Investigating the Concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis

To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa-like and CMS classification with overall survival. Fifty-one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal-like, based on the CMS and the TGFBa-like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell-intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC

Detection of erbB2 copy number variations in plasma of patients with esophageal carcinoma

<p>Abstract</p> <p>Background</p> <p>Mortality is high in patients with esophageal carcinoma as tumors are rarely detected before the disease has progressed to an advanced stage. Here, we sought to isolate cell-free DNA released into the plasma of patients with esophageal carcinoma, to analyze copy number variations of marker genes in the search for early detection of tumor progression.</p> <p>Methods</p> <p>Plasma of 41 patients with esophageal carcinoma was prospectively collected before tumor resection and chemotherapy. Our dataset resulted heterogeneous for clinical data, resembling the characteristics of the tumor. DNA from the plasma was extracted to analyze copy number variations of the <it>erbB2 </it>gene using real-time PCR assays.</p> <p>Results</p> <p>The real-time PCR assays for <it>erbB2 </it>gene showed significant (<it>P </it>= 0.001) copy number variations in the plasma of patients with esophageal carcinoma, as compared to healthy controls with high sensitivity (80%) and specificity (95%). These variations in <it>erbB2 </it>were negatively correlated to the progression free survival of these patients (<it>P </it>= 0.03), and revealed a further risk category stratification of patients with low VEGF expression levels.</p> <p>Conclusion</p> <p>The copy number variation of <it>erbB2 </it>gene from plasma can be used as prognostic marker for early detection of patients at risk of worse clinical outcome in esophageal cancer.</p

L'olivicoltura in Italia tra localizzazione produttiva e tendenze evolutive. Alcune indicazioni di policy

This paper proposes a descriptive analysis of the structural features of olive cultivations and olive oil production in Italy, through a longitudinal approach. The time period analyzed is mostly 1990-2010. The work is based on the integration of selected statistical data with the number of agricultural holdings which have olive trees, their agricultural surfaces, the estimated production, the quality productions and the recourse to organic farming. The territorial detail is regional, with additional details by province. The main purpose is verifying the level of production concentration in few regions, its development along time and the role played by geographical location as regards recent trends. The work also develops some policy reflections in the light of the problems arising from the recent reform of the Common Agricultural Policy (CAP). Data derive from the integration of various sources: agricultural censuses, farm structure sampling surveys, crop statistics, administrative data, household budget surveys. Some estimations were needed as regards olive oil production. Amounts, longitudinal changes and specific ratio indicators have been calculated at regional level. The whole analysis is based on official statistics data and start from 1980, since before 1980 different definitions and concepts were adopted in the framework of agricultural censuses. The main results show the persistence of strong localization of olive oil production among few Southern regions, the late development of quality and organic farming productions spread among Central and Southern Italy and the steadiness of household olive oil consumption along time, with slight differences among regions. Some of the main outcomes are the following: a) since 1990 the number of agricultural holdings and their utilized agricultural area has sharply decreased, while the decrease of holdings with olive trees has been very much slower and their agricultural area has increased; b) as regards olive cultivations, the percentage of micro-holdings (less than one hectare) increased along time; c) the degree of concentration of olive oil production in Southern regions did not decrease along time, and also yields remained steady; d) quality olive oil productions are becoming more and more relevant in Southern regions, while organic farming cultivations characterize some regions located in Central Italy

Bevacizumab plus chemotherapy as salvage treatment in chemorefractory patients with metastatic colorectal cancer.

Taking into account the retrospective nature of the study which can influence the selection of patients, bevacizumab given in advanced lines after failure of conventional chemotherapy and antiepidermal growth factor receptor agents can result in high disease control rates in patients with mCRC

The Direct Interaction between Two Morphogenetic Proteins Is Essential for Spore Coat Formation in Bacillus subtilis

In Bacillus subtilis the protective layers that surround the mature spore are formed by over seventy different proteins. Some of those proteins have a regulatory role on the assembly of other coat proteins and are referred to as morphogenetic factors. CotE is a major morphogenetic factor, known to form a ring around the forming spore and organize the deposition of the outer surface layers. CotH is a CotE-dependent protein known to control the assembly of at least nine other coat proteins. We report that CotH also controls the assembly of CotE and that this mutual dependency is due to a direct interaction between the two proteins. The C-terminal end of CotE is essential for this direct interaction and CotH cannot bind to mutant CotE deleted of six or nine C-terminal amino acids. However, addition of a negatively charged amino acid to those deleted versions of CotE rescues the interaction

DETECTION OF BIOLOGICAL PROFILE OF CUTANEOUS MALIGNANT MELANOMA: A ROLE FOR CAF-1/P60 PROTEIN AND STEM-CELL MARKER CD133 EXPRESSION?

Cutaneous melanoma (CM) is the most lethal skin malignancy, with a constant increase in incidence. These tumors show a biological behavior unpredictable by the classical parameters Moreover, conventional therapies are ineffective to treat advanced stage case. Therefore, the identification of molecular alterations involved in their biological aggressiveness represents a major challenge for researchers. Accumulating evidence supports the involvement of cancer stem cells (CSC) in initiation, progression, chemoresistance and therapeutic failure of malignant melanoma, and the aggressive subsets of melanoma cells have been frequently associated with molecular markers shared by stem cells

Mechanisms of soluble beta-amyloid impairment of endothelial function

Alzheimer's disease ( AD) has been recently associated with vascular risk factors. beta-amyloid peptides (AbetaP), the main component of senile plaques typical of AD, circulate in soluble globular form in bloodstream. Interestingly, AbetaP is able to induce endothelial dysfunction, and this effect may represent the link between vascular and neuronal pathophysiological factors involved in AD. We aimed to clarify the molecular mechanisms underlying globular AbetaP-induced vascular toxicity. Using several methodological approaches, we have observed that in vascular tissues globular AbetaP is unable to induce oxidative stress, one of the mechanisms hypothesized involved in beta-amyloid toxicity. More important, we have demonstrated that globular AbetaP is able to localize on vascular endothelium, where it inhibits eNOS enzymatic activity. In particular, AbetaP enhances eNOS phosphorylation on threonine 495 and serine 116 and reduces acetylcholine-induced phosphorylation on serine 1177. Such an effect depends on a PKC signaling pathway, as suggested by its phosphorylation on serine 660. In fact, selective inhibition of the calcium-dependent group of PKC is able to rescue beta-amyloid-induced alteration of eNOS phosphorylation, NO production, and endothelial vasorelaxation. The activation of these Ca2+-dependent pathways is probably due to the ability of AbetaP to evoke Ca2+ leakage from inositol 1,4,5-triphosphate receptors on endoplasmic reticulum. Our data demonstrate that globular AbetaP-induced endothelial NO dysfunction can be attributed to an alteration of intracellular Ca2+ homeostasis, which could lead to the activation of calcium-dependent group of PKC with a consequent change of the eNOS phosphorylation pattern. These mechanisms could contribute to shed further light on the toxic effect of beta-amyloid in vascular tissues