Mean number of genomic aberrations (MNGA) per patient and age or smoking status in oral potentially malignant disordes (OPMDs) and oral squamous cell carcinomas (OSCCs) patients.

<p>The average number of aberrations per patient is represented as gray dots superimposed over boxes. These present a thick horizontal line indicating the median number per group, and delimitate the 25^th and 75^th percentile, while whiskers show the 95% confidence interval. A) average number of aberrations per patients’ age; B) average number of aberrations per patients’ smoking habit.</p

Patients’ tobacco consumption details (54 former and 76 current smokers).

<p>Patients’ tobacco consumption details (54 former and 76 current smokers).</p

Discovery of Novel and Selective SIRT6 Inhibitors

SIRT6 is an NAD⁺-dependent deacetylase with a role in the transcriptional control of metabolism and aging but also in genome stability and inflammation. Broad therapeutic applications are foreseen for SIRT6 inhibitors, including uses in diabetes, immune-mediated disorders, and cancer. Here we report on the identification of the first selective SIRT6 inhibitors by in silico screening. The most promising leads show micromolar IC₅₀s, have significant selectivity for SIRT6 versus SIRT1 and SIRT2, and are active in cells, as shown by increased acetylation at SIRT6 target lysines on histone 3, reduced TNF-α secretion, GLUT-1 upregulation, and increased glucose uptake. Taken together, these results show the value of these compounds as starting leads for the development of new SIRT6-targeting therapeutic agents

Additional file 3: of EIF2A-dependent translational arrest protects leukemia cells from the energetic stress induced by NAMPT inhibition

Effects of CHS-828 and chemotherapeutics on protein translation. A) Jurkat cells were treated for 48 h with or without (Mock) the indicated concentration of CHS-828. Caspase 3/7 activity was quantified (using 5 μM of Camptothecin for 4 h as a positive control of apoptosis) and relative ATP levels were determined and then normalized to the number of viable cells. The levels of total AMPK, p-AMPK, total EIF2A and p-EIF2A, total 4EBP1, p-4EBP1 were evaluated by WB. Histogram shows the densitometric analysis of p-AMPK and p-EIF2A (* indicates p-value <0.05). Mean and SD of a biological triplicate. B) Jurkat cells were treated with the indicated concentration of drugs for 48 h and cell viability was measured by Cell Titer Glo. Data are represented as mean and SD of three independent experiments. C) Click-it chemistry based on the incorporation of an aminoacid analog (AHA) was used to monitor protein synthesis. Jurkat cells were treated for 48 h with or without (Mock) the indicated concentration of FK866, Rapamycin (RAPA), Doxorubicin (DOXO), Cisplatin (CIS) and Dexamethasone (DEXA). The histogram quantifies the % of AHA positive cells (active protein-synthesizing cells) in the viable cell population. Flow-cytometry experiments were carried out on two biological replicates and statistics were based on acquisition of 20000 events/sample. D) Jurkat cells were treated as in C and the level of p-EIF2A and p-4EBP1 was evaluated. Histogram shows the densitometric analysis of p-EIF2A (* indicates p-value <0.05). Mean and SD of a biological triplicate. E) Primary B-CLL cells were treated for 48 h with or without 30 nM FK866 in the presence or absence of 1 mM NA. Histogram shows the densitometric analysis of p-AMPK/AMPK. (PDF 691 kb

Genomic spectrum of acquired driver alterations.

A) The circle graph represents for each case (n = 74) the proportion of driver mutations detected in primary and/or metastatic tumor samples. Outer numbers represent mutations of eBC, inner numbers represent mutations of mBC. B) Cumulative frequency of the difference (Δ) between number of mutations in metastatic vs. primary tumor samples (Δ vs. metastatic tumor; Δ > 0, number of driver mutations in the primary sample lower than in the metastatic sample. C) Non-linear relationship between the difference of driver mutations in metastasis/primary pair (Δ, x-axis), and DRFS hazard ratio of Schoenfeld residuals (y-axis). The analysis is adjusted for T/N status, Ki67, menopausal status and tumor grade. The solid line represents a penalized spline fit of the predicting variables, while the dashed lines show 95% confidence intervals. D) Functional analysis of Gene Ontology (GO) terms associated to cell cycle, DDR, epigenetic regulation, androgen receptor activity and WNT signaling pathway. The size of the dots is inversely proportional to the p values of estimated hazard ratio (x-axis) displayed in log10 scale. P values are reported in S5 Table.</p

<i>ESR1</i> enrichment in metastatic HR+ HER2- BC samples.

A) ESR1 gene sCNV in three representative cases. Each row represents a case, and each box indicates the log-ratio levels for matched primary and metastatic tumor specimens. Red square shows the exact ESR1 region. The red background highlights the amplification of the ESR1 gene. FISH-based validation of each ESR1 amplification is also shown (right panel). B) Recurrent genomic alterations in metastatic tumor specimens, and their association with different types of endocrine therapy (ET). ET is classified according to specific clinically relevant groups. Statistically significant associations are shown as stars (adjusted p-value = 0.1).</p

(Associations between gene alteration and ET, broad classes).

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