Next-to-leading order strong interaction corrections to the Delta F=2 effective Hamiltonian in the MSSM

We compute the next-to-leading order strong interaction corrections to gluino-mediated Delta F=2 box diagrams in the Minimal Supersymmetric Standard Model. These corrections are given by two loop diagrams which we have calculated in three different regularization schemes in the mass insertion approximation. We obtain the next-to-leading order Wilson coefficients of the Delta F=2 effective Hamiltonian relevant for neutral meson mixings. We find that the matching scale uncertainty is largely reduced at the next-to-leading order, typically from about 10-15% to few percent.Comment: 26 pages, 8 figure

Giant lysosomes as a chemotherapy resistance mechanism in hepatocellular carcinoma cells

Despite continuous improvements in therapeutic protocols, cancer-related mortality is still one of the main problems facing public health. The main cause of treatment failure is multi-drug resistance (MDR: simultaneous insensitivity to different anticancer agents), the underlying molecular and biological mechanisms of which include the activity of ATP binding cassette (ABC) proteins and drug compartmentalisation in cell organelles. We investigated the expression of the main ABC proteins and the role of cytoplasmic vacuoles in the MDR of six hepatocellular carcinoma (HCC) cell lines, and confirmed the accumulation of the yellow anticancer drug sunitinib in giant (four lines) and small cytoplasmic vacuoles of lysosomal origin (two lines). ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes. MTT assays showed that the cell lines with giant lysosomes were more resistant to sorafenib treatment than those with small lysosomes (p,0.01), and that verapamil incubation can revert this resistance, especially if it is administered after drug pre-incubation. The findings of this study demonstrate the involvement of PGP-positive lysosomes in drug sequestration and MDR in HCC cell lines. The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment

The contribution of microlensing surveys to the distance scale

In the early nineties several teams started large scale systematic surveys of the Magellanic Clouds and the Galactic Bulge to search for microlensing effects. As a by product, these groups have created enormous time-series databases of photometric measurements of stars with a temporal sampling duration and accuracy which are unprecedented. They provide the opportunity to test the accuracy of primary distance indicators, such as Cepheids, RRLyrae stars, the detached eclipsing binaries, or the luminosity of the red clump. We will review the contribution of the microlensing surveys to the understanding of the physics of the primary distance indicators, recent differential studies and direct distance determinations to the Magellanic Clouds and the Galactic Bulge.Comment: Invited review article to appear in: `Post-Hipparcos Cosmic Candles', A. Heck & F. Caputo (Eds), Kluwer Academic Publ., Dordrecht, in press. 21 pages; uses Kluwer's crckapb.sty LaTeX style file, enclose

miR-494-3p is a novel tumor driver of lung carcinogenesis

Lung cancer is the leading cause of tumor-related death worldwide and more efforts are needed to elucidate lung carcinogenesis. Here we investigated the expression of 641 miRNAs in lung tumorigenesis in a K-Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model and 113 human tumors. The conserved miRNA cluster on chromosome 12qF1 was significantly and progressively upregulated during murine lung carcinogenesis. In particular, miR-494-3p expression was correlated with lung cancer progression in mice and with worse survival in lung cancer patients. Mechanistically, ectopic expression of miR-494-3p in A549 lung cancer cells boosted the tumor-initiating population, enhanced cancer cell motility, and increased the expression of stem cell-related genes. Importantly, miR-494-3p improved the ability of A549 cells to grow and metastasize in vivo, modulating NOTCH1 and PTEN/PI3K/AKT signaling.Overall, these data identify miR-494-3p as a key factor in lung cancer onset and progression and possible therapeutic target

Evidence of Distinct Tumour-Propagating Cell Populations with Different Properties in Primary Human Hepatocellular Carcinoma

Increasing evidence that a number of malignancies are characterised by tumour cell heterogeneity has recently been published, but there is still a lack of data concerning liver cancers. The aim of this study was to investigate and characterise tumour-propagating cell (TPC) compartments within human hepatocellular carcinoma (HCC).After long-term culture, we identified three morphologically different tumour cell populations in a single HCC specimen, and extensively characterised them by means of flow cytometry, fluorescence microscopy, karyotyping and microarray analyses, single cell cloning, and xenotransplantation in NOD/SCID/IL2Rγ/⁻ mice.The primary cell populations (hcc-1, -2 and -3) and two clones generated by means of limiting dilutions from hcc-1 (clone-1/7 and -1/8) differently expressed a number of tumour-associated stem cell markers, including EpCAM, CD49f, CD44, CD133, CD56, Thy-1, ALDH and CK19, and also showed different doubling times, drug resistance and tumorigenic potential. Moreover, we found that ALDH expression, in combination with CD44 or Thy-1 negativity or CD56 positivity identified subpopulations with a higher clonogenic potential within hcc-1, hcc-2 and hcc-3 primary cell populations, respectively. Karyotyping revealed the clonal evolution of the cell populations and clones within the primary tumour. Importantly, the primary tumour cell population with the greatest tumorigenic potential and drug resistance showed more chromosomal alterations than the others and contained clones with epithelial and mesenchymal features.Individual HCCs can harbor different self-renewing tumorigenic cell types expressing a variety of morphological and phenotypical markers, karyotypic evolution and different gene expression profiles. This suggests that the models of hepatic carcinogenesis should take into account TPC heterogeneity due to intratumour clonal evolution

Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells

Inflammatory bowel disease (IBD) pathogenesis has been linked to the aberrant activation of the Gut-associated lymphoid tissues against components of the intestinal microbiota. Although the contribution of CD4+ T helper cells to inflammatory processes is being increasingly acknowledged, the functional engagement of human invariant natural killer T (iNKT) cells is still poorly defined. Here, we evaluated the functional characteristics of intestinal iNKT cells during IBD pathogenesis and to exploit the role of mucosa-associated microbiota recognition in triggering iNKT cells' pro-inflammatory responses in vivo. Lamina propria iNKT cells, isolated from surgical specimens of active ulcerative colitis and Crohn's disease patients and non-IBD donors, were phenotypically and functionally analyzed ex vivo, and stable cell lines and clones were generated for in vitro functional assays. iNKT cells expressing a pro-inflammatory cytokine profile were enriched in the lamina propria of IBD patients, and their exposure to the mucosa-associated microbiota drives pro-inflammatory activation, inducing direct pathogenic activities against the epithelial barrier integrity. These observations suggest that iNKT cell pro-inflammatory functions may contribute to the fuelling of intestinal inflammation in IBD patients

Pathogenicity of in-vivo generated intestinal Th17 lymphocytes is IFNγ dependent

Th17 cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of IL17A, the Th17 signature cytokine, yielded negative results in patients with Crohn's disease (CD), and attempts to elucidate the determinants of Th17 cells pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells

Utilizzo delle mappe ADC nella valutazione non invasiva dello stato di mutazione dell\u2019IDH in gliomi di alto grado.

Testo dell'abstract Scopo La nuova classificazione dei tumori cerebrali (2016 WHO) distingue i gliomi diffusi in base alle caratteristiche molecolari dell\u2019isocitrato deidrogenasi (IDH) in IDH mutati, IDH wild type e non altrimenti specificati. La valutazione dello stato di mutazione dell\u2019IDH ha implicazioni diagnostiche, prognostiche e terapeutiche. Lo scopo di questo studio \ue8 valutare se l\u2019analisi quantitativa delle mappe ADC possa predire in modo non invasivo lo stato di mutazione dell\u2019IDH. Materiale e metodi Sono state esaminate retrospettivamente RM e mappe ADC di 28 pazienti (11 F, 17 M) con diagnosi istologica di glioma diffuso di alto grado (G-III, G-IV WHO) e valutazione dello stato di mutazione dell\u2019IDH1 (18 MUT, 10 WT). Gli esami sono stati condotti su apparecchio RM 1,5 T. Le mappe ADC sono state elaborate e co-registrate con le immagini T2w e T1 post mdc in modo da posizionare le ROI sulle componenti solide della lesione, evitando le componenti emorragica, cistica o necrotica. Sono state posizionate 4-5 ROI per ogni tumore e calcolati i valori medi di ADC (ADCmean) scegliendo tra i valori pi\uf9 bassi per ogni Paziente. La comparazione dei valori ADCmean tra IDH-MUT e IDH-WT \ue8 stata condotta utilizzando il \u201ct\u201d test di Student, considerando statisticamente significativo un valore di p<0. Risultati I valori ADCmean nei pazienti IDH-WT (0,86x10-3mm2 /s)(+/- 0,06) sono risultati pi\uf9 bassi rispetto a quelli dei pazienti IDH-MUT (1,24x10-3mm2 /s)(+/- 0,19) con differenza tra i due gruppi significativa per p<0,01. Il valore minimo di ADC =1,01 x10-3mm2 /s pu\uf2 essere considerato come\u201ccut-off \u201cper differenziare lo stato di mutazione. Conclusioni L\u2019aggiunta di dati quantitativi come la valutazione dell\u2019ADC all\u2019imaging RM convenzionale potrebbe essere utilizzata di routine come marker non-invasivo di pattern molecolari specifici