Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand- independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.

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Summary:Donor leukocyte infusion (DLI) has well-documented activity in CML, but the role of DLI in other diseases is less well defined. To evaluate the strategy in multiple myeloma (MM) we evaluated 25 MM patients from 15 centers who were treated with DLI. Patients with persistent or recurrent disease after allogeneic BMT received DLI from the original marrow donor (23 matched related, one mismatched family, and one matched unrelated). Chemotherapy was given before DLI in three patients. Two of 22 patients responded completely to DLI alone and three patients responded to the combination of DLI and chemotherapy. Nine patients who had not had sufficient disease control after DLI were given additional DLIs; five of these patients had either complete (two) or partial (three) responses. Thirteen of 25 evaluable patients developed acute GVHD and 11 of 21 evaluable patients developed chronic GVHD; all responders developed GVHD. No patients developed post-DLI pancytopenia. Four patients had responses which lasted Ͼ1 year after DLI, three patients had responses which lasted Ͻ1 year, and three patients had ongoing responses but with followup Ͻ1 year. In conclusion, DLI has anti-myeloma activity but the strategy is limited by no response or short duration of response in a significant percentage of patients and by significant GVHD in the majority of the responders. Graft-versus-host disease (GVHD) occurs in approximately 60% of patients and is closely correlated with disease response. 13 The role of DLI in multiple myeloma (MM) is less certain. Several case reports and small series have documented an apparent graft-versus-myeloma (GVM) effect of DLI, [13][14][15][16][17][18][19][20][21][22][23] and a recent review of the literature 24 suggested an approximately 66% likelihood of response to DLI in myeloma. However, because of the relatively small number of patients reported thus far, and because of the potential for positive reporting bias, the overall usefulness of the approach in MM remains uncertain. To investigate further the role of DLI in MM, we analyzed 25 cases reported from 15 BMT centers. Patients and methods DesignWe collected detailed information from 15 BMT centers about DLIs in 25 patients with MM. Data were collected retrospectively in 13 patients and prospectively in 12. Information collected included the following: demographicspatient sex and age; diagnosis -disease, date of diagnosis, treatment before BMT, and response to treatment; BMTpre-BMT disease status, donor relationship, sex, and degree of histocompatibility, whether the BMT was T cell depleted, occurrence of acute and chronic GVHD; post-BMT relapse -date and extent of relapse, donor chimerism at relapse, and treatment of relapse and response to treatment; DLI -disease extent, pre-DLI chemotherapy and response, date of DLI, total nucleated cell dose, mononuclear cell dose, T cell dose, and concomitant cytokine usage; post-DLI response and complications -response to DLI and date, occurrence of pancytopenia and date, treatment of pancytopenia and res...

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Boron-containing heterocycles are important in a variety of applications from drug discovery to materials science; therefore a clear understanding of their structure and reactivity is desirable to optimize these functions. Although the boranol (B−OH) unit of boronic acids behaves as a Lewis acid to form a tetravalent trihydroxyborate conjugate base, it has been proposed that pseudoaromatic hemiboronic acids may possess sufficient aromatic character to act as Brønsted acids and form a boron oxy conjugate base, thereby avoiding the disruption of ring aromaticity that would occur with a tetravalent boronate anion. Until now no firm evidence existed to ascertain the structure of the conjugate base and the aromatic character of the boron-containing ring of hemiboronic "naphthoid" isosteres. Here, these questions are addressed with a combination of experimental, spectroscopic, X-ray crystallographic, and computational studies of a series of model benzoxazaborine and benzodiazaborine naphthoids. Although these hemiboronic heterocycles are unambiguously shown to behave as Lewis acids in aqueous solutions, boraza derivatives possess partial aromaticity provided their nitrogen lone electron pair is sufficiently available to participate in extended delocalization. As demonstrated by dynamic exchange and crossover experiments, these heterocycles are stable in neutral aqueous medium, and their measured pK a values are consistent with the ability of the endocyclic heteroatom substituent to stabilize a partial negative charge in the conjugate base. Altogether, this study corrects previous inaccuracies and provides conclusions regarding the properties of these compounds that are important toward the methodical application of hemiboronic and other boron heterocycles in catalysis, bioconjugation, and medicinal chemistry.

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BackgroundTraumatic brain injury (TBI) is a major cause of death and disability. TBI results in a prolonged secondary central neuro-inflammatory response. Previously, we have demonstrated that multiple doses (2 and 24 h after TBI) of multipotent adult progenitor cells (MAPC) delivered intravenously preserve the blood-brain barrier (BBB), improve spatial learning, and decrease activated microglia/macrophages in the dentate gyrus of the hippocampus. In order to determine if there is an optimum treatment window to preserve the BBB, improve cognitive behavior, and attenuate the activated microglia/macrophages, we administered MAPC at various clinically relevant intervals.MethodsWe administered two injections intravenously of MAPC treatment at hours 2 and 24 (2/24), 6 and 24 (6/24), 12 and 36 (12/36), or 36 and 72 (36/72) post cortical contusion injury (CCI) at a concentration of 10 million/kg. For BBB experiments, animals that received MAPC at 2/24, 6/24, and 12/36 were euthanized 72 h post injury. The 36/72 treated group was harvested at 96 h post injury.ResultsAdministration of MAPC resulted in a significant decrease in BBB permeability when administered at 2/24 h after TBI only. For behavior experiments, animals were harvested post behavior paradigm. There was a significant improvement in spatial learning (120 days post injury) when compared to cortical contusion injury (CCI) in groups when MAPC was administered at or before 24 h. In addition, there was a significant decrease in activated microglia/macrophages in the dentate gyrus of hippocampus of the treated group (2/24) only when compared to CCI.ConclusionsIntravenous injections of MAPC at or before 24 h after CCI resulted in improvement of the BBB, improved cognitive behavior, and attenuated activated microglia/macrophages in the dentate gyrus.