Role of Tcf7l2 Mediated Wnt/Beta-Catenin Signaling in the Establishment of Habenular Asymmetry

Brain asymmetries are a conserved feature of the vertebrate nervous systems that allows an efficient processing of complex neuronal tasks. Given that alterations in asymmetrically formed areas of the human brain can have devastating consequences it is surprising that the genetic basis underlying their development is still poorly understood. In the zebrafish epithalamus, medial and lateral neurons of the habenulae are differentially distributed on the left and right side of the brain. Recent advances shed light on signaling pathways involved in the establishment of asymmetric habenulae. However, the underlying mechanisms and epistatic relationships between them are unclear. This study reveals that Tcf7l2 is a key component of habenular asymmetry establishment. In its absence the habenulae develop symmetric neuronal specification as habenular progenitors differentiate mainly into lateral neurons on both sides of the brain. Interestingly, Tcf7l2 is expressed asymmetrically in habenular precursor cells. The data obtained are consistent with a model by which Tcf7l2 mediated Wnt/beta-catenin signaling switches the differentiation program of precursor cells and promotes medial habenula cell fate. On the left side, this activity is suppressed by signals derived from the adjacent parapineal cells, which results in continued generation of lateral habenula neurons. Thus, a combination of parapineal and Tcf7l2 signals can promote the asymmetric habenular organization

Autologous Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Drug Induction: A Retrospective Single-Center Analysis.

Within this retrospective single-center study, we analyzed the survival of 320 multiple myeloma (MM) patients receiving melphalan high-dose chemotherapy (HDCT) and either single (n = 286) or tandem (n = 34) autologous stem cell transplantation (ASCT) from 1996 to 2012. Additionally, the impact of novel induction regimens was assessed. Median follow-up was 67 months, median overall survival (OS) 62 months, median progression-free survival (PFS) 33 months (95% CI 27-39), and treatment-related death (TRD) 3%. Multivariate analysis revealed age ≥60 years (p = 0.03) and stage 3 according to the International Staging System (p = 0.006) as adverse risk factors regarding PFS. Median OS was significantly better in newly diagnosed MM patients receiving induction therapy with novel agents, e.g., bortezomib, thalidomide, or lenalidomide, compared with a traditional regimen (69 vs. 58 months; p = 0.01). More patients achieved at least a very good partial remission in the period from 2005 to 2012 than from 1996 to 2004 (65 vs. 30%; p < 0.001), with a longer median OS in the later period (71 vs. 52 months, p = 0.027). In conclusion, our analysis confirms HDCT-ASCT as an effective therapeutic strategy in an unselected large myeloma patient cohort with a low TRD rate and improved prognosis due to novel induction strategies