Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases

Although >66% of melanomas harbor activating mutations in BRAF and exhibit constitutive activity in the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway, it is unclear how effective MEK inhibition will be as a sole therapeutic strategy for melanoma. We investigated the anticancer activity of MEK inhibition in a panel of cell lines derived from radial growth phase (WM35) and vertical growth phase (WM793) of primary melanomas and metastatic melanomas (1205Lu, 451Lu, WM164, and C8161) in a three-dimensional spheroid model and found that the metastatic lines were completely resistant to MEK inhibition (U0126 and PD98059) but the earlier stage cell lines were not. Similarly, these same metastatic melanoma lines were also resistant to inhibitors of the phosphatidylinositol 3-kinase/Akt pathway (LY294002 and wortmannin). Under adherent culture conditions, the MEK inhibitors blocked growth through the induction of cell cycle arrest and up-regulation of p27, but this was readily reversible following inhibitor washout. However, when the phosphatidylinositol 3-kinase and MEK inhibitors were combined, the growth and invasion of the metastatic melanoma three-dimensional spheroids were blocked. Taken together, these results suggest that the most aggressive melanomas are resistant to strategies targeting one signaling pathway and that multiple signaling pathways may need to be targeted for maximal therapeutic efficacy. It is further suggested that BRAF mutational status is not predictive of response to MEK inhibition under three-dimensional culture conditions.     

Intestinal leishmaniasis and Sézary syndrome: endoscopic diagnosis

Sézary syndrome is a non-Hodgkin's lymphoma of cutaneous origin that provokes severe cellular immunosuppression leading to greater susceptibility to opportunistic infections. We present the case of a male patient with a diagnosis of Sézary syndrome complicated by visceral leishmaniasis and Mycobacterium avium complex coinfection, with intestinal involvement of both pathogens -an exceptional finding in the absence of HIV infection. The diagnosis was confirmed by bone marrow biopsy and oral endoscopy with intestinal biopsy. Because of the severity of the infection and the failure of conventional treatment, miltefosine, a new antiparasitic agent still under investigation, was administered with favorable response. However the patient developed fatal pneumonia.     

Antimalarials: an update in rheumatic diseases

Antimalarials are long-standing drugs that have been used since the nineteenth century for the treatment of skin rashes and lesions in lupus and rheumatoid arthritis. In recent decades, their use in these disorders has been consolidated, and new mechanisms of action have been incorporated, broadening the therapeutic perspectives of these drugs. Antimalarials are the treatment of choice in mild and moderate manifestations of systemic lupus erythematosus and are established as part of combined therapy in rheumatoid arthritis. They have been shown to have beneficial effects on atherosclerosis, as well as a possible role in the early treatment of antiphospholipid syndrome. Lastly, they have been shown to have a potential use in other rheumatic diseases such as Sj?gren's Syndrome and palindromic rheumatism. This review aims to provide an update on the use of these drugs in rheumatology and to discuss their toxicity profile.     

Embryonic and early postnatal abnormalities contributing to the development of hippocampal malformations in a rodent model of dysplasia

While there are many recent examples of single gene deletions that lead to defects in cortical development, most human cases of cortical disorganization can be attributed to a combination of environmental and genetic factors. Elucidating the cellular or developmental basis of teratogenic exposures in experimental animals is an important approach to understanding how environmental insults at particular developmental junctures can lead to complex brain malformations. Rats with prenatal exposure to methylazoxymethanol (MAM) reproduce many anatomical features seen in epilepsy patients. Previous studies have shown that heterotopic clusters of neocortically derived neurons exhibit hyperexcitable firing activity and may be a source of heightened seizure susceptibility; however, the events that lead to the formation of these abnormal cell clusters is unclear. Here we used a panel of molecular markers and birthdating studies to show that in MAM-exposed rats the abnormal cell clusters (heterotopia) first appear postnatally in the hippocampus (P1-2) and that their appearance is preceded by a distinct sequence of perturbations in neocortical development: 1) disruption of the radial glial scaffolding with premature astroglial differentiation, and 2) thickening of the marginal zone with redistribution of Cajal-Retzius neurons to deeper layers. These initial events are followed by disruption of the cortical plate and appearance of subventricular zone nodules. Finally, we observed the erosion of neocortical subventricular zone nodules into the hippocampus around parturition followed by migration of nodules to hippocampus. We conclude that prenatal MAM exposure disrupts critical developmental processes and prenatal neocortical structures, ultimately resulting in neocortical disorganization and hippocampal malformations.     

Human mortality due to invertebrate and vertebrate envenomation in Monagas State, Venezuela

Human mortality due to envenomation by animals in Monagas state, Venezuela was evaluated. In this state 47 deaths due to envenomations produced by vertebrates and invertebrates (scorpions = 21, snakes = 20, bees = 6) during the period 1980-2000 were registered. The mountainous area, at the north of the state (Turimiquire sub-region) and its piedmonts reported most of the mortality by scorpionism (57.2%) and ophidism (70.0%). The age group of the patients was related with the sort of envenomation causing the death. During the period of dry season the highest percentage of deaths by scorpions and bees occurred; and the deaths produced by snakes were more frequent in the median raining season. The most frequent causes of death (61.9%) by scorpionism were the acute lung edema and congestive heart failure. In 40% of the deaths caused by snakes, alterations of the blood coagulability were observed. Bee envenomation was responsible of 50% of the deaths produced by anaphylactic shock. In none of the deaths, the species responsible of the accident was identified. The annual mean mortality rate/100,000 inhabitants, in the 21 years registered was 0.20 for the scorpion envenomation, 0.19 for ophidism and 0.06 for bee envenomation. The data suggest the importance of the mortality produced by scorpions and snakes, particularly at the north of the state.