Activation of the ER stress and calcium signaling in angiomyolipoma.

Renal angiomyolipomas (AMLs) are uncommon benign tumors that occur sporadically or as a part of tuberous sclerosis complex (TSC). Risk of life threatening hemorrhage is the main clinical concern. Although several evidences suggest that hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is crucial for these tumors, modulation of other metabolic pathways might affect tumor growth and progression. Therefore, we aimed to further characterize angiomyolipoma by TSC1/TSC2 expression, hypoxic status, expression of endoplasmic reticulum (ER) stress markers and calcium transport from the ER through the inositol 1,4,5-trisphosphate (IP3) receptors. Despite our expectations, angiomyolipoma were not hypoxic, as determined by absent expression of the carbonic anhydrase IX, which is a reliable marker of hypoxia. This was in accord with very low expression of TSC1 (that is associated with HIF activation) and a high expression of TSC2. Angiomyolipoma specimens also showed a significant upregulation of an anti-apoptotic marker Bcl2 when compared to healthy kidney tissue supporting the induction of pro-survival signaling. Moreover, angiomyolipoma specimens showed the overexpression of the ER stress markers XBP1, CHOP and ATF4 as well as of the mediators of calcium metabolism, namely the type 1 and 2, but not the type 3 IP3 receptors. These data suggest that the ER stress response, survival and calcium metabolism-related pathways but not hypoxia is an important component of the angiomyolipoma pathogenesis.

Endosialin: molecular and functional links to tumor angiogenesis.

Endosialin, alternatively named tumor endothelial marker 1 (TEM1) or CD248, is a bulk transmembrane glycoprotein expressed both in developing and adult tissues undergoing active physiological or pathological angiogenesis. Endosialin is often overexpressed in tumors, particularly in stromal cells and in vessels-covering pericytes, and its transcription is induced by hypoxia via HIF-2 transcription factor. Based on the expression pattern, molecular characteristics and phenotypes of genetic models, endosialin has been proposed to function as a receptor implicated in sprouting angiogenesis, vasculogenesis and/or pruning of vessels. Here we provide an overview of the recent knowledge linking endosialin to diverse aspects of angiogenesis. Based on data-mining, our experimental data and available literature, we suggest that endosialin cross-talks with both pro- and anti-angiogenic signals and ECM components, and participates in dynamic vascular remodeling, which facilitates tumor growth. Tumor-selective targeting of endosialin may therefore contribute to improvement of existing anti-angiogenic therapies.

[Tumour Hypoxia -  Molecular Mechanisms and Clinical Relevance]. / Nádorová hypoxia -  molekulárne mechanizmy a klinický význam.

Oxygen is absolutely essential for correct functioning of living organisms and alterations in its concentration lead to serious consequences. In tumor tissues, oxygen plays an important role in energy production and modulation of red- ox balance. Insufficient oxygen supply within tissues results in hypoxia that is a characteristic feature of the tumor microenvironment. Hypoxia- inducible transcriptional factor represents a key executor of a cellular and molecular response to hypoxia and can activate the expression of more than hundred genes involved in various essential cellular processes. From the clinical point of view, phenotypic alterations caused by hypoxia are serious. Tumor hypoxia has been associated with resistance to therapy, disease progression and recurrence as well as increased mortality. Therefore, intratumoral hypoxia represents a clinically relevant problem, and its detection within tumors is very important for patient stratification for a suitable treatment. Currently available strategies directed towards the detection of hypoxic regions within tumor tissue suffer from numerous limitations e. g. invasiveness, inaccessibility of tumor tissue, low sensibility, inaccurate interpretation etc. On the other hand, the use of an intrinsic endogenous hypoxic marker, which can be detected through immunohistochemistry, is relatively simple, routinely available, and reproducible and can be performed on both prospective and retrospective samples. These include carbonic anhydrase IX (CA IX), one of the most strongly hypoxia-induced proteins and a prominent indicator of chronic hypoxia. Moreover, hypoxia-induced proteins (including CA IX) are also potential targets of anticancer therapy, and their practical application is a subject of intense research.

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype.

CA IX is a hypoxia-induced, cancer-associated carbonic anhydrase isoform with functional involvement in pH control and cell adhesion. Here we describe an alternative splicing variant of the CA9 mRNA, which does not contain exons 8-9 and is expressed in tumour cells independently of hypoxia. It is also detectable in normal tissues in the absence of the full-length transcript and can therefore produce false-positive data in prognostic studies based on the detection of the hypoxia- and cancer-related CA9 expression. The splicing variant encodes a truncated CA IX protein lacking the C-terminal part of the catalytic domain. It shows diminished catalytic activity and is intracellular or secreted. When overexpressed, it reduces the capacity of the full-length CA IX protein to acidify extracellular pH of hypoxic cells and to bind carbonic anhydrase inhibitor. HeLa cells transfected with the splicing variant cDNA generate spheroids that do not form compact cores, suggesting that they fail to adapt to hypoxic stress. Our data indicate that the splicing variant can functionally interfere with the full-length CA IX. This might be relevant particularly under conditions of mild hypoxia, when the cells do not suffer from severe acidosis and do not need excessive pH control.

Meningococcal meningitis is still the commonest neuroinfection in the community in tropics: overview of 62 cases.

Within last 17 years we went through all charts of bacterial meningitis within our nationwide survey and among 372 cases we found 62 cases of MM, in 12 cases with meningococcal disease (with shock, petechial effusions or disseminated intravascular coagulation or digital gangrenes). MM was usually observed in young adults without any of investigated risk factors like neoplasia, ENT (ear, nose, throat) focuses, elderly age, sepsis, diabetes, alcoholism, trauma, neonatal VLBW etc. Trauma, diabetes mellitus, alcohol abuse and chronic sinusitis/otitis were significantly less frequently found as a risk factor for MM. Mortality was very low, only 4.8% and was lower than overall mortality in CBM (12.4%, NS). Also the proportion of neurologic sequellae (9.7%) and initial treatment failure (8.1%) were comparable or even lower. This positive outcome results are probably because all N. meningitis strains were susceptible to penicillin, chloramphenicol, cefotaxim, cotrimoxazol or ciprofloxacin. Other reason for low mortality was that most cases received oral antibiotic immediately, even before admission (50 of 62). 95.2% of cases survived, 90.3% without any transient neurological residual symptoms.