The host tissue microenvironment influences malignant cell proliferation and metastasis, but little is known about how tumor-induced changes in the microenvironment affect benign cellular ecosystems. Applying dynamic in vivo imaging to a mouse model, we show that leukemic cell growth disrupts normal hematopoietic progenitor cell (HPC) bone marrow niches and creates abnormal microenvironments that sequester transplanted human CD34 + (HPC-enriched) cells. CD34 + cells in leukemic mice declined in number over time and failed to mobilize into the peripheral circulation in response to cytokine stimulation. Neutralization of stem cell factor (SCF) secreted by leukemic cells inhibited CD34 + cell migration into malignant niches, normalized CD34 + cell numbers, and restored CD34 + cell mobilization in leukemic mice. These data suggest that the tumor microenvironment causes HPC dysfunction by usurping normal HPC niches and that therapeutic inhibition of HPC interaction with tumor niches may help maintain normal progenitor cell function in the setting of malignancy.

Two hundred eighty methicillin-resistant

Aqueous solution studies regarding the identification and characterization of complexes formed by the VIVO ion and 11 3-hydroxy-4-pyridinone derivatives have been performed using EPR and UV/vis spectroscopic techniques. For the three ligands (HL) adequately soluble in water (1-methyl-3-hydroxy-4-pyridinone, 1-methyl-2-ethyl-3-hydroxy-4-pyridinone, and 1,2-diethyl-3-hydroxy-4-pyridinone), potentiometric titrations were performed; the results are consistent with the formation of [V(IV)OL]+, [V(IV)OL2], [V(IV)OL2H(-1)]-, [(V(IV)O)2L2H(-2)], and [V(IV)L3]+ species. Bis chelated complexes are characterized by a cis-trans isomerism, the trans isomer being strongly favored with respect to the cis arrangement. Tris chelated non-oxo V(IV) species were prepared in CH3COOH; their spectroscopic features point to a d(z2) ground state and a geometry intermediate between an octahedron and a trigonal prism, related to the steric requirements of the substituent on the carbon atom in position 2 of the pyridinone ring. Four new solid derivatives, [V(IV)O(1,2-diethyl-3-hydroxy-4-pyridinonato)2], [V(IV)O(1-(p-tolyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], [V(IV)O(1-(p-(n-butyl)phenyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], and [V(IV)O(1-(p-(n-hexyl)phenyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], were isolated and characterized; they exhibited a five-coordinate geometry close to square-pyramid. A criterion for establishing the degree of distortion toward the trigonal-bipyramid on the basis of the electronic absorption spectra is provided. Relationships between the pKa of the -OH group in position 3 of the ring and (i) log K of mono and bis chelated complexes, (ii) pK of the water molecule in cis-[V(IV)OL2(H2O)], (iii) log K of tris chelated species [V(IV)L3]+, and (iv) 51V hyperfine coupling constant (Az) have been established and discussed for a number of pyrone, pyridinone, and catechol ligands. The results are rationalized by assuming for pyridinones an electronic structure intermediate between that of pyrones and catechols. The relationships are valuable to the understanding of the behavior of VIVO species in aqueous solution.

Indolent natural killer (NK) cell lymphoproliferative disorders include a heterogeneous group of patients in whom persistent expansions of mature, typically CD56 ؉ , NK cells in the absence of any clonal marker are present in the peripheral blood. In the present study we report on the clinical, hematological, immunophenotypic, serological, and molecular features of a series of 26 patients with chronic large granular NK cell lymphocytosis, whose NK cells were either CD56 ؊ or expressed very low levels of CD56 (CD56 ؊/؉dim NK cells), in the context of an aberrant activation-related mature phenotype and proved to be monoclonal using the human androgen receptor gene polymerase chain reaction-based assay. As normal CD56 ؉ NK cells, CD56 ؊/؉dim NK cells were granzyme B ؉ , CD3 ؊ , TCR␣␤/ ␥␦ ؊ , CD5 ؊ , CD28 ؊ , CD11a ؉bright , CD45RA ؉bright , CD122 ؉ , and CD25 ؊ and they showed variable and heterogeneous expression of both CD8 and CD57. Nevertheless, they displayed several unusual immunophenotypic features. Accordingly, besides being CD56 ؊/؉dim , they were CD11b ؊/؉dim (heterogeneous), CD7 ؊/؉dim (heterogeneous), CD2 ؉ (homogeneous), CD11c ؉bright (homogeneous), and CD38 ؊/؉dim (heterogeneous). Moreover, CD56 ؊/؉dim NK cells heterogeneously expressed HLA-DR. In that concerning the expression of killer receptors, CD56 ؊/؉dim NK cells showed bright and homogeneous CD94 expression, and dim and heterogeneous reactivity for CD161, whereas CD158a and NKB1 expression was variable. From the functional point of view, CD56 ؊/؉dim showed a typical Th1 pattern of cytokine production (interferon-␥ ؉ , tumor necrosis factor-␣ ؉ ). From the clinical point of view, these patients usually had an indolent clinical course, progression into a massive lymphocytosis with lung infiltration leading to death being observed in only one case. Despite this, they frequently had associated cytopenias as well as neoplastic diseases and/or viral infections. In summary, we describe a unique and homogeneous group of monoclonal chronic large granular NK cell lymphocytosis with an aberrant activation-related CD56 ؊/؉dim /CD11b ؊/؉dim phenotype and an indolent clinical course, whose main clinical features are related to concomitant diseases. (Am J