Cell proliferation index predicts relapse of brain metastases in non-irradiated patients.

BACKGROUND: Brain metastasis is a common complication and a major cause of morbidity and mortality in human malignancies. We investigated whether the proliferating cell index of surgically treated single brain metastasis would predict the relapse at a location remote from the initial resection site within 2 months of the excision in patients with uncontrolled systemic disease and not subjected to adjuvant whole brain radio-therapy. MATERIALS AND METHODS: Tissue biopsies derived from 25 patients with brain metastases specifically selected to be a single totally resected lesion and not treated subsequently by radiotherapy to the whole brain were stained by immunohistochemistry for the marker CDC47 and the proliferation index was calculated. The index was then analysed with respect to clinical parameters, including the incidence of brain relapse within 2 months of the first resection, the timing of diagnosis of brain metastasis as compared to the primary cancer diagnosis, and the perifocal brain oedema. RESULTS: Statistical evaluation of the indexes in the patients with brain metastases relapsing within 2 months after the first craniotomy (n = 13) revealed significantly higher values as compared to the patients with lesions which had not relapsed or which had relapsed more than 2 months after first craniotomy (n = 12). The synchronous brain metastasis (that is, those occurring before or within 2 months of the primary cancer diagnosis) had a significantly higher proliferation index than the metachronous lesions (those occurring more than 2 months after primary cancer diagnosis). CONCLUSIONS: The synchronous brain metastasis relapses within 2 months of primary resection and have a significantly higher proliferation index than the metachronous lesions which did not recur within 2 months. These results indicate that the estimation of the proliferation index of metastatic brain tumours may be helpful in predicting the course of disease progression.

Homo obesus: a metabotrophin-deficient species. Pharmacology and nutrition insight.

In most countries the prevalence of obesity now exceeds 15%, the figure used by the World Health Organization to define the critical threshold for intervention in nutritional epidemics. Here we describe Homo obesus (man the obese) as a recent phenotypic expression of Homo sapiens. Specifically, we classified Homo obesus as a species deficient of metabotrophic factors (metabotrophins), including endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing. Here we propose that pharmaceuticals, nutraceuticals and xenohormetics targeting transcriptional, secretory and/or signaling pathways of metabotrophins, particularly adiponectin, nerve growth factor, brain-derived neurotrophic factor, interleukin-10, and sirtuins, might be new tools for therapy of Homo obesus. Brief comment is also given to (i) exogenous metabotrophic agents represented by various classes of drugs, and (ii) adiponutrigenomics of lifespan.

Streptozotocin-induced diabetes is associated with changes in NGF levels in pancreas and brain.

Type 1 diabetes mellitus (DM), a "classical" result of a pancreatic-beta cell damage, is associated with various metabolic, neuronal, endocrine and immune alterations at cellular, tissue and organ levels. Nerve growth factor (NGF) is one of the most extensively studied neurotrophic factors, which is produced and released by numerous cells including the pancreatic beta cells. NGF plays an important role during brain development and may be able to delay or even reverse damaged forebrain cholinergic neurons that undergo degeneration in aged animals and in Alzheimer's disease (AD). Recent reports indicate that experimentally induced DM in rodents can cause brain biochemical and molecular alterations similar to those observed in sporadic AD. Given the importance of NGF in the pathophysiology of brain cholinergic neurons, we looked for NGF changes in the pancreas and brain of diabetic rats. The aim of this study was, therefore, to investigate the effect of streptozotocin-induced DM on NGF and NGF receptor expression in pancreas and brain. The results showed that DM is associated with altered NGF, NGF-receptor expression in both pancreas and brain.

Distribution and phenotype of proliferating cells in the forebrain of adult macaque monkeys after transient global cerebral ischemia.

We performed transient global cerebral ischemia on adult macaque monkeys by reversibly stopping blood flow to the brain. We labeled de novo-generated cells in postischemic animals as well as in sham-operated controls by infusing the DNA synthesis indicator BrdU, and subsequently investigated the distribution and phenotype of BrdU-labeled cells in several telencephalic regions at various time-points after ischemia. The ischemic insult significantly increased the number of proliferating cells in the hippocampus, SVZ, neocortex, and striatum, but had no such effect in PHR. In the olfactory bulb, ischemia did not change the proliferating cell levels in the first two postischemic weeks, but did increase these levels at long-term survival time periods. The majority of newly generated cells outside the germinative centers were of a glial phenotype, while neurons constituted only 1% of these cells. Notably, no new neurons were observed in the hippocampal CA1 sector, the region exhibiting the highest vulnerability to ischemia. Within the germinative centers, most BrdU-labeled cells were of a progenitor phenotype and a large proportion of these precursors sustained their existence in the niche for months after ischemia. Furthermore, cells with a progenitor phenotype were identified in brain parenchyma, and these might be responsible for the limited parenchymal neurogenesis as well as for the oligodendrogliogenesis and astrogliogenesis in striatum and neocortex. Our results show that ischemia differentially activates endogenous neural precursors residing in diverse locations of the adult primate CNS. A limited endogenous potential for postischemic neuronal repair exists in neocortex and striatum, but not in the hippocampus proper of the adult macaque monkey brain. The presence of putative parenchymal progenitors and of sustained progenitors in germinative centers opens novel possibilities for precursor cell recruitment to sites of injury. The molecular manipulation of this process may advance our ability to effectively apply brain progenitor cells in the treatment of human neurological diseases.

What are subcutaneous adipocytes really good for?

Our acute awareness of the cosmetic, psychosocial and sexual importance of subcutaneous adipose tissue contrasts dramatically with how poorly we have understood the biology of this massive, enigmatic, often ignored and much-abused skin compartment. Therefore, it is timely to recall the exciting, steadily growing, yet underappreciated body of evidence that subcutaneous adipocytes are so much more than just 'fat guys', hanging around passively to conspire, at most, against your desperate attempts to maintain ideal weight. Although the subcutis, quantitatively, tends to represent the dominant architectural component of human skin, conventional wisdom confines its biological key functions to those of energy storage, physical buffer, thermoregulation and thermoinsulation. However, already the distribution of human superficial adipose tissue, by itself, questions how justified the popular belief is that 'skin fat' (which actually may be more diverse than often assumed) serves primarily thermoinsulatory purposes. And although the metabolic complications of obesity are well appreciated, our understanding of how exactly subcutaneous adipocytes contribute to extracutaneous disease - and even influence important immune and brain functions! - is far from complete. The increasing insights recently won into subcutaneous adipose tissue as a cytokine depot that regulates innate immunity and cell growth exemplarily serve to illustrate the vast open research expanses that remain to be fully explored in the subcutis. The following public debate carries you from the evolutionary origins and the key functional purposes of adipose tissue, via adipose-derived stem cells and adipokines straight to the neuroendocrine, immunomodulatory and central nervous effects of signals that originate in the subcutis - perhaps, the most underestimated tissue of the human body. The editors are confident that, at the end, you shall agree: No basic scientist and no doctor with a serious interest in skin, and hardly anyone else in the life sciences, can afford to ignore the subcutaneous adipocyte - beyond its ample impact on beauty, benessence and body mass.

Expression of angiogenic and neurotrophic factors in the progenitor cell niche of adult monkey subventricular zone.

The subventricular zone along the anterior horn (SVZa) of the cerebral lateral ventricle of adult mammals contains multipotent progenitor cells, which supposedly exist in an angiogenic niche. Numerous signals are known to modulate the precursor cell proliferation, migration or differentiation, in rodent models. In contrast, the data on signals regulating the primate SVZa precursors in vivo are scarce. We analyzed the expression at protein level of a panel of angiogenic and/or neurotrophic factors and their receptors in SVZa of adult macaque monkeys, under normal condition or after transient global ischemia which enhances endogenous progenitor cell proliferation. We found that fms-like tyrosine kinase 1 (Flt1), a receptor for vascular endothelial cell growth factor, was expressed by over 30% of the proliferating progenitors, and the number of Flt1-positive precursors was significantly increased by the ischemic insult. Smaller fractions of mitotic progenitors were positive for the neurotrophin receptor tropomyosin-related kinase (Trk) B or the hematopoietic receptor Kit, while immature neurons expressed Flt1 and the neurotrophin receptor TrkA. Further, SVZa astroglia, ependymal cells and blood vessels were positive for distinctive sets of ligands/receptors, which we characterized. The presented data provide a molecular phenotypic analysis of cell types comprising adult monkey SVZa, and suggest that a complex network of angiogenic/neurotrophic signals operating in an autocrine or paracrine manner may regulate SVZa neurogenesis in the adult primate brain.

Cellular localization of NGF and NGF receptors in aged human thymus.

Recent evidence indicates that some thymic cells of developing and adult laboratory animals express the neurotrophin NGF and its low-affinity p75NTR and high-affinity TrkA receptor. Less is known as to whether the thymus of adult and aged humans express these markers. We hypothesize that the presence and distribution of immunopositive cells for NGF and NGF receptors undergo some alterations during the involution of human thymus. Specimens from normal thymuses of old individuals were obtained from autopsy and surgery cases, and examined immunocytochemically at the light and transmission electron microscopic level. The immunoreactivity of NGF, p75NTR, TrkA and cytokeratin was found in the epithelial thymocyte microenvironment. Our results provide the first ultrastructural evidence for NGF/receptor immunocytochemical localization in human thymus. They suggest a possible immunotrophic/immunoregulatory role of the NGF-p75NTR-TrkA system for T-cell development in human thymus during senile involution.

Adipobiology of disease: adipokines and adipokine-targeted pharmacology.

In recent years, the simple paradigm of adipose tissue as merely a fat store is rapidly evolving into a complex paradigm of this tissue as multipotential secretory organ, partitioned into a few large depots, including visceral and subcutaneous location, and many small depots, associated with a variety of organs in the human body. The major secretory compartment of adipose tissue consists of adipocytes, fibroblasts, and mast cells. These cells, using endocrine, paracrine and autocrine pathways, secrete multiple bioactive molecules, conceptualized as adipokines or adipocytokines. This review examines current information in adipobiology of various diseases besides obesity and related diseases such as type 2 diabetes, metabolic syndrome, and cardiovascular disease. Finally, we emphasize the possibilities for adipokine-targeted pharmacology in adiponectin (Acrp30, apM1, AdipoQ, GBP28), angiotensin II, estrogens, nerve growth factor, tumor necrosis factor-alpha, and also adipose mast cells.

Nerve growth factor levels and mast cell distribution in human coronary atherosclerosis.

Nerve growth factor (NGF), in addition to its neurotrophic function, acts on a variety of non-neuronal cells including immune cells and vascular smooth muscle cells. The aim of the present study was to determine the NGF levels and the distribution of NGF and low-affinity NGF receptor (p75NGFR) and mast cells (MC) in human atherosclerotic coronary arteries. Specimens of human coronary arteries obtained from autopsy cases (n=12, subjects with atherosclerotic lesions; n=9, subjects without atherosclerotic lesions/controls) were used. The present study showed that in the atherosclerosis-lesioned arteries, the amount of NGF decreased, whereas the expression of p75NGFR immunoreactivity and the number, both of MC and vasa vasorum, particularly in the adventitia, significantly increased, compared with the control arteries. Cumulatively, our findings help to set the neurotrophic theory and its currently extended neuroimmune framework into the context of pathobiology of atherosclerosis, suggesting that altered presence of NGF, p75NGFR, and MC may play a role in neuroimmune mechanisms of human coronary atherosclerosis.

NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome.

While multiple growth factor, cytokines, and immune cells are identified in atherosclerotic lesions, as well as an essential nonneuronal function of neurotrophins implicated in cardiovascular tissue development and in lipid and glucose metabolism, the role of the neurotrophins NGF and BDNF and also the adipokine leptin in human coronary atherosclerosis and related disorders, such as metabolic syndrome, remains unclear. Here we report that (i) both the amount and the immunoreactivity of NGF was reduced and the expression of p75NGF receptor and the number of mast cell increased in human atherosclerotic coronary arteries (n = 12) compared with control specimens (n = 9) obtained from autopsy cases, and (ii) NGF and BDNF plasma levels were reduced in patients with metabolic syndrome (n = 23) compared with control subjects (n = 10). Also, in metabolic syndrome patients, a positive correlation between the plasma leptin levels and the number of adipose tissue mast cells was found, suggesting that leptin may be a novel adipoimmune mediator. Altogether, the results provide the first correlative evidence for the potential involvement of NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome, implying neuroimmune and adipoimmune pathways in the pathobiology of these cardiovascular disorders.