Variable Responses of MYC Translocation Positive Lymphoma Cell Lines To Different Combinations of Novel Agents: Impact of BCL2 Family Protein Expression

Several newly developed drugs including JQ1 (BET inhibitor), ABT199 (BCL2 inhibitor), and bortezomib (proteasome inhibitor) may offer novel therapeutic strategies for aggressive diffuse large B-cell lymphoma (DLBCL). We tested these drugs together with doxorubicin in a series of combinations in 16 DLBCL cell lines including 4 ABC-DLBCL (OCI-Ly3, OCI-Ly10, SUDHL2, RIVA) and 12 GCB-DLBCL lines (OCI-Ly4, OCI-Ly18, BJAB, SUDHL4, SUDHL6, SUDHL10, DB, PR1, VAL, SC1, Karpas-231, Karpas-422). Among these cell lines, ABT199 and doxorubicin, and to a lesser extent JQ1 and bortezomib, showed high variations in their ED50 values. Of the six cell lines showing high ABT199 ED50 values, four (SUDHL10, OCI-Ly4, SUDHL2, and BJAB) had no or little BCL2 expression, and SUDHL6 also displayed a low BCL2 expression. There was no association between the ED50 value of doxorubicin, JQ1 and bortezomib, and TP53/MYC/BCL2 genetic abnormalities or cell of origin subtype. A synergistic effect in all or the majority of drug combinations was seen in 11 cell lines, while an antagonistic effect in a high proportion of drug combinations was observed in the remaining 5 cell lines including the 3 (SUDHL10, OCI-Ly4, and SUDHL2) with little BCL2 expression, and additionally OCI-Ly18 and RIVA. Extensive Western blot analyses revealed high MCL1 expression in SUDHL10 and OCI-Ly4 but no apparent alterations in other cell lines. The molecular mechanism underlying the antagonistic effect of drug combinations in DLBCL is heterogeneous with the altered BCL2 family protein expression (absent BCL2, but high MCL1) in some cell lines.     

Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer

OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178). Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.     

Implications of changes in arthropod distribution following chemical application

The influence of pesticide application on the within-field distribution of arthropods was investigated for Tetranychus urticae, the twospotted spider mite, on strawberries. Analyses of dispersions based onGreen's coefficient,Iwao's regression of mean crowding on the mean, andTaylor's power law all indicated that mite populations were highly aggregated initially. As densities increased, more of the avialable niches were filled, leading to a less clumped dispersion. However, pesticide applications causing greater than 99.9% mortality acted in a nearly density independant fashion and, although the originating populations were similar in number, did not produce dispersions equivalent to the initial migrants. As a result, ignoring these changes by developing sampling plans based on dispersion indices which generated a single slope for an entire data set, led to statistical errors that invalidated the sampling programs. In order to accurately reflect the field biology of the spidermites, sampling plans for pre and post-treatment populations were substantially different. The impact of such changes in dispersion were graphically demonstrated using both sequential and binomial sampling techniques. Both methods showed that fewer samples were necessary to estimate densities at a given precision level for post-treatment populations. Also, these techniques indicated that post-treatment populations had similar, but significantly different, dispersions. The implications of changes in pre and post-treatment dispersions, as well as problems associated with inconsistant dispersions following pesticide use, are discussed.     

A Note on the Bias of O'Brien's OLS Test

O'Brien's Ordinary Least Squares (OLS) test is a well known procedure for testing the multivariate one-sided hypothesis when the covariance matrix is unknown. Simulation results have been reported where the actual test level exceeds the nominal one. Here it is shown analytically that the actual level is always larger than the nominal one if the covariance matrix is nonnegative.     

Development of phosphatized hardgrounds in the miocene Globigerina Limestone of the maltese archipelago,including a description ofGamopleura melitensis sp. nov. (Gastropoda,Euthecosomata)

In the Maltese Islands two phosphorite layers occur in the Globigerina Limestone Formation (?Aquitanian to Langhian). These layers, labeled C1 and C2, display a multi-stage development with a two-stage hardground development on top (labelled lower and upper hardground). In the lower hardground, lithification and mineralization followed a sedimentary framework betweenThalassinoides burrows, resembling the Cretaceous ‘nodular chalks’ which were marginally phosphatized when they became exposed to the sea floor. In Phosphorite Layer C2, development of this lower hardground has been superimposed by small-scale cycles. It is underlain by one or more omission surfaces each followed by phosphate-rich, bioturbated biomicrites.