Blood
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Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. ⋯ Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.
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Little information exists regarding long-term psychological health of hematopoietic cell transplantation (HCT) survivors. Using resources offered by the Bone Marrow Transplant Survivor Study (BMTSS), we evaluated adverse psychological outcomes in 1065 long-term HCT survivors and a healthy comparison group composed of siblings. Psychological health status was evaluated using the Brief Symptom Inventory-18. ⋯ Seven percent of the HCT survivors expressed suicidal ideation; patients with higher scores on depression subscale were most vulnerable. This study demonstrates that somatic distress is the biggest challenge faced by survivors long after HCT. These results identify vulnerable subpopulations and provide patients, families, and healthcare providers with necessary information to plan for post-HCT needs many years after HCT.
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Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesive proteins on endothelial cells facilitates metastasis. The role of tumor-secreted C-terminal fibrinogen-like domain of angiopoietin-like 4 (cANGPTL4) in vascular leakiness and metastasis is controversial because of the lack of understanding of how cANGPTL4 modulates vascular integrity. Here, we show that cANGPTL4 instigated the disruption of endothelial continuity by directly interacting with 3 novel binding partners, integrin α5β1, VE-cadherin, and claudin-5, in a temporally sequential manner, thus facilitating metastasis. ⋯ In vivo vascular permeability and metastatic assays performed using ANGPTL4-knockout and wild-type mice injected with either control or ANGPTL4-knockdown tumors confirmed that cANGPTL4 induced vascular leakiness and facilitated lung metastasis in mice. Thus, our findings elucidate how cANGPTL4 induces endothelial disruption. Our findings have direct implications for targeting cANGPTL4 to treat cancer and other vascular pathologies.