GAP-independent functions of DLC1 in metastasis.

Metastases are responsible for most cancer-related deaths. One of the hallmarks of metastatic cells is increased motility and migration through extracellular matrixes. These processes rely on specific small GTPases, in particular those of the Rho family. Deleted in liver cancer-1 (DLC1) is a tumor suppressor that bears a RhoGAP activity. This protein is lost in most cancers, allowing malignant cells to proliferate and disseminate in a Rho-dependent manner. However, DLC1 is also a scaffold protein involved in alternative pathways leading to tumor and metastasis suppressor activities. Recently, substantial information has been gathered on these mechanisms and this review is aiming at describing the potential and known alternative GAP-independent mechanisms allowing DLC1 to impair migration, invasion, and metastasis formation

Inhibition of cell migration and invasion mediated by the TAT-RasGAP317-326 peptide requires the DLC1 tumor suppressor.

TAT-RasGAP317-326, a peptide corresponding to the 317-326 sequence of p120 RasGAP coupled with a cell-permeable TAT-derived peptide, sensitizes the death response of various tumor cells to several anticancer treatments. We now report that this peptide is also able to increase cell adherence, prevent cell migration and inhibit matrix invasion. This is accompanied by a marked modification of the actin cytoskeleton and focal adhesion redistribution. Interestingly, integrins and the small Rho GTP-binding protein, which are well-characterized proteins modulating actin fibers, adhesion and migration, do not appear to be required for the pro-adhesive properties of TAT-RasGAP317-326. In contrast, deleted in liver cancer-1, a tumor suppressor protein, the expression of which is often deregulated in cancer cells, was found to be required for TAT-RasGAP317-326 to promote cell adherence and inhibit migration. These results show that TAT-RasGAP317-326, besides its ability to favor tumor cell death, hampers cell migration and invasion

The Anticancer Peptide TAT-RasGAP317-326 Exerts Broad Antimicrobial Activity.

Antibiotic resistance has become a major health issue. Nosocomial infections and the prevalence of resistant pathogenic bacterial strains are rising steadily. Therefore, there is an urgent need to develop new classes of antibiotics effective on multi-resistant nosocomial pathogenic bacteria. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP), called TAT-RasGAP317-326, induces cancer cell death, inhibits metastatic progression, and sensitizes tumor cells to various anti-cancer treatments in vitro and in vivo. We here report that TAT-RasGAP317-326 also possesses antimicrobial activity. In vitro, TAT-RasGAP317-326, but not mutated or truncated forms of the peptide, efficiently killed a series of bacteria including Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa. In vivo experiments revealed that TAT-RasGAP317-326 protects mice from lethal E. coli-induced peritonitis if administrated locally at the onset of infection. However, the protective effect was lost when treatment was delayed, likely due to rapid clearance and inadequate biodistribution of the peptide. Peptide modifications might overcome these shortcomings to increase the in vivo efficacy of the compound in the context of the currently limited antimicrobial options

A Fully Differential Digital CMOS Pulse UWB Generator

A new fully-digital CMOS pulse generator for impulse-radio Ultra-Wide-Band (UWB) systems is presented. First, the shape of the pulse which best fits the FCC regulation in the 3.1-5 GHz sub-band of the entire 3.1-10.6 GHz UWB bandwidth is derived and approximated using rectangular digital pulses. In particular, the number and width of pulses that approximate an ideal template is found through an ad-hoc optimization methodology. Then a fully differential digital CMOS circuit that synthesizes the pulse sequence is conceived and its functionality demonstrated through post-layout simulations. The results show a very good agreement with the FCC requirements and a low power consumptio

The TAT-RasGAP317-326 anti-cancer peptide can kill in a caspase-, apoptosis-, and necroptosis-independent manner.

Tumor cell resistance to apoptosis, which is triggered by many anti-tumor therapies, remains a major clinical problem. Therefore, development of more efficient therapies is a priority to improve cancer prognosis. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP), called TAT-RasGAP317-326, bears anti-malignant activities in vitro and in vivo, such as inhibition of metastatic progression and tumor cell sensitization to cell death induced by various anti-cancer treatments. Recently, we discovered that this RasGAP-derived peptide possesses the ability to directly kill some cancer cells. TAT-RasGAP317-326 can cause cell death in a manner that can be either partially caspase-dependent or fully caspase-independent. Indeed, TAT-RasGAP317-326-induced toxicity was not or only partially prevented when apoptosis was inhibited. Moreover, blocking other forms of cell death, such as necroptosis, parthanatos, pyroptosis and autophagy did not hamper the killing activity of the peptide. The death induced by TAT-RasGAP317-326 can therefore proceed independently from these modes of death. Our finding has potentially interesting clinical relevance because activation of a death pathway that is distinct from apoptosis and necroptosis in tumor cells could lead to the generation of anti-cancer drugs that target pathways not yet considered for cancer treatment

Crescimento pós-menarca

Although menarche is a late event in the puberal process, most parents do not realize until this moment that their daughters are no longer children. At that time, they usually turn to the pediatrician for enlightenment and serenity. They frequently ask about the girl's growth potential and for an estimate of her final height. There are only a few studies in the scientific literature on postmenarcheal growth, perhaps due to the special characteristics of adolescence, which makes interpretation of the results difficult. The purpose of this review is to provide pediatricians with a means of making more accurate prognosis than populational means on growth after menarche for the adolescent girl, taking into account she has already had menarche. There is no correlation between age at the peak of height velocity and final height. At menarche the adolescent has already reached 95.5% of her final height. Progressively smaller increments in stature continue for 3 to 4.8 years. The early matures (menarche earlier than the mean age of 12.6 years) probably will grow more than the mean of 6 or 7cm, and for a longer period than the ones who are later matures until they reach their final height.Embora a menarca seja um fenômeno tardio dentro do processo puberal, muitos pais percebem, só neste momento, que suas filhas não são mais crianças. Os pediatras são procurados nessa ocasião para esclarecer certas dúvidas e tranqüilizá-los. Com certa freqüência, indagam sobre o potencial de crescimento da menina e pedem que seja estimada sua estatura final. A literatura a respeito do crescimento pós-menarca é escassa, talvez devido às próprias características da adolescência que, por envolver inúmeras variáveis, dificulta a interpretação dos resultados. Esta revisão bibliográfica tem como objetivo focalizar alguns aspectos relacionados ao crescimento, que auxiliem o médico a oferecer um prognóstico um pouco mais preciso do que médias populacionais, para a adolescente que o questiona a respeito, considerando-se que ela já tenha menstruado. Não existe correlação entre a idade em que o pico de velocidade de crescimento ocorre e a estatura final. Na menarca, a adolescente já alcançou 95,5% da estatura final. Por mais 3 ou 4,8 anos, incrementos progressivamente menores irão ocorrer. As meninas que maturam mais cedo (menstruando antes da idade mediana de 12,6 anos para a ocorrência da menarca) provavelmente crescerão mais do que a média de 6 ou 7cm, e por mais tempo, do que as que maturam mais tarde, até atingirem sua estatura final.19520

A WXW Motif Is Required for the Anticancer Activity of the TAT-RasGAP317-326 Peptide.

TAT-RasGAP317-326, a cell-permeable 10-amino acid-long peptide derived from the N2 fragment of p120 Ras GTPase-activating protein (RasGAP), sensitizes tumor cells to apoptosis induced by various anticancer therapies. This RasGAP-derived peptide, by targeting the deleted in liver cancer-1 (DLC1) tumor suppressor, also hampers cell migration and invasion by promoting cell adherence and by inhibiting cell movement. Here, we systematically investigated the role of each amino acid within the RasGAP317-326 sequence for the anticancer activities of TAT-RasGAP317-326. We report here that the first three amino acids of this sequence, tryptophan, methionine, and tryptophan (WMW), are necessary and sufficient to sensitize cancer cells to cisplatin-induced apoptosis and to reduce cell migration. The WMW motif was found to be critical for the binding of fragment N2 to DLC1. These results define the interaction mode between the active anticancer sequence of RasGAP and DLC1. This knowledge will facilitate the design of small molecules bearing the tumor-sensitizing and antimetastatic activities of TAT-RasGAP317-326

Survival, Reproduction and Calcification of Three Benthic Foraminiferal Species in Response to Experimentally Induced Hypoxia

An experiment was conducted to test the survival rates, growth (calcification), and reproduction capacities of three benthic foraminiferal species (Ammonia tepida, Melonis barleeanus and Bulimina marginata) under strongly oxygen-depleted conditions alternating with short periods of anoxia. Protocols were determined to use accurate methods (1) to follow oxygen concentrations in the aquaria (continuously recorded using microsensors), (2) to distinguish live foraminifera (fluorogenic probe), (3) to determine foraminiferal growth (calcein-marked shells and automatic measurement of the shell size). Our results show a very high survival rate, and growth of A. tepida and M. barleeanus in all experimental conditions, suggesting that survival and growth are not negatively impacted by hypoxia. Unfortunately, no reproduction was observed for these species, so that we cannot draw firm conclusions on their ability to reproduce under hypoxic/anoxic conditions. The survival rates of Bulimina marginata are much lower than for the other two species. In the oxic treatments, the presence of juveniles is indicative of reproductive events, which can explain an important part of the mortality. The absence of juveniles in the hypoxic/anoxic treatments could indicate that these conditions inhibit reproduction. Alternatively, the perceived absence of juveniles could also be due to the fact that the juveniles resulting from reproduction (causing similar mortality rates as in the oxic treatments) were not able to calcify, and remained at a propagule stage. Additional experiments are needed to distinguish these two options