bluuebunny/crossref_metadata_2025 huggingface dataset:
Geological age by instrumental analysis: the 29th Hallimond Lecture
Authors: Compston W.
Published: July 2002

The need in geology for in situ U-Pb age
determinations of minerals is illustrated by two examples: the internal age
dispersion developed within the zircon SL13 shortly after original
crystallization, and the occurrence within minerals of old cores and later
overgrowths. SL13 contains rare μm-sized patches of unsupported radiogenic Pb and
a mainly bimodal distribution of
206Pb/238U ages otherwise. Both
observations are consistent with original crystallization at 580 Ma and Pb loss at
565 Ma. Age precision is controlled by the ions counted for radiogenic Pb, and
varies with instrumental sensitivity, age and U contents of the target.
Laser-ablation ICPMS has similar spatial resolution and sensitivity to SIMS but
consumes more sample because of much greater hole-depth in practice. Like SIMS,
the measured Pb+/U+ is biased and also
changes with depth so comparison with a standard mineral is necessary. Analyses of
reference zircons reported here indicate that the reproducibility of Pb/U ages by
ICPMS is limited by residual bias, not ion counting errors. For multipurpose ICPMS
at least, the Hg background at mass 204 prohibits the measurement of
204Pb for common Pb estimation. A third micro-analytical
method, ‘CHIME’, and future developments in SIMS and ICPMS are discussed
briefly.
Clonal evolution in Waldenstrom macroglobulinemia highlights functional role of B-cell receptor
Authors: Ciric Bogoljub , VanKeulen Virginia , Rodriguez Moses , Kyle Robert A. , Gertz Morie A. , Pease Larry R.
Published: July 2002

The course of clonal evolution of 2 related clones in the blood of a patient with Waldenstrom macroglobulinemia (WM) indicates the functional importance for the expression of the B-cell receptor for the survival of these malignant cells. Protein and nucleotide sequencing of the paraproteins' variable regions revealed 2 predominant Vλ and 2 VH sequences, each set comprised in the ratio 1:1.5. The 2 VH sequences and 2 Vλ sequences shared the same VDJ and VJ junctional sequences, respectively, indicating that 2 malignant clones had evolved from a common ancestor. This is the first report on intraclonal heterogeneity in WM. Comparison of the Vλ and VH sequences with the closest matching known germline genes showed that they contained approximately 10 somatic mutations each. The distribution and type of mutations demonstrate that mutations have continued to accumulate in the malignant clones and that selection has been operating to preserve immunoglobulin structure.
Larger numbers of CD4bright dendritic cells in donor bone marrow are associated with increased relapse after allogeneic bone marrow transplantation
Authors: Waller Edmund K. , Rosenthal Hilary , Jones Terry W. , Peel Jennifer , Lonial Sagar , Langston Amelia , Redei Istvan , Jurickova Ingrid , Boyer Michael W.
Published: July 2002

Relapse is the major cause of death after allogeneic bone marrow transplantation (BMT). This study tested the hypothesis that the numbers of donor mononuclear cells, lymphocytes, and CD34+cells influence relapse and event-free survival (EFS) after BMT. The study population consisted of 113 consecutive patients with hematologic malignancies who underwent non–T-cell–depleted BMT from HLA-matched siblings. Sixty-four patients had low-risk diagnoses (ALL/AML CR1, MDS RA/RARS, and CML CP1); 49 patients had high-risk diagnoses (all others). CD34+ cells, T cells, B cells, natural killer cells, monocytes, and a rare population of CD3−, CD4bright cells in the allografts were measured by flow cytometry. The CD3−, CD4bright cells in bone marrow had the same frequency and phenotype as CD123brighttype 2 dendritic cell (DC) progenitors, and they differentiated into typical DCs after short-term culture. Cox regression analyses evaluated risk strata, age, gender, and the numbers of nucleated cells, CD3+ T cells, CD34+ hematopoietic cells, and CD4bright cells as covariates for EFS, relapse, and nonrelapse mortality. Recipients of larger numbers of CD4bright cells had significantly lower EFS, a lower incidence of chronic graft-versus-host disease (cGVHD), and an increased incidence of relapse. Recipients of larger numbers of CD34+ cells had improved EFS; recipients of fewer CD34+ cells had delayed hematopoietic engraftment and increased death from infections. In conclusion, the content of donor CD4bright cells was associated with decreased cGVHD and graft-versus-leukemia effects in recipients of allogeneic bone marrow transplantation, consistent with a role for donor DCs in determining immune responses after allogeneic BMT.
Natural killer cell–dependent apoptosis of peripheral murine hematopoietic progenitor cells in response to Fas cross-linking: involvement of tumor necrosis factor-α
Authors: Moreau Géraldine , Leite-de-Moraes Maria , Ezine Sophie , Di Santo James P. , Dy Michel , Schneider Elke
Published: July 2002

Recently, a marked extramedullary myelopoiesis in Fas/CD95- or FasL/CD95L-deficient mice has been reported. In the present in vitro study, the mechanisms underlying Fas-induced apoptosis of normal peripheral colony-forming unit-C (CFU-C) progenitors in the spleen were analyzed. Surprisingly, it was found that clonogenic progenitors were protected from γIFN plus Fas-induced programmed cell death when Lin+ cells were removed from cultured splenocytes. The cells that rendered CFU-C sensitive to the activation of the Fas pathway did not belong to the T or the myelocytic–monocytic lineage but comprised a non–B-cell subset expressing the activation marker B220. Among CD19− B220+ splenocytes, nearly half were natural killer (NK) 1.1+ cells whose in vivo depletion or deficiency in RAG2-γc−/− mice abrogated the effect of Fas cross-linking. NK cells exerted their accessory function, at least in part, through tumor necrosis factor–α (TNF-α), which they readily produced during pretreatment with the anti-Fas/CD95 monoclonal antibody and IFN-γ and whose addition could compensate for the loss of sensitivity. In conclusion, this study provides evidence that peripheral clonogenic progenitors are not directly responsive to Fas cross-linking, even in the presence of IFN-γ, but require NK cells as a source of TNF-α to make them susceptible to this death pathway.
In vivo and in vitro apoptosis of human thymocytes are associated with nitrotyrosine formation
Authors: Moulian Nathalie , Truffault Frédérique , Gaudry-Talarmain Yvette Morot , Serraf Alain , Berrih-Aknin Sonia
Published: July 2002

Most thymocytes are deleted by thymic selection. The mechanisms of cell death are far from being clear. Peroxynitrite is a powerful oxidant produced in vivo by the reaction of superoxide (O2•−) with nitric oxide (NO•) and is able to mediate apoptosis. The aim of this study was to analyze whether NO and peroxynitrite could play a role in human thymocyte apoptosis. The results indicate that 3-(4-morpholinyl)-sydnonimine (SIN-1, an O2•− and NO• donor) and chemically synthesized peroxynitrite, but not S-nitroso-N-acetyl-D,L-penicillamine (SNAP, an NO• donor), have a strong apoptotic effect on human thymocytes (annexin V staining and TUNEL reaction). This effect was inhibited by exogenous superoxide dismutase (SOD), which interacts with O2•− and inhibits the formation of peroxynitrite. Because peroxynitrite formation requires NO•, thymic stromal cells were investigated to determine if they produced NO•. Inducible NOS was synthesized in cultured thymic epithelial cells in certain conditions of cytokine stimulation, as shown by messenger RNA levels, protein analysis, and nitrite production in the supernatants. SIN-1–treated thymocytes had high levels of tyrosine nitration, abolished by the addition of exogenous SOD. Tyrosine nitration was also detected in thymus extracts and sections, suggesting the presence of peroxynitrite in situ. In thymus sections, clusters of nitrotyrosine-positive cells were found in the cortex and corticomedullary areas colocalized with cells positive in the TUNEL reaction. These data indicate an association between human thymocyte apoptosis and nitrotyrosine formation. Thus, the results support the notion of a physiologic role for peroxynitrite in human thymocyte apoptosis.
Mitochondria-targeting drugs arsenic trioxide and lonidamine bypass the resistance of TPA-differentiated leukemic cells to apoptosis
Authors: Sordet Olivier , Rébé Cédric , Leroy Ingrid , Bruey Jean-Marie , Garrido Carmen , Miguet Carole , Lizard Gérard , Plenchette Stéphanie , Corcos Laurent , Solary Eric
Published: July 2002

Exposure of U937 human leukemic cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) induces their differentiation into monocyte/macrophage-like cells. This terminal differentiation is associated with a resistant phenotype to apoptosis induced by the topoisomerase II inhibitor etoposide. The inhibition occurs upstream of the mitochondrial release of cytochrome c and the activation of procaspase-2, -3, -6, -7, -8, and -9. By using cell-free systems, it was demonstrated that the mitochondrial pathway to cell death that involves mitochondrial membrane depolarization, cytochrome c release and cytosolic activation of procaspases by cytochrome c/dATP remains functional in TPA-differentiated U937 cells. Accordingly, 2 drugs recently shown to target the mitochondria, namely lonidamine and arsenic trioxide, bypass the resistance of TPA-differentiated U937 cells to classical anticancer drugs. Cell death induced by the 2 compounds is associated with mitochondrial membrane depolarization, release of cytochrome c and Smac/Diablo from the mitochondria, activation of caspases, poly(ADP-ribose) polymerase cleavage and internucleosomal DNA fragmentation. Moreover, the decreased glutathione content associated with the differentiation process amplifies the ability of arsenic trioxide to activate the mitochondrial pathway to cell death. Similar results were obtained by comparing undifferentiated and TPA-differentiated human HL60 leukemic cells. These data demonstrate that mitochondria-targeting agents bypass the resistance to classical anticancer drugs induced by TPA-mediated leukemic cell differentiation.
Plasmin-induced expression of cytokines and tissue factor in human monocytes involves AP-1 and IKKβ-mediated NF-κB activation
Authors: Syrovets Tatiana , Jendrach Marina , Rohwedder Angela , Schüle Almut , Simmet Thomas
Published: July 2002

It was previously shown that plasmin activates human peripheral monocytes in terms of lipid mediator release and chemotactic migration. Here it is demonstrated that plasmin induces proinflammatory cytokine release and tissue factor (TF) expression by monocytes. Plasmin 0.043 to 1.43 CTA U/mL, but not active site-blocked plasmin, triggered concentration-dependent expression of mRNA for interleukin-1α (IL-1α), IL-1β, tumor necrosis factor-α (TNF-α), and TF with maximum responses after 4 hours. Plasmin-mediated mRNA expression was inhibited in a concentration-dependent manner by the lysine analoguetrans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA). Increases in mRNA levels were followed by concentration- and time-dependent release of IL-1α, IL-1β and TNF-α and by TF expression on monocyte surfaces. Neither cytokines nor TF could be detected when monocytes were preincubated with actinomycin D or cycloheximide. Electrophoretic mobility shift assays indicated plasmin-induced activation of NF-κB; DNA-binding complexes were composed of p50, p65, and c-Rel, as shown by supershift experiments. Nuclear translocation of NF-κB/Rel proteins coincided with IκBα degradation. At variance with endotoxic lipopolysaccharide, plasmin elicited the rapid degradation of another cytoplasmic NF-κB inhibitor, p105. Proteolysis of NF-κB inhibitors was apparently due to transient activation of IκB kinase (IKK) β that reached maximum activity at 1 hour after plasmin stimulation. In addition, AP-1 binding was increased in plasmin-treated monocytes, with most complexes composed of JunD, c-Fos, and FosB. These findings further substantiate the role of plasmin as a proinflammatory activator of human monocytes and reveal an important new link between the plasminogen-plasmin system and inflammation.
Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia
Authors: Auer Rebecca L. , Jones Christopher , Mullenbach Roman A. , Syndercombe-Court Denise , Milligan Donald W. , Fegan Christopher D. , Cotter Finbarr E.
Published: July 2002

Chromosome 11q deletions are frequently observed in chronic lymphocytic leukemia (CLL) in association with progressive disease and a poor prognosis. A minimal region of deletion has been assigned to 11q22-q23. Trinucleotide repeats have been associated with anticipation in disease, and evidence of anticipation has been observed in various malignancies including CLL. Loss of heterozygosity at 11q22-23 is common in a wide range of cancers, suggesting this is an unstable area prone to chromosome breakage. The location of 8 CCG-trinucleotide repeats on 11q was determined by Southern blot analysis of a 40-Mb YAC and PAC contig spanning 11q22-qter. Deletion breakpoints in CLL are found to co-localize at specific sites on 11q where CCG repeats are located. In addition, a CCG repeat has been identified within the minimal region of deletion. Specific alleles of this repeat are associated with worse prognosis. Folate-sensitive fragile sites are regions of late replication and are characterized by CCG repeats. The mechanism for chromosome deletion at 11q could be explained by a delay in replication. Described here is an association between CCG repeats and chromosome loss suggesting that in vivo “fragile sites” exist on 11q and that the instability of CCG repeats may play an important role in the pathogenesis of CLL.
STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma
Authors: Brender Christine , Nielsen Mette , Kaltoft Keld , Mikkelsen Gitte , Zhang Qian , Wasik Mariusz , Billestrup Nils , Ødum Niels
Published: July 2002

A characteristic feature of neoplastic transformation is the loss of external control by cytokines and extracellular matrix of cellular differentiation, migration, and mitogenesis. Because suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine-induced signaling, it has been hypothesized that an aberrant SOCS expression plays a role in neoplastic transformation. This study reports on a constitutive SOCS-3 expression in cutaneous T-cell lymphoma (CTCL) cell lines. SOCS-3 protein is constitutively expressed in tumor cell lines (but not in nonmalignant T cells) obtained from affected skin from a patient with mycosis fungoides (MF) and from peripheral blood from a patient with Sezary syndrome (SS). In contrast, constitutive SOCS-3 expression is not found in the leukemic Jurkat T-cell line, the MOLT-4 acute lymphoblastic leukemia cell line, and the monocytic leukemic cell line U937. Expression of SOCS-3 coincides with a constitutive activation of STAT3 in CTCL tumor cells, and stable transfection of CTCL tumor cells with a dominant negative STAT3 strongly inhibits SOCS-3 expression, whereas transfection with wild-type STAT3 does not. Moreover, the reduced SOCS-3 expression in cells transfected with the dominant negative STAT3 is associated with an increased sensitivity to interferon-α (IFN-α). In conclusion, evidence is provided for a constitutive SOCS-3 expression in cancer cells obtained from patients with CTCL. Moreover, the findings indicate that the aberrant expression of SOCS-3 is mediated by a constitutive activation of STAT3 in CTCL cells and affects the IFN-α sensitivity of these cells.
Human peripheral blood eosinophils express stem cell factor
Authors: Hartman Mor-Li , Piliponsky Adrian M. , Temkin Vladislav , Levi-Schaffer Francesca
Published: July 2002

Stem cell factor (SCF) or c-Kit ligand is a cytokine associated with the differentiation, survival, and activation of mast cells. Eosinophils have pleiotropic functions in several diseases and, together with mast cells, are key cells in allergy. Mast cell–eosinophil interactions can take place during the late and chronic phases of allergy. It was, therefore, investigated whether eosinophils can produce SCF and consequently influence mast cells. Human peripheral blood eosinophils variably expressed mRNA for the soluble and uncleaved forms of SCF (reverse transcription–polymerase chain reaction) and produced the 18.5-kd protein backbone of SCF (Western blot analysis). After overnight incubation in medium, eosinophils also produced SCF of higher molecular weight (42-45 kd) that might represent its glycosylated forms. Eosinophils expressed cytoplasmic SCF that colocalized with major basic protein (confocal laser microscopy). Freshly isolated eosinophils contained 8.9 ± 1.7 pg SCF/106 (mean ± SEM; enzyme-linked immunosorbent assay). Although overnight incubation of the eosinophils in either culture medium or in phorbol 12-myristate 13-acetate–calcium ionophore did not cause the secretion of SCF, the addition of chymase induced SCF release. In summary, it was demonstrated that human peripheral blood eosinophils are a source of SCF. These results may contribute to a better understanding of the interactions between eosinophils and mast cells in allergic inflammation.
The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts
Authors: Smolich Beverly D. , Yuen Helene A. , West Kristina A. , Giles Francis J. , Albitar Maher , Cherrington Julie M.
Published: July 2002

SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of receptor tyrosine kinases, including those of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors and, although not expressed on mature peripheral blood cells, is expressed in leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) patients. The c-kit kinase inhibitory activity of SU5416 and SU6668 was evaluated in MO7E cells, a human myeloid leukemia cell line. Tyrosine autophosphorylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC50] 0.1-1 μM). Inhibition of extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation, a signaling event downstream of c-kit activation, was also inhibited in a dose-dependent manner. Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC50 0.1 μM for SU5416; 0.29 μM for SU6668). Furthermore, both SU5416 and SU6668 induced apoptosis in a dose- and time-dependent manner as measured by the increase in activated caspase-3 and the enhanced cleavage of its substrate poly(ADP-ribose) polymerase. These findings with MO7E cells were extended to leukemic blasts from c-kit+ patients. In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis. These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML.
A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the docking model of STAT activation
Authors: Barber Dwayne L. , Beattie Bryan K. , Mason Jacqueline M. , Nguyen Melody H.-H. , Yoakim Monique , Neel Benjamin G. , D'Andrea Alan D. , Frank David A.
Published: July 2002

Erythropoietin (EPO) specifically activates the Janus kinase JAK2 and the transcription factor signal transducer and activator of transcription-5 (STAT5). All members of the STAT family are tyrosine phosphorylated in response to cytokine stimulation at a conserved carboxy-terminal tyrosine, Y694, in the case of STAT5. To determine structural features important for STAT signaling, we generated an activation-specific STAT5 antibody using a phosphopeptide containing amino acids 687 to 698 of STAT5 as antigen. This antibody specifically recognizes tyrosine- phosphorylated STAT5 but not nonphosphorylated STAT5. In immunoprecipitation reactions from cell lines and primary erythroblasts, 2 distinct polyclonal activation-specific STAT5 antibodies selectively immunoprecipitate the tyrosine phosphorylated EPO receptor (EPO-R) in addition to STAT5 under native and denaturing conditions. We propose that the activation-specific STAT5 antibody recognizes the 2 substrates to which the STAT5 SH2 domain interacts, namely, the tyrosine- phosphorylated EPO-R and STAT5 itself. Several studies have implicated EPO-R Y343, Y401, Y431, and Y479 in the recruitment of STAT5. Using a series of EPO-R tyrosine mutants expressed in Ba/F3 cells, we have shown that the activation-specific STAT5 antibody immunoprecipitates an EPO-R containing only 2 tyrosines at positions 343 and 401, confirming the importance of these tyrosines in STAT5 recruitment. These data uncover a novel aspect of STAT SH2 domain recognition and demonstrate the utility of activation-specific antibodies for examining the specificity of STAT–cytokine receptor interactions.
Fas ligand–induced caspase-1–dependent accumulation of interleukin-18 in mice with acute graft-versus-host disease
Authors: Itoi Hisayuki , Fujimori Yoshihiro , Tsutsui Hiroko , Matsui Kiyoshi , Futatsugi Shizue , Okamura Haruki , Hara Hiroshi , Hada Toshikazu , Kakishita Eizo , Nakanishi Kenji
Published: July 2002

Acute graft-versus-host disease (aGVHD), the fatal side effects of bone marrow transplantation, was shown to be accompanied by elevation of serum levels of interleukin 18 (IL-18). In this study, the mechanism underlying the accumulation of IL-18 in aGVHD in mice was investigated. Lethally irradiated recipients having transplantation with H-2 disparate donor splenocytes demonstrated aGVHD and contained markedly elevated serum levels of IL-18. In contrast, recipients having transplantation with gld/gld spleen cells, which lack functional Fas ligand (FasL), contained only normal ranges of IL-18, indicating FasL-mediated IL-18 release in aGVHD. The wild-type hosts engrafted with caspase-1–deficient cells revealed marked increases of IL-18 similar to those engrafted with wild-type cells, whereas caspase-1–deficient recipients engrafted with wild-type cells showed only a slight elevation of serum IL-18, indicating that IL-18 elevation is derived from host cells in a caspase-1–dependent manner. These results suggest FasL-mediated caspase-1–dependent IL-18 secretion in aGVHD in mice.
Role of the liver in regulating numbers of circulating neutrophils
Authors: Shi Jialan , Gilbert Gary E. , Kokubo Yoshihiro , Ohashi Takashi
Published: July 2002

Neutrophils (polymorphonuclear leukocytes [PMNs]) carry potent destructive enzymes that can destroy invasive bacteria or damage normal tissue. PMNs have a half-life of only 6 hours in the blood, but the details of this homeostasis are unknown. In a rat model of endotoxemia, P-selectin was selectively up-regulated in hepatic sinusoids and veins where it was necessary for phagocytosis of PMNs by Kupffer cells in the liver, as opposed to the spleen or the lungs. Apoptotic PMNs appeared in the lungs and spleen only after inactivation of Kupffer cells by gadolinium chloride (GdCl3). Blocking of Fas protein reduced the number of apoptotic cells in the liver; binding of annexin V to phosphatidylserine (PS) reduced the number of PMNs phagocytosed by Kupffer cells. The results support a clearance pathway in which apoptosis and phagocytosis are effected by Kupffer cells after P-selectin–mediated sequestration.
Expression of complement inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma
Authors: Weng Wen-Kai , Levy Ronald
Published: July 2002

Rituximab is a chimeric monoclonal antibody that targets B-cell–specific antigen CD20 and an effective treatment for B-cell non-Hodgkin lymphoma. Although it is readily used in clinical practice, the exact mechanism of its antitumor effect is unclear. One potential mechanism involves complement-mediated cytotoxicity. It has been shown that rituximab induces complement-mediated cytotoxicity in follicular lymphoma cells in vitro, and complement inhibitors CD55 and CD59 may regulate this process. To determine whether complement inhibitors play a role in regulating the antitumor effect of rituximab, the expression of complement inhibitors CD46, CD55, and CD59 was analyzed in pretreatment tumor cells from 29 rituximab-treated follicular lymphoma patients. Among them, 8 patients achieved complete responses, 11 patients achieved partial responses, and 10 patients showed no or minimal responses to rituximab treatment. Expression of surface CD20, CD46, CD55, and CD59 was determined by 2-color flow cytometry. Although the CD59 level was slightly lower in the complete response group, there was no statistically significant difference in the expression of individual complement inhibitor CD46 (mean channel fluorescence [MCF]: NR, 26.4; PR, 21.9; CR, 29.9), CD55 (MCF: NR, 16.4; PR, 14.9; CR, 23.2), or CD59 (MCF: NR, 41.6; PR, 40.6; CR, 30.6), the combination of any 2 inhibitors, or all 3 on tumor cells from 3 response groups. In addition, there was no difference in the rituximab-induced complement-mediated cytotoxicity in an in vitro assay using tumor cells from 3 response groups. Thus, CD46, CD55, and CD59 expression on pretreatment tumor cells, or their susceptibility to in vitro complement-mediated killing, does not predict clinical outcome after rituximab treatment.
Regulation of interferon-γ gene expression by nuclear factor of activated T cells
Authors: Kiani Alexander , Garcı́a-Cózar Francisco J. , Habermann Ivonne , Laforsch Stefanie , Aebischer Toni , Ehninger Gerhard , Rao Anjana
Published: July 2002

Transcription factors of the nuclear factor of activated T cells (NFAT) family are thought to regulate the expression of a variety of inducible genes such as interleukin-2 (IL-2), IL-4, and tumor necrosis factor-α. However, it remains unresolved whether NFAT proteins play a role in regulating transcription of the interferon- γ (IFN-γ) gene. Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-γ production in vivo. Compared with T cells expressing NFAT1, T cells lacking NFAT1 display a substantial IL-4–independent defect in expression of IFN-γ mRNA and protein. Reduced IFN-γ production by NFAT1−/−× IL-4−/− T cells is observed after primary in vitro stimulation of naive CD4+ T cells, is conserved through at least 2 rounds of T-helper cell differentiation, and occurs by a cell-intrinsic mechanism that does not depend on overexpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT1−/−× IL-4−/− mice show increased susceptibility to infection with the intracellular parasiteLeishmania major. Moreover, IFN-γ production in a murine T-cell clone is sensitive to the selective peptide inhibitor of NFAT, VIVIT. These results suggest that IFN-γ production by T cells is regulated by NFAT1, most likely at the level of gene transcription.
Hypodiploidy is a major prognostic factor in multiple myeloma
Authors: Smadja Nicole Véronique , Bastard Christian , Brigaudeau Christophe , Leroux Dominique , Fruchart Christophe
Published: July 2002

Conventional karyotypes performed before any treatment in 208 patients with multiple myeloma were reviewed by the Groupe Français de Cytogénétique Hématologique. A total of 138 patients displayed complex chromosomal abnormalities (CCAs). According to the chromosome number pattern, a first group of 75 patients had a hyperdiploid karyotype. A second group of 63 patients referred to as the hypodiploid group had either pseudodiploid, hypodiploid, or near-tetraploid karyotypes. Of 159 treated patients available for survival analysis, 116 had an abnormal karyotype. The comparison of overall survival (OS) between hyperdiploid and hypodiploid patients showed a highly significant difference (median OS 33.8 vs 12.6 months, respectively, P < .001). The presence of 14q32 rearrangements (36 of 116 patients) worsened the prognosis (median OS 17.6 vs 29.9 months, P < .02). The presence of chromosome 13q abnormalities (13qA, 63 patients) did not modify OS in CCA patients (median OS 20.6 vs 27.8 months,P < .59). However, taking into account the whole series including normal karyotypes, 13qA (63 of 159 patients) had a significant impact on OS (median 20.6 vs 37.1 months,P < .04). In the same way, the presence of a hypodiploid karyotype (52 of 159 patients) had a strong prognostic value (OS 12.8 vs 44.5 months, P < .000 01). A multivariate analysis including stage, β2-microglobulin, bone marrow plasmocytosis, treatment type, 13qA, and hyperdiploidy and hypodiploidy showed that a hypodiploid karyotype was the first independent factor for OS (P < .001), followed by treatment approach. These results confirm that the chromosome number pattern of malignant plasma cells is a very powerful prognostic factor in newly diagnosed multiple myeloma patients.
Impact of the lymphoma idiotype on in vivo tumor protection in a vaccination model based on targeting antigens to antigen-presenting cells
Authors: Kronenberger Konrad , Dieckmann Andreas , Selmayr Michael , Strehl John , Wahl Ulrich , Lindhofer Horst , Kraal Georg , Mocikat Ralph
Published: July 2002

Trioma cell vaccination is a potent new immunologic approach for the therapy of malignant B-cell lymphoma. It is based on targeting tumor antigens to internalizing receptors on antigen-presenting cells (APCs). Tumor cells are fused to an APC-specific hybridoma, where they are converted to trioma cells that include potentially all lymphoma-derived antigens and that express the APC-binding arm. In this study, the mechanisms of trioma-mediated tumor immunity in immunocompetent mice were dissected, and it was shown in this model system that humoral anti-idiotypic immunity is indeed detectable after idiotype-specific immunization but that it does not reflect the degree of tumor protection obtained in vivo. Immunization against the idiotype alone was not sufficient for efficient tumor rejection in vivo. Targeting tumor antigens to APCs is only successful in terms of inducing tumor protection when designed as a polyvalent vaccination protocol.
Intensified and Shortened Cyclical Chemotherapy for Adult Acute Lymphoblastic Leukemia
Authors: Linker Charles , Damon Lloyd , Ries Curt , Navarro Willis
Published: July 2002

PURPOSE: To assess the efficacy and toxicity of a new treatment program of intensified and shortened cyclical chemotherapy (protocol 8707) in adults with acute lymphoblastic leukemia (ALL).

PATIENTS AND METHODS: Previously untreated adults ≤ 60 years old with ALL were treated with a four-agent induction chemotherapy regimen. This was followed by cyclical postremission therapy with high-dose cytarabine/etoposide; high-dose methotrexate/6-mercaptopurine; and daunorubicin, vincristine, prednisone, and asparaginase. Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above.

RESULTS: Seventy-eight of 84 patients (93%) achieved complete remission. With a median follow-up of 5.6 years, 5-year event-free survival (EFS) of all remission patients is 52%. Patients with high-risk features including adverse cytogenetics, failure to achieve remission with the first cycle of chemotherapy, and B-precursor disease with WBC counts more than 100,000/μL all relapsed unless taken off study for transplantation. For patients without these high-risk features, 5-year EFS was 60%. Compared with our previous treatment regimen, results appear to be improved for patients with standard-risk B-precursor disease (5-year EFS, 66% v 34%; P = .01).

CONCLUSION: Intensified and shortened chemotherapy may improve the outcome for patients with ALL with B-precursor disease lacking high-risk features. Further trials of this regimen are warranted.
Phase II Trial of the Pegylated Liposomal Doxorubicin in Previously Treated Metastatic Endometrial Cancer: A Gynecologic Oncology Group Study
Authors: Muggia Franco M. , Blessing John A. , Sorosky Joel , Reid Gary C.
Published: July 2002

PURPOSE: To determine whether pegylated liposomal doxorubicin (PLD) has antitumor activity in pretreated patients with persistent or recurrent endometrial carcinoma and to define the nature and degree of toxicity of PLD.

PATIENTS AND METHODS: Women with histologically documented recurrent or persistent measurable endometrial carcinoma and with failure of one prior treatment regardless of prior anthracycline therapy were enrolled. PLD was administered intravenously over a 1-hour period at a dose of 50 mg/m2 every 4 weeks; the dosage was modified in accordance with observed toxicity.

RESULTS: Of 46 patients entered, 42 were assessable for response, as three were declared ineligible on central pathology review and one was not assessable for response. Forty had received prior chemotherapy, 11 hormonal therapy, and 29 radiation therapy. Doxorubicin had been given to 32 patients, carboplatin with paclitaxel to six, carboplatin to one, and fluorouracil to one. Four patients had partial responses lasting 1.1, 2.1, 3.3, and 5.4 months; the overall response rate was 9.5% (95% confidence interval, 2.7% to 22.6%). Three of these responses (in liver and in lymph node) occurred in patients who had progressed after doxorubicin with either paclitaxel or cisplatin. The median number of courses was 2.5 (range, one to 14). Toxicity was generally mild: only 25 patients experienced leukopenia, with a median WBC count of 2,900 (range, 800 to 3,900) at nadir. The only grade 4 toxicities were one episode each of esophagitis, hematuria, and vomiting. The median overall survival was 8.2 months.

CONCLUSION: PLD has only limited activity in pretreated advanced, recurrent endometrial cancer, but further trials in anthracycline-naive patients and in previously untreated patients are ongoing. Its toxicity profile should permit its use in combination with myelosuppressive drugs.
Physician EHR Time and Visit Volume Following Adoption of Team-Based Documentation Support
Authors: Apathy Nate C. , Holmgren A. Jay , Cross Dori A.
Published: August 2024

Importance

Physicians spend the plurality of active electronic health record (EHR) time on documentation. Excessive documentation limits time spent with patients and is associated with burnout. Organizations need effective strategies to reduce physician documentation burden; however, evidence on team-based documentation (eg, medical scribes) has been limited to small, single-institution studies lacking rigorous estimates of how documentation support changes EHR time and visit volume.

Objectives

To analyze how EHR documentation time and visit volume change following the adoption of team-based documentation approaches.

Design, Setting, and Participants

This national longitudinal cohort study analyzed physician-week EHR metadata from September 2020 through April 2021. A 2-way fixed-effects difference-in-differences regression approach was used to analyze changes in the main outcomes after team-based documentation support adoption. Event study regression models were used to examine variation in changes over time and stratified models to analyze the moderating role of support intensity. The sample included US ambulatory physicians using the EHR. Data were analyzed between October 2022 and September 2023.

Exposure

Team-based documentation support, defined as new onset and consistent use of coauthored documentation with another clinical team member.

Main Outcomes and Measures

The main outcomes included weekly visit volume, EHR documentation time, total EHR time, and EHR time outside clinic hours.

Results

Of 18 265 physicians, 1024 physicians adopted team-based documentation support, with 17 241 comparison physicians who did not adopt such support. The sample included 57.2% primary care physicians, 31.6% medical specialists, and 11.2% surgical specialists; 40.0% practiced in academic settings and 18.4% in outpatient safety-net settings. For adopter physicians, visit volume increased by 6.0% (2.5 visits/wk [95% CI, 1.9-3.0]; P < .001), and documentation time decreased by 9.1% (23.3 min/wk [95% CI, −30.3 to −16.2]; P < .001). Following a 20-week postadoption learning period, visits per week increased by 10.8% and documentation time decreased by 16.2%. Only high-intensity adopters (>40% of note text authored by others) realized reductions in documentation time, both for the full postadoption period (−53.9 min/wk [95% CI, −65.3 to −42.4]; 21.0% decrease; P < .001) and following the learning period (−72.2 min/wk; 28.1% decrease). Low adopters saw no meaningful change in EHR time but realized a similar increase in visit volume.

Conclusions and Relevance

In this national longitudinal cohort study, physicians who adopted team-based documentation experienced increased visit volume and reduced documentation and EHR time, especially after a learning period.
Outcomes Following Surgical and Nonsurgical Treatment for Uncomplicated Appendicitis in Older Adults
Authors: Ashbrook Matthew , McGing Maggie , Cheng Vincent , Schellenberg Morgan , Martin Matthew , Inaba Kenji , Matsushima Kazuhide
Published: August 2024

Importance

The optimal treatment of acute uncomplicated appendicitis in older adults with frailty is not defined.

Objective

To examine outcomes associated with treatment strategies for acute uncomplicated appendicitis in older adults with or without frailty.

Design, Setting, and Participants

This retrospective cohort study used National Inpatient Sample data from adults 65 years or older with a diagnosis of uncomplicated appendicitis from January 1, 2016, to December 31, 2018. Data were analyzed from July to November 2023. The National Inpatient Sample database approximates a 20% stratified sample of all inpatient hospital discharges in the US.

Exposures

Study patients were categorized into 3 groups: nonoperative management, immediate operation, and delayed operation.

Main Outcomes and Measures

Clinical outcomes, including hospital complications and in-hospital mortality, were assessed among older adults with and without frailty, identified using an adapted claims-based frailty index.

Results

A total of 24 320 patients were identified (median [IQR] age, 72 [68-79] years; 50.9% female). Of those, 7290 (30.0%) were categorized as having frailty. Overall, in-hospital mortality was 1.4%, and the incidence of complications was 37.3%. In patients with frailty, multivariable analysis showed both nonoperative management (odds ratio [OR], 2.89; 95% CI, 1.40-5.98; P < .001) and delayed appendectomy (OR, 3.80; 95% CI, 1.72-8.43; P < .001) were associated with increased in-hospital mortality compared with immediate appendectomy. In patients without frailty, immediate appendectomy was associated with increased hospital complications compared with nonoperative management (OR, 0.77; 95% CI, 0.64-0.94; P = .009) and lower hospital complications compared with delayed appendectomy (OR, 2.05; 95% CI, 1.41-3.00; P < .001).

Conclusions and Relevance

In this cohort study of older adults with uncomplicated appendicitis, outcomes differed among management strategies based on frailty status. Routine frailty assessments incorporated in the care of older adult patients may help guide discussions for shared decision-making.
B‐cell depletion limits HTLV‐1‐infected T‐cell expansion and ameliorate HTLV‐1‐associated myelopathy
Authors: Lv Aowei , Fang Yaofeng , Lin Xiaohong , Chen Jiaying , Song Huanhuan , Wang Ning , Chen Wan‐Jin , Fu Ying , Li Rui , Lin Yi
Published: August 2024

Objective

Human T‐cell leukemia virus type 1‐associated myelopathy (HAM) is a chronic, progressive, inflammatory disease with unclear pathogenesis and no effective treatments. We aimed to investigate a novel mechanistic theory and treat HAM patients with rituximab, which can deplete CD20+ B lymphocytes in circulation.

Methods

Single‐cell RNA sequencing (scRNA‐seq) data was analyzed to identify HTLV‐1‐associated B cells and their effect on T cells. An observational analysis of our HAM cohort was conducted to elucidate changes in the immunological microenvironment of these patients. Peripheral blood mononuclear cells (PBMC) from HAM patients were isolated to explore the efficacy of B cell depletion in vitro. To assess the effect of B‐cell depletion on HAM patients, eligible participants in our cohort received rituximab therapy (NCT04004819).

Results

ScRNA‐seq results suggest a significant effect of HTLV‐1‐associated B cells on T cells. Additionally, HTLV‐1 was found to infect B cells and depletion of B cells inhibited the proliferation of T cells. Number of B cells in HAM patients had positive correlation with the proviral load and infected cell counts. Depletion of B cells led to a reduction in HTLV‐1 proviral load in vitro. Furthermore, in clinical trial, 14 HAM patients were enrolled. Three patients (21.4%) who received rituximab failed to achieve remission, compared to 24 (85.7%) patients received any other therapy that failed to achieve remission. With a low level of circulating B cells, the proportion of Ki67‐positive cells in CD4+ T cells fell.

Interpretation

This study provided evidence that depleting B‐lymphocytes is an innovative strategy for treating patients with HAM and broadens the understanding of the role of B cells in infectious immunity.
“Society Isn't Designed for Us to Win”: Trauma and Sexual Healthcare Experiences Among Transgender Women in the Southeastern United States
Authors: Van Gerwen Olivia T. , Muzny Christina A. , Turan Bulent , Siwakoti Krishmita , Batey D. Scott
Published: August 2024

Transgender women (TGW) are disproportionately affected by sexually transmitted infections (STIs). Experienced trauma threatens TGW's commitment to sexual healthcare. Trauma‐informed approaches to sexual healthcare can improve engagement. This study aimed to characterize the trauma experienced by TGW in the Southeastern US, especially related to sexual health. TGW completed in‐depth individual interviews guided by the Modified Social Ecological Model (MSEM) and Minority Stress framework. Interviews explored the nature of trauma, sexual health, and their intersection in TGW's lives, and a thematic analysis was performed. Between August 2022 and January 2023, 13 TGW enrolled (69% Black, 31% White). Mental illness was common (77%). Five participants (38%) were HIV+, and seven (54%) reported lifetime STI history. Themes reflected societal (barriers to healthcare, anti‐transgender legislation), community (misgendering/deadnaming), network (limited support), and individual (dysphoria, sex work, fear for physical safety, stigma, mental health conditions, race) stressors. The physical/sexual violence and resilience themes pervaded all stressor levels. Medical mistrust was exacerbated by past traumatic experiences within sexual healthcare settings. Resilience and transgender representation in healthcare settings were protective. Various experienced traumas and their cumulative effects were pervasive in the daily lives of TGW. Development of targeted interventions to improve sexual health engagement of TGW must optimize personal strengths and provide holistic support.
Non‐Coding RNA in Schwann Cell and Peripheral Nerve Injury: A Review
Authors: Huang Li‐Xin , Sun Tao , Sun Jun , Wu Zhi‐Min , Ling Cong , Zhang Bao‐Yu , Chen Chuan , Wang Hui
Published: August 2024

Peripheral nerve injury (PNI) can result in severe disabilities, profoundly impacting patients' quality of life and potentially endangering their lives. Therefore, understanding the potential molecular mechanisms that facilitate the regeneration of damaged nerves is crucial. Evidence indicates that Schwann cells (SCs) play a pivotal role in repairing peripheral nerve injuries. Previous studies have shown that RNA, particularly non‐coding RNA (ncRNA), plays a crucial role in nerve regeneration, including the proliferation and dedifferentiation of SCs. In this review, the individual roles of ncRNA in SCs and PNI are analyzed. This review not only enhances the understanding of ncRNA's role in nerve injury repair but also provides a significant theoretical foundation and inspiration for the development of new therapeutic strategies.
Uncovering the Intrinsic High Fracture Toughness of Titanium via Lowered Oxygen Impurity Content
Authors: Zou Xiao‐Wei , Han Wei‐Zhong , Ma En
Published: August 2024

Titanium (Ti) and its alloys are known to exhibit room‐temperature fracture toughness below 130 MPa m1/2, only about one half of the best austenitic stainless steels. It is purported that this is not the best possible fracture resistance of Ti, but a result of oxygen impurities that sensitively retard the activities of plasticity carriers in this hexagonal close‐packed metal. By a reduction of oxygen content from the 0.14 wt% in commercial purity Ti to 0.02 wt%, the mode‐Ι fracture toughness of the low‐oxygen Ti is measured to be as high as KJIc ≈ 255 MPa m1/2, corresponding to J‐integral‐based crack‐initiation toughness of up to JIc ≈ 537 kJ m−2. This extraordinary toughness, reported here for the first time for pure Ti, places Ti among the toughest known materials. The intrinsic high fracture resistance is attributed to the profuse plastic deformation in a significantly enlarged plastic zone, rendered by the pronounced deformation twinning ahead of the crack tip along with ample twin‐stimulated 〈c+a〉 dislocation activities, in the absence of impeding oxygen. Controlling the content of a property‐controlling impurity thus holds the promise to be a readily applicable strategy to reach for unprecedented damage tolerance in some other structural alloys.
Optimization of the Transmission X‐Ray Target Toward Obtaining Monochromatic Radiation
Authors: Urbański Paweł , Grzebyk Tomasz , Krysztof Michał , Nowak Damian
Published: August 2024

The article presents a process of designing and optimizing a transmission X‐ray target allowing to obtaining of near monochromatic radiation. It describes how the choice of materials, their thickness, and the energy of electrons influence the generated X‐ray spectra and which of the physical phenomena plays the most important role in this process. Due to the analytical, experimental, and simulation results, the authors prepared a Ni‐Si bilayer structure, which produces radiation confined to more than 50% within a single 7.2 keV emission peak.
Ba2+‐Si4+‐Incorporated High‐Efficiency and Excellent Thermal Stable YAG:Ce3+ Ceramic Phosphors for Laser‐Driven Lighting
Authors: Hu Pan , Liu Yongfu , Sun Peng , Luo Zhaohua , Jiang Jun
Published: August 2024

Y3Al5O12:Ce3+ (YAG:Ce3+) ceramic phosphor (CP) is the predominant color convert utilized in laser‐diode (LD) driven lighting. How to obtain a high‐efficiency CP is the challenge. A strategy to depress lattice defects by the Ba2+‐Si4+ replacement for the Y3+‐Al3+ pair is proposed. On the basis of charge equilibrium, the heavy element Ba also can enhance the thermal stability of CPs. The luminous intensity at 200 °C is improved from 83% to 97% of that at room temperature, and then the luminous efficiency reaches 262 lm W−1 from blue lasers to white light. The luminous flux of the white LD flashlight using the CP increases by 30% compared with that of the commercial LD flashlight. These results demonstrate that the strategy is effective in optimizing YAG:Ce3+ CP performance. The luminescence saturation coupled with optics and heat is investigated.