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The molecular mechanisms underlying the development of hepatocellular carcinoma (HCC) are not yet fully understood. Preneoplastic foci of altered hepatocytes regularly precede HCC in various species. The predominant earliest type of foci of altered hepatocytes, the glycogen storage focus (GSF), shows an excess of glycogen (glycogenosis) in the cytoplasm. During progression from GSF to HCC, the stored glycogen is gradually reduced, resulting in complete loss in basophilic HCC. We have previously shown that in N-nitrosomorpholine–induced hepatocarcinogenesis, insulin receptor substrate (IRS-1) is strongly expressed in GSF and reduced during progression to HCC, thus correlating with the glycogen content. In the present study, we observed increased levels of insulin receptor, IGF-I receptor (IGF-IR), IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 in GSF, following the same pattern of expression as IRS-1. We conclude that the abundance of IRS-1, IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 coincides with a concerted upregulation of both IR and IGF-IR induced by the hepatocarcinogen. Our data suggest that in early hepatocellular preneoplasia, the upregulation of IR elicits glycogenosis through IRS-1 and/or IRS-2, whereas the increased level of the IGF-IR may lead to the increased cell proliferation previously reported in GSF. Therefore, the concerted upregulation of both IR and IGF-IR may represent initial events in hepatocarcinogenesis. [ABSTRACT FROM PUBLISHER]

Abstract: Eosinophils are multifunctional leukocytes implicated in the pathogenesis of numerous inflammatory processes, such as allergies and parasitic infections. Increased number of these cells has been described in many human cancers, including oral squamous cell carcinoma, and its presence related to favourable as well as unfavourable prognosis. Although the exact role of eosinophils in tumours is not yet defined, the anti-tumour activity of these rare granulocytes has been associated with the release of their cytotoxic proteins, especially the eosinophil cationic protein, a single polypeptide chain with a molecular mass ranging from 15 to 22kDa encoded by the RNSE3 gene located on chromosome 14q11.2. Functional studies have implicated ECP in numerous processes, such as tissue remodelling in allergic inflammation; however its most striking function is the cytotoxic activity. The aim of this review is to summarise the role and functions of eosinophils and their granule-derived products in oral malignant tumours and the clinical value of the tumour-associated tissue eosinophilia for patients’ prognosis. [Copyright &y& Elsevier]

Pancreatic cancer is a disease with high resistance to most common therapies and therefore has a poor prognosis, which is partly due to a lack of reaction to apoptotic stimuli. Signal transduction of such stimuli includes a death receptor-mediated extrinsic pathway as well as an intrinsic pathway linked to the mitochondria. Defects in apoptotic pathways and the deregulation of apoptotic proteins, such as Survivin, Bcl-2, Bcl-xL and Mcl-1, play decisive roles in the development of pancreatic cancer. Investigation of the molecular mechanism allowing tumors to resist apoptotic cell death would lead to an improved understanding of the physiology and the development of new molecular strategies in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Although the high mobility group A1 (HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. HMGA1 functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, HMGA1 is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from HMGA1a transgenic mice at different stages in tumorigenesis. Results: RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors. Conclusions: We found that HMGA1 induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. HMGA1 also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into HMGA1 function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant could serve as therapeutic targets in lymphoid and other human cancers with aberrant HMGA1 expression. [ABSTRACT FROM AUTHOR]

Number of various sources of wireless communication is had been incredibly increased in the recent decade. One of the most popular wireless communication equipment is mobile phones. However, another widespread part of wireless communications is Wi-Fis. As it is known, smart phones has many function such as speaking, Wi-Fi, bluetooth etc. Therefore, their radiofrequency radiation (RFR) level is higher than the first generation mobile phones. It means that smart phones emit higher RFR. The results of studies performed on the effects of RFR on animal or human indicated that mobile phones are not innocent. Because of that RFRs classified as 2B (Possible carcinogen) by World Health Organization in 2011. Most of the studies usually performed on RFR and health focused on the brain tumors and other diseases. No one pay attention to the potential health effects of this electromagnetic pollutant on oral tissues and teeth, which are one of the most RFR exposed parts of heads at the beginning. Although limited number of the studies had been done on oral tissues, the results of the studies are worth considering. Therefore, the aim of this review is to summarize the results of the limited studies here. In conclusion, the results of the studies investigated the effects of RF exposure on oral tissues and teeth indicated that uncontrolled exposures may have potential to cause some dental health problems. Finally, further studies including human studies are necessary to illuminate this topic. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a malignant plasma cell dyscrasia localized in the bone marrow. Recent studies have shown that MM is preceded in virtually all cases by a premalignant state called monoclonal gammopathy of undetermined significance (MGUS). This review focuses on non-IgM MGUS and its progression to MM. Although certain clinical markers of MGUS progression have been identified, it currently is not possible to accurately determine individual risk of progression. This review focuses on the various biologic and molecular markers that could be used to determine the risk of MM progression. A better understanding of the pathogenesis will allow us to define the biological high-risk precursor disease and, ultimately, to develop early intervention strategies designed to delay and prevent full-blown MM. [ABSTRACT FROM AUTHOR]

Macrophages are tightly associated with inflammatory diseases as well as carcinogenesis, and therefore represent promising targets for drug delivery and gene transfer. We have recently established a novel protein delivery system based on the binary C2 toxin of Clostridium botulinum and streptavidin, allowing the uptake of exogenous biotinylated molecules into mammalian cells. Here, we applied this C2-streptavidin delivery system to macrophages and other leukocytes. First, the effect of wild-type C2 toxin on different leukocyte cell lines was tested, indicating no differences in sensitivity. Next, the uptake and stability of the engineered C2-streptavidin was analyzed in macrophages and Jurkat T-cells, showing internalization into the cytosol of both cell types with similar kinetics. The transporter did not exhibit any cytotoxic effect and did not interfere with phagocytosis in primary human macrophages. The C2-streptavidin system promoted specific uptake of biotinylated fluorophores into the cytosol of macrophages as revealed by confocal microscopy. In addition, flow cytometry analysis showed a significantly enhanced uptake of biotinylated fluorescent tracers in Jurkat leukemia cells mediated by the C2-streptavidin transporter. Our results demonstrate that C2-streptavidin is a functional delivery system for transport of biotinylated molecules into macrophages and other leukocytes without compromising cell viability and intrinsic functions such as phagocytosis. [ABSTRACT FROM AUTHOR]

Abstract: Pituitary tumours are benign neoplasms that may cause major endocrine dysfunction. Transgenic disruption of the cell cycle machinery frequently leads to pituitary adenoma formation in animal models. The molecular analysis of human pituitary tumours has found various alterations in the expression of cell cycle regulators: cyclins, cyclin-dependent kinases and their inhibitors. There are also different mechanisms (e.g. hypermethylation, frameshift mutations, increased proteasome degradation) responsible for changed expression in cyclin mRNA and protein. It is probable that the primary initiating events lie beyond the cell cycle and may be related to co-activation of Akt, MAP-kinase and β-catenin pathways. Nevertheless, molecular CDK inhibitors may play a role in pituitary tumour treatment in the future. [ABSTRACT FROM AUTHOR]

Background: Epigenetic silencing of Wnt antagonists and expression changes in genes associated with Wnt response pathways occur in early sporadic colorectal tumourigenesis, indicating that tumour cells are more sensitive to Wnt growth factors and respond differently. In this study, we have investigated whether similar changes occur in key markers of the Wnt response pathways in the genetic form of the disease, familial adenomatous polyposis (FAP).Methods: We investigated epigenetic and expression changes using pyrosequencing and real-time RT-PCR in samples from seven patients without neoplasia, and matched normal and tumour tissues from 22 sporadic adenoma and 14 FAP patients.Results: We found that 17 out of 24 (71%) FAP adenomas were hypermethylated at sFRP1, compared with 20 out of 22 (91%) of sporadic cases. This was reflected at the level of sFRP1 transcription, where 73% of FAP and 100% of sporadic cases were down-regulated. Increased expression levels of c-myc and FZD3 were less common in FAP (35 and 46% respectively) than sporadic tumours (78 and 67% respectively).Conclusion: Overall, the changes in expression and methylation were comparable, although the degree of change was generally lower in the FAP adenomas. Molecular heterogeneity between multiple adenomas from individual FAP patients may reflect different developmental fates for these premalignant tumours. [ABSTRACT FROM AUTHOR]

Abstract: Centrosome amplification (CA) as a potential marker of mitotic disruptions in multiple myeloma (MM) was investigated in two populations of B-cell lineage: B-cells and plasma cells (PCs). Using immunofluorescent staining, it was shown that CA in B-cells is present in 3.2±2.5% in healthy donors versus 9.9±7.9% in MM patients (p <0.0001). Based on the calculated threshold value of CA in B-cells, 37% (14/38) of MM patients were positive. There was no significant correlation between CA-positive MM cases (based on PC samples evaluation) and the occurrence of cytogenetic abnormalities in PCs, including del(13)(q14), del(17)(p13), gain(1)(q21) and hyperdiploidy. [Copyright &y& Elsevier]

During the initial stages of carcinogenesis, transformation events occur in a single cell within an epithelial monolayer. However, it remains unknown what happens at the interface between normal and transformed epithelial cells during this process. In Drosophila, it has been recently shown that normal and transformed cells compete with each other for survival in an epithelial tissue; however the molecular mechanisms whereby ''loser cells'' undergo apoptosis are not clearly understood. Lgl (lethal giant larvae) is a tumor suppressor protein and plays a crucial role in oncogenesis in flies and mammals. Here we have examined the involvement of Lgl in cell competition and shown that a novel Lgl-binding protein is involved in Lgl-mediated cell competition. Using biochemical immunoprecipitation methods, we first identified Mahjong as a novel binding partner of Lgl in both flies and mammals. In Drosophila, Mahjong is an essential gene, but zygotic mahjong mutants (mahj-/-) do not have obvious patterning defects during embryonic or larval development. However, mahj-/- cells undergo apoptosis when surrounded by wild-type cells in the wing disc epithelium. Importantly, comparable phenomena also occur in Mahjong-knockdown mammalian cells; Mahjong-knockdown Madin-Darby canine kidney epithelial cells undergo apoptosis, only when surrounded by non-transformed cells. Similarly, apoptosis of lgl-/- cells is induced when they are surrounded by wild-type cells in Drosophila wing discs. Phosphorylation of the c-Jun N-terminal kinase (JNK) is increased in mahj-/- or lgl-/- mutant cells, and expression of Puckered (Puc), an inhibitor of the JNK pathway, suppresses apoptosis of these mutant cells surrounded by wild-type cells, suggesting that the JNK pathway is involved in mahj- or lgl-mediated cell competition. Finally, we have shown that overexpression of Mahj in lgl-/- cells strongly suppresses JNK activation and blocks apoptosis of lgl-/- cells in the wild-type wing disc epithelium. These data indicate that Mahjong interacts with Lgl biochemically and genetically and that Mahjong and Lgl function in the same pathway to regulate cellular competitiveness. As far as we are aware, this is the first report that cell competition can occur in a mammalian cell culture system. [ABSTRACT FROM AUTHOR]

Abstract: Despite the fact that the current histopathologic classification for bladder cancer has led to improved concepts for the clinical management of the disease, key questions with regard to assessment of risk for recurrence and/or progression to invasive disease remain. In addition, response to specific therapies cannot be predicted accurately. Bladder tumors comprise a heterogeneous group with respect to both histopathology and clinical behavior. Thus, it is anticipated that a thorough knowledge and interpretation of the molecular alterations involved in tumor development and progression will lead to greater prognostic and predictive power. This may not only lead to better comprehension of the biology of the disease, but may also lead to the development of novel individualized therapies. Novel means of stratification are urgently needed to provide a new subclassification of urothelial lesions. This review discusses and summarizes the genetic alterations that have been reported in bladder cancer and relates these to the current 2-pathway model for tumor development. The molecular pathogenesis of high-grade noninvasive papillary tumors and of T1 tumors is not yet clear, and possibilities are discussed. [Copyright &y& Elsevier]

Abstract: Bladder cancer is the fifth most common human malignancy and the second most frequently diagnosed genitourinary tumor after prostate cancer. The majority of malignant tumors arising in the urinary bladder are urothelial carcinomas. Clinically, superficial bladder tumors (stages Ta and Tis) account for 75% to 85% of neoplasms, while the remaining 15% to 25% are invasive (T1, T2–T4) or metastatic lesions at the time of initial presentation. Several studies have revealed that distinct genotypic and phenotypic patterns are associated with early vs. late stages of bladder cancer. Early superficial disease appears to segregate into 2 main pathways: (1) superficial papillary bladder tumors, which are characterized by gain-of-function mutations affecting oncogenes such as H-RAS, FGFR3, and PI3K, and deletions of the long arm of chromosome 9 (9q); (2) Carcinoma in situ, a “flat” high grade lesion considered to be a precursor of invasive cancer, is characterized by loss-of-function mutations affecting tumor suppressor genes, such as p53, RB, and PTEN. Based on these data, a model for bladder tumor progression has been proposed in which 2 separate genetic pathways characterize the evolution of early bladder neoplasms. Several molecular markers have been correlated with tumor stage, but the rationale for these 2 well-defined genetic pathways still remains unclear. Normal urothelium is a pseudo-stratified epithelium that coats the bladder, composed of 3 cell types: basal, intermediate, and superficial (“umbrella”) cells. We have identified a series of markers that are differently expressed in these distinct cells types, and postulated a novel model for urothelium development and configuration. Briefly, it is our working hypothesis that 2 distinct progenitor cells are responsible for basal/intermediate cells and “umbrella” cells, respectively. Basal and intermediate cells are characterized by a p63 positive phenotype, as well as expression of high molecular weight cytokeratins (CKs), such as CK5, CK10, and CK14. On the contrary, “umbrella” cells display a p63 negative phenotype and are characterized by expression of 2 specific low molecular weight CKs: CK18 and CK20. Neither urothelial stem cells nor bladder cancer stem cells have been identified to date. In this review, we will further expand on the issues discussed above. [Copyright &y& Elsevier]

Abstract: Advances in the molecular biology of ageing, insulin resistance, inflammation, carcinogenesis and caloric restriction have elucidated commonalities relevant to the chronic overnutrition syndrome termed obesity. Not until the expanded acceptance and availability of surgical treatment of obesity (“bariatric surgery”) has it been possible to explore the beneficial effects of sustained voluntary weight loss through controlled undernutrition in freely living people. Bariatric surgery is 58 years old and has undergone dramatic improvements recently becoming significantly safer and more accessible owing to the development of minimally invasive approaches and other advances. Furthermore, it is cost-effective compared to all forms of non-operative treatment. Thus older candidates, with more numerous and severe comorbidities are being recruited, increasing the pool of patients who have had operations which extend the otherwise shorter lives of the obese. Here we describe two mechanistically different operations, gastric restrictive and diversionary, and address their risks, complications, side-effects and beneficial outcomes, in aggregate increasing longevity, reducing morbidity and most important: improving health-related quality-adjusted life years. [Copyright &y& Elsevier]

Germline polymorphisms of genes involved in different steps of tumorigenesis like p53, the tumor suppressor gene, are reported to determine the individual susceptibility to cancer. Lung cancer is one of the most common and lethal cancers and tobacco smoking remains its most important etiologic factors. The most frequently p53 mutated codons of lung cancer are 72 (exon 4) and 249 (exon 7). Since mutations in the p53 gene are present in ∼40% of all human lung cancers and are more common in smokers than in nonsmokers, we aimed to detect the status of p53 at codon 72 for Arg/Arg or Arg/Pro or Pro/Pro allele polymorphism and p53 codon 249 mutation in smokers and nonsmokers of South India. Allele frequencies in the nonsmokers were 0.16 for the Arg/Pro allele and 0.84 for the Pro/Pro allele in our study population. Among the smokers, the frequencies of the Arg/Pro, Arg/Arg, and Pro/Pro alleles were 0.88, 0.04, and 0.08, respectively. No mutation was detected in both smokers and nonsmokers in p53 codon 249. From the worldwide scenario, it can be speculated that the smokers, with Arg/Pro genotype are more prone for lung cancer or to other types of cancer. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have led to the identification of more than 100 common, low-penetrance loci for cancer. At these loci, common genetic variants are associated with moderate increases in risk, typically <1.5-fold. Almost all loci lie in genomic regions not previously suspected to be involved in cancer. A plausible functional basis for a few loci, such as FGFR2 for breast cancer and MSMB for prostate cancer, has been elucidated, but the majority are not understood and suggest new mechanisms of carcinogenesis. Most loci are specific to a single cancer type, and are often subtype specific (e.g. ER-positive breast cancer). There are notable differences in the genetic architecture for different cancer types, with a greater contribution of common variants for prostate cancer. The clinical utility of variants to predict individual disease risk of disease is currently limited, but this may change as more variants are identified. [Copyright &y& Elsevier]

Pancreatic cancer is an aggressive malignancy with a poor prognosis. The overall 5-year survival rate of pancreatic cancer is less than 5%, and has not improved significantly for years. Further understanding of the molecular carcinogenesis of pancreatic cancer is critical for designing effective ways to treat this type of malignancy. In this study, we examine expression of hedgehog signaling molecules in 54 surgically removed pancreatic cancer specimens as well as seven available pancreatic cancer cell lines. We find that expression of Ptch is associated with tumor size, tumor differentiation, lymph node metastasis, and clinical stages, whereas expression of Smo is associated with tumor differentiation and lymph node metastasis. Our studies from pancreatic cancer cell lines indicate that targeted inhibition of hedgehog signaling by Smo signaling inhibitor KAAD-cyclopamine causes hedgehog target gene expression (Gli1) suppression, induces P21 expression and G1 cell population, and reduced expression of Cyclin D1 and IGF2. These results indicate that hedgehog signaling activation is a very common event in pancreatic cancer and that targeted inhibition of hedgehog signaling may be effective in treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Unlike autosomal genes, the majority of X-linked genes are subject to dosage compensation. As a result, female tissues comprise cells exclusively expressing X-linked genes from one or other parent. The implication of having only one allele of active X-linked genes in cancer pathogenesis, i.e. somatic single-hit inactivation and dominant inheritance, has not been extensively explored. Recent studies have identified FOXP3 and WTX as two X-linked tumor suppressor genes that are somatically inactivated by single genetic hits. Because the predicted dominant inheritance of cancer risk has not been demonstrated in humans, we will discuss the possible conditions that might prevent such dominant inheritance. We also argue that the existence of a genetically intact allele in cancer cells in women, together with apparent abnormal X inactivation in cancer cells, might provide an opportunity to selectively reactivate tumor suppressor genes for cancer therapy. [Copyright &y& Elsevier]

The article discusses the pseudotumors of the urinary bladder. It describes the pseudotumors of the urinary bladder as a mass-like lesion that is nonneoplastic. It cites several types of pseudotumors which include the nephrogenic adenoma, papillary-polypoid cystitis, and the mullerian lesions. It mentions that the mullerian lesions is characterized by a prominent part of endocervical-type epithelium.

The article presents an analysis on the development of triple negative (TN) phenotype in node-negative patients with invasive breast carcinoma. It mentions the need for reliable prognostic factors for node-negative tumors since adjuvant therapy is limited to patients with lymph node involvement. It also concludes that TN tumors were correlated with the expression of an important factor in breast carcinogenesis and they are also associated with the aggressive biologic behavior of the patients.

Aims: To evaluate potential risk factors for intrahepatic cholangiocarcinoma (ICC) and analyse clinicopathologic characteristics of ICC patients with seropositive hepatitis B surface antigen (HBsAg). Methods: A retrospective case–control study was conducted. Cases were 317 ICC patients referred to the Eastern Hepatobiliary Surgery Hospital in China between 2003 and 2006. Controls were 634 healthy individuals. Adjusted odds ratios (ORs) were calculated in logistic regression analysis. Among 317 consecutively enrolled ICC patients, 154 patients were seropositive HBsAg (48.6%). We compared clinicopathologic characteristics of these patients (group I) with ICC patients seronegative for HBsAg (group II; n =163) and compared the age and sex distributions of patients in group I with randomly selected hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) (group III; n =1140). Results: Compared with the controls, ICC patients had a high prevalence of seropositive HBsAg, cirrhosis, hepatolithiasis and hepatic schistosomiasis. Compared with seronegative-HBsAg ICC patients, seropositive-HBsAg ICC patients were younger, more frequently male and had a higher proportion of abnormal aminotransferase and serum alpha-fetoprotein (AFP) level, histological inflammation and cirrhosis, right-lobe focus, poor tumour differentiation, tumour encapsulation and microvascular invasion; had a lower proportion of abnormal serum carbohydrate antigen 19-9 (CA19-9) level and lymphatic metastasis. The age and sex distribution profiles were nearly identical between seropositive-HBsAg ICC patients and HBV-associated HCC patients. Conclusions: The HBV infection, cirrhosis, hepatolithiasis and hepatic schistosomiasis may be potential risk factors for ICC. HBV-associated ICC shares many clinicopathological similarities with HBV-associated HCC. The result indicated HBV-associated ICC and HBV-associated HCC may hold common disease process for carcinogenesis. [Copyright &y& Elsevier]

Group IVA cytosolic phospholipase A2 (cPLA2α) plays a key role in tumorigenesis via generating arachidonic acids as the substrate of cyclooxygenase. The aim of this study was to elucidate the possible associations between cPLA 2α gene polymorphisms and phenotypic features of patients with familial adenomatous polyposis (FAP). A tag single nucleotide polymorphisms (SNPs)-based genotype–phenotype association study of the cPLA 2α gene was conducted in 73 Japanese patients from 59 families with FAP. Based on the HapMap database, seven tag SNPs of the cPLA 2α gene were selected and genotyped by direct sequencing analysis. The genotype–phenotype association in relation to the adenomatous polyposis coli ( APC) gene mutation was also assessed. The single SNP analysis showed that rs3820185 C allele [odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2–4.9] and rs127446200 GG genotype (OR, 10.9; 95%CI, 1.6–69.8), were more frequent in patients with gastric fundic gland polyposis (FGP) than in those without. Rs12749354 C allele was more frequently found in patients with small intestinal adenoma (OR, 7.0; 95% CI, 1.5–30.4; p = 0.008). This association was also significant when adjusted for covariates (age, sex, and APC mutation) in a logistic regression analysis (adjusted OR, 7.4; 95% CI, 1.2–64.2; p = 0.027). The cPLA 2α gene may be a possible disease modifier gene in FAP. [ABSTRACT FROM AUTHOR]

The aurora kinase family members, Aurora-A, -B, and -C (listed as AURKA, AURKB and AURKC respectively in the HUGO Database), are serine/threonine kinases involved in the regulation of chromosome segregation and cytokinesis, and alterations in their expression are associated with malignant cell transformation and genomic instability. Deregulation of the expression of the aurora kinases has been shown to occur also in testicular germ cell tumors (TGCTs) identifying them as putative anticancer therapeutic targets. We here evaluated the in vitro effects of MK-0457, an aurora kinases inhibitor, on cell proliferation, cell cycle, ploidy, apoptosis, and tumorigenicity on the TGCT-derived cell line NT2-D1. Treatment with MK-0457 inhibited cell proliferation in a time- and dose-dependent manner, with IC50=17.2±3.3 nM. MK-0457 did not affect the expression of the three aurora kinases, but prevented their ability to phosphorylate substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it, presenting after short time the typical features of apoptotic cells. Cytofluorimetric analysis confirmed that the treatment with MK-0457 for 6 h induced NT2-D1 cells accumulation in the G2/M phase of the cell cycle and the subsequent appearance of sub-G0nuclei. The latter result was further supported by the detection of caspase-3 activation following 24-h treatment with the inhibitor. Finally, MK-0457 prevented the capability of the NT2-D1 cells to form colonies in soft agar. In conclusion, the above findings demonstrate that inhibition of aurora kinase activity is effective in reducing in vitro growth and tumorigenicity of NT2-D1 cells, and indicate its potential therapeutic value for TGCT treatment. [ABSTRACT FROM AUTHOR]

Cancer chemoprevention is thought to occur either by blocking the initiation of or suppressing the promotion of carcinogenesis. Phase II detoxification enzymes are known to play important roles in cancer chemoprevention because they enhance cytoprotection through detoxification and elimination of activated carcinogens at tumor initiation. Apoptosis is one of the most important inhibitory targets for tumor promotion. In this study, we have investigated the cancer chemopreventive activity of the ethanolic extract of Carpesium abrotanoides (CAE). We found that CAE induced quinone reductase [also known as NAD(P)H:quinone oxidoreductase (NQO1)] activity, increased NQO1 mRNA and protein expression, and had a relatively high chemoprevention index (12.04). CAE also significantly activated the antioxidant response element through the nuclear accumulation of NF-E2-related factor 2 in HCT116. Interestingly, we also found that CAE induced apoptosis, as evidenced by the externalization of phosphatidylserine, increased sub-G0/G1 content, chromatin condensation, poly(ADP-ribose) polymerase cleavage, and p53. These data suggest that the chemopreventive effects of C. abrotanoides can result from both the induction of phase II detoxification enzymes and from apoptosis. Thus, CAE could potentially be developed as a cancer chemopreventive agent for prevention or treatment of human cancers.

Background: Inorganic arsenic is a ubiquitous environmental carcinogen affecting millions of people worldwide. Evolving theory predicts that normal stem cells (NSCs) are transformed into cancer stem cells (CSCs) that then drive oncogenesis. In humans, arsenic is carcinogenic in the urogenital system (UGS), including the bladder and potentially the prostate, whereas in mice arsenic induces multiorgan UGS cancers, indicating that UGS NSCs may represent targets for carcinogenic initiation. However, proof of emergence of CSCs induced by arsenic in a stem cell population is not available. Methods: We continuously exposed the human prostate epithelial stem/progenitor cell line WPE-stem to an environmentally relevant level of arsenic (5 μM) in vitro and determined the acquired cancer phenotype. Results: WPE-stem cells rapidly acquired a malignant CSC-like phenotype by 18 weeks of exposure, becoming highly invasive, losing contact inhibition, and hypersecreting matrix metalloproteinase-9. When hetero-transplanted, these cells (designated As-CSC) formed highly pleomorphic, aggressive tumors with immature epithelial- and mesenchymal-like cells, suggesting a highly pluripotent cell of origin. Consistent with tumor-derived CSCs, As-CSCs formed abundant free-floating spheres enriched in CSC-like cells, as confirmed by molecular analysis and the fact that only these floating cells formed xenograft tumors. An early loss of NSC self-renewal gene expression (p63, ABCG2, BMI-1, SHH, OCT-4, NOTCH-1) during arsenite exposure was subsequently reversed as the tumor suppressor gene PTEN was progressively suppressed and the CSC-like phenotype acquired. Conclusions: Arsenite transforms prostate epithelial stem/progenitor cells into CSC-like cells, indicating that it can produce CSCs from a model NSC population. [ABSTRACT FROM AUTHOR]

Background: Prognostic factors in patients who are diagnosed with T4 breast carcinomas are widely awaited. We here evaluated the clinical role of some molecular alterations involved in tumorigenesis in a well-characterized cohort of T4 breast cancer patients with a long follow-up period. Methods: A consecutive series of 53 patients with T4 breast carcinoma was enrolled between 1992 and 2001 in Sardinia, and observed up for a median of 125 months. Archival paraffin-embedded tissue sections were used for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses, in order to assess alterations in expression levels of survivin, p53, and pERK1-2 proteins as well as in amplification of CyclinD1 and h-prune genes. The Kaplan-Meier and Cox regression methods were used for survival assessment and statistical analysis. Results: Overall, patients carrying increased expression of pERK1-2 (p = 0.027) and survivin (p = 0.008) proteins as well as amplification of h-prune gene (p = 0.045) presented a statistically-significant poorer overall survival in comparison with cases found negative for such alterations. After multivariate analysis, the pathological response to primary chemotherapy and the survivin overexpression in primary carcinoma represented the main parameters with a role as independent prognostic factors in our series. Conclusions: Although retrospective, our study identified some molecular parameters with a significant impact on prediction of the response to therapy or prognosis among T4 breast cancer patients. Further large prospective studies are needed in order to validate the use of such markers for the management of these patients. [ABSTRACT FROM AUTHOR]

In this article the author discusses the role of growth factors in carcinogenesis. It cites several kinds of growth factors including the epidermal growth factor family, insulin-like growth factor, and the fibrolast growth factors. It also mentions the use of hematopoietic cytokines in treating side effects of cancer chemotherapy. The author infers that growth factors are essential in improving side effects of cytotoxic and/or myelosuppressive chemotherapy.

Abstract: A growing amount of experimental evidences has progressively shown that aging and carcinogenesis share many molecular pathways. During aging, the accumulation of genetic and epigenetic changes, the diminishing of telomere length, the progressive disruption of mechanisms for DNA damage repair, glucose metabolism regulation, cell cycle control, and stem cells self-renewal lead to induction of senescence or apoptosis and loss of replicative capacity. The same cellular dysfunctional mechanisms characterizing the aging process have been found to be involved, with different level of evidence, in cancerogenesis and are reviewed herein. [Copyright &y& Elsevier]

Abstract: Wnt proteins constitute a family of secreted signaling molecules that regulate highly conserved pathways essential for development and, when aberrantly activated, drive oncogenesis in a number of human cancers. A key feature of the most widely studied Wnt signaling cascade is the stabilization of cytosolic β-catenin, resulting in β-catenin nuclear translocation and transcriptional activation of multiple target genes. In addition to this canonical, β-catenin-dependent pathway, Wnt3A has also been shown to stimulate RhoA GTPase. While the importance of activated Rho to non-canonical Wnt signaling is well appreciated, the potential contribution of Wnt3A-stimulated RhoA to canonical β-catenin-dependent transcription has not been examined and is the focus of this study. We find that activated Rho is required for Wnt3A-stimulated osteoblastic differentiation in C3H10T1/2 mesenchymal stem cells, a biological phenomenon mediated by stabilized β-catenin. Using expression microarrays and real-time RT-PCR analysis, we show that Wnt3A-stimulated transcription of a subset of target genes is Rho-dependent, indicating that full induction of these Wnt targets requires both β-catenin and Rho activation. Significantly, neither β-catenin stabilization nor nuclear translocation stimulated by Wnt3A is affected by inhibition or activation of RhoA. These findings identify Rho activation as a critical element of the canonical Wnt3A-stimulated, β-catenin-dependent transcriptional program. [Copyright &y& Elsevier]

Abstract: Despite the significance of cigarette smoke for carcinogenesis, the molecular mechanisms that lead to increased susceptibility of human cancers are not well-understood. In our present study, the oncogenic transforming effects of cigarette smoke condensate (CSC) were examined using papillomavirus-immortalized human bronchial epithelial cells (BEP2D). Growth kinetics, saturation density, resistance to serum-induced terminal differentiation, anchorage-independent growth and tumorigenicity in nude mice were used to investigate the various stages of transformation in BEP2D cells. Illumina microarray platforms were used to explore the CSC-induced alteration of global mRNA expression profiles of the earlier period and the advanced stage of CSC-treated BEP2D cells. We showed here that a series of sequential steps arose among CSC-treated immortalized human bronchial epithelial cells, including altered growth kinetics, resistance to serum-induced terminal differentiation, and anchorage-independence growth. In the earlier period of CSC treatment, 265 genes were down-regulated and 63 genes were up-regulated, respectively, and in the advanced stage of CSC treatment, 313 genes were down-regulated and 145 genes were up-regulated, respectively. Notably, among those genes, the expression of some of imprinted genes such as IGF2, NDN, H19 and MEG3 were all silenced or down-regulated in CSC-treated cells. These genes reactivated after 5μM 5-aza-2-deoxycytidine (5-aza-dC) treatment. These results demonstrated that long-term treatment of human bronchial epithelial cells with CSC may adversely affect their genetic and epigenetic integrity and lead to further transformation. [Copyright &y& Elsevier]

Acrylamide is widely used worldwide in industry and it can also be produced by the cooking and processing of foods. It is harmful to human beings, and human brain CK (HBCK) has been proposed to be one of the important targets of acrylamide. In this research, we studied the effects of acrylamide on HBCK activity, structure and the potential binding sites. Compared to CKs from rabbit, HBCK was fully inactivated at several-fold lower concentrations of acrylamide, and exhibited distinct properties upon acrylamide-induced inactivation and structural changes. The binding sites of acrylamide were located at the cleft between the N- and C-terminal domains of CK, and Glu232 was one of the key binding residues. The effects of acrylamide on CK were proposed to be isoenzyme- and species-specific, and the underlying molecular mechanisms were discussed. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase (CA) IX is a plasma membrane-associated member of the α-CA enzyme family, which is involved in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in several human cancers. An aberrant increase in CA IX expression in chronic hypoxia and during development of various carcinomas contributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control. Here we report the X-ray structure of the catalytic domain of CA IX in complex with a classical, clinically used sulfonamide inhibitor, acetazolamide. The structure reveals a typical α-CA fold, which significantly differs from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulfide bond. The active site clefts and the PG domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. A correlation between the threedimensional structure and the physiological role of the enzyme is here suggested, based on the measurement of the pH profile of the catalytic activity for the physiological reaction, CO2 hydration to bicarbonate and protons. On the basis of the structural differences observed between CA IX and the other membrane-associated α-CAs, further prospects for the rational drug design of isozymespecific CA inhibitors are proposed, given that inhibition of this enzyme shows antitumor activity both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Summary: Among the 278 092 publications indexed into PubMed in 1979, a handful of articles stand out as the foundation of one of the most profound forays into the molecular basis of carcinogenesis: the discovery of the p53 tumour-suppressor protein. In the 30 years since then, understanding of p53 has progressed from obscure oncogene to key tumour-suppressor gene with clinical potential. Yet, p53 research has not followed a straight course. In this Historical Review, we describe how the 1979 discovery has shaped our view of the molecular basis of cancer, and identify some crucial steps ahead to transfer the wealth of knowledge accumulated on p53 into applications to cancer prevention and treatment. [Copyright &y& Elsevier]

Abstract: Smad signaling pathway plays an important role in tumorigenesis and progression in cancer (Halder, S.K., Rachakonda, G., Deane, N.G., Datta, P.K., 2008. Smad7 induces hepatic metastasis in colorectal cancer. Br. J. Cancer 99, 957–965). The protein level of Smad is associated with growth, inhibition, and metastasis in different cancers. It is unclear if the differentiation, metastasis and apoptosis are reduced by Smad expression pattern in gastric cancer. To determine the effect of Smad on gastric cancer cells, we investigated the relationship of Smad4/Smad7 expression, and differentiation, metastasis, and apoptosis in different gastric cancer. The results show that Smad4 expression in the gastric cancer tissue was dramatically lower than that in the peritumoral tissue. A lower expression of Samd4 was significantly lower in the poorly differentiated tissue than that in the well and middle differentiated tissues (P <0.01). In contrast, Smad7 expression in gastric cancer tissues was significantly higher than that in the peritumoral tissue. Smad7 was overexpressed in poorly differentiated tissue, also higher than those in the middle, and well differentiated tissues (P <0.05). The Smad4 or Smad7 expression obviously related with the lymphatic metastasis in gastric cancer. There were 45 cases with lymphatic metastasis in all 78 patients. Smad4 expression in the cases with lymphatic metastasis was lower than the cases without metastasis (P <0.01), whereas Smad7 expression in the cases with lymphatic metastasis was much higher than the case without metastasis (P <0.01). To better understand the mechanisms involved in tumorigenesis of gastric cancer, we established SGC7901 gastric cancer cell lines transduced with Smad4 or Smad7 plasmid DNA. Apoptosis and survival of cancer cells was induced after Smad4 and Smad7 transduction. This effect is concentration and time dependent. Thus, this study provides a mechanism by which a balance between Smad4 and Smad7 in human gastric cancer is critical for differentiation, metastasis, and apoptosis of tumor cells. [Copyright &y& Elsevier]

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Abstract: The double-stranded RNA-dependent protein kinase (PKR) plays a critical role in various biological responses including antiviral defense, cell differentiation, apoptosis, and tumorigenesis. In this study, we investigated whether PKR could affect the post-translational modifications of STAT1 protein and whether these modifications regulate osteoblast differentiation. We demonstrated that PKR was necessary for the ubiquitination of STAT1 protein. The expressions of bone-related genes such as type I collagen, integrin binding sialoprotein, osteopontin, and osterix were suppressed in osteoblasts lacking PKR activity. In contrast, the expressions of interleukin-6 and matrix metalloproteinases 8 and 13 increased in PKR-mutated osteoblasts. The expression and degradation of STAT1 protein were regulated by PKR in a SLIM-dependent pathway. Inhibition of SLIM by RNA interference resulted in the decreased activity of Runx2 in osteoblasts. Stimulation of interleukin-6 expression and suppression of alkaline phosphatase activity were regulated through by SLIM-dependent pathway. However, expressions of bone-related genes and MMPs were regulated by SLIM-independent pathway. Our present results suggest that the aberrant accumulation of STAT1 protein induced by loss of PKR regulate osteoblast differentiation through both SLIM/STAT1-dependent and -independent pathways. [Copyright &y& Elsevier]

Regulated proteolysis of cellular factors is pivotal to tissue development and homeostasis, whereas uncontrolled proteolytic activity is linked to disease. Type II transmembrane serine proteases (TTSPs) are expressed at the cell surface and are thus ideally located to regulate cell–cell and cell–matrix interactions. Increasing evidence demonstrates that aberrant expression of TTSPs is a hallmark of several cancers and recent studies have defined molecular mechanisms underlying TTSP-promoted carcinogenesis. In addition, new findings suggest that influenza and other respiratory viruses could exploit TTSPs to promote their spread, making these proteases potential targets for intervention in cancer and viral infections. Here, we review the role of TTSPs in tumorigenesis and viral infection and discuss potential approaches to therapy. [Copyright &y& Elsevier]

Abstract: Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm−/− mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm−/− thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm−/− thymocytes. Administration of rapamycin to Atm−/− mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals. [Copyright &y& Elsevier]

The article presents a review on the molecular pathology of invasive lobular breast carcinoma (ILBC). It focuses on ILBC's molecular evolution, genetic changes, putative precursor lesions, and epigenetic changes. It notes that breast carcinogenesis is considered as a multistep process associated to hyperplastic changes. Its cytogenetic characterization reveals vital changes during tumor development and differences between invasive ductal carcinoma and subtypes.

Abstract: Activin, a member of the TGF-β superfamily, inhibits the proliferation of breast cancer cells. Activin interacts with its type I and type II receptors to induce phosphorylation of intracellular signaling molecules known as Smads. Previous studies showed that mouse ARIP2 can reduce activin signaling by interacting with activin type II receptors (ActRIIs); however, the activity of ARIP2 in breast cancer is still unclear. In this study, we used RT-PCR to obtain a human homologue of mouse ARIP2, human activin receptor-interacting protein 2 (hARIP2). Like murine ARIP2, hARIP2 has a PDZ domain in its NH2-terminal region and can interact specifically with ActRIIs. Overexpression of hARIP2 reduced activin-induced transcriptional activity and enhanced cell proliferation and colony formation in human breast adenocarcinoma MCF-7 cells and MDA-MB-231 cells. However, down-regulation of hARIP2 expression by RNAi enhanced activin-induced transcriptional activity and reduced cell proliferation and colony formation. Immunohistochemistry revealed that hARIP2 was expressed more frequently and much more intensely in malignant breast tissues such as simple carcinoma, invasive ductal carcinoma and mucinous adenocarcinoma than in benign hyperplasia or fibroadenoma cases. These results suggest that hARIP2 is a putative growth-promoting factor involved in breast tumorigenesis and tumor development. [Copyright &y& Elsevier]

Abstract: The protein giant neurofibromin (320kDa) is the protein product of the NF1 tumor suppressor gene, alterations of which are responsible for the pathogenesis of neurofibromatosis type 1 (NF1). Neurofibromin is a Ras-specific GTPase activating protein (RasGAP) that, 15 years after the cloning of the gene, remains the only clearly defined function of the protein. In a structural proteomics approach, we aimed at defining functions beyond RasGAP activity based on the discovery of structural modules. Given the poor outcome of domain prediction tools, we have undertaken a fragment solubility survey covering the full protein sequence, with the aim of defining new domain boundaries or fragments that could be investigated by biochemical methods including structural analysis. More than 200 constructs have been expressed and tested for solubility in small scale assays. Boundaries were chosen based upon secondary structure predictions, sequence conservation among neurofibromin orthologues and chemical properties of amino acids. Using this strategy we recently discovered a novel bipartite module in neurofibromin. We have expanded our study to include ESPRIT, a library-based construct screen, to perform fragment testing at a finer level with respect to the choice of terminal residues. Our study confirms earlier notions about the challenges neurofibromin presents to the biochemist and points to strategies whereby the success rate may be enhanced in the future. [Copyright &y& Elsevier]

Abstract: Cyclooxygenase-2 (COX-2), overexpressed in inflammatory conditions and cancer, regulates angiogenesis and tumorigenesis via the production of biologically active prostanoids. Previously, we showed that COX-2 over-expression in the mammary gland of transgenic mice induces an angiogenic switch and transforms the mammary epithelium into invasive mammary carcinoma. Since COX-2-derived prostanoids can activate the nuclear receptor PPARδ, we crossed Pparδ −/− mice with COX-2 transgenic mice in the FVB/N background. PPARδ was expressed constitutively in the mammary gland of virgin, pregnant and lactating mice. Mammary hyperplasia and tumorigenesis in the COX-2 transgenic mice was markedly reduced in the Pparδ −/− mice compared to their wild type counterparts. Analysis of the mammary tissues indicated that immunoreactive Ki-67, cyclin D1 and phosphorylated histone 3 (Phospho H3) were reduced in Pparδ −/− mice, suggesting that PPARδ activation regulates cell proliferation in the mammary gland. We postulate that activation of the nuclear receptor PPARδ by COX-2-derived prostanoids may be involved in the proliferation of mammary epithelial cells and therefore contribute to mammary cancer development. [Copyright &y& Elsevier]

N-nitroso compounds (NOC) are genotoxic, carcinogenic to animals, and may play a role in human cancer development. Because the gastro-intestinal tract is an important route of exposure through endogenous nitrosation, we hypothesize that NOC exposure targets genetic processes relevant in colon carcinogenesis. To investigate these genomic responses, we analyzed the transcriptomic effects of genotoxic concentrations of two nitrosamides, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG, 1μM) and N-methyl-N-nitrosurea (MNU, 1mM), and four nitrosamines, N-nitrosodiethylamine (NDEA, 50mM), N-nitrosodimethylamine (NDMA, 100mM), N-nitrosopiperidine (NPIP, 40mM), and N-nitrosopyrrolidine (NPYR, 100mM), in the human colon carcinoma cell line Caco-2. Gene Ontology gene group, consensus motif gene group and biological pathway analysis revealed that nitrosamides had little effect on gene expression after 24 h of exposure, whereas nitrosamines had a strong impact on the transcriptomic profile. Analyses showed modifications of cell cycle regulation and apoptosis pathways for nitrosamines which was supported by flow cytometric analysis. We found additional modifications in gene groups and pathways of oxidative stress and inflammation, which suggest an increase in oxidative stress and proinflammatory immune response upon nitrosamine exposure, although less distinct for NDMA. Furthermore, NDEA, NPIP, and NPYR most strongly affected several developmental motif gene groups and pathways, which may influence developmental processes. Many of these pathways and gene groups are implicated in the carcinogenic process and their modulation by nitrosamine exposure may therefore influence the development of colon cancer. In summary, our study has identified pathway modifications in human colon cells which may be associated with cancer risk of nitrosamine exposure in the human colon. [ABSTRACT FROM AUTHOR]

Summary : Multiple genetic and epigenetic events, including the aberrant expression and function of molecules regulating cell signaling, growth, survival, motility, angiogenesis, and cell cycle control, underlie the progressive acquisition of a malignant phenotype in squamous carcinomas of the head and neck (HNSCC). In this regard, there has been a recent explosion in our understanding on how extracellular components, cell surface molecules, and a myriad of intracellular proteins and second messenger systems interact with each other, and are organized in pathways and networks to control cellular and tissue functions and cell fate decisions. This emerging ability to understand the basic mechanism controlling inter- and intra-cellular communication has provided an unprecedented opportunity to understand how their dysregulation contributes to the growth and dissemination of human cancers. Here, we will discuss the emerging information on how the use of modern technologies, including gene array and proteomic studies, combined with the molecular dissection of aberrant signaling networks, including the EGFR, ras, NFκB, Stat, Wnt/β-catenin, TGF-β, and PI3K-AKT-mTOR signaling pathways, can help elucidate the molecular mechanisms underlying HNSCC progression. Ultimately, we can envision that this knowledge may provide tremendous opportunities for the diagnosis of premalignant squamous lesions, and for the development of novel molecular-targeted strategies for the prevention and treatment of HNSCC. [Copyright &y& Elsevier]

The ubiquitin system is a network of proteins dedicated to the ubiquitylation of cellular targets and the subsequent control of numerous cellular functions. The deregulation of components of this elaborate network leads to human pathogenesis, including the development of many types of tumour. Alterations in the ubiquitin system that occur during the initiation and progression of cancer are now being uncovered, and this knowledge is starting to be exploited for both molecular diagnostics and the development of novel strategies to combat cancer. [ABSTRACT FROM AUTHOR]

Abstract: The mitotic regulator Aurora-A is an oncogenic protein that is over-expressed in many types of human tumors. However, the underlying mechanism through which Aurora-A promotes tumorigenesis remains unclear. Here, we show that overexpression of Aurora-A causes an elevation of Cyclin B1 expression. Cyclin B1 degradation is delayed in Aurora-A over-expressing cells, which depends on Aurora-A kinase activity. In contrast, Aurora-A RNAi enhances Cyclin B1 degradation. Furthermore, we found that Aurora-A interacts with Cyclin B1, and that Aurora-A overexpression reduces the interaction of Cyclin B1 with APC subunits. In human esophageal squamous cell carcinomas (ESCC), overexpression of Aurora-A was correlated with deregulated expression of Cyclin B1. Taken together, these findings suggest that overexpression of Aurora-A may stabilize Cyclin B1 through inhibiting its degradation. These results provide new insight into the mechanism of how deregulated Aurora-A contributes to genomic instability and carcinogenesis. [Copyright &y& Elsevier]

The antioxidant activity of fresh and dried plant extracts of Paederia foetida and Syzygium aqueum were studied using β-carotene bleaching and the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation assay. The percentage of antioxidant activity for all extract samples using both assays was between 58 and 80%. The fresh samples of both plants had higher antioxidant activity than the dried samples. The results of the β-carotene bleaching assay were correlated (R2 = 0.9849) with those of the ABTS assay. [ABSTRACT FROM AUTHOR]

Abstract: Malignant gliomas (MGs), including glioblastomas and anaplastic astrocytomas are the most common primary brain tumors. Despite treatment advances, the outcome of patients diagnosed with MGs is poor. The current standard treatment protocols for managing these tumors include maximally safe surgical resection, followed by fractioned radiation therapy of the tumor and surrounding brain parenchyma. Until recently, the use of systemic chemotherapy was restricted and ineffective, due to the fact that the blood brain barrier inhibits the adequate therapeutic concentrations of most chemotherapeutic agents into the tumor and peritumoral area. Genetic transformation, like the expression of the DNA repair enzyme methylguanine methyltransferase (MGMT) and specific characteristics of these neoplasms are also causal factors, accounting for the development of treatment resistance to standard chemotherapy options with alkylating compounds. Recent advances, mostly, in thorough understanding of the complex molecular pathogenesis of MGs have led to arousal of rational development of new molecularly targeted treatment options that simultaneously affect multiple signalling pathways. Currently, several molecularly targeted agents, like tyrosine kinase and growth factor inhibitors have been tested in clinical trials to establish future directions in the therapy of MGs. A number of novel targeted strategies, including among others radio-immuno and ligand–toxin conjugates and RNA-based therapies, are also under investigation. We herein review and discuss the standard treatment options and recent advances in the therapy of MGs, with emphasis on the current knowledge towards the molecular pathogenesis of MGs as well as molecularly targeted therapies. We also highlight areas of future research. [Copyright &y& Elsevier]

Summary: In the advancing era of molecular therapy of solid tumours, emergency treatment of complications, such as bowel perforation, haemorrhage, and tumour rupture, is likely to evolve into one of the main challenges of surgical oncology. These complications might be caused by disease progression from resistance to therapy, side-effects of therapy on normal vasculature, and therapeutic induction of excessively responding tumours. This Review outlines the probability and management of emergency operations during molecularly targeted therapy of solid tumours. Special attention is given to advanced gastrointestinal stromal tumours and colorectal cancer, and therapy with imatinib, sunitinib, and bevacizumab. [Copyright &y& Elsevier]

Tissue factor (TF) is the primary initiator of blood coagulation and plays a central role in hemostasis and the maintenance of vascular integrity after injury. In addition to its procoagulant activity, TF modulates cellular processes such as growth, migration and adhesion. TF mediates cell signaling directly through its cytoplasmic domain, or indirectly by activating cell surface receptors as a consequence of activation of the coagulation cascade. TF procoagulant and signaling functions play an important role in cancer biology, mediating tumor growth, angiogenesis, metastasis, and cancer-associated intravascular thrombosis. This review discusses the role TF plays in cancer biology. [ABSTRACT FROM AUTHOR]