Inhibition of specific NF-κB activity contributes to the tumor suppressor function of 14-3-3σ in breast cancer

14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting.     

How dung beetles respond to a human‐modified variegated landscape in Mexican cloud forest: a study of biodiversity integrating ecological and biogeographical perspectives

Aim To analyse how the dung beetles (Scarabaeinae) respond to a modified, variegated landscape, taking into account the biogeographical peculiarities of the Mexican Transition Zone. Location This study covers cloud forest (CF) of the Sierra Norte de Puebla mountain range and part of the Sierra Madre Oriental mountain range (Mexico). Methods We applied proportional sampling based on the landscape variegation model with Scarabaeinae as the indicator group, and using two approaches: structural units (vegetation type) and spatial units (windows). We used two measures – richness and Shannon diversity – and applied multiplicative diversity partitioning to obtain independent alpha and beta diversities for the landscape, windows and vegetation types. We grouped species by biogeographical distribution pattern for the biogeographical analysis and by whether they were originally from CF. Results The transformation of CF into secondary forest, pastures and other types of vegetation increases the Scarabaeinae diversity of the landscape, in vegetation types and windows. This increase is the result of species arriving from the tropical lowlands. However, the original dung beetle community of the CF dominates at different scales in the number of species, abundance and biomass. With increasing habitat modification, beta diversity increases in the windows, and species with the Tropical Palaeoamerican distribution pattern increase in abundance in vegetation types and windows. Main conclusions The variegated character of the landscape explains well the distribution and diversity of this dung beetle community. The peculiar characteristics of the Mexican Transition Zone have an effect owing to the overlap of fauna with different biogeographical origins. The conversion of fragmented landscapes to variegated landscapes could be a conservation goal in human‐modified mountain landscapes. Sampling proportional to the area of different types of vegetation and the use of windows offer an alternative experimental design in variegated landscapes.     

Determinants of plant species invasions in an arid island: evidence from Socotra Island (Yemen)

Understanding the factors which affect the distribution of alien plants in arid islands is complicated by the complex and stochastic nature of the invasion process per se, the harsh environmental conditions, and the low number of researchers and sampling effort. We present the results of the most comprehensive inventory to date of alien vascular plant species occurring in Socotra Island, a global biodiversity hotspot just beginning to be developed. A floristic survey was conducted between 2006 and 2008 in 36 grid cells of 10?×?10?km. We integrated this data from this survey with those from scientific literature. We recorded 88 alien plant species. Tree and herbaceous species were the most common growth forms. Species from Asia and edible species were prevalent. We identified 80 species considered weeds worldwide with >50?% adapted to arid conditions. We used a two-part model to analyze the spatial distribution of naturalized and alien plant species in relation to environmental and anthropogenic factors. Altitude and human-related factors play a significant role in the distribution of both naturalized and invasive species. Notably, the latter can potentially spread mainly in the alluvial basal areas. This study underpins the knowledge about alien species and their spatial distribution in Socotra Island. It provides a baseline for plant invasion management and contributes data for the analyses of invasion processes on islands worldwide.     

Proposed local diagnostic reference levels in angiography and interventional neuroradiology and a preliminary analysis according to the complexity of the procedures

The aim of this study was to propose local diagnostic reference levels (DRL) for exposure to radiation during diagnostic procedures and neuroradiological interventions such as cerebral angiography and embolisation of cerebral aneurysms (intra-cranial aneurysms and arteriovenous malformations). Hospitals should adopt the national DRLs for use locally or establish their own DRLs based on local practice, if sufficient local data are available.For this purpose we studied a sample of 113 cerebral angiography procedures and 82 embolisations of cerebral aneurysms. The data recorded included the kerma-area product (KAP), the fluoroscopy time and the number of frames for each procedure: third quartiles from the total dosimetric databank were calculated and proposed as provisional local DRL. Since the complexity of a procedure must be taken into account when evaluating the radiation dose, in the case of embolisation of aneurysms (intra-cranial), in this initial phase we assessed whether the complexity of the embolisation procedure is related to the size of the aneurysm and/or its site. We, therefore, re-calculated the DRL for only intra-cranial aneurysms, leaving aside the arteriovenous malformations. Considering that the DRL calculated for all the therapeutic procedures are similar to those calculated considering only intra-cranial aneurysms, at the moment we propose, besides the DRL for cerebral angiography, a single DRL for all interventional procedures, even when the clinical pictures are very different. Local preliminary DRLs were proposed as follows: 180 Gy cm², 12 min and 317 frames for cerebral angiography and 487 Gy cm², 46 min and 717 frames for interventional procedures (intra-cranial aneurysms and arteriovenous malformations).     

Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape

Aim

We compared the expression of genes related to inflammatory and cytotoxic functions between MSI and MSS (HLA-class I-negative and HLA-class I-positive) colorectal cancers (CRCs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two CRCs were divided into three study groups as a function of HLA class I expression and MSI phenotype: 8 MSI tumours, 6 MSS/HLA? tumours and 6 MSS/HLA+ tumours (controls).

Findings

A first comparison between eight MSI and six MSS/HLA-positive (control) cancers, based on microarray analysis on an Affymetrix^? HG-U133-Plus-PM plate, identified 1974 differentially expressed genes (P?P?=?5.5·10^?3), leucocyte activation (43 genes, P?=?1.8·10^?5), T-cell activation (24 genes, P?=?6.3·10^?4), inflammatory response (40 genes, 2.3·10^?2) and cytokine production (10 genes, P?=?1.9·10^?2). Real-time PCR and immunohistochemical evaluation were used to validate the data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+T lymphocytes in the MSI group (P?AP2, B2m) were downregulated in MSS/HLA-class I-negative CRCs (n?=?6) in comparison to controls.

Conclusions

In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour–host interactions and differentiate MSI from MSS cancers. The two types of tumour, MSI/HLA-class I-negative and MSS/HLA-class I-negative, showed marked differences in the composition and intensity of infiltrating leucocytes, suggesting that their immune escape strategies involve distinct pathways.     

Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease

Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.