SummaryPharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.

Highlights d NK cells drive broad inflammatory remodeling characteristic of T-cell-inflamed tumors d PGE2 acting on EP2 and EP4 on NK cells prevents the TME switch enabling immune escape d Opposing inflammatory profiles found in many human cancer types have prognostic value d A signature capturing pro-and anti-tumor factors predicts response to immunotherapy

New results are presented for Ps(1s) scattering by H(1s), He(1 1 S) and Li(2s). Calculations have been performed in a coupled state framework, usually employing pseudostates, and allowing for excitation of both the Ps and the atom. In the Ps(1s)-H(1s) calculations the H − formation channel has also been included using a highly accurate H − wave function. Resonances resulting from unstable states in which the positron orbits H − have been calculated and analysed. The new Ps(1s)-He(1 1 S) calculations still fail to resolve existing discrepancies between theory and experiment at very low energies. The possible importance of the Ps − formation channel in all three collision systems is discussed.

Introduction: SCLC accounts for approximately 250,000 deaths worldwide each year. Acquisition of adequate tumor biopsy samples is challenging, and liquid biopsies present an alternative option for patient stratification and response monitoring. Methods: We applied whole genome next-generation sequencing to circulating free DNA (cfDNA) from 39 patients with limited-stage (LS) SCLC and 30 patients with extensive-stage SCLC to establish genome-wide copy number aberrations and also performed targeted mutation analysis of 110 SCLC associated genes. Quantitative metrics were calculated for copy number aberrations, including percent genome amplified (PGA [the percentage of genomic regions amplified]), Z-score (a measure of standard deviation), and Moran's I (a measure of spatial autocorrelation). In addition CellSearch, an epitopedependent enrichment platform, was used to enumerate circulating tumor cells (CTCs) from a parallel blood sample. Results: Genome-wide and targeted cfDNA sequencing data identified tumor-related changes in 94% of patients with LS SCLC and 100% of patients with extensive-stage SCLC. Parallel analysis of CTCs based on at least 1 CTC/7.5 mL of blood increased tumor detection frequencies to 95% for LS SCLC. Both CTC counts and cfDNA readouts correlated with disease stage and overall survival. Conclusions: We demonstrate that a simple cfDNA genomewide copy number approach provides an effective means of monitoring patients through treatment and show that targeted cfDNA sequencing identifies potential therapeutic targets in more than 50% of patients. We are now incorporating this approach into additional studies and trials of targeted therapies.

Serial biopsy of pancreatic ductal adenocarcinoma (PDAC), to chart tumour evolution presents a significant challenge. We examined the utility of circulating free DNA (cfDNA) as a minimally invasive approach across a cohort of 55 treatment-naïve patients with PDAC; 31 with metastatic and 24 with locally advanced disease. Somatic mutations in cfDNA were detected using next generation sequencing in 15/24 (62.5%) and 27/31 (87%) of patients with locally advanced and metastatic disease, respectively. Copy number changes were detected in cfDNA of 10 patients of whom 7 exhibited gain of chromosome 12p harbouring KRAS as well as a canonical KRAS codon 12 mutation. In multivariable Cox Regression analysis, we show for the first time that patients with KRAS copy number gain and KRAS mutation have significantly worse outcomes, suggesting that this may be linked to PDAC progression. The simple cfDNA assay we describe will enable determination of the presence of KRAS copy number gain and KRAS mutations in larger studies and clinical trials.

In this paper, we discuss the possibility of using x-ray Compton scattering as a probe of the outer electronic structure of ions immersed in warm dense matter. It is proposed that the x-ray free-electron lasers currently under construction will provide an ideal tool for this, with the main pulse being used to create a uniform well-defined sample and the third harmonic providing a clean monochromatic probe. We model the plasma photon scatter spectrum by combining self-consistent finite-temperature electronic structure calculations with molecular dynamics simulations of the ion-ion structure factor. In particular, we present bound-free Compton profiles that are more accurate that those obtained using form factor or impulse approximations.

Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.

It has been suggested (Gribakin et al 1999 Aust. J. Phys. 52 443-57, Flambaum et al 2002 Phys. Rev. A 66 012713) that strongly enhanced lowenergy electron recombination observed in Au 25+ (Hoffknecht et al 1998 J. Phys. B: At. Mol. Opt. Phys. 31 2415-28) is mediated by complex multiply excited states, while simple dielectronic excitations play the role of doorway states for the electron capture process. We present the results of an extensive study of configuration mixing between doubly excited (doorway) states and multiply excited states which account for the large electron recombination rate on Au 25+. A detailed analysis of spectral statistics and statistics of eigenstate components shows that the dielectronic doorway states are virtually 'dissolved' in complicated chaotic multiply excited eigenstates. This work provides a justification for the use of statistical theory to calculate the recombination rates of Au 25+ and similar complex multiply charged ions. We also investigate approaches which allow one to study complex chaotic many-body eigenstates and criteria of strong configuration mixing, without diagonalizing large Hamiltonian matrices.