DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells.

AIM: To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabine resistant and sensitive lymphocytes from chronic lymphocytic leukemia (CLL) patients. METHODS: Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated. RESULTS: Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine-sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS. CONCLUSION: Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL.

[Unstable chromosome aberrations in lymphocytes of liquidators of the Chernobyl accident consequences]. / Nestabil'nye khromosomnye aberratsii v limfotsitakh uchastnikov likvidatsii posledstvii avarii na Chernobyl'skoi AES.

AIM: Analysis of peripheral blood lymphocytes for detecting unstable chromosome aberrations in liquidators of the Chernobyl disaster consequences and in residents of territories contaminated after the accident. MATERIALS AND METHODS: Peripheral blood lymphocytes were tested for unstable chromosome aberrations in 216 subjects who worked for different periods after the Chernobyl accident in 1986-1987 in the 30-km zone and at adjacent territories. The results were correlated to the duration of stay in the zone, terms of examination after the work, exposure dose fixed in the files, deviations in the health status and blood values, and with similar data on 21 residents of the stringent control regions of the Gomel district and 265 patients with different hematological diseases and donor blood samples exposed in vitro. RESULTS: Chromosome aberrations detected in the examined group are represented by dicentrics, paired and nonpaired fragments, acentric rings, and gaps. CONCLUSION: Although not everything is yet clear, we consider that detection of unstable chromosome aberrations of the dicentric type in lymphocytes of subjects who participated in liquidation of the accident consequences in remote periods after exposure persuasively proves that a radiation exposure, no matter what its dose was, took place, and hence, there are good grounds for including the subjects with aberrations in the high risk group. On the other hand, the absence of such aberrations does not rule out the detrimental effect of radiation on the organism.

[The radioprotective action of an extract of regenerating spleen]. / Protivoluchevoe deistvie ékstrakta regeneriruiushchei selezenki.

An extract from regenerating calf spleen increases the survival rate of mice when injected after irradiation. The studies of the blood and immune systems characteristics at the subcellular, cellular and tissue levels have been shown that the preparation containing a complex of hemoregulating compounds modifies the processes responsible for radiation damage and repair.

Global climate change and intensification of coastal ocean upwelling.

A mechanism exists whereby global greenhouse warning could, by intensifying the alongshore wind stress on the ocean surface, lead to acceleration of coastal upwelling. Evidence from several different regions suggests that the major coastal upwelling systems of the world have been growing in upwelling intensity as greenhouse gases have accumulated in the earth's atmosphere. Thus the cool foggy summer conditions that typify the coastlands of northern California and other similar upwelling regions might, under global warming, become even more pronounced. Effects of enhanced upwelling on the marine ecosystem are uncertain but potentially dramatic.

[Postradiation life span of mice in relation to the modifying action of leukemic cells administered]. / Postradiatsionnaia prodolzhitel'nost' zhizni myshei v zavisimosti ot modifitsiruiushchego deistviia vvedennykh leikoznykh kletok.

Leukemic cells administered to X-irradiated mice modify the radiobiological effect to a degree that depends on the radiation dose, bone marrow transplantation, the quantity and quality of leukemic cells, and the time of their administration.

[Induction of the antileukemic activity in nonimmune allogeneic splenocytes using spleen hemoregulators]. / Induktsiia protivoleikoznoi aktivnosti u neimmunnykh allogennykh splenotsitov s pomoshch'iu gemoregulinov iz selezenki.

The leukemic mice treated with cyclophosphamide were injected twice a week with the allogenic splenocytes treated for 4 h with the substance isolated from the calf spleen. The leukemia growth inhibition was observed. Syngenic splenocytes were inactive. Allogenic but not syngenic splenocytes manifested a certain antileukemic activity observed in the Winn neutralization and 51Cr release tests, however this activity did not correlate quantitatively with more pronounced antileukemic action of cells in vivo.

Mechanisms of immunity to infection with typhus rickettsiae: infected fibroblasts bear rickettsial antigens on their surfaces.

As with any immune response to infectious organisms, both antibody and T cell-mediated immune responses to infection with Rickettsia typhi require the appropriate presentation of rickettsial antigens to immunocompetent cells. Considering the obligate intracellular nature of rickettsiae, the exact mechanisms by which lymphocytes and macrophages encounter and respond to rickettsial antigens may depend on certain aspects of pathogenesis and on the availability of organisms or their antigens to cells of the immune system. One potential mode of rickettsial antigen presentation, not previously identified, is the appearance in vitro of rickettsial antigens on the cell membrane of R. typhi-infected L-929 fibroblasts. Polyvalent fluoresceinated rabbit antisera directed against whole R. typhi cells used in flow cytometric analysis of infected fibroblasts showed an increasing presence of R. typhi antigen on the host cell membrane 1 to 3 days postinfection. The significance of this finding in the pathophysiology of rickettsia-host interactions and the generation of cytotoxic T cell-mediated immunity and antibody immunity is discussed.

[Effect of a substance isolated from the regenerating spleen on the chromatin structural organization and the leukosogenic activity of transplanted cells]. / Vliianie veshchestva, vydelennogo iz regeneriruiushchei selezenki, na strukturnuiu organizatsiiu khromatina i leikozogennuiu aktivnost' transplantirovannykh kletok.

When leukemic cells in vitro are treated with the substance isolated from the regenerating calf spleen, incorporation of 3H-thymidine into DNA is rapidly inhibited. The completeness of DNA synthesis restoration after washing off cells from the substance depends on the duration of the previous contact with the substance. It is the change in the structural organization of chromatin but not the very fact of inhibition of the ability of the cells to the DNA synthesis that is important for a decrease of transplantability of mice cells treated by the substance. The quicker the stability of the DNA/protein interaction in chromatin weakens due to the effect of the substance, the earlier the leukosogenic potential of the treated cells decreases.

[Nuclease activity in leukemia altered lymphoid tissue]. / Nukleaznaia aktivnost' v leikozno izmenennoi limfoidnoi tkani.

Activities of DNAase I, DNAase II, RNAase I and RNAase II were altered in lymphoid tissue during development of lymphoid leukosis in mice of AKR strain, during survival of the leukemic cells as well as in leukemic spleen tissue of mice C57BI with transplantable leukosis La. The enzymatic activity correlated with the step of the process, the rate of leukemic cells proliferation, with dimensions of organs. Variations in the enzymatic activity, as compared with normal state were dissimilar in development of leukosis; activity of the enzymes was either increased or decreased apparently due to their multiple functions in metabolism of nucleic acids.

[Ergometric tests in cardiology (problems of standardization and automation)]. / Ergometricheskie testy v kardiologii (problemy standartizatsii i avtomatizatsii).

A method of ergometric tests furnishing a quantitative evaluation of the coronary and contractile function reserves and also ensuring safe examination has been devised. The veloergometric tests proceed under a continuous ECG and integral rheographic control with automatic throwing-off the load in case of ischemic changes of the ECG or reduction of the circulation volume. The amount of work done by the moment of throwing off the load was taken as a quantitative measure of the corresponding functional reserve. This principle served as a basis for constructing an electronic system automating the conduct and assessment of the veloergometric test. Examinations covered 890 healthy persons and patients. Future prospects for the use of biologically controlled ergometric tests are outlined.