CDK1 and Cyclin A Expression is Linked to Cell Proliferation and Associated with Prognosis in Non-Hodgkin's Lymphomas

Cellular proliferation is regulated by several kinasic complexes associating cyclins and their catalytic subunits cyclin-dependent kinases (CDKs). In order to gain insight into the mechanisms underlying proliferation in non-Hodgkin's lymphoma (NHL), we examined the expression of certain cell cycle regulatory proteins normally expressed in lymphoid cells, cyclins A, B, D3 and E and cdkl, 2, 4, and 6. In 70 patients presenting a previously untreated lymphoma, cyclins and CDKs were studied by Western blotting and quantified by densitomerry. Flow cytometry study of DNA content was canied out for all patients in order to study cell proliferation and level of ploidy. The results were analysed according to the histological types, the immunological phenotypes of the lymphomas and the outcome of the patients.

Cdk1 and cyclin A were correlated with the percentage of cells in S and S+G2/M phases, and significantly different according to the grade of malignancy, with the lowest expression in low-, and the highest in high-grade NHL according to the Working Formulation. In B-NHLs, cdkl, cyclin A, as well as cdk2, cyclin D3 and E expression was higher in the aneuploid than in the euploid group. Our results point to some particularities of cell cycle regulation in two lymphoma sub-types: I) a low expression of cyclin D3 and cdk6 in mantle cell lymphomas and 2) a discrepancy between the high proliferative activity and the level of protein expression in Burkitt's lymphomas. CDKl and cyclin A showed a significant prognostic value for achievement of complete remission (Cdk 1) and for both disease free (cyclin A) and overall survival (cyclin A and cdkl): low protein level was associated with the best prognosis in B-NHLs.

Our results show that differential cell cycle regulating protein expression may be associated with different biological and clinical behaviour of NHLs and confirm the usefulness of the study of cell cycle regulation as a tool for understanding lymphoid malignancies.     

Myelodysplastic syndromes. A multiparametric study of prognostic factors in 336 patients

Two groups of patients with a myelodysplastic syndrome (MDS) were analyzed by univariate (log-rank test) and multivariate (logistic regression) analyses to detect the most important prognostic factors. By stepwise analysis, the variables found to have prognostic significance for death were as follows: age, percentage of marrow blasts, presence of circulating blasts, and number of platelets. The variables found significant for predicting progression to acute leukemia (AL) were as follows: hemoglobin level, percentage of marrow blasts, and presence of circulating blasts. The first group of 193 patients was used to build a prognostic index which reflected the probability of a given patient dying or progressing to AL within 6, 9, or 12 months. The application of this prognostic index to a test group of 143 patients was used to determine the expected error rate and the validity of the prediction rule.     

Eating Disorders and Disturbance in Children and Adolescents With Cystic Fibrosis

People with cystic fibrosis are considered at risk for developing anorexia (Raymond et al., 2000), but studies have used methodologically flawed measures. Using improved methodology, the current study examines the prevalence of eating disorders/disturbance in adolescents with CF. Method: 55 adolescents with CF, age range 11-17 years (mean 14.2 years) randomly selected were administered the Child Eating Disorder Examination (Bryant-Waugh, Cooper, Taylor, & Lask, 1996). Results: No participant met full criteria for a diagnosis of anorexia or bulimia. Of those with a BMI ≤ 17.5, 5% avoided weight gain. Fifty-three percent demonstrated disturbed eating attitudes and 16% disturbed eating behaviours. Discussion: The study finds that gold standard diagnostic methods indicate the prevalence of disturbed eating attitudes and behaviors in CF.     

Cell-cycle prognostic value in adult acute myeloid leukemia. The choice of the best variables

Flow cytometry with simultaneous analysis of DNA and protein content allows a most exhaustive study of cell-cycle for the prognostic evaluation of acute myeloid leukemia (AML). Sixty-seven cases of AML were studied before any form of chemotherapy had been undertaken. We determined the following cell-cycle variables: S, S + G2 + M, low protein content fraction (LPC-fraction) and high protein content fraction of G1 (HPC-G1). Patients were stratified according to age: S and S + G2 + M phases were higher for patients over 50 who did not achieve a complete remission. LPC-fraction was significantly lower for patients older than 50 who did not achieve a complete remission not only compared to the complete remission group of patients over 50, but also compared to the younger non responder group. The duration of survival was significantly longer when LPC-fraction was higher than 26% and HPC-G1 lower than 70%. Length of survival was also better when S + G2 + M was longer than 5.75%. Analysis of the therapy failure showed that S + G2 + M and LPC-fraction were significantly different between the complete remission group and the group of patients dying in aplasia. Overall, patients older than 50 with a proliferative leukemia had a worse prognosis.     

The Impact of Diabetes on Patient Outcomes After Total Knee Arthroplasty in an Asian Population

Background

Diabetes is implicated with poorer outcomes and more complications after total knee arthroplasty (TKA). We aim to determine whether diabetes affects infection risk, functional outcomes, patient-reported outcome measures, and patient satisfaction in Asian patients after TKA.

Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers

Hepatic oval cells (HOC) are thought to be a type of facultative stem cell that arises as a result of certain forms of hepatic injury. A new and more efficient model has been established to activate the oval cell compartment in mice by incorporating 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) in a standard chow at a concentration of 0.1%. At the present time, very few markers exist for the mouse oval cells. One accepted marker is A6, an uncharacterized epitope recognized by mouse hepatic oval cells and it is accepted to be an oval cell marker. Sca-1 is a cell surface marker used to identify hematopoietic stem cells in conjunction with Thy-1+, CD34+, and lineage-specific markers. Both the CD34 and Sca-1 antigens are not normally expressed in adult liver, but are expressed in fetal liver, presumably on the hematopoietic cells. We report herein that mouse oval cells express high levels of Sca-1 and CD34, as well as CD45 surface proteins. Immunohistochemistry revealed that the cells expressing Sca-1/CD34/CD45 were indeed oval cells because they co-expressed the oval cell-specific marker A6 (94.57% +/- 0.033%), as well as alpha-fetoprotein (AFP) (75.92% +/- 0.071%). By using Sca-1 antibody in conjunction with magnetic activated cell sorting (MACS), followed with a flow cytometric cell sorting (FACS) method for CD34 and CD45, we have developed a rapid oval cell isolation protocol with high yields of greater than 90%. In conclusion, we have an efficient murine model for the production and isolation of large numbers of highly purified oval cells. Our system works with most strains of mouse, which will facilitate both in vivo and in vitro studies of mouse hepatic oval cells.     

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

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Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration

BACKGROUND AND AIMS: The ability of the bone marrow cells to differentiate into liver, pancreas, and other tissues led to the speculation that these cells might be the source of adult stem cells found in these organs. The present study analyzed whether the bone marrow cells are a source of hepatic oval cells involved in rat liver regeneration induced by 2-acetylaminofluorene (2-AAF) and 70% partial hepatectomy (PHx). METHODS: Three groups of mutant F344 dipeptidyl peptidase IV-deficient (DPPIV(-)) rats were required for the study. Groups A and B received the mitotic inhibitor monocrotaline, followed by male F344 (DPPIV(+)) bone marrow transplantation. Next, group A received PHx only, while group B received the 2-AAF/PHx required for the oval cell activation. The last group C was used to analyze the effects of monocrotaline on transplanted bone marrow cells. These rats underwent transplantation with bone marrow cells and were then treated with monocrotaline. Subsequently, the animals were treated with 2-AAF/PHx. RESULTS: In group A, DPPIV(+) hepatocytes were found in the liver. Group B showed that approximately 20% of the oval cell population expressed both donor marker (DPPIV) and alpha-fetoprotein, and some differentiated into hepatocytes. In contrast, animals in group C failed to significantly induce oval cells with the donor DPPIV antigen. In addition, X/Y-chromosome analysis revealed that fusion was not contributing to differentiation of donor-derived oval cells. CONCLUSIONS: Our results suggest that under certain physiologic conditions, a portion of hepatic stem cells might arise from the bone marrow and can differentiate into hepatocytes.     

Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats

BACKGROUND AND AIMS: Hepatic regeneration is a heterogeneous phenomenon involving several cell populations. Oval cells are considered liver stem cells, a portion of which derive from bone marrow (BM). Recent studies have shown that granulocyte-colony stimulating factor (G-CSF) may be effective in facilitating liver repair. However, it remains unclear if G-CSF acts by mobilizing BM cells, or if it acts locally within the liver microenvironment to facilitate the endogenous restoration program. In the present study, we assessed the involvement of G-CSF during oval cell activation. METHODS: Dipeptidyl-peptidase-IV-deficient female rats received BM transplants from wild-type male donors. Four weeks later, rats were subjected to the 2-acetylaminofluorene/partial hepatectomy model of oval cell-mediated liver regeneration, followed by administration of either nonpegylated G-CSF or pegylated G-CSF. Control animals did not receive further treatments after surgery. The magnitude of oval cell reaction, the entity of BM contribution to liver repopulation, as well as the G-CSF/G-CSF-receptor expression levels were evaluated. In addition, in vitro proliferation and migration assays were performed on freshly isolated oval cells. RESULTS: Oval cells were found to express G-CSF receptor and G-CSF was produced within the regenerating liver. G-CSF administration significantly increased both the magnitude of the oval cell reaction, and the contribution of BM to liver repair. Finally, G-CSF acted as a chemoattractant and a mitogen for oval cells in vitro. CONCLUSIONS: We have shown that G-CSF facilitates hepatic regeneration by increasing the migration of BM-derived progenitors to the liver, as well as enhancing the endogenous oval cell reaction.