Bmp induces osteoblast differentiation through both Smad4 and mTORC1 signaling

The bone morphogenetic protein (Bmp) family of secreted molecules has been extensively studied in the context of osteoblast differentiation. However, the intracellular signaling cascades that mediate the osteoblastogenic function of Bmp have not been fully elucidated. By profiling mRNA expression in the bone marrow mesenchymal progenitor cell line ST2, we discover that BMP2 induces not only genes commonly associated with ossification and mineralization but also genes important for general protein synthesis. We define the two groups of genes as mineralization related versus protein anabolism signatures of osteoblasts. Although it induces the expression of several Wnt genes, BMP2 activates the osteogenic program largely independently of de novo Wnt secretion. Remarkably, although Smad4 is necessary for the activation of the mineralization-related genes, it is dispensable for BMP2 to induce the protein anabolism signature, which instead critically depends on the transcription factor Atf4. Upstream of Atf4, BMP2 activates mTORC1 to stimulate protein synthesis, resulting in an endoplasmic reticulum stress response mediated by Perk. Thus, Bmp signaling induces osteoblast differentiation through both Smad4- and mTORC1-dependent mechanisms

Assessing the volcanic hazard for Rome. 40Ar/39Ar and In-SAR constraints on the most recent eruptive activity and present-day uplift at Colli Albani Volcanic District

We present new 40Ar/39Ar data which allow us to refine the recurrence time for the most recent eruptive activity occurred at Colli Albani Volcanic District (CAVD) and constrain its geographic area. Time elapsed since the last eruption (36 kyr) overruns the recurrence time (31 kyr) in the last 100 kyr. New interferometric synthetic aperture radar data, covering the years 1993–2010, reveal ongoing inflation with maximum uplift rates (>2 mm/yr) in the area hosting the most recent (<200 ka) vents, suggesting that the observed uplift might be caused by magma injection within the youngest plumbing system. Finally, we frame the present deformation within the structural pattern of the area of Rome, characterized by 50 m of regional uplift since 200 ka and by geologic evidence for a recent (<2000 years) switch of the local stress-field, highlighting that the precursors of a new phase of volcanic activity are likely occurring at the CAVD

Anticancer effects of selenium compounds on human colonic carcinoma cells

Studies performed so far on different human carcinoma cell lines, as well as numerous case-control and epidemiological studies have given proof to the protective effects of selenium against cancer. However, the anticancer properties of selenium are site-specific. The aim of this work was to evaluate the cytotoxic effect of selenium against CaCo2 human colon carcinoma cells, and SW620 lymph node metastasis of colon carcinoma cell line. Three selenium compounds, seleno-DL-cystine (SeC), seleno-L-methionine (SeM) and sodium selenite were used. Initial number of cells was 210 4 and the cells were incubated for 72 h with the aforementioned Se compounds at 10, 100 and 1000 µmol Se concentrations. Cytotoxicity was measured by the MTT cell survival assay. In the present study, decreased viabilities of both CaCo2 and SW620 cells were established following the treatment with selenite, SeC, and SeM. At 10 µmol Se levels all three chemical forms exerted a more or less anticipated cytotoxic effect with viability decreases ranging from 22 to 37%. However, the other two levels of 100 and 1000 µmol Se did not exhibit an expected proportional rise in cytotoxic effect compared to 10 µmol, which warrants further research on the reasons for increased resistance of these cells. Cell morphology also indicates that investigated Se forms induced apoptotic cell death in both cell lines. The results confirm the applicability of Se in the prevention and treatment of the investigated cancer sites

Targeting prominin2 transcription to overcome ferroptosis resistance in cancer

Understanding how cancer cells resist ferroptosis is a significant problem that impacts ongoing efforts to stimulate ferroptosis as a therapeutic strategy. We reported that prominin2 is induced by ferroptotic stimuli and functions to resist ferroptotic death. Although this finding has significant implications for therapy, specific prominin2 inhibitors are not available. We rationalized that the mechanism by which prominin2 expression is induced by ferroptotic stress could be targeted, expanding the range of options to overcome ferroptosis resistance. Here, we show that that 4-hydroxynonenal (4HNE), a specific lipid metabolite formed from the products of lipid peroxidation stimulates PROM2 transcription by a mechanism that involves p38 MAP kinase-mediated activation of HSF1 and HSF1-dependent transcription of PROM2. HSF1 inhibitors sensitize a wide variety of resistant cancer cells to drugs that induce ferroptosis. Importantly, the combination of a ferroptosis-inducing drug and an HSF1 inhibitor causes the cytostasis of established tumors in mice, although neither treatment alone is effective. These data reveal a novel approach for the therapeutic induction of ferroptosis in cancer

Abundance and distribution of planktonic Archaea and Bacteria in the waters west of the Antarctic Peninsula

Polyribonucleotide probes targeting planktonic archaeal (Group I and II) and bacterial rRNA revealed that Archaea comprised a significant fraction of total prokaryote cell abundance in the marine waters west of the Antarctic Peninsula. Determinations of Archaea and Bacteria cell abundances were made during two research cruises to the Palmer Long‐Term Ecological Research region during the austral winter and summer of 1999. During the austral summer, surface water abundances of Group I (GI) Archaea were generally low, averaging 4.7 x 103 cells ml−1 and accounting for 1% of the total picoplankton assemblage. The abundance of GI Archaea increased significantly with depth, averaging 2.1 X 104 cells ml−1 and comprising 9–39% of the total picoplankton abundance in the meso‐ (150–1,000 m) and bathypelagic (1,000–3,500 m) circumpolar deep water (CDW). Relative to summertime distributions, GI cells were more evenly distributed throughout the water column during the winter, averaging 10% of the picoplankton in the surface waters and 13% in the CDW. Surface water GI abundance increased 44% between the summer and winter, coincident with a fivefold decrease in GI abundance in the deeper waters. The abundance of Group II (GII) Archaea was persistently \u3c2% of the total picoplankton throughout the water column in both summer and winter. Bacterial abundance was greatest in the upper water column (0–100 m) during the summer, averaging 3.9 x 105 cells ml−1 and comprised 89% of the total picoplankton assemblage. Generally, GI Archaea varied seasonally in the deeper waters, whereas bacterial abundance varied more in the upper waters. The observed variability in bacterial and archaeal abundance suggests that these two groups of marine picoplankton are dynamic components of Southern Ocean microbial food webs

Genetic analysis of multiple synchronous lesions of the colon adenoma–carcinoma sequence

The colorectal adenoma–carcinoma sequence represents a well-known paradigm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma–carcinoma sequence is well investigated, studies about tumours of different dignity co-existent in the same patient are seldom. In order to address the distribution of genetic alterations in different lesions of the same patient, we coincidently investigated carcinomas, adenomas and aberrant crypt foci in patients with sporadic colon cancer. By utilizing polymerase chain reaction, single-strand conformation polymorphism, heteroduplex-analysis, restriction fragment length polymorphism, protein truncation test and sequencing techniques we looked for mutations and microsatellite instability of APC, H- ras, K- ras, p53, DCC and the DNA repair genes hMLH1/hMSH2. In accordance with the suggested adenoma–carcinoma sequence of the colon, four patients reflected the progressive accumulation of genetic defects in synchronously appearing tumours during carcinogenesis. However, two patients with non-hereditary malignomas presented different genetic instabilities in different but synchronously appearing tumours suggesting non-clonal growth under almost identical conditions of the environment. Thus, sporadically manifesting multiple lesions of the colon were not necessarily driven by similar genetic mechanisms. Premalignant lesions may transform into malignant tumours starting from different types of genetic instability, which indicates independent and simultaneous tumorigenesis within the same organ. © 2000 Cancer Research Campaig

Learning a novel technique to identify possible melanomas: are Australian general practitioners better than their U.K. colleagues?

Abstract Background Spectrophotometric intracutaneous analysis (SIAscopy™) is a multispectral imaging technique that is used to identify 'suspicious' (i.e. potentially malignant) pigmented skin lesions for further investigation. The MoleMate™ system is a hand-held scanner that captures SIAscopy™ images that are then classified by the clinician using a computerized diagnostic algorithm designed for the primary health care setting. The objectives of this study were to test the effectiveness of a computer program designed to train health care workers to identify the diagnostic features of SIAscopy™ images and compare the results of a group of Australian and a group of English general practitioners (GPs). Methods Thirty GPs recruited from the Perth (Western Australia) metropolitan area completed the training program at a workshop held in March 2008. The accuracy and speed of their pre- and post-test scores were then compared with those of a group of 18 GPs (including 10 GP registrars) who completed a similar program at two workshops held in Cambridge (U.K.) in March and April, 2007. Results The median test score of the Australian GPs improved from 79.5% to 86.5% (median increase 5.5%; p < 0.001) while the median test score of the English GPs improved from 74.5% to 86.5% (median increase 9.5%; p < 0.001). The Australian GPs had significantly higher pre-test scores but there were no significant differences in post-test scores between the Australian and English GPs or between the GPs and GP registrars. There was no significant difference in scores between GPs with previous dermoscopy experience or dermatology training. Conclusion Most of the SIAscopy™ features can be learnt to a reasonable degree of accuracy with this brief computer training program. Although the Australian GPs scored higher in the pre-test, both groups had similar levels of accuracy and speed in interpreting the SIAscopy™ features after completing the program. Scores were not affected by previous dermoscopy experience or dermatology training, which suggests that the MoleMate™ system is relatively easy to learn