Expression of Wilms’ tumor gene (WT1) is associated with survival in malignant pleural mesothelioma

INTRODUCTION: Calretinin and Wilms' tumor gene (WT1) are mesothelial markers routinely used to confirm the diagnosis of malignant pleural mesothelioma (MPM). We investigated the prognostic value of calretinin and WT1 expression in predicting survival in a series of patients diagnosed with MPM in our institution. MATERIALS AND METHODS: Fifty-two patients diagnosed of MPM were retrospectively reviewed. Calretinin and WT1 were stained for IHC analysis in formalin-fixed, paraffin-embedded sections and positivity was considered for tumors with >1 % of tumor cells stained. Survival data were calculated by the Kaplan-Meier method and Cox regression was used to evaluate the prognostic value of the variables. RESULTS: Calretinin IHC expression was positive in 83.7 % of patients and WT1 in 78.1 %. A significant association of calretinin and WT1 expression with epithelial histology was detected (p = 0.030 and p = 0.010). We found a significant increase in OS in patients with epithelial subtype, PS1 and neutrophil-lymphocyte ratio (NLR) ≤5 (p < 0.05). In the IHC markers analysis, we found a significant increase in OS for patients with WT1 positive expression (16.4 vs. 2.3 m, p = 0.013), but not differences for calretinin expression (16.6 vs. 5.0 months, p = 0.37). In the multivariate analysis, epithelial histology and WT1 remained as significant prognostic factors for survival (p = 0.004 and p = 0.010, respectively). CONCLUSION: In our series of 52 MPM patients, epithelial histology, PS, NLR and WT1 expression are significant prognostic factors for survival. We concluded that WT1, but not calretinin, is a useful prognostic factor in MPM. The role of WT1 assessment is worth of prospective validation in future studies on MPM (AU)

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Expression of Wilms' tumor gene (WT1) is associated with survival in malignant pleural mesothelioma.

INTRODUCTION: Calretinin and Wilms' tumor gene (WT1) are mesothelial markers routinely used to confirm the diagnosis of malignant pleural mesothelioma (MPM). We investigated the prognostic value of calretinin and WT1 expression in predicting survival in a series of patients diagnosed with MPM in our institution. MATERIALS AND METHODS: Fifty-two patients diagnosed of MPM were retrospectively reviewed. Calretinin and WT1 were stained for IHC analysis in formalin-fixed, paraffin-embedded sections and positivity was considered for tumors with >1 % of tumor cells stained. Survival data were calculated by the Kaplan-Meier method and Cox regression was used to evaluate the prognostic value of the variables. RESULTS: Calretinin IHC expression was positive in 83.7 % of patients and WT1 in 78.1 %. A significant association of calretinin and WT1 expression with epithelial histology was detected (p = 0.030 and p = 0.010). We found a significant increase in OS in patients with epithelial subtype, PS1 and neutrophil-lymphocyte ratio (NLR) ≤5 (p < 0.05). In the IHC markers analysis, we found a significant increase in OS for patients with WT1 positive expression (16.4 vs. 2.3 m, p = 0.013), but not differences for calretinin expression (16.6 vs. 5.0 months, p = 0.37). In the multivariate analysis, epithelial histology and WT1 remained as significant prognostic factors for survival (p = 0.004 and p = 0.010, respectively). CONCLUSION: In our series of 52 MPM patients, epithelial histology, PS, NLR and WT1 expression are significant prognostic factors for survival. We concluded that WT1, but not calretinin, is a useful prognostic factor in MPM. The role of WT1 assessment is worth of prospective validation in future studies on MPM.

Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM).

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM. PATIENTS AND METHODS: Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil-lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis. RESULTS: Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p = 0.04) and overall survival (OS: 23.4 vs 5.6 months; p = 0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p = 0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p = 0.02 and p = 0.04 respectively), but pS6 only showed a trend (p = 0.8). CONCLUSIONS: This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.

Effects of age, gender, and senescence on beta-adrenergic responses of isolated F344 rat brown adipocytes in vitro.

We previously reported greater age-related attenuation of cold-induced thermoregulation and brown adipose tissue thermogenic capacity in male vs. female F344 rats. With onset of the rapid weight loss that occurs near the end of the lifespan, this age-related attenuation becomes severe. We refer to this "end-of-life" physiological state of older rats as senescence. Here, we measured oxygen consumption of isolated brown adipocytes and found no age (6 vs. 12 vs. 26 mo) or gender effects on maximal norepinephrine (NE)- or CL-316,243 (beta 3-adrenergic agonist)-induced responses. In contrast, brown adipocytes from 22- to 26-mo-old senescent rats (males and females) consumed 51-60% less oxygen during maximal stimulation with NE and CL-316,243 than did cells from 26-mo-old presenescent rats. This attenuation was associated with lower (65-72%) uncoupling protein 1 concentrations but no alterations in NE-induced cAMP levels or lipolysis. Our data indicate that senescence, but not chronological age, significantly impacts NE-/beta 3-mediated thermogenesis of isolated brown adipocytes and that this effect involves altered mitochondrial rather than altered membrane or cytosol events.

Tyrosine hydroxylase-containing neurons in the spinal cord of the chicken. I. Development and analysis of catecholamine synthesis capabilities.

1. The development of tyrosine hydroxylase-immunoreactive (TH-IR) neurons was examined in the spinal cord of the chick embryo and hatchling. 2. Two groups of TH-IR cells are described, both of which appear to reach their full complement in number relatively late in embryonic development. One group is comprised of numerous cells located ventral to the central canal which make direct contact with the lumen of the canal. The other group consists of large multipolar neurons that reside in the dorsal horn, more commonly along the outer margin of the gray matter within lamina I and II, and less frequently deeper in the dorsal horn within medial portions of laminae V, VI or VII. 3. TH-IR cells ventral to the central canal in the chick are comparable in location to dopamine (DA)-containing spinal cord cells in lower vertebrate species. In contrast, the dorsally-suited TH-IR cells in the chick are known only to occur in similar positions in higher vertebrates. Therefore, the chick is novel in that the presence of both groups of TH-IR cells appearing together in significant numbers within the spinal cord has not been shown in any other species studied to date. 4. The TH-containing cells in the chick cord do not appear to contain the catecholamine biosynthesis enzymes, DBH or PNMT. Moreover, using anti-DA immunocytochemistry, neither group of TH-IR cells demonstrated detectable levels of DA in control animals nor in animals pretreated with inhibitors of MAO (MAO-I). 5. However, a difference was noted though between the two TH-IR cell groups in terms of their responses to exogenously supplied L-DOPA, the immediate precursor to DA. With the administration of L-DOPA and a MAO-I to chick hatchlings, cells in the region ventral to the central canal stained intensely for DA. In contrast, the same treatment failed to produce DA-immunoreactive cells in the dorsal horn. 6. One reasonable hypothesis for these results is that the TH-IR cells ventral to the central canal contain an active form of AADC, the enzyme that converts L-DOPA to DA. With this interpretation, if these cells can produce DA from L-DOPA, yet do not appear to synthesize DA endogenously, it would appear that the TH enzyme contained in these cells occurs in an inactive form. Whether the TH enzyme in the dorsally located immunoreactive cells is also inactive is uncertain since it remains unclear whether they contain AADC.

Effects of age and gender on brown fat and skeletal muscle metabolic responses to cold in F344 rats.

Older male Fischer 344 (F344) rats do not maintain core temperature as well as do older females during cold exposure. To elucidate factors contributing to the decreased thermoregulatory ability of older males, the metabolic potentials of interscapular brown adipose tissue (IBAT) and skeletal muscle were evaluated at rest (26 degrees C) and during 4 h of cold (6 degrees C) in male and female F344 rats, aged 6, 12, and 26 mo. Compared with 26-mo-old females, cold-exposed 26-mo-old males exhibited a greater drop in core temperature and lower amounts of IBAT mitochondrial uncoupling protein (UCP) and IBAT thyroxine 5'-deiodinase (T5'D) activity. Unlike females, 26-mo-old males showed no cold-induced increase in total IBAT UCP or T5'D activity. In contrast, plasma norepinephrine was higher in cold-exposed 26-mo-old males vs. females, whereas plasma insulin and thyroxine did not differ with gender. Skeletal muscle oxidative capacity (measured by citrate synthase activity) and carbohydrate availability (measured by muscle glycogen and plasma glucose levels) did not differ between the 26-mo-old males and females. Our data suggest that altered regulation of IBAT UCP levels during cold exposure of aged rats, due at least in part to attenuated cold-induced IBAT T5'D activity, contributes to the gender difference in thermoregulatory ability of older males vs. females.

Holoendemicity of malaria: an avian model.

In the Llanos (Flatlands) of Venezuela a high malaria parasite rate was found in nesting birds, mainly in many species of Ciconiiformes, in contrast to a very low one in adults. Species of Plasmodium in birds of this order have seldom been reported. The high densities and sporozoite rates of the local vector, Aedeomyia squamipennis, and the increasing parasite rates with age, suggest a great intensity of transmission, leading to 100% infection by the time the young birds leave their nests. The situation is regarded as a form of holoendemicity equivalent to that described in man in certain parts of Africa and elsewhere, which also produces a high mortality and is probably the cause of population control. Double and triple infections of different subgenera of Plasmodium were extremely frequent, and probably also of different species in the same sub-genus. Such mixed infections with high densities of parasites suggest the possibility of hybridization, and the presence of hybrids may explain the difficulties in the identification of many of the isolates.

What can and cannot be achieved with conventional anti-malaria measures.

Malaria eradication has been based on interception of the vectors through the spraying of houses with DDT. With proper strategy and adequate execution this goal should be achieved in the extensive areas where the vector is responsive to the insecticide, but in large regions where it is refractory other conventional measures against the vectors are more costly and cannot produce eradication. In such cases new ways should be sought to tackle the other primary epidemiological factors--the parasite and the susceptible human being. There is so far no drug which can eliminate the parasites from man with one or two doses and that has a long-lasting protective effect against new infections, the two conditions required for effectiveness in the field. The development of a vaccine to protect susceptible human beings is the other possibility being explored at the present time. Let us hope that such a vaccine may become available.