MLPA analysis of uveal melanoma predicts metastatic death if statistically insignificant losses of chromosome 3 are considered together with gains in 8q as well as clinical stage and histologic grade of malignancy.
Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies.
We examined the effect of small changes in extracellular Na+ concentration ([Na+]e) on myogenic tone (MT) in isometrically mounted ring segments of the rabbit facial vein and in pressurized cannulated posterior cerebral artery segments. Decreasing [Na+]e from 150 to 120 mM in the vein increased MT by 24%, and raising [Na+]e to 165 mM attenuated it by 30%. In pressurized posterior cerebral arteries, decreasing [Na+]e to 120 mM reduced the intraluminal diameter by 12%, whereas increasing [Na+]e to 165 mM increased it by 17%. MT was inhibited by amiloride [50% inhibitory concentration (IC50) = 17 +/- 6 microM], an inhibitor of Na(+)-H+ exchange. Diisothiocyanatostilbene sulfonic acid, a Na(+)-Cl(-)-HCO3- cotransporter blocker, inhibited MT with an IC50 of 4.4 +/- 0.65 microM. Ouabain increased MT [50% effective concentration (EC50) = 0.10 +/- 0.04 microM] as did the reintroduction of HCO3- (EC50 5.0 +/- 1.5 mM). Our study suggests that MT in the rabbit posterior cerebral artery and rabbit facial vein is modulated by changes in [Na+]e. This effect is independent of the method used to register changes in wall force. The sensitivity of the tone to changes in [Na+]e and the independence of vessel diameter at different pressures at various [Na+]e may reflect changes in the sensitivity of smooth muscle stretch or mechanoreceptors to [Na+]e.
A second opinion from an expert pathologist on problem-prone melanocytic lesions improves patient care, in our series in 27% of cases.
It is often very difficult to confidently distinguish benign and malignant Spitz lesions, and a diagnosis of Spitz tumor of unknown malignant potential (STUMP) is rendered. To address this problem, we performed molecular genetic analysis in a large group of Spitz tumors (93 Spitz nevi and 77 STUMPs) and identified a subgroup of 24 lesions harboring a HRAS mutation. This subgroup lay predominantly in the dermis, had a relatively low cellularity, showed desmoplasia (with single cells interspersed between the collagen bundles), and had an infiltrating base. In 7 of these 24 cases (29%) melanoma had been the initial diagnosis, or an important differential diagnostic consideration, mainly based on the presence of multiple or deeply located mitotic figures, especially in adult patients. In our series none of the patients with the HRAS-mutated lesions developed recurrences or metastases (mean and median follow-up: 10.5 y). This was in accordance with the literature: review showed that no HRAS mutations had so far been reported in Spitzoid melanomas. We therefore conclude that HRAS mutation analysis may be a useful diagnostic tool to help differentiate between Spitz nevus and Spitzoid melanoma, thereby reducing the frequency of overdiagnosis of melanoma, and to help predict the biological behavior of a STUMP. Moreover, this might be a first step toward a more reproducible classification of Spitz tumors combining histological and genetic data.
A clinical Ibuprofen dose showed potential to inhibit kidney development in neonatal rats. FR did not modulate these effects.
Background: Many premature born neonates receive antibiotic drugs to treat infections, which are applied during active nephrogenesis. We studied the impact of clinical concentrations of gentamicin and alternatives, ceftazidime and meropenem, on ureteric branching. Methods: Mice metanephroi were dissected at embryonic day 13 and cultured in media with or without various concentrations of gentamicin, ceftazidime, or meropenem. Zero and 24 h kidney size were assessed by surface area measurements, and the ureteric tree was visualized by whole mount staining and confocal microscopy. Branching was evaluated by counting and gene expression levels of Wt1, Sox9, Bmp7, Fgf8, and Gdnf were investigated. results: A concentration of 2,000 μmol/l ceftazidime impaired ureteric development. In addition, a 4.5-fold and a 2.5-fold downregulation was noted in Fgf8 and Gdnf, respectively. No adverse effects were noted after gentamicin or meropenem treatment. No relationship was noted between surface area expansion and ureteric bud formation, but surface area at explantation related to bud count after 24 h of culture. conclusion: Ceftazidime, but not gentamicin or meropenem reduced ureteric branching in mice and suggest a role for Fgf8 and Gdnf in its mechanism. Metanephros surface area measurements can be used to reduce intra-and inter-litter variation. k idney development, leading to the formation of nephrons, starts around the 5th wk of gestation and terminates before term birth, around the 34th-36th wk of gestation. Many factors have been described to disturb this developmental process, leading to long-term problems such as hypertension and chronic kidney disease (1).One such disturbing factor may be the use of (nephrotoxic) drugs during kidney development, such as in pregnant women or neonates born before termination of nephrogenesis. Gentamicin, as well as other aminoglycosides, is widely used as part of the first line treatment of (suspected) bacterial infection in neonates to combat Gram-negative infections. Based on data from the Netherlands Perinatal Registry, 62% of neonates born before 32 wk, who can be considered the most vulnerable group, are treated with aminoglycosides (2). However, due to the fact that gentamicin is classified as a nephrotoxic drug, controversy remains on its safety as aminoglycosides have been shown to disturb kidney development and lead to a reduced nephron number in some experimental animals (3-6) and organ culture studies (7).The aim of our research was to study the impact of antibiotic treatments on nephrogenesis in a model of early nephrogenesis. Gentamicin was studied as well as clinically relevant, alternative drug treatments to compare the toxic potentials of these drugs in a clinical dose range. As alternative treatments, we chose a third generation cephalosporin, ceftazidime, and the carbapenem meropenem. These two drugs both have properties to deal with Gram-negative bacteria and have different mechanisms of action compared to gentamicin. Although beta-lactams have their own potencies to...
The kidney is one of the key organs in clearing foreign compounds. The effects of drugs on the developing kidney are relatively unknown. We studied the direct effect of furosemide, hydrochlorothiazide, ibuprofen, and indomethacin on kidney development in an ex vivo embryonic kidney model. At embryonic day 13, metanephroi were dissected from mice and cultured in control media or media supplemented with various clinically relevant concentrations of drugs. The ureteric tree was visualized by whole-mount staining and branching was evaluated by counting. Additionally, gene expression levels of Wt1, Sox9, Bmp7, Fgf8, and Gdnf were investigated. No distinct differences were noted on either ureteric tip development or gene expression analysis for each drug after 24 hr of exposure. Even though short-term exposure to clinically relevant concentrations seems not to disturb renal development, future research is needed to study prolonged or repeated exposures.
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