A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE).

Durvalumab, a PD-L1 inhibitor, is part of an immunotherapeutic drug class shown to have prolonged survival benefit in patients with advanced stage hepatocellular carcinoma (HCC). Tivozanib is a potent and selective VEGFR 1, 2 and 3 tyrosine kinase inhibitor. While these medications have both demonstrated single-agent activity in HCC and have been combined safely with other therapies, there is no data on their concurrent therapeutic effects. In the phase Ib DEDUCTIVE trial, the combination of tivozanib plus durvalumab is evaluated for safety and tolerability. Here, the design of and rationale for this trial in both treatment naive patients and those who progress on atezolizumab and bevacizumab for advanced or metastatic HCC are described. Clinical Trial Registration: NCT03970616.

The role of a low erythropoietin level for the polycythemia vera diagnosis.

A low erythropoietin (EPO) level is a minor diagnostic criterion for polycythemia vera (PV). Controversies exist regarding the diagnostic value of a low EPO level when considering increasing availability of advanced molecular testing. We assessed the role of low EPO level for PV diagnosis in the context of positive JAK2 mutation status as well as other diagnostic parameters. Of 138 patients, 75 patients had PV and 63 had secondary erythrocytosis. Of the 75 patients with PV, 32% had EPO levels within the normal range. EPO level positively correlated with obesity and smoking status, making it an unreliable diagnostic marker in those patients. Although EPO level below normal as a standalone diagnostic modality was significantly associated with PV (odds ratio [OR] 0.857; p < 0.001), when JAK2V617F mutation status was included in the prediction model, the association of low EPO was not statistically significant (OR 0.962, p = 0.269). Positive JAK2V617F demonstrated a strong predictive value for PV (OR 670.5, p = 0.006) either alone or in combination with other variables. Results show that EPO level is not a reliable diagnostic marker due to physiologic variation in association with obesity and smoking.

A phylogenomic and molecular signature based approach for characterization of the phylum Spirochaetes and its major clades: proposal for a taxonomic revision of the phylum.

The Spirochaetes species cause many important diseases including syphilis and Lyme disease. Except for their containing a distinctive endoflagella, no other molecular or biochemical characteristics are presently known that are specific for either all Spirochaetes or its different families. We report detailed comparative and phylogenomic analyses of protein sequences from Spirochaetes genomes to understand their evolutionary relationships and to identify molecular signatures for this group. These studies have identified 38 conserved signature indels (CSIs) that are specific for either all members of the phylum Spirochaetes or its different main clades. Of these CSIs, a 3 aa insert in the FlgC protein is uniquely shared by all sequenced Spirochaetes providing a molecular marker for this phylum. Seven, six, and five CSIs in different proteins are specific for members of the families Spirochaetaceae, Brachyspiraceae, and Leptospiraceae, respectively. Of the 19 other identified CSIs, 3 are uniquely shared by members of the genera Sphaerochaeta, Spirochaeta, and Treponema, whereas 16 others are specific for the genus Borrelia. A monophyletic grouping of the genera Sphaerochaeta, Spirochaeta, and Treponema distinct from the genus Borrelia is also strongly supported by phylogenetic trees based upon concatenated sequences of 22 conserved proteins. The molecular markers described here provide novel and more definitive means for identification and demarcation of different main groups of Spirochaetes. To accommodate the extensive genetic diversity of the Spirochaetes as revealed by different CSIs and phylogenetic analyses, it is proposed that the four families of this phylum should be elevated to the order level taxonomic ranks (viz. Spirochaetales, Brevinematales ord. nov., Brachyspiriales ord. nov., and Leptospiriales ord. nov.). It is further proposed that the genera Borrelia and Cristispira be transferred to a new family Borreliaceae fam. nov. within the order Spirochaetales.

Erratum: A phylogenomic and molecular signature based approach for characterization of the Phylum Spirochaetes and its major clades: proposal for a taxonomic revision of the phylum.

[This corrects the article on p. 217 in vol. 4, PMID: 23908650.].

Ectopic γ-catenin expression partially mimics the effects of stabilized ß-catenin on embryonic stem cell differentiation.

ß-catenin, an adherens junction component and key Wnt pathway effector, regulates numerous developmental processes and supports embryonic stem cell (ESC) pluripotency in specific contexts. The ß-catenin homologue γ-catenin (also known as Plakoglobin) is a constituent of desmosomes and adherens junctions and may participate in Wnt signaling in certain situations. Here, we use ß-catenin((+/+)) and ß-catenin((-/-)) mouse embryonic stem cells (mESCs) to investigate the role of γ-catenin in Wnt signaling and mESC differentiation. Although γ-catenin protein is markedly stabilized upon inhibition or ablation of GSK-3 in wild-type (WT) mESCs, efficient silencing of its expression in these cells does not affect ß-catenin/TCF target gene activation after Wnt pathway stimulation. Nonetheless, knocking down γ-catenin expression in WT mESCs appears to promote their exit from pluripotency in short-term differentiation assays. In ß-catenin((-/-)) mESCs, GSK-3 inhibition does not detectably alter cytosolic γ-catenin levels and does not activate TCF target genes. Intriguingly, ß-catenin/TCF target genes are induced in ß-catenin((-/-)) mESCs overexpressing stabilized γ-catenin and the ability of these genes to be activated upon GSK-3 inhibition is partially restored when wild-type γ-catenin is overexpressed in these cells. This suggests that a critical threshold level of total catenin expression must be attained before there is sufficient signaling-competent γ-catenin available to respond to GSK-3 inhibition and to regulate target genes as a consequence. WT mESCs stably overexpressing γ-catenin exhibit robust Wnt pathway activation and display a block in tri-lineage differentiation that largely mimics that observed upon overexpression of ß-catenin. However, ß-catenin overexpression appears to be more effective than γ-catenin overexpression in sustaining the retention of markers of naïve pluripotency in cells that have been subjected to differentiation-inducing conditions. Collectively, our study reveals a function for γ-catenin in the regulation of mESC differentiation and has implications for human cancers in which γ-catenin is mutated and/or aberrantly expressed.