Whether human cancer follows a hierarchical or stochastic model of differentiation is controversial. Furthermore, the factors that regulate cancer stem-like cell (CSC) differentiation potential are largely unknown. We used a novel microfluidic single-cell culture method to directly observe the differentiation capacity of four heterogeneous ovarian cancer cell populations defined by the expression of the CSC markers aldehyde dehydrogenase (ALDH) and CD133. We evaluated 3,692 progeny from 2,833 cells. CD133+ cell expansion while suppressing the proliferation of ALDH − CD133 − cells. As such, BMP2 suppressed bulk cancer cell growth in vitro but increased tumor initiation rates, tumor growth, and chemotherapy resistance in vivo whereas BMP2 knockdown reduced CSC numbers, in vivo growth, and chemoresistance. These data suggest a hierarchical differentiation pattern in which BMP2 acts as a feedback mechanism promoting ovarian CSC expansion and suppressing progenitor proliferation. These results explain why BMP2 suppresses growth in vitro and promotes growth in vivo. Together, our results support BMP2 as a therapeutic target in ovarian cancer.ovarian cancer | cancer stem cells | BMP2 | differentiation capacity | hierarchical

High grade serous ovarian cancer (HGSOC) is a disease with a high relapse rate and poor overall survival despite good initial responses to platinum-based therapy. Cell cycle inhibition with targeted CDK4/6 inhibitors is a new therapeutic approach showing promise as a maintenance therapy in cancer. As multiple genes in the CDK4/6 pathway are commonly mutated or dysregulated in ovarian cancer, we evaluated the efficacy of the CDK4/6 inhibitor Ribociclib alone, in combination with chemotherapy, and as maintenance therapy in several models of HGSOC. Ribociclib restricted cellular proliferation in multiple ovarian cancer cell lines. Restricted proliferation was associated with a pseudo-senescent cellular phenotype; Ribociclib-treated cells expressed markers of senescence, but could rapidly re-enter the cell cycle with discontinuation of therapy. Surprisingly, concurrent Ribociclib and cisplatin therapy followed by Ribociclib maintenance was synergistic. Evaluation of the cell cycle suggested that Ribociclib may also act at the G2/M check point via dephosphorylation of ATR and CHK1. Consistent with this mechanism, Ribociclib demonstrated clear activity in both platinum-resistant and platinum-sensitive tumor models in vivo. This work supports clinical trials using Ribociclib in combination with cisplatin and as a maintenance therapy in ovarian cancer.

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Comparing electrophoretic mobility patterns of 14 enzymes of nine strains of cultured avian trypanosomes and two strains of cultured mammalian trypanosomatids revealed marked differences between the strains isolated from Falco sparverius and those isolated from other host raptors as well as among the avian trypanosomatids and the mammalian ones. These results supported the differentiation of two species of raptor trypanosomes based on other criteria: size, form, in vitro growth behavior, surface carbohydrate expression, lectin-mediated agglutination, and qualitative activity profiles of 19 enzymes. The results indicate that biochemical characteristics, particularly isoenzyme electrophoretic data, are useful and objective additions to the traditional criteria used to type and classify Trypanosoma spp. of birds. Trypanosoma bennetti n. sp. from F. sparverius is described as a new species, and the other avian trypanosome strains are identified as T. avium Danilewsky, 1885. A phylogenetic tree, constructed by methods of numerical taxonomy, revealed that T. bennetti n. sp. is distantly related to T. avium as well as to T. rhodesiense and Leishmania chagasi.

SUMMARY Bacillus subtilis is capable of producing the antibiotic bulbiformin in soil. Antibiotic production is considerably enhanced when the soil is sterile and enriched with nutrients such as aspartic acid or asparagin, and dextrose or certain root residues. In the presence of the root supplements the antibiotic persists in soil over several weeks in fairly high concentrations.Under favourable conditions for antibiotic production such as the presence of root residues, inoculation of B. subtilis into soil results in a marked lowering of the incidence of pigeon‐pea wilt due to Fusarium udum.