Unexpected activities of Smad7 in Xenopus mesodermal and neural induction

Neural induction is widely believed to be a direct consequence of inhibition of BMP pathways. Because of conflicting results and interpretations, we have reexamined this issue in Xenopus and chick embryos using the powerful and general TGFβ inhibitor, Smad7, which inhibits both Smad1- (BMP) and Smad2- (Nodal/Activin) mediated pathways. We confirm that Smad7 efficiently inhibits phosphorylation of Smad1 and Smad2. Surprisingly, however, over-expression of Smad7 in Xenopus ventral epidermis induces expression of the dorsal mesodermal markers Chordin and Brachyury. Neural markers are induced, but in a non-cell-autonomous manner and only when Chordin and Brachyury are also induced. Simultaneous inhibition of Smad1 and Smad2 by different approaches does not acount for Smad7 effects, indicating that Smad7 has activities other than inhibition of the TGFβ pathway. We provide evidence that these effects are independent of Wnt, FGF, Hedgehog and retinoid signalling. We also show that these effects are due to elements outside of the MH2 domain of Smad7. Together, these results indicate that BMP inhibition is not sufficient for neural induction even when Nodal/Activin is also blocked, and that Smad7 activity is considerably more complex than had previously been assumed. We suggest that experiments relying on Smad7 as an inhibitor of TGFβ-pathways should be interpreted with considerable caution

A phase I trial of recombinant human thrombopoietin in patients with delayed platelet recovery after hematopoietic stem cell transplantation

Delayed platelet recovery is a significant complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). A multicenter, phase I dose-escalation study of recombinant human thrombopoietin (rhTPO) was conducted to assess its safety and to obtain preliminary data on its efficacy in patients with persistent severe thrombocytopenia (35 days after HSCT. Thirty-eight patients, 37 of whom were evaluable, were enrolled in the study from April 1996 through January 1997. rhTPO was administered at doses of 0.6, 1.2, and 2.4 microg/kg as a single dose (group A) or in multiple doses every 3 days for a total of 5 doses (group B). No significant adverse effects were observed. Ten patients had recovery of platelet counts during the 28-day study period; 3 of these 10 had an increase in marrow megakaryocyte content 7 days after completing treatment with rhTPO. When all baseline marrows were compared with samples after rhTPO treatment, there was no difference in marrow megakaryocyte content (P = 0.49). This study design could not answer the question of whether the recoveries of platelet counts observed in some patients were spontaneous or influenced by rhTPO treatment; nonetheless, the authors found no correlation between the dose of rhTPO and the recovery of platelet counts. Increases in serum TPO levels were dose-dependent and remained significantly elevated for up to 72 hours after treatment. To evaluate response, further studies of treatment strategies with rhTPO in patients with delayed platelet recovery are required. Biol Blood Marrow Transplant 2000;6(1):25-34

Prolonged haematological toxicity from the hyper-CVAD regimen: Manifestations, frequency, and natural history in a cohort of 125 consecutive patients

The hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) regimen has impressive efficacy in several haematological malignancies but is associated with considerable short-term haematological toxicity. Secondary myelodysplasia (MDS) or acute myeloid leukaemia (AML) also occurs. In this retrospective study, we also describe other prolonged haematological sequelae of this regimen. One hundred and twenty-five patients were treated with a median of six hyper-CVAD cycles and followed for a median of 28 months. Follow-up for cytopenias was censored at the next cytotoxic therapy. At 3 months post-therapy, 77 patients were evaluable. Cytopenias persisted in 59% of patients. Requirement for dose attenuation was the only factor significantly associated with persisting cytopenias (p < 0.05). The median time to normalisation of counts for those with post-treatment cytopenias in the respective lineages was 9 months (range, 6-12) for anaemia, 6 months (range, 6-30) for neutropenia and 9 months (range, 6-30) for thrombocytopenia. MDS/AML was diagnosed in four patients at 4, 21, 24 and 37 months after therapy with a cumulative incidence rate of 4.43% at 4 years. These results indicate a considerable rate of prolonged haematological toxicity after hyper-CVAD and a modest rate of MDS at this limited follow-up. These findings likely reflect cumulative damage to haematopoietic stem cells