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Dvorak: Jazz Pharmaceuticals: Consultancy; Chimerix, Inc.: Membership on an entity's Board of Directors or advisory committees. Shenoy:Novartis, Vertex, Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

Background:Primary malignant disease relapse, graft-versus-host disease (GvHD) and infection are the most common causes of death following allogeneic hematopoietic cell transplantation (alloHCT). We investigated whether infection following initial alloHCT influenced subsequent risk for hematologic malignant disease relapse.

Background:Identifying factors that influence donor-derived immune response may ultimately enable its therapeutic redirection, lessening risk for complications following allogeneic hematopoietic cell transplantation (alloHCT) like acute graft-versus-host disease (aGvHD) and promoting protection against infection and malignant disease relapse. Viral reactivation seems poised to influence donor-derived immune response, potentially disrupting the balance between immune surveillance in eradicating malignancy and infection and immune tolerance in preventing aGvHD. Cytomegalovirus (CMV) is a clinically-significant virus with immunomodulatory capabilities. However, studies interrogating such effects are limited in the modern transplant era. The primary study aim was to estimate the cumulative incidence of initial CMV reactivation (RA) and aGvHD in alloHCT patients and to assess reciprocal influence between CMV RA and aGvHD. The secondary study aim was to define whether CMV RA predisposed alloHCT patients to infection or increased relapse risk.

Boeckh: Chimerix: Consultancy, Research Funding; Viropharma: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

Observations in recent years have shown that the catecholamines may play an important rôle in reproductive physiology, though there is a lack of data on the effects of these compounds in early pregnancy. Epinephrine has been shown to influence ovum transport and the motility of the rabbit oviduct (Longley, Black & Currie, 1968a, b). Recently, Crist & Hulka (1970) have shown that subcutaneous injections of epinephrine impair implantation in rats when given on Days 1 to 6 after mating, but have no effect on embryo survival when administered after implantation has occurred. The purpose of the present study was to determine the effect of epinephrine on ovum implantation and foetal survival in the rabbit.Virgin female Dutch-Belted rabbits were mated to fertile bucks and injected with 100 i.u. hcg(Ayerst Laboratories,

Samples of the title system are prepared by solid state reaction of Bi2O3, MnO2, and Fe2O3(825 °C).

Solchaga: Bimemetic Therapeutics: Employment. Cooke:Amgen: Provides experimental drug and central pharmacy support for 2 trials for which I am Co-PI.

The article evaluates a collection of towels and bedding from Ralph Lauren under its Lauren Spa product line.

The article features the Julia Child Rose, a winner in the 2006 All-America Rose Selections competition. The rose was created by Tom Carruth of Weeks Roses in Upland, California. According to the article, the Child rose is a hybrid of a rose and a shrub rose, varieties that produce huge blooms. A contact information is provided.

Human mesenchymal stem cells (MSCs) produce soluble factors that inhibit T-cell proliferation and alloreactivity. We have previously shown that MSCs require activation by CD14+ monocytes in cell culture. Toll-like receptors (TLRs) critically modulate antigen-presenting cell (APC) activation, maturation and function. Therefore, we aimed to determine whether TLR agonists could enhance CD14-mediated MSC activation and subsequent MSC-mediated T-cell inhibition. TLR agonists and human IL-1β were used to stimulate CD14+ cells isolated from peripheral blood of normal donors. TLR agonists included formalin-fixed Staphylococcus aureus Cowan A strain (SAC, TLR-2), Pam3CysSerLys4 (Pam3Cys, TLR-2), Salmonella enteriditis lipopolysaccharide (LPS, TLR-4), and R848 (Resiquimod, TLR7/8) in complete RPMI media (heat-inactivated FBS, glutamine, and antibiotics). TLR-stimulated CD14+ cells and supernatants from TLR-stimulated CD14+ cells were then used to stimulate third- and fourth-passage human MSCs (CD45−CD105+CD90+CD80−CD73+HLA-I+) expanded from normal volunteer bone marrow aspirate specimens. After a 24-hour culture with stimulant cells or supernatants, stimuli were removed, MSCs were washed twice with sterile PBS, and then were cultured for an additional 24 h in FBS-free RPMI media. Supernatants from TLR-stimulated CD14+ cell cultures and from washed MSC cultures were used to measure cytokine and chemokine production and to inhibit T-cell alloreactivity using an established mixed lymphocyte reaction (MLR) IFN-γ ELISPOT. MLR was also performed in the presence of TLR agonists and media alone. TLR stimulation resulted in high-level soluble factor induction (IL-1β, IL-6, TNF-α, and RANTES) from CD14+ cells. For example, levels of inducible IL-6 measured in CD14+ cell culture supernatants following LPS, SAC and R848 stimulation were 5.2 (70.3 ± 26.2 ng/ml), 4.7 (64.1 ± 16.3 ng/ml), and 4.6 (63.4 ± 13.1 ng/ml)-fold higher than after IL-1β stimulation (13.7 ± 4.0 ng/ml) (Mean ± SEM, 4 independent experiments). Supernatants of TLR-stimulated CD14+ cells induced higher levels of soluble factors from MSCs than stimulation with CD14+ cells themselves, suggesting that soluble factors from CD14+ cells activate MSCs. Not all supernatants of TLR-stimulated CD14+ cells were similar in their capacity to activate MSC-mediated inhibition of T-cell alloreactivity. For example, supernatants of Pam3Cys-, R848- and SAC-stimulated CD14+ cells all induced high levels of TNF-α in washed MSC cultures; but only supernatant from Pam3Cys-stimulated CD14+ cells resulted in MSC-mediated inhibition of T-cell alloreactivity (63.7 ± 12.9 % inhibition, Mean ± SEM, 4 independent ELISPOTs). Ongoing studies are being performed to define these immunomodulatory factors. Together, these results suggest that ex vivo TLR stimulation enhances soluble factor production from CD14+ cells, which, in turn, increases MSC production of immunomodulatory factors that mediate inhibition of T-cell alloreactivity.

Human mesenchymal stem cells (MSCs) produce soluble factors that inhibit T-cell proliferation and alloreactivity. We have previously shown that MSCs require activation by CD14+monocytes in cell culture. Toll-like receptors (TLRs) critically modulate antigen-presenting cell (APC) activation, maturation and function. Therefore, we aimed to determine whether TLR agonists could enhance CD14-mediated MSC activation and subsequent MSC-mediated T-cell inhibition. TLR agonists and human IL-1β were used to stimulate CD14+cells isolated from peripheral blood of normal donors. TLR agonists included formalin-fixed Staphylococcus aureusCowan A strain (SAC, TLR-2), Pam3CysSerLys4(Pam3Cys, TLR-2), Salmonella enteriditislipopolysaccharide (LPS, TLR-4), and R848 (Resiquimod, TLR7/8) in complete RPMI media (heat-inactivated FBS, glutamine, and antibiotics). TLR-stimulated CD14+cells and supernatants from TLR-stimulated CD14+cells were then used to stimulate third- and fourth-passage human MSCs (CD45−CD105+CD90+CD80−CD73+HLA-I+) expanded from normal volunteer bone marrow aspirate specimens. After a 24-hour culture with stimulant cells or supernatants, stimuli were removed, MSCs were washed twice with sterile PBS, and then were cultured for an additional 24 h in FBS-free RPMI media. Supernatants from TLR-stimulated CD14+cell cultures and from washed MSC cultures were used to measure cytokine and chemokine production and to inhibit T-cell alloreactivity using an established mixed lymphocyte reaction (MLR) IFN-γ ELISPOT. MLR was also performed in the presence of TLR agonists and media alone. TLR stimulation resulted in high-level soluble factor induction (IL-1β, IL-6, TNF-α, and RANTES) from CD14+cells. For example, levels of inducible IL-6 measured in CD14+cell culture supernatants following LPS, SAC and R848 stimulation were 5.2 (70.3 ± 26.2 ng/ml), 4.7 (64.1 ± 16.3 ng/ml), and 4.6 (63.4 ± 13.1 ng/ml)-fold higher than after IL-1β stimulation (13.7 ± 4.0 ng/ml) (Mean ± SEM, 4 independent experiments). Supernatants of TLR-stimulated CD14+cells induced higher levels of soluble factors from MSCs than stimulation with CD14+cells themselves, suggesting that soluble factors from CD14+cells activate MSCs. Not all supernatants of TLR-stimulated CD14+cells were similar in their capacity to activate MSC-mediated inhibition of T-cell alloreactivity. For example, supernatants of Pam3Cys-, R848- and SAC-stimulated CD14+cells all induced high levels of TNF-α in washed MSC cultures; but only supernatant from Pam3Cys-stimulated CD14+cells resulted in MSC-mediated inhibition of T-cell alloreactivity (63.7 ± 12.9 % inhibition, Mean ± SEM, 4 independent ELISPOTs). Ongoing studies are being performed to define these immunomodulatory factors. Together, these results suggest that ex vivoTLR stimulation enhances soluble factor production from CD14+cells, which, in turn, increases MSC production of immunomodulatory factors that mediate inhibition of T-cell alloreactivity.

Reflects on issues related to evolutionism. Distinction between evolution and evolutionism according to the book "The Evolution-Creation Struggle," by Michael Ruse; Opinion of psychologist James Mark Baldwin on the forms of selection in human beings; Tendency of organisms to determine their own development by themselves contributing to the conditions and occasions of further progress.

Human mesenchymal stem cells (MSCs) suppress T-cell activation and proliferation by inducible expression and secretion of soluble inhibitory factors. We have previously shown that MSCs require activation by antigen-presenting cells (APCs) to secrete these factors. Toll-like receptors (TLRs) and their associated agonists have critical roles in APC activation, maturation and function. Therefore, we investigated whether TLR agonists induce cytokine and chemokine production from MSCs and if such soluble factors mediate inhibition of T-cell alloreactivity. Human MSCs (CD45-CD105+CD90+CD80-CD73+HLA−I+) were expanded from normal volunteer bone marrow aspirate specimens. MSCs were characterized morphologically by light microscopy, phenotypically by flow cytometry and functionally by ex vivo cell culture stimulation and inhibition of T-cell IFN-γ production. Cytokine and chemokine induction of third and fourth-passage MSCs co-cultured in triplicate with established TLR agonists were measured and compared to soluble factor induction from human IL-1β stimulated MSCs. TLR agonists included formalin-fixed Staphylococcus aureus Cowan A strain (SAC, TLR-2), Pam3CysSerLys4 (Pam3Cys, TLR-2), polyinosine:polycytidylic acid (poly I:C, TLR-3), Salmonella enteriditis lipopolysaccharide (LPS, TLR-4), R848 (TLR7/8) and unmethylated CpG oligodeoxynucleotides 1826 and 2216 (TLR-9). 24h MSC-culture supernatants were assessed for levels of soluble factors using standard and multiplex ELISA and for inhibition of T-cell alloreactivity using an established mixed lymphocyte reaction (MLR) IFN-γ ELISPOT. MLR was also performed in the presence of TLR agonists alone and agonist-stimulated MSCs. In general, TLR-MSC supernatants contained 2 to 5-fold lower levels of inducible IL-6, IL-8, IL-10 and RANTES than IL-1β-MSC supernatants. LPS- and poly I:C-MSC supernatants had comparable levels of inducible factors as IL-1β-MSC supernatant. Neither stimulation with IL-1β nor TLR agonists induced phenotypic changes in MSCs, as measured by surface expression of MSC markers as well as activation markers (HLA-DR, CD40, CD40L, CD80, HLA-I and HLA-II). However, supernatant from TLR-MSC cultures (CpG 1826 and poly I:C) and from IL-1β-MSC cultures did inhibit T-cell IFN-γ production. For example, percent IFN-γ inhibition using supernatant from MSC-CpG 1826 culture versus supernatant from IL-1β-MSC culture was 46.5% ± 22.8 and 66.8% ± 13.5, respectively (mean ± SEM, n=3 separate experiments involving different donor MSCs). Likewise, TLR- and IL-1β-stimulated MSCs themselves inhibited T-cell IFN-γ. Together, these results demonstrate that ex vivo culture with TLR agonists activates human MSCs to inhibit ex vivo T-cell alloreactivity likely via inducible soluble factors. Optimization of cell culture conditions is needed to define the soluble factors mediating this inhibitory effect. Our results suggest the presence of a potentially novel immunomodulatory interface at which TLR agonists are uniquely positioned to influence immune effector cell and mesenchymal stem cell responses.

Innate cellular-mediated immunity (iCMI) responses are initiated through activation of pattern recognition receptors like Toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS). FL (Flt3 ligand) is a hematopoietic growth factor that promotes the expansion of dendritic cells (DCs) and natural killer (NK) cells, key immunomodulatory effector cells involved in host defense. We have previously shown that reconstituted splenocyte iCMI following murine syngeneic BMT occurs in distinct phases in which donor-derived, innate effector cell recovery correlates with inducible cytokine production. Therefore, we studied whether post-transplant administration of FL could enhance reconstitution of innate effector cells and their cytokine responses to established TLR agonists. After split-fraction radiation with 12 Gy 137Cs, C57BL/6 recipient mice were tail-vein injected with 5x106unselected BM cells from congeneic donor mice. Transplant mice were injected intraperitoneally (IP) with either 10μg FL/100ml 0.1%MSA/PBS (FL) or 100ml 0.1%MSA/PBS alone (Sham) for 10 consecutive days starting the first day after transplant (D1). Non-transplant C57BL/6 mice served as controls and were similarly treated with IP injections. At 2 (D12) and 10 days (D22) post-FL and sham therapy, splenocytes were harvested and pooled per group and were characterized phenotypically by flow cytometry and functionally via ex vivocell-culture stimulation with established PAMP and cell-specific agonists. Unselected splenocytes were cultured in triplicate in the following stimulation conditions: media only; Staphylococcus aureusconsorbin (SAC, TLR-2); polyinosine-polycytidylic acid (polyI:C, TLR-3); Salmonella enteriditislipopolysaccharide (LPS, TLR-4); anti-CD40 alone; anti-CD40 plus recombinant IL-4 (rIL-4); combination anti-CD40, rIL-4, and anti-IL-10; R848 (TLR7/8); unmethylated CpG oligodeoxynucleotide 1826 (CpG, TLR-9); and lastly, combination rIL-12 and rIL-18. 24h cell-culture supernatants were assessed for cytokine levels using standard ELISA. Three main observations were noted. First, FL therapy increased total numbers of splenocyte innate effector cells in both control and D12 transplants by 6.2- and 3.2-fold, respectively. Of effector cell expansion, DC increases were the most dramatic (16.4 and 9.7-fold for control and D12 transplants, respectively). Specifically, numbers of reconstituted lymphoid, myeloid and plasmacytoid DCs were 17-, 7- and 5-fold higher, respectively, in FL than sham D12 transplants. Reconstituted NK cells had only modest increases (2-fold) after FL therapy. Second, levels of TLR-2 and TLR-9 induction of IL-12p70 and IFN-γ were 3 to 5-fold higher and DC-specific p70 induction was 5-fold higher in FL than sham D12 mice. Finally, FL augmentation of cellularity and cytokine responses was not long-lasting, as post-FL and sham D22 transplant mice had similar levels of innate effector cells and inducible cytokines. Together, these results show that post-transplant FL immunotherapy transiently enhances reconstituted iCMI and cytokine responses to PAMP agonists. Therapy targeting iCMI response could potentially be used to improve anti-microbial host defense during absent or incomplete adaptive immune recovery.

Chronic Toxicity, Oncogenic Potential, and Reproductive Toxicity of p-Nitroaniline in Rats. NAIR, R. S., AULETTA, C. S., SCHROEDER, R. E., AND JOHANNSEN, F. R. (1990). Fundam. Appl. Toxicol 15, 607–621. Dose levels for these studies were selected mainly on the basis of subchronic studies, although consideration was also given to workplace exposure levels and proposed mechanism of tumor formation with structurally similar compounds. For the chronic study, groups of 60 male and 60 female Sprague—Dawley CD (Registered Trademark of Charles River Breeding Laboratories, Portage, Ml) rats were given 0, 0.25, 1.5, or 9.0 mg/kg/day para-nitroaniline (PNA) by gavage in corn oil for a period of 2 years. Parameters monitored included clinical observations, ophthalmoscopic exams, body weights, food consumption, hematology, clinical chemistry, and urinalysis at regular intervals throughout the study. All gross lesions and over 40 tissues were examined histologically for all control and high-dosage-level animals. Gross lesions, spleens, and livers of low- and mid-dosage groups were also examined histologically. For the reproduction study, groups of 15 male and 30 female rats, designated as F0 generation, were given PNA at the same levels as the chronic study for 14 weeks prior to mating and during mating, gestation, and lactation. Selected groups of 15 male and 30 female rats of the F1 generation received the same dose of PNA for 18 weeks prior to mating and during mating, gestation, and lactation. F2 pups were observed through weaning at which time they were euthanized. Observations made during the study included body weights, food consumption, mating and fertility indices, pup and litter survival indices, and histopathology of selected tissues. In the chronic study, except for a slight decrease in survival of high-dose male rats late in the study, survival in all treated groups was comparable to controls. Blood methemoglobin levels were elevated in the mid- and high-dosage groups, while slight anemia was observed in the high-dosage group also. Spleen weights were significantly increased in the high-dosage groups. An accumulation of brown pigment was observed in the cytoplasm of the sinusoidal macrophages or littoral cells of the liver and in the reticuloendothelial cells of the spleen. No treatment-related increase in tumor incidence was observed. In the reproduction study, no consistent pattern of effect from treatment between the F0 and F1 generation was seen in mating, pregnancy, or fertility indices. Thus, administration of PNA at levels which produced significant methemoglobin-emia and low-level anemia in the rat and histological changes in the spleen produced no tumors or reproducible effects on reproductive performance.

Several letters to the editor are presented in response to the articles in the January 2007 issue including "Industry works to fill blanks," which discussed the launch campaign by nonprofit manufacturing group Magnet and how it is vitally important, "Beyond limits," which talks about the current term limits law, and "Who'll pay the higher ed bill? Guess," by Mark Dodosh.