Asymmetry-defective oligodendrocyte progenitors are glioma precursors

Postnatal oligodendrocyte progenitor cells (OPC) self-renew, generate mature oligodendrocytes, and are?a cellular origin of oligodendrogliomas. We show that the proteoglycan NG2 segregates asymmetrically during mitosis to generate OPC cells of distinct fate. NG2 is required for asymmetric segregation of EGFR to the NG2(+) progeny, which consequently activates EGFR and undergoes EGF-dependent proliferation and self-renewal. In contrast, the NG2(-) progeny differentiates. In a mouse model, decreased NG2 asymmetry coincides with premalignant, abnormal self-renewal rather than differentiation and with tumor-initiating potential. Asymmetric division of human NG2(+) cells is prevalent in non-neoplastic tissue but is decreased in oligodendrogliomas. Regulators of asymmetric cell division are misexpressed in low-grade oligodendrogliomas. Our results identify loss of asymmetric division associated with the neoplastic transformation of OPC.     

VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex

Inhibition of VEGF signaling leads to a proinvasive phenotype in mouse models of glioblastoma multiforme (GBM) and in a subset of GBM patients treated with bevacizumab. Here, we demonstrate that vascular endothelial growth factor (VEGF) directly and negatively regulates tumor cell invasion through enhanced recruitment of the protein tyrosine phosphatase 1B (PTP1B) to a MET/VEGFR2 heterocomplex, thereby suppressing HGF-dependent MET phosphorylation and tumor cell migration. Consequently, VEGF blockade restores and increases MET activity in GBM cells in a hypoxia-independent manner, while inducing a program reminiscent of epithelial-to-mesenchymal transition highlighted by a T-cadherin to N-cadherin switch and enhanced mesenchymal features. Inhibition of MET in GBM mouse models blocks mesenchymal transition and invasion provoked by VEGF ablation, resulting in substantial survival benefit.     

Ultrastructural abnormalities in the skin nerves of a patient with scleredema adultorum (Buschke) and diabetes mellitus.

In an electron-microscopic study of the skin of a patient with scleredema adultorum (Buschke) and diabetes mellitus, the unmyelinated nerve fibres showed accumulations of glycogen. On morphological grounds, these accumulations appeared to be located in the axons.     

Intranuclear particles in keratoacanthoma: possible association with malignant degeneration.

Electron microscopic investigation of 12 patients with keratoacanthoma is reported. Intranuclear virus-like particles, as described by Zelickson and Lynch, were seen in 3 cases; 2 of these subsequently underwent malignant degeneration. These findings suggest that it is particularly important to exclude the possibility of malignant change in those tumours when intranuclear particles are found.     

Immunohistochemical features of cutaneous granulomas in primary immunodeficiency disorders: a comparison with cutaneous sarcoidosis

Background:  Cutaneous granulomas can occur in patients with a primary immunodeficiency disorder. In some cases, an infectious cause cannot be revealed. The pathogenesis of these granulomas still remains to be elucidated. The aim of this study was to study differences or overlap between these rare granulomas and sarcoidosis-related granulomas.
Methods:  Markers for T-cell subsets (CD3, CD4, CD8 and CD45RO), Langerhans' cells (CD1a), macrophages (CD68), B cells (CD20) and NK cells (CD56) were stained immunohistochemically. The amount of CD4+ and CD8+ cells in the granulomas was counted. Results were compared with the CD4+/CD8+ ratio in peripheral blood.
Results:  In the granulomas of two of three patients with a primary immunodeficiency disorder, the cytotoxic T cells (CD8+) outnumbered the T-helper cells (CD4+) with a counted CD4+/CD8+ ratio <<1. In contrast, the granulomas in the cutaneous sarcoidosis patients showed a predominance of CD4+ cells, with CD4+/CD8+ ratios >2.
Conclusions:  A lower CD4+/CD8+ ratio was found in the cutaneous granulomas of patients with a primary immunodeficiency disorder (unclassified combined immunodeficiency, autoimmune lymphoproliferative syndrome and ataxia teleangiectasia) as compared with the patients with cutaneous sarcoidosis. The possible implications of these findings are discussed in this paper.     

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.     

Changes in circulatory white blood cells of mice and rats due to acute trichothecene intoxication

In mice, administration of pure T-2 toxin caused a rapid decrease of lymphocyte counts, which was linear with respect to dose, whereas granulocyte counts showed a delayed decrease. The blood cell counts of both cell types attained normal values after 4-7 days. Similar results were obtained for crude A-, B- and macrocyclic type trichothecene. Intoxication of rats with T-2 toxin or crude A-type trichothecene caused changes in white blood cells, which differed quantitatively from those in the mouse: lymphocyte counts decreased less and a rapid transient increase of granulocytes was more obvious. Results of this study show that lymphocyte and granulocyte blood cell counts of small rodents respond sensitively to acute intoxication with various trichothecenes.     

Epidermal transglutaminase in the ichthyoses.

Membrane-bound transglutaminase (TGm) is responsible for the cross-linking of proteins to form the cornified envelope. Since abnormalities have been reported in the envelope in certain ichthyoses, we have carried out a survey of TGm concentrations in scales from these disorders. Surprisingly, a striking and specific increase in enzyme activity was found in patients with non-erythrodermic autosomal recessive lamellar ichthyosis. It is not clear how this increase is related to the underlying recessive mutation.     

Tumorigenesis and the angiogenic switch

It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.