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[en] DNA damage can be assessed by the single cell gel electrophoresis(SCGE), alias, Comet assay; a fast, simple and sensitive technique. Within the last 20 years, the comet assay has been used to investigate primary DNA damage, such as double-strand breaks, single strand breaks, alkali-labile sites, incomplete repair sites and crosslingks. Therefore, comet assay has been applied in a great number of studies to investigate the early biological effects of DNA-damaging agents in environmental, occupational and pathological conditions or exposure to chemicals at the cellular level. From this reason, we investigated the DNA damage in melanoma cells B16F0 treated with boron compounds such as BPA and BSH after neutron irradiation in vitro
[en] T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored member of the cadherin superfamily involved in the guidance of migrating cells. We have previously shown that in vivo T-cadherin overexpression leads to increased melanoma primary tumor growth due to the recruitment of mesenchymal stromal cells as well as the enhanced metastasis. Since tumor progression is highly dependent upon cell migration and invasion, the aim of the present study was to elucidate the mechanisms of T-cadherin participation in these processes. Herein we show that T-cadherin expression results in the increased invasive potential due to the upregulated expression of pro-oncogenic integrins, chemokines, adhesion molecules and extracellular matrix components. The detected increase in chemokine expression could be responsible for the stromal cell recruitment. At the same time our previous data demonstrated that T-cadherin expression inhibited neoangiogenesis in the primary tumors. We demonstrate that T-cadherin overexpression leads to the increase in the expression of anti-angiogenic molecules and reduction in pro-angiogenic factors. Thus, T-cadherin plays a dual role in melanoma growth and progression: T-cadherin expression results in anti-angiogenic effects in melanoma, however, this also stimulates transcription of genes responsible for migration and invasion of melanoma cells
[en] Increased level of serum S100B can serve as a marker of metastatic spread in patients with cutaneous melanoma (CM). In patients with elevated S100 B and/or clinical signs of disease progression PET-CT scan is a valuable tool for discovering metastases and planning treatment. The aims of this study were to determine whether regular measurements of serum S100B are a useful tool for discovering patients with CM metastases and to evaluate the diagnostic value of PET-CT during the follow-up. From September 2007 to February 2010, 115 CM patients included in regular follow up at the Institute of Oncology Ljubljana were appointed to PET-CT. There were 82 (71.3%) patients with clinical signs of disease progression and 33 (28.7%) asymptomatic patients with two subsequent elevated values of S100B. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) of S100B and PET-CT were calculated using standard procedures. Disease progression was confirmed in 81.7% of patients (in 86.5% of patients with clinical signs of disease progression and in 69.7% of asymptomatic patients with elevated S100B). Sensitivity, specificity, PPV and NPV of S100B was 33.8%, 90.9%, 96.0% and 17.5% in patients with clinical signs of disease progression. In 20.0% of patients increased serum S100B was the only sign of disease progression. Sensitivity and PPV of S100 in this group of patients were 100.0% and 69.7%. With PET-CT disease progression was diagnosed in 84.2% of symptomatic patients and in 72.7% of asymptomatic patients with elevated S100B. The sensitivity, specificity, PPV and NPV of PET-CT for symptomatic patients was 98.5%, 90.9%, 98.5% and 90.9% and 100%, 90.0%, 95.8% and 100% for asymptomatic patients with elevated S100. Measurements of serum S100B during regular follow-up of patients with CM are a useful tool for discovering disease progression in asymptomatic patients. The value of its use increases if measurements are followed by extended whole body PET-CT
[en] Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. We describe the characteristics of UM patients at a tertiary referral center in the Mid-Southern United States, and explore associations and predictors of outcomes. This is a retrospective cohort study of patients with UM seen at West Cancer Center, from 07/2006 to 08/2017. Clinical characteristics and their relationship to outcomes (time-to-death and metastasis) were explored using Cox regression analysis. We identified 208 patients, 51% males, 97% Caucasians, 80% were symptomatic, with a median follow-up of 2.34 years, IQR (1.01–3.03), of which 19.2% died during follow-up. Metastases were diagnosed in 19% (4 older patients had metastases at diagnosis), 53% of those by surveillance. Without considering metastases as a time-varying covariate, age (HR = 1.06/year, CI 1.0–1.1; p < 0.001), headaches (HR = 5.7, CI 1.6–20.5; p = 0.03), and tumor stage (T) were significant covariates for time-to-death. Tumor stages T3 versus T1 (HR = 6.4; CI 1.5–27.7; p = 0.01) and T4 versus T1 (HR = 5.98; CI 1.3–27.8; p = 0.02) were associated with worse outcomes. When considering metastases as a time-varying covariate (HR = 35.8, CI 17–75.2; p < 0.001), only age remains in the model (HR = 1.04/year; p < 0.001). However, tumor stage (p < 0.001), headaches (p = 0.008), and age (p < 0.001) are associated with time-to-metastasis. One in five patients developed metastasis which was the most influential factor on mortality. Predictors of mortality were metastasis, age, tumor stage, and headache as a reported symptom. Surveillance successfully diagnosed metastatic disease in most patients. Most patients had symptoms preceding their UM diagnosis highlighting an opportunity for earlier recognition of UM.
[en] Abnormal BRAF and p16INK4A co-exist in 60% of melanomas. BRAF mutation also occurs in 80% of benign nevi where it turns-on p16INK4A resulting in proliferative senescence; loss of p16INK4A removes the inhibitory block leading to melanoma development. Since only melanomas with wild-type BRAF have amplified CDK4 and cyclin D1 genes, p16INK4A-CDK4/6-cyclin D pathway is viewed as linearly downstream of BRAF. Thus, co-occurrence of aberrant BRAF and INK4A may be remnant of changes during melanoma formation without functional significance. To explore this notion, we simultaneously knocked down BRAF (via siRNA) and expressed INK4A cDNA in melanoma cells and observed enhanced growth inhibition. Notably, although each alone had no statistically significant effect on apoptosis, co-expression of BRAF siRNA and INK4A cDNA caused potent apoptosis, which was associated with up-regulation of BIM and down-regulation of BCL2. Our results suggest that aberrant BRAF and INK4A cooperate to promote proliferation and survival of melanoma cells
[en] Non melanoma skin cancers (NMSCs), which include basal and squamous cell cancers are the most common human cancers. BCCs have a relatively low metastatic rate and slow growth and are frequently underreported. Whilst there is a definite role of sun exposure in the pathogenesis of BCC, several additional complex genotypic, phenotypic and environmental factors are contributory. The high prevalence and the frequent occurrence of multiple primary BCC in affected individuals make them an important public health problem. This has led to a substantial increase in search for newer noninvasive treatments for BCC. Surgical excision with predetermined margins remains the mainstay treatment for most BCC. Of the newer non-invasive treatments only photodynamic therapy and topical imiquimod have become established in the treatment of certain BCC subtypes, while the search for other more effective and tissue salvaging therapies continues. This paper focuses on the pathogenesis and management of BCC.
[en] The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3’ UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A–allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes
[en] In summary these preliminary results indicate that Imatinib is able to induce apoptosis in metastatic cells and to sensitize these cells to pro-apoptotic agents commonly used in melanoma therapy, e.g. radiation or Cisplatin. Conversely, primary melanoma cells seem to be intrinsically resistant either to Imatinib given alone or in combination with Cisplatin or radiation. By contrast, these cells underwent autophagy and replicative senescence boostering their survival. Interestingly, the use of Imatinib in combination with anti-CD95/Fas antibodies sensitizes primary melanoma cells to apoptosis
[en] The optimal management of uveal melanoma is still a matter of controversy. To determine the effect of Gamma Knife surgery for patients with uveal malanoma. The authors reviewed the results of 5 patients underwent Gamma Knife surgery between Sep. 1993 and Dec. 1996. The mean age was 60.7 years ranging from 42.5 to 76.5 years. Median follow-up was 13.29 months and the patient with follow up period more than 6 months was 4. The mean tumor volume was 3442 mm3 (mean diameter 15.3 mm) and all patients were irradiated with a mean maximum dose of 74 Gy (range 60-80 Gy), using the 50% isodose. After Gamma Knife surgery. One patient showed complete disappearance in tumor size with follow-up 32 months, One enucleation due to progression, and 2 no interval change. In regard to vision, one patient blind. One enucleation, and 2 patients had no interval change. According to our experiences, Gamma Knife surgery for uveal melanoma be able to achieve local tumor control, spare the eyeball, and have possibility of save vision.
[en] Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in mutation-bearing tumors. Recently, advances have been made which are revolutionizing the standard of care for patients with BRAF mutant melanoma. This paper provides an overview on the pathogenic ramifications of mutant BRAF signaling, the latest molecular testing methods to detect BRAF mutations, and the most recent clinical data of BRAF pathway inhibitors in patients with melanoma and BRAF mutations. Finally, emerging mechanisms of resistance to BRAF inhibitors and ways of overcoming this resistance are discussed.