Search

Although B-RafV600E is the most common somatic mutation in papillary thyroid carcinoma (PTC). how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-RafV600E gene set signature associated with tumor progression in PTCs. An independent cohort of B-RafV600E positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-i (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-RafV600E resulted in TSP-1 downregulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-RafV600E cells in which either B-RafV600E or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated i week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-RafV600E, caused a significant tumor growth delay and decreased distant metastases. without evidence of toxicity. In conclusion, B-RafV600E plays an important role in PTC progression through genes (i.e., TSP-i) important in tumor invasion and metastasis. Testing of a patient's thyroid cancer for B-RafVV600E will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-RafV600E inhibitors, such as PLX4720. [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transitions (EMTs) play an important role in tissue construction during embryogenesis, and evidence suggests that this process may also help to remodel some adult tissues after injury. Activation of the hedgehog (Hh) signaling pathway regulates EMT during development. This pathway is also induced by chronic biliary injury, a condition in which EMT has been suggested to have a role. We evaluated the hypothesis that Hh signaling promotes EMT in adult bile ductular cells (cholangiocytes). In liver sections from patients with chronic biliary injury and in primary cholangiocytes isolated from rats that had undergone bile duct ligation (BDL), an experimental model of biliary fibrosis, EMT was localized to cholangiocytes with Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis. [ABSTRACT FROM AUTHOR]

Abstract: Tp53 is frequently mutated or inactivated in glioblastomas. Due to the impairment of p53 activity, glioblastomas show a high degree of radioresistance. In an attempt to convert the radioresistant phenotype to a more radiosensitive one, we evaluated the efficacy of the combination of Adp53 gene transfer and X-ray irradiation. The combination of Adp53, at low multiplicity in order to mimic the low in vivo efficiency of virus-mediated gene delivery, with X-ray irradiation resulted in a marked decrease of glioblastoms cell survival. Interestingly, Adp53 was able to induce low dose (<2Gy) hypersensitivity. The data suggest the possibility for the development of new therapeutic strategies. [Copyright &y& Elsevier]

Shows that p53 oncosuppresor protein regulates myoblast differentiation by triggering activity of pRb, a cell-cycle regulator. Comparison of the expression of myogenesis-regulated genes in parental and dominant-negative p53-expressing myoblasts; Serial analysis of gene expression of p53.

Many studies about classification and the functional annotation of intrinsically disordered proteins (IDPs) are based on either the occurrence of long disordered regions or the fraction of disordered residues in the sequence. Taking into account both criteria we separate the human proteome, taken as a case study, into three variants of proteins: i) ordered proteins (ORDPs), ii) structured proteins with intrinsically disordered regions (IDPRs), and iii) intrinsically disordered proteins (IDPs). The focus of this work is on the different functional roles of IDPs and IDPRs, which up until now have been generally considered as a whole. Previous studies assigned a large set of functional roles to the general category of IDPs. We show here that IDPs and IDPRs have non-overlapping functional spectra, play different roles in human diseases, and deserve to be treated as distinct categories of proteins. IDPs enrich only a few classes, functions, and processes: nucleic acid binding proteins, chromatin binding proteins, transcription factors, and developmental processes. In contrast, IDPRs are spread over several functional protein classes and GO annotations which they partly share with ORDPs. As regards to diseases, we observe that IDPs enrich only cancer-related proteins, at variance with previous results reporting that IDPs are widespread also in cardiovascular and neurodegenerative pathologies. Overall, the operational separation of IDPRs from IDPs is relevant towards correct estimates of the occurrence of intrinsically disordered proteins in genome-wide studies and in the understanding of the functional spectra associated to different flavors of protein disorder. [ABSTRACT FROM AUTHOR]

This review article explores the possibility of developing an integrated approach to the management of the different needs of endometrial cancer (EC) patients seeking to become pregnant. Life preservation of the woman, health preservation of the baby, a precocious and—as much as possible—minimally invasive characterization of the health and fertility parameters of the patient, together with the concerns regarding the obstetric, neonatal, and adult health risks of the children conceived via assisted reproductive techniques (ART) are all essential aspects of the problem to be taken into consideration, yet the possibility to harmonize such needs through a concerted and integrated approach is still very challenging. This review aims to illustrate the main features of EC and how it affects the normal physiology of pre-menopausal women. We also focus on the prospect of a miR-based, molecular evaluation of patient health status, including both EC early diagnosis and staging and, similarly, the receptivity of the woman, discussing the possible evaluation of both aspects using a single specific panel of circulating miRs in the patient, thus allowing a relatively fast, non-invasive testing with a significantly reduced margin of error. Finally, the ethical and legal/regulatory aspects of such innovative techniques require not only a risk-benefit analysis; respect for patient autonomy and equitable health care access allocation are fundamental issues as well. [ABSTRACT FROM AUTHOR]

The p53 oncosuppressor is strictly maintained in an inactive form under normal conditions, while it is post-translationally activated by a variety of stresses, enacting different protective biological functions. Since one critical issue in cancer gene therapy is tumor specificity, we asked whether the tight p53 regulation applies also to exogenously transferred p53. In principle, this type of regulation could allow p53 gene transfer in both normal and tumor cells to produce detrimental effects only in the latter ones. Here, we report that primary bone marrow cells infected with a p53 recombinant retrovirus and transplanted into irradiated mice reconstitute the hematopoietic system, with no detectable alterations in any of its compartments. Furthermore, simultaneous infection of leukemia and bone marrow cells depleted the neoplastic contamination, allowing lifelong, disease-free survival of 65% of the transplanted animals. These results show that exogenous p53 is controlled as tightly as the endogenous one, and opens the way to p53 gene therapy, without requiring tumor targeting.Oncogene (2004) 23, 418-425. doi:10.1038/sj.onc.1207042 [ABSTRACT FROM AUTHOR]

According to data of the International Agency for Research on Cancer and theWorld Health Organization (Cancer Incidence in Five Continents, GLOBOCAN, and theWorld Health Organization Mortality), bladder is among the top ten body locations of cancer globally, with the highest incidence rates reported in Southern andWestern Europe, North America, Northern Africa andWestern Asia. Males (M) are more vulnerable to this disease than females (F), despite ample frequency variations in different countries, with a M:F ratio of 4.1:1 for incidence and 3.6:1 for mortality, worldwide. For a long time, bladder cancer was genetically classified through mutations of two genes, fibroblast growth factor receptor 3 (FGFR3, for low-grade, non-invasive papillary tumors) and tumor protein P53 (TP53, for high-grade, muscle-invasive tumors). However, more recently scientists have shown that this disease is far more complex, since genes directly involved are more than 150; so far, it has been described that altered gene expression (up- or down-regulation) may be present for up to 500 coding sequences in low-grade and up to 2300 in high-grade tumors. Non-coding RNAs are essential to explain, at least partially, this ample dysregulation. In this review, we summarize the present knowledge about long and short non-coding RNAs that have been linked to bladder cancer etiology. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: We provide a review of the literature about the onset and development of hypertrophy of the labia minora, together with some expert opinions on the appropriateness of labiaplasty. Methods: We searched PubMed and used popular search engines, with a greater emphasis on the physiology and hormone-mediated metabolism of these structures, and less emphasis on their surgical treatment. Results: We describe major embryological, cytological, and biochemical features of this anatomical part and summarize the clinical aspects of its hypertrophy, evaluating types of discomfort reported by women and the medical treatments available. Also, based on what is known about the artificial elongation and spontaneous hypertrophy of the inner labia, we illustrate and discuss the main biological factors that may trigger this medical condition. There are not enough data identifying a clear inheritance of inner labia hypertrophy in the absence of other pathological conditions; instead, we found indirect evidence for an association with transient episodes of local inflammation either before birth or during puberty. We also analyze the role played by estrogen receptors and other factors with regard to the onset of this condition and highlight the importance of their timing in determining the size of women's labia minora. Remarkably, most cases of enlarged labia minora should be considered as outliers that are within the physiological range of size variation described for these structures. Conclusions: We generally advise against surgical treatment of labia minora, especially in young, pre-pubertal girls, unless specific medical conditions are also present and/or the psychological impact on the patient is deemed particularly negative. [ABSTRACT FROM AUTHOR]

Abstract: The viral surface glycoprotein neuraminidase (NA) allows the influenza virus penetration and the egress of virions. NAs are classified as A, B, and C. Type-A NAs from influenza virus are subdivided into two phylogenetically distinct families, group-1 and group-2. NA inhibition by oseltamivir represents a therapeutic approach against the avian influenza virus H5N1. Here, structural bases for oseltamivir recognition by group-1 NA1, NA8 and group-2 NA9 are highlighted by the ScrewFit algorithm for quantitative structure comparison. Oseltamivir binding to NA1 and NA8 affects the geometry of Glu119 and of regions Arg130-Ser160, Val240-Gly260, and Asp330-Glu382, leading to multiple NA conformations. Additionally, although NA1 and NA9 share almost the same oseltamivir-bound final conformation, they show some relevant differences as suggested by the ScrewFit algorithm. These results indicate that the design of new NA inhibitors should take into account these family-specific effects induced on the whole structure of NAs. [Copyright &y& Elsevier]

Feline soft tissue sarcomas are spontaneous, rapidly growing, and aggressive neoplasms that mimic their human counterpart. The purpose of this study was to evaluate the feasibility and efficacy of electrochemotherapy (ECT) in an adjuvant fashion for the treatment of feline sarcomas, and the possibility of repeated treatments in the case of recurrence. Cats with fibrosarcoma (FSA) were assigned to receive surgery or surgery plus ECT. Feline patients recruited in the ECT study were enrolled in a microscopic arm (39 patients) or a macroscopic arm (19 patients) on the basis of their tumor status (absence or presence of gross disease). Patients received local injection of bleomycin followed by bursts of eight biphasic pulses at a voltage of 1,300 V/cm for postoperative and of 800 V/cm for intraoperative treatments. The median time to recurrence was 4 months for cats treated with surgery alone, 19 months for the postoperative cohort, and 12 months for the intraoperative group. Moreover, ten patients with recurring neoplasms were retreated and experienced responses lasting 6 to 28+ months. Side effects were minimal. Of interest, the metastatic rate (1.7%) in our patients was negligible: only one cat had distant spread. The results suggest that ECT is a well tolerated and potentially useful addition to surgery in controlling high-grade sarcomas. On the basis of these results, additional evaluations are warranted in pets and in humans. [ABSTRACT FROM AUTHOR]

Summary: Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage. [Copyright &y& Elsevier]

Summary: Aside from the well-established roles of c-Myc in the regulation of cell cycle, differentiation, and apoptosis, a recent picture is beginning to emerge linking c-Myc to the regulation of metabolic pathways. Here, we define a further function for c-Myc in determining cellular redox balance, identifying glutathione (GSH) as the leading molecule mediating this process. The link between c-Myc and GSH is γ-glutamyl-cysteine synthetase (γ-GCS), the rate-limiting enzyme catalyzing GSH biosynthesis. Indeed, c-Myc transcriptionally regulates γ-GCS by binding and activating the promoters of both γ-GCS heavy and light subunits. Exposure to H2O2 enhances c-Myc recruitment to γ-GCS regulatory regions through ERK-dependent phosphorylation. Phosphorylation at Ser-62 is required for c-Myc recruitment to γ-GCS promoters and determines the cellular response to oxidative stress induced by different stimuli. Thus, the c-Myc phosphorylation-dependent activation of the GSH-directed survival pathway can contribute to oxidative stress resistance in tumor cells, which generally exhibit deregulated c-Myc expression. [Copyright &y& Elsevier]

Y RNA are a class of small non-coding RNA that are largely conserved. Although their discovery was almost 40 years ago, their function is still under investigation. This is evident in cancer biology, where their role was first studied just a dozen years ago. Since then, only a few contributions were published, mostly scattered across different tumor types and, in some cases, also suffering from methodological limitations. Nonetheless, these sparse data may be used to make some estimations and suggest routes to better understand the role of Y RNA in cancer formation and characterization. Here we summarize the current knowledge about Y RNA in multiple types of cancer, also including a paragraph about tumors that might be included in this list in the future, if more evidence becomes available. The picture arising indicates that Y RNA might be useful in tumor characterization, also relying on non-invasive methods, such as the analysis of the content of extracellular vesicles (EV) that are retrieved from blood plasma and other bodily fluids. Due to the established role of Y RNA in DNA replication, it is possible to hypothesize their therapeutic targeting to inhibit cell proliferation in oncological patients. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) defines infertility as the inability of a sexually active, non-contracepting couple to achieve spontaneous pregnancy within one year. Statistics show that the two sexes are equally at risk. Several causes may be responsible for male infertility; however, in 30–40% of cases a diagnosis of idiopathic male infertility is made in men with normal urogenital anatomy, no history of familial fertility-related diseases and a normal panel of values as for endocrine, genetic and biochemical markers. Idiopathic male infertility may be the result of gene/environment interactions, genetic and epigenetic abnormalities. Numerical and structural anomalies of the Y chromosome represent a minor yet significant proportion and are the topic discussed in this review. We searched the PubMed database and major search engines for reports about Y-linked male infertility. We present cases of Y-linked male infertility in terms of (i) anomalies of the Y chromosome structure/number; (ii) Y chromosome misbehavior in a normal genetic background; (iii) Y chromosome copy number variations (CNVs). We discuss possible explanations of male infertility caused by mutations, lower or higher number of copies of otherwise wild type, Y-linked sequences. Despite Y chromosome structural anomalies are not a major cause of male infertility, in case of negative results and of normal DNA sequencing of the ascertained genes causing infertility and mapping on this chromosome, we recommend an analysis of the karyotype integrity in all cases of idiopathic fertility impairment, with an emphasis on the structure and number of this chromosome. [ABSTRACT FROM AUTHOR]