Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability

Checkpoint pathways help cells maintain genomic integrity, delaying cell cycle progression in response to various risks of fidelity, such as genotoxic stresses, compromised DNA replication, and impaired spindle control. Cancer cells frequently exhibit genomic instability, and recent studies showed that checkpoint pathways are likely to serve as a tumor-suppressive barrier in vivo. The cell cycle-promoting phosphatase CDC25A is an activator of cyclin-dependent kinases and one of the downstream targets for the CHK1-mediated checkpoint pathway. Whereas CDC25A overexpression is observed in various human cancer tissues, it has not been determined whether deregulated CDC25A expression triggers or promotes tumorigenesis in vivo. Here, we show that transgenic expression of CDC25A cooperates markedly with oncogenic ras or neu in murine mammary tumorigenesis. MMTV-CDC25A transgenic mice exhibit alveolar hyperplasia in the mammary tissue but do not develop spontaneous mammary tumors. The MMTV-CDC25A transgene markedly shortens latency of tumorigenesis in MMTV-ras mice. The MMTV-CDC25A transgene also accelerates tumor growth in MMTV-neu mice with apparent cell cycle miscoordination. CDC25A-overexpressing tumors, which invade more aggressively, exhibit various chromosomal aberrations on fragile regions, including the mouse counterpart of human 1p31-36, according to array-based comparative genomic hybridization and karyotyping. The chromosomal aberrations account for substantial changes in gene expression profile rendered by transgenic expression of CDC25A, including down-regulation of Trp73. These data indicate that deregulated control of cellular CDC25A levels leads to in vivo genomic instability, which cooperates with the neu-ras oncogenic pathway in mammary tumorigenesis.     

Tumor-released microvesicles as vehicles of immunosuppression

Tumor-released microvesicles, or exosomes, which are abundant in the body fluids of patients with cancer, are likely to be involved in tumor progression. We recently showed that microvesicles released by human melanoma and colorectal carcinoma cells can promote the differentiation of monocytes to myeloid-derived suppressor cells which support tumoral growth and immune escape. These findings underscore an important role for these extracellular organelles in remodeling tumor-stromal interactions to promote malignancy.     

Metaplastic carcinoma of the breast,an unusual disease with worse prognosis: the experience of the European Institute of Oncology and review of the literature

The contribution of BRCA1 and BRCA2 to breast cancer incidence in Brazil has not yet been explored. In order to estimate the proportion of breast cancers due to BRCA1 and BRCA2 mutations in Brazil, we conducted a study of unselected breast cancer patients from Rio de Janeiro, Brazil. We enrolled 402 women with breast cancer from a large public hospital and two private medical clinics in the city. A detailed family history was obtained from each patient and a blood sample was obtained for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques, but all mutations were confirmed by direct sequencing. Overall, nine mutations were identified (six in BRCA1 and three in BRCA2) representing 2.3% of the total. The most common mutation, 5382insC in BRCA1, was seen five times and accounted for 56% of all identified mutations. A second mutation, in BRCA2 (6633del5) was seen in two unrelated women. In summary, BRCA1 and BRCA2 mutations are not uncommon in Brazilian women with breast cancer. It appears that a small number of founder mutations may be predominant. Moreover, a small number of founder mutations may be prevalent in Brazil, raising the possibility that a rapid and inexpensive genetic test may be developed to screen for inherited susceptibility to breast cancer in Brazil. All studies listed in this paper are in accordance with the ethical standards of the regional hospitals in the listed study area.     

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

Many studies have shown that resveratrol has a lot of therapeutic effects on liver disorders. Its administration can significantly increase the survival rate after liver transplantation, reduce fat deposition and ischemia-induced necrosis and apoptosis in Wistar rats. Resveratrol can provide Liver protection against chemical, cholestatic, and alcohol-mediated damage. It can improve glucose metabolism and lipid profile, reduce liver fibrosis, and steatosis. Additionally, it is capable of altering the fatty acid composition of the liver cells. Resveratrol may be a potential treatment option for the management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant, and calorie-restricting effects. There are also studies that have evaluated the effect of resveratrol on lipid and liver enzyme profiles among patients with metabolic syndrome (MetS) and related disorders. Based on the extent of liver disease worldwide and the need to find new treatment possibilities, this review critically examines current in vitro and in vivo preclinical studies and human clinical studies related to liver protection.     

Myocardial ischemia and reperfusion-induced cell death depends on JNK activation and leads to phosphorylation of mitochondrial p46

Ｍｕｌｔｉｐｌｅｓｉｇｎａｌｉｎｇｐａｔｈｗａｙｓ,ｉｎｃｌｕｄｉｎｇｔｈｅｃ ＪｕｎＮ ｔｅｒｍｉｎａｌｋｉｎａｓｅ (ＪＮＫ)ｐａｔｈｗａｙ ,ａｒｅａｃｔｉｖａｔｅｄｉｎｍｙｏｃａｒｄｉａｌｉｓｃｈｅｍｉａａｎｄｒｅｐｅｒｆｕｓｉｏｎ (ＭＩ/Ｒ)ａｎｄｃｏｒｒｅｌａｔｅｗｉｔｈｃｅｌｌｄｅａｔｈ .Ｈｏｗｅｖｅｒ,ｔｈｅｒｏｌｅｏｆｔｈｅＪＮＫｐａｔｈｗａｙｗｉｔｈｒｅｓｐｅｃｔｔｏｐｒｏｔｅｃｔｉｏｎｏｒｄｅｓｔｒｕｃｔｉｏｎｉｎＭＩ/Ｒ ｉｎｄｕｃｅｄｃｅｌｌｄｅａｔｈｉｓｐｏｏｒｌｙｕｎｄｅｒｓｔ…     

Comparison of two carbonated apatite ceramics in vivo

Carbonated apatite ceramics, with a composition similar to that of bone mineral, are potentially interesting synthetic bone graft substitutes. In the present study, two porous carbonated apatite ceramics were developed, characterized and tested for their bone repair capacity and osteoinductive potential in a goat model. Although the two ceramics were prepared from a similar starting powder, their physico-chemical and structural characteristics differed as a consequence of different preparation methods. Both ceramics had an open and interconnected porous structure with a porosity of about 80%. The morphology of the surface of CA-A and CA-B at the submicron level differed significantly: CA-A consisted of irregular grains with a size of 5–20 μm, with 1–10 μm large micropores among the grains, whereas CA-B surface consisted of much smaller and regular shaped grains (0.05–0.5 μm), with most micropores smaller than 1 μm. The specific surface area of CA-B was about 10 times larger than that of CA-A due to its significantly smaller grain size. CA-A and CA-B ceramics contained 3 and 5 wt.% of B-type carbonated apatite, respectively. Although neither ceramic succeeded in completely bridging the 17 mm iliac wing defect with new bone after 12 weeks of implantation, CA-A showed significantly more bone formation in the pores of the implant than CA-B. The total area percentage of new bone in the total defect area was 12.7 ± 1.81 and 5.51 ± 1.37 (mean ± SEM) for CA-A and CA-B, respectively. Intramuscular implantation of the ceramics led to ectopic bone formation by CA-A in all three implanted specimens, in contrast to CA-B, where no new bone was observed in any of the 11 animals. CA-A showed a more pronounced degradation than CA-B both in vitro and in vivo at both implantation sites, which was unexpected based on the physico-chemical and structural properties of the two ceramics. Both physico-chemical and structural properties of the ceramics could, dependently or independently, have affected their in vivo behaviour, emphasizing the importance to control individual parameters for successful bone repair.     

In vitro activity of a partially purified and characterized bark extract of Castanea sativa Mill. (ENC®) against Chlamydia spp

Castanea sativa Mill (ENC®), containing tannins against 33 Chlamydia strains, was compared to SMAP-29 with inhibitory effect against C. trachomatis and C. pneumoniae. The ENC® activity against Chlamydia spp. was evaluated determining the lowest concentration to achieve more than half reduction of intact chlamydial inclusions versus controls. ENC® reduced all Chlamydia strains tested at 1 µg/mL, while SMAP-29 induced reductions of C. trachomatis and C. pneumoniae infectivity at 10 µg/mL. A great reduction of C. trachomatis, C. pneumoniae, and C. abortus infectivity was achieved with a 10 µg/mL ENC® concentration, whereas their infectivity was almost inhibited at 100 µg/mL ENC® concentration.