To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis.

Endothelial cells are a major component of the bone marrow (BM) microenvironment that regulate the trafficking and homing of hematopoietic progenitor and stem cells. In this paper, we provide evidence that BM endothelial cells (BMECs) also support multilineage hematopoiesis by elaboration of soluble cytokines. Hematopoietic progenitor cells incubated in direct contact with BMEC monolayers, or physically separated by microporous membrane, expanded five-fold to sevenfold at 7 days, in the absence of exogenous cytokines. Flow cytometric analysis of proliferating progenitor cells grown in the presence of BMEC monolayers showed that by day 14 of coculture, 70% to 80% of hematopoietic cells were myeloid, expressing CD15 or CD14, and 14% to 19% were megakaryocytic, expressing GPIIb/IIIa or GPIb. CD34+ cells derived from umbilical cord blood, cultured in the upper chamber of transwell culture plates, as well as the cells grown in direct contact with BMEC monolayers, generated progenitors for up to 70 days. Unstimulated BMEC monolayers constitutively produce interleukin-6, Kit- ligand, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor. These data suggest that BMEC regulate proliferation of hematopoietic progenitor cells and long-term culture initiating cells by elaboration of lineage-specific cytokines.

(1) Paclitaxel administered as a 1-hour infusion is well tolerated; (2) this schedule of administration does not result in cumulative myelosuppression; and (3) this schedule of administration results in dose-intensive paclitaxel delivery with a favorable toxicity profile.

The bone marrow microenvironment is a complex three dimensional structure where hematopoietic stem cells proliferate, mature, migrate into the sinusoidal space, and enter the circulation in an exquisitely regulated fashion. Stromal cells within the BM microenvironment provide a suitable environment for self-renewal, proliferation and differentiation of hematopoietic stem cells. Within the hematopoietic microenvironment, whether it is embryonic yolk sac, fetal liver, or adult bone marrow, microvascular endothelium not only acts as a gatekeeper controlling the trafficking and homing of hematopoietic progenitors, but also provides cellular contact and secretes cytokines that allows for the preservation of the steady state hematopoiesis. Recently, homogenous monolayers of bone marrow endothelial cells (BMEC) have been isolated and cultivated in tissue culture. Long-term coculture studies have shown that BMEC monolayers are unique type of endothelium and can support long-term proliferation of hematopoietic progenitor cells particularly megakaryocytic and myeloid progenitor cells by constitutive elaboration of lineage-specific cytokines such as G-CSF, GM-CSF, M-CSF, Kit-ligand, IL6, FLK-2 ligand, and leukemia inhibitory factor. Direct cellular contact between hematopoietic progenitor cells and BMEC monolayers through specific adhesion molecules including beta1, beta2 integrins and selectins play a critical role in trafficking and possibly proliferation of hematopoietic stem cells. Dysfunction of microvascular endothelial cells within the hematopoietic microenvironment may result in stem cell disorders and progression to aplastic anemias, and contribute to graft failure during bone marrow transplantation. Further studies on the role of microvascular endothelium in the regulation of hematopoietic stem cell homing and proliferation may enhance our understanding of the pathophysiology of stem cell and leukemic disorders.