Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM

Characterizing Dissipation in Fluid-Fluid Displacement Using Constant-Rate Spontaneous Imbibition

When one fluid displaces another in a confined environment, some energy is dissipated in the fluid bulk and the rest is dissipated near the contact line. Here we study the relative strengths of these two sources of dissipation with a novel experimental setup: constant-rate spontaneous imbibition experiments, achieved by introducing a viscous oil slug in front of the invading fluid inside a capillary tube. We show that a large fraction of dissipation can take place near the contact line, and rationalize the observations by means of a theoretical analysis of the dynamic contact angles of the front and back menisci of the oil slug. Our results bear important implications for macroscopic descriptions of multiphase flows in microfluidic systems and porous media

Characterizing dissipation in fluid-fluid displacement using constant-rate spontaneous imbibition

When one fluid displaces another in a confined environment, some energy is dissipated in the fluid bulk and the rest is dissipated near the contact line. Here we study the relative strengths of these two sources of dissipation with a novel experimental setup: constant-rate spontaneous imbibition experiments, achieved by introducing a viscous oil slug in front of the invading fluid inside a capillary tube. We show that a large fraction of dissipation takes place near the contact line, and rationalize the observations by means of a theoretical analysis of the dynamic contact angles of the front and back menisci of the oil slug—a result that bears important implications for macroscopic descriptions of multiphase flows in microfluidic systems and porous media