Matrix Metalloproteinases MMP-1 and MMP-9 and Their Inhibitor TIMP-1 as Markers of Dilated Cardiomyopathy in Patients of Different Age.

We studied the expression of MMP-2, MMP-9, and inhibitor TIMP-1 in myocardial autopsy samples from subjects of different age and in cardiomyocyte cultures in the norm and in dilated cardiomyopathy. In autopsy samples of normal myocardium and in cardiomyocyte cultures, expression of molecules involved in extracellular matrix remodeling did not change during aging. In dilation cardiomyopathy, expression of MMP-2, MMP-9, and TIMP-1 and their ratios in autopsy material and in cultures was elevated by 1.5-9 times. Remodeling of extracellular matrix plays an important role in the pathogenesis of dilated cardiomyopathy. MMP-2, MMP-9, and their inhibitor TIMP-1 and the MMP/TIMP ratios can be regarded as promising predictors of dilated cardiomyopathy and used for evaluation of the effectiveness of treatment of this conditions in patients of different ages.

[Impact of preoperative drug therapy on the expression of angiogenesis markers in colorectal liver metastases]. / Vliyanie predoperatsionnoi lekarstvennoi terapii na ekspressiyu markerov angiogeneza v metastazakh kolorektal'nogo raka v pecheni.

AIM: to study changes in the expression of angio- and vasculogenesis markers in colorectal adenocarcinoma metastases to the liver during combined cytotoxic and targeted anti-VEGF therapy versus cytotoxic monotherapy. SUBJECTS AND METHODS: Intraoperative samples from 96 patients with colorectal adenocarcinomas metastases to the liver were immunohistochemically examined. The investigation enrolled patients who had preoperatively received either combined FOLFOX6 cytotoxic therapy and targeted anti-VEGF therapy with bevacizumab or only FOLFOX6 therapy, as well as patients who had not received preoperative anti-tumor drug treatment. The expression of SDF1α, CXCR4, CXCR7, and VEGF-A was compared in these groups. Statistical significance was accepted at p<0.05. RESULTS: The expression of CXCR4 in the vessel endothelial cells was significantly less frequently detected in the patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy as compared to those had not drug therapy. Comparing the patients treated with cytotoxic drugs with those who had not received anti-tumor therapy revealed similar results in the women. CXCR7 expression in the tumor cells and stromal cells from the metastatic foci was significantly more common in the group of male patients treated with cytotoxic drugs according to the FOLFOX6 regimen. The expression of SDF1α in the tumor cells was significantly more often observed in the male patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy than in those who had not drug therapy. VEGF expression in the stromal cells was significantly less frequently seen in the patients who had received the combined therapy. CONCLUSION: Combined cytotoxic therapy and targeted anti-VEGF therapy for colorectal adenocarcinoma metastases to the liver leads to some suppression of the alternative pathway in the formation of new vessels, by reducing the expression of CXCR4 in the vessel endothelial cells and that of VEGF in the stromal cells from the metastatic foci. In men, this therapy simultaneously causes an increase in the expression of SDF1α in the tumor cells and in that of CXCR4 in the stroma. Preoperative FOLFOX6 therapy significantly increases the expression of CXCR7 in the tumor cells and stromal cells in the male patients, which may suggest that this pathway in vessel formation can be activated.

[The forensic medical evaluation of traumatic and spontaneous ruptures of the organs affected by the tumours]. / Sudebno-meditsinskaia otsenka travmaticheskikh i spontannykh razryvov organov pri porazhenii opukhol'iu.

The present article was designed to report the results of the analysis of the cases of traumatic and spontaneous ruptures of the organs affected by the tumours based on the original observations and the literature data. It is shown that the probability of the tumour rupture depends on its histological type, localization, the size, and the distance from the capsule of the affected organ, the degree of involvement of the major blood vessels, the severity of the necrotic changes, the presence of cysts in the neoplasm, and the regimens of radio- and chemotherapy. Moreover, the rupture can be facilitated by anticoagulation therapy, intake or oral contraceptives, pregnancy, concomitant diseases, alcoholic intoxication, splenomegaly, and hypocoagulation resulting from dissemination of the neoplastic process or the metastatic lesions of the liver. Even a minimal injury to the skin can provoke the tumour rupture associated with the fatal hemorrhage. A delayed rupture within a few hours or days is possible.

[On the possibility to determine genetic identity of the tissues with malignant tumours imbedded in paraffin blocks].

The results of analysis of the literature data were used to develop the forensic medical criteria for the assessment of the suitability of paraffin blocks containing the imbedded malignant tumours for the genetic identification of the tissues. The forensic medical criteria and the algorithm for the preliminary characteristic of the material of interest were proposed to avoid the potential errors. It is not recommended to use gastrointestinal carcinomas, breast tumours, and poorly differentiated ovarian tumours. Also unsuitable is the material formerly exposed to radio- and chemotherapeutic agents or paraffin blocks stored during more than 5-7 years. In the doubtful cases, immunohistochemical studies must be carried out to confirm microsatellite instability. Moreover, the tumour genotype and DNA composition from the patients' blood should be confirmed.

[THE ROLE OF ENDOTHELIAL SIGNAL MOLECULES IN PATHOGENESIS OF AGE-ASSOCIATED DISEASES].

The article gives a summary of endothelial signal molecules that take part in homeostasis regulation and age-associated pathology development. Regulation of the endothelium function is realized by the system of signal molecules (NO, NOS, prostacyclin, thrombomodulin, tromboxan, antithrombin, endothelins, fibronectin, Willebrand's factor et al.). The change of their synthesis is the reason for the development of hypertonic disease, atherosclerosis, ischemic heart disease, myocardial infarction and other age-related pathology. The investigation of molecular mechanisms of endothelium functional activity is very important for creating new methods of diagnostics and treatment of cardio-vascular system age-associated pathology.

[Portal hypertensive gastropathy].

In spite of a great number of publications, as yet there is no agreement that which of the detected morphological changes should be considered pathognomonic in portal hypertensive gastropathy (PHG). The study of the pathogenesis of PHG suggested a diversity of mechanisms involved in varying degrees in the development of this abnormality. The paper summarizes the data available in the literature on the role of endothelial dysfunction, apoptosis, damaging factors, and H. pylori infection in the development of this abnormality. A differential diagnosis was made between PHG and GAVE syndrome and histological features in both groups were revealed.

[Impact of preoperative chemotherapy on the expression of apoptosis factors in colorectal cancer liver metastases].

OBJECTIVE: To study the effects of cytotoxic and targeted anti-VEGF drugs on some mechanisms of apoptosis. MATERIAL AND METHODS: The effects of cytotoxic and targeted anti-VEGF drugs on the expression of the apoptosis activators Bax and PML and the apoptosis inhibitor Bcl-2 were studied in the colorectal cancer (CRC) liver metastases; a comparison group comprised patients receiving no chemotherapy. RESULTS: Immunohistochemical examination revealed lower Bax and PML expressions and higher Bcl-2 expression in the majority of untreated patients, suggesting the suppressed mechanisms triggering tumor cell apoptosis. Cytotoxic therapy resulted in a statistically significant rise in the expression of the apoptosis activator Bax (p = 0.01), a reduction in the level of the apoptosis inhibitor Bcl-2 (p = 0.04) and a slight increase in PML that controlled the induction of apoptosis. Adding an anti-VEGF agent to cytotoxic therapy exerted no statistically significant impact on Bax and Bcl-2, but caused more frequent positive PML expression than in the control and cytotoxic chemotherapy groups. CONCLUSION: Our study showed that cytotoxic and targeted anti-VEGF agents activate the apoptosis of tumor cells in the CRC liver metastases.

[IgG4-related chronic periaortitis with retroperitoneal fibrosis].

The paper describes a case of IgG4-related chronic periaortitis in a 56-year-old man. Computed tomography revealed stenosis of the abdominal aorta and both common iliac arteries due to calcified atherosclerotic plaques, in this connection, bifurcation aorta-common femoral bypass surgery was performed. Intraoperatively, a solid retroperitoneal mass intimately connected with the walls of vessels was revealed in the retroperitoneal space around the aorta and iliac arteries. Histological examination ascertained rough fibrous connective tissue growth, a marked lymphoplasmacytic infiltration with an admixture of eosinophils, and formation of lymphoid follicles with germinal centers. Immunohistochemical examination revealed the plasma cell expression of CD20, IgG, IgG4, and kappa and lambda light chains in the inflammatory infiltrate. Because of active immune inflammation, further conservative therapy was recommended.

[Expression of some biomarkers in primary colon adenocarcinomas and their lymph node metastases].

The samples of colon adenocarcinomas (CAC) and their lymph node metastases from 22 patients were studied. The expression of thymidylate synthase (TS), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), E-cadherin, beta-catenin, tenascin C (TN), and KAI-1/CD82 in primary CAC and their lymph node metastases was compared using an immunohistochemical method. The expression of TS, VEGF, EGFR, E-cadherin, TNC, and KAI-1 was statistically significant different in primary CAC and involved lymph nodes. Comparison of the expression of the markers in the pairs of primary CAC and metastasis revealed equal values for TNC and EFGR in 45.5 and 41% of cases, respectively; the number of coincidences in the expression of the other markers was insignificant. Determination of the expression of molecular biological markers in primary CAC and their lymph nodes may serve as a predictor of therapy response and have a prognostic value.

[Molecular markers of colorectal adrenocarcinoma progression].

Colorectal adenocarcinoma and its lymph node metastases from 72 patients and 14 control samples were studied. Expression of adhesive molecules - E-cadherin and beta-catenin, antiadhesive molecule - tenascin C and tumor metastasis suppressor KAI-1 (CD82) were studied by immunohistochemistry. The expression of E-cadherin and beta-catenin, tenascin C and KAI-1 was significantly different in adenocarcinoma and control samples. The expression of E-cadherin, tenascin C and KAI-1 was diverse in primary tumor compared to lymph node metastases. The analysis of current data showed the association of E-cadherin expression with stage of disease and depth of invasion, such as the correlation of beta-catenin nuclear expression and tenascin C expression with depth of adenocarcinoma invasion. These data may be a useful indicator of disease progression.

[Modification of direct immunofluorescence assay to study paraffin-embedded renal and skin tissue sections].

Immunofluorescence assay has been widely used so far to diagnose glomerular and some skin diseases. The optimal antigen persistence is achieved using the frozen sections; however, their considerable shortcoming is the impossibility to long store preparations and to use a morphology archive. Our laboratory has modified a direct immunofluorescence study on paraffin-embedded renal and skin tissue sections, substantially increasing its accessibility.

[Multiple gliosarcoma metastases in the cauda equina roots].

The authors report a rare a case of gliosarcoma metastases in a 28-year-old male patient. The cauda equina roots were involved after brain tumor 16 months ago, which, on microscopic study, had a biphasic pattern and heterogeneous staining in the reaction with antibody to GFAP and vimentin; the tumor cells did not express EMA, EA, and desmin. Gliosarcoma was diagnosed, by taking into account morphological and immunohistochemical data. Tumor tissue of the cauda equine roots had the same immunophenotype as the brain tumor with a predominance of glial component, which permitted the source of metastases to be ascertained.

[Urokinase-type plasminogen activator and its inhibitor type 1 in the diagnosis of evolving complications in coronary heart disease].

Fibrinolytic system components are important in the regulation of thrombogenesis therefore the aim of the investigation was to compare the level of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) in the monocytes of patients with stable coronary heart disease (CHD) and acute coronary syndrome (ACS) to reveal an association of the content of these proteins with the severity of disease, by applying two different techniques: immunocytochemistry and flow cytofluorimetry. The counts of uPA- and PAI-1-expressing monocytes were equal in each case and accounted for 81.9-99.9% in all groups. At the same time, the level of PAI-1 was higher than that of uPA and significantly higher in patients with ACS than in those without ACS and in the controls. No significant differences were found in uPA levels between the ACS and stable CHD groups; however, it was significantly higher in the patient groups than in the control one. The detection of the higher expression of PAI-1 in the peripheral blood monocytes of patients with ACS suggests that it can be used as a marker of disease severity.

[Molecular-genetic analysis of clonal intratumoral heterogeneity on colorectal adenocarcinomas].

We have examined the existence of intratumoral genetic heterogeneity for LOH on chromosomes 9p21 (p16, p15, p19), 13p14 (RB1), 10q23 (PTEN), 17p (TP53), microsatellite instability and K-RAS point mutations on four different segments of sporadic colorectal cancers. The intratumoral genetic heterogenity was detected in 9/11 (81%) colorectal adenocarcinomas and morphologically validated. These results show that colorectal cancer is highly heterogeneous for these molecular markers. Furthermore, the analysis has shown the order (succession) of the appearance of these molecular anomalies during tumorigenesis on sporadic CRC, and supposed, that K-RAS point mutations, and anomalies of p16-RB1-cyclin D pathway could occur before LOH on 10q23 (PTEN) and microsatellite instability during tumor progression.

[Influence of immunosuppressors on remodeling of extracellular matrix in experimental nephropathies]. / Vliianie immunosupressorov na remodelirovanie vnekletochnogo matriksa pri éksperimental'nykh nefropatiiakh.

Influence of methylprednisolone (MP) and cyclosporine A (CsA) on the extracellular matrix and growth factors was studied on the model of rapid nephrotoxic nephritis (RNN) and puromycin-aminonucleoside nephrosis (PAN). MP decreased accumulation of type IV collagen in RNN and increased the content of laminine in both models. CsA decreased deposits of type IV collagen but increased accumulation of fibronectin in both models. CsA reduced the content of a free form of oPRP in both models but MP did so in RNN only. CsA and MP decreased the level of active PRP in both models but MP did so in RNN only. CsA and MP decreased the level of active TPR-beta and increased the content of latent forms but CsA was more active in PAN. In experimental models of inflammatory RNN and non-inflammatory CPAN nephropathy CsA raised fibronectin production, MP increased deposition of laminine. CsA in both models suppressed production of basic fibrogenic factor TPR-beta while MP inhibited this in RNN only.

[Prognostic, diagnostic, and therapeutic prospects of using adiponectine as a biomarker in cardiobascular diseases].

The role of adipose tissue as an important endocrine organ is today beyond doubt. The adipose tissue is known to be a source of many biologically active substances, adipocitokines, one of them being the adiponectine possessing anti-inflammatory, antiatherogenic and cardioprotective properties; it is believed to be one of prospective biomarkers for risk assessment, for diagnostics and, possibly, for therapy of cardiovascular diseases.

[Clinical significance of markers of endothelial dysfunction and angiogenesis in progressing of the lung interstitial diseases].

The data obtained suggest an important role of the FRES and ET-1 in progressing of the lung interstitial diseases; they can be used as diagnostic criteria of the disease activity, risk of pulmonary hypertension, and extra-pulmonary manifestations.