processes nucleic acids are shed into the blood by apoptotic and necrotic cells. In cancer patients, circulating DNA carries tumour-related genetic and epigenetic alterations that are relevant to cancer development, progression and resistance to therapy. These alterations include loss of heterozygosity (LOH) and mutations of tumour suppressor genes (such as TP53 ) and oncogenes (such as KRAS and BRAF ). Additional genetic alterations that are detectable on circulating DNA and used as biomarkers in cancer include the integrity of non-coding genomic DNA repeat sequences (such as ALU and LINE1 ). Although still in their infancy, DNA integrity assays have the potential to become a universal blood biomarker for multiple cancers. Epigenetic alterations in genes (such as glutathione S -transferase P1 ( GSTP1 and septin 9 ( SEPT9 )) and adenomatous polyposis coli ( APC )) that are relevant to tumorigenesis and the progression of solid tumours have been detected on circulating DNA in cancer patients, and their potential clinical utility is indicated by the launch of commercial tests for cancer screening. The detection of circulating nucleosomes in blood indicates that cell-free DNA (cfDNA) retains at least some features of the nuclear chromatin during the process of DNA release. Initial clinical studies have indicated that monitoring the abundance of nucleosomes has potential utility for monitoring the efficacy of therapy in cancer patients. Dying tumour cells also discharge miRNAs, which circulate stably in the blood. The pivotal functions of miRNAs in cancer development and progression may explain the promising results of pilot studies on cancer patients using miRNA blood tests for tumour detection and prognosis. The cellular source of tumour-derived circulating nucleic acids is still subject to debate. After complete removal of the primary tumour the detection of cfDNA may signal the presence of micrometastatic cells in distant organs, such as the bone marrow, which pose a risk of relapse. Metastatic and primary tumours from the same patient can vary at the genomic, epigenomic and transcriptomic levels. Minimally invasive blood analyses of cell-free nucleic acid allow repetitive real-time monitoring of these events and will, therefore, gain clinical utility in the determination of prognosis and treatment efficacy. DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. This Review discusses the potential clinical utility of cell-free nucleic acids as blood biomarkers. DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.

Next-generation sequencing of cell-free circulating solid tumor DNA addresses two challenges in contemporary cancer care. First this method of massively parallel and deep sequencing enables assessment of a comprehensive panel of genomic targets from a single sample, and second, it obviates the need for repeat invasive tissue biopsies. Digital Sequencing™ is a novel method for high-quality sequencing of circulating tumor DNA simultaneously across a comprehensive panel of over 50 cancer-related genes with a simple blood test. Here we report the analytic and clinical validation of the gene panel. Analytic sensitivity down to 0.1% mutant allele fraction is demonstrated via serial dilution studies of known samples. Near-perfect analytic specificity (> 99.9999%) enables complete coverage of many genes without the false positives typically seen with traditional sequencing assays at mutant allele frequencies or fractions below 5%. We compared digital sequencing of plasma-derived cell-free DNA to tissue-based sequencing on 165 consecutive matched samples from five outside centers in patients with stage III-IV solid tumor cancers. Clinical sensitivity of plasma-derived NGS was 85.0%, comparable to 80.7% sensitivity for tissue. The assay success rate on 1,000 consecutive samples in clinical practice was 99.8%. Digital sequencing of plasma-derived DNA is indicated in advanced cancer patients to prevent repeated invasive biopsies when the initial biopsy is inadequate, unobtainable for genomic testing, or uninformative, or when the patient's cancer has progressed despite treatment. Its clinical utility is derived from reduction in the costs, complications and delays associated with invasive tissue biopsies for genomic testing.

The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC. Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.

When Spider-Man gets himself a cool new black-and-white costume, that ol' Parker luck must finally be turning, right? Wrong! In the ultimate fashion nightmare, the costume is alive - and it doesn't want to come off! If Peter can somehow get out of the black and back into the red-and-blues, the poor shunned symbiote will bear a grudge - and when it finds Eddie Brock, who is no fan of Spider-Man himself, the terrifying Venom is born! He's destined to be the wall-crawler's deadliest villain. But if that doesn't work out, he'll be Spidey's sidekick instead! It's hard to work out which is worse! Plus, a rivalry for the ages is born when the Venom symbiote bonds with ... Peter's best pal, Harry Osborn!

MicroRNAs (miRs) are a class of small noncoding RNAs whose expression changes have been associated with cancer development and progression. Current techniques to isolate miRs for expression analysis from blood are inefficient. We developed a reverse-transcription quantitative real-time PCR (RT-qPCR) assay for direct detection of circulating miRs in serum. We hypothesized that serum concentrations of miR-21, a biomarker increased in breast tumors, would correlate with the presence and extent of breast cancer. The RT-qPCR applied directly in serum (RT-qPCR-DS) assay for circulating miR-21 was tested in sera from 102 patients with different stages of breast cancer and 20 healthy female donors. The assay was sensitive for detection of miR-21 in 0.625 μL of serum from breast cancer patients. For differentiation of samples from patients with locoregional breast cancer from those from healthy donors, the odds ratio was 1.796 and the area under the curve was 0.721. In a multivariate analysis that included standard clinicopathologic prognostic factors, high circulating miR-21 concentrations correlated significantly (P < 0.001) with visceral metastasis. A novel RT-qPCR-DS can improve the efficiency of miR assessment. Use of this assay to detect circulating miR-21 has diagnostic and prognostic potential in breast cancer.

An anthology of top-selected sports writing from the past year is culled from hundreds of national, regional, and specialty publications as well as a variety of leading sports blogs.

The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1–STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy.