bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription
Authors: Stein Harald , Marafioti Theresa , Foss Hans-Dieter , Laumen Helmut , Hummel Michael , Anagnostopoulos Ioannis , Wirth Thomas , Demel Gudrun , Falini Brunangelo 
Published: July 2002

Abstract
In contrast to the tumor cells (L&H cells) of lymphocyte predominant Hodgkin disease (LPHD), Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD) are unable to transcribe immunoglobulin, despite the presence of rearranged immunoglobulin genes. Although initial studies have suggested crippling immunoglobulin gene mutations to be the cause of absent immunoglobulin expression in cHD, recent work of our group has demonstrated an impaired activation of the immunoglobulin promoter as a superior mechanism. As immunoglobulin transcription is mainly regulated by the B-cell transcription factors Oct2 and BOB.1/OBF.1, we analyzed 35 cases of LPHD, 32 cases of cHD, and 2 Hodgkin disease cell lines for the expression of these transcription factors and also in parallel for immunoglobulin expression. Our results demonstrate an absence of Oct2 and/or BOB.1/OBF.1 in cHD and a striking overexpression of Oct2 in LPHD. Immunoglobulin expression was lacking in cHD but present in LPHD. Furthermore, the reintroduction of BOB.1/OBF.1 and Oct2 into cultured HRS cells restored the activity of cotransduced immunoglobulin promoter constructs. Our findings dismiss the concept that the different immunoglobulin expression in cHD and LPHD is due to disrupting mutations of immunoglobulin V genes in cHD but is most likely due to a down-regulation of Oct2 and/or BOB.1/OBF.1. This study further revealed Oct2 as a new and valuable marker for the identification of L&H cells and their distinction from HRS cells. The impairment of immunoglobulin transcription with a down-regulated synthesis of Oct2 and BOB.1/OBF.1 is the first established general recurrent defect found in HRS cells.
New mutations inactivating transferrin receptor 2 in hemochromatosis type 3
Authors: Roetto Antonella , Totaro Angela , Piperno Alberto , Piga Antonio , Longo Filomena , Garozzo Giovanni , Calı̀ Angelita , De Gobbi Marco , Gasparini Paolo , Camaschella Clara 
Published: July 2002

Abstract
Hereditary hemochromatosis usually results from C282Y homozygosity in the HFE gene on chromosome 6p. Recently, a new type of hemochromatosis (HFE3) has been characterized in 2 unrelated Italian families with a disorder linked to 7q. Patients with HFE3 have transferrin receptor 2 (TFR2) inactivated by a homozygous nonsense mutation (Y250X). Here the identification of 2 newTFR2 mutations is reported. In a large inbred family from Campania, a frameshift mutation (84-88 insC) in exon 2 that causes a premature stop codon (E60X) is identified. In a single patient with nonfamilial hemochromatosis, a T→A transversion (T515A), which causes a Methionine→Lysine substitution at position 172 of the protein (M172K), has been characterized. TFR2 gene gives origin to 2 alternatively spliced transcripts—the α-transcript, which may encode a transmembrane protein, and the β-transcript, a shorter, possibly intracellular variant. Based on their positions, the effects of the identified mutations on the 2 TFR2 forms are expected to differ. Y250X inactivates both transcripts, whereas E60X inactivates only the α-form. M172K has a complex effect: it causes a missense in the α-form, but it may also prevent the β-form production because it affects its putative initiation codon. Analysis of the clinical phenotype of 13 HFE3 homozygotes characterized at the molecular level has shown a variable severity, from nonexpressing patients to severe clinical complications. The identification of new mutations of TFR2 confirms that this gene is associated with iron overload and offers a tool for molecular diagnosis in patients without HFE mutations.
Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation
Authors: Koseki Shiori , Souri Masayoshi , Koga Shinichiro , Yamakawa Mitsunori , Shichishima Tsutomu , Maruyama Yukio , Yanai Fumio , Ichinose Akitada 
Published: July 2002

Abstract
Two Japanese patients were newly diagnosed as having B subunit (XIIIB) deficiency of factor XIII (former type I deficiency). Both patients have a previously described one-base deletion at the boundary between intron A/exon II in the XIIIB gene, heterozygously or homozygously. A founder effect was proposed for this mutation because 3 unrelated patients with XIIIB deficiency also share 2 3′-polymorphisms. In one patient heterozygous for the above mutation, a novel mutation was also identified: a deletion of guanosine in exon IX (delG) of the XIIIB gene. To understand the molecular and cellular pathology of the delG mutation, expression studies were performed using a cultured mammalian cell line. Pulse-chase experiments showed that a resultant truncated XIIIB remained inside the cells and could not be secreted into the culture medium. Furthermore, immunocytochemical examinations by epifluorescence, confocal, and electron microscopes indicated impaired intracellular transportation of the truncated XIIIB from the endoplasmic reticulum to the Golgi apparatus. No mutations in the gene for the A subunit (XIIIA) were identified in this patient. Therefore, secretion of the truncated XIIIB must also be impaired in vivo, leading to a secondary XIIIA deficiency. These results support a previous conclusion that genetic defects of XIIIB are the basis for the former type I factor XIII deficiency.
Missense mutation of the interleukin-12 receptor β1 chain–encoding gene is associated with impaired immunity againstMycobacterium avium complex infection
Authors: Sakai Tatsunori , Matsuoka Masao , Aoki Manabu , Nosaka Kisato , Mitsuya Hiroaki 
Published: July 2002

AbstractInterleukin-12 (IL-12) plays an important role in the production of interferon gamma (IFN-γ) and is essential for protection against intracellular pathogens such as Mycobacterium andSalmonella. A 31-year-old man had disseminatedMycobacterium avium complex (MAC) infection. The production of IFN-γ by peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA-PBMCs) was found severely impaired (40.7 pg/mL compared with 833  ± 289 pg/mL for the patient's and healthy subjects' (n = 3) PHA- PBMCs, respectively), and the patient's PHA-PBMCs completely lacked surface IL-12 receptor β1 (IL-12Rβ1) chain. The IL-12Rβ1 gene transcript in his PHA-PBMCs had an R213W substitution in each allele. Family history showed that both parents were heterozygotes in the R213W substitution. Transfection of a human embryonal kidney cell line 293 (HEKC293) with wild-type IL-12Rβ1wt gene led to cell surface IL-12Rβ1 expression; however, no expression was seen in HEKC293 transfected with the mutated IL-12Rβ1R213W gene. TheIL-12Rβ1 gene transcript, but no IL-12Rβ1 protein, was detected in PHA-PBMCs and T cells, suggesting a post-translational event(s), most likely a shortened turnover of the protein. The R213W substitution was not detected in the cells of 32 healthy persons or of 25 patients with tuberculosis or MAC infection. Six amino acid substitutions (Q214R, M365T, G378R, H438Y, A525T, and G594E) were identified, but the incidences of such substitutions were not significantly different between the groups. The Q214R substitution is reportedly linked to IL-12Rβ1 deficiency; however, the study showed that 19 and 10 of 57 Japanese and 6 and 4 of 33 healthy white persons were heterozygous and homozygous for Arg-214, respectively, suggesting that the Q214R substitution represents a polymorphism and is not related to IL-12Rβ1 deficiency but that the R213W substitution is responsible for IL-12Rβ1 deficiency.
Endogenous CD28 expressed on myeloma cells up-regulates interleukin-8 production: implications for multiple myeloma progression
Authors: Shapiro Virginia Smith , Mollenauer Marianne Newton , Weiss Arthur 
Published: July 2002

AbstractCD28 is the major costimulatory molecule on T cells. CD28 activation, in conjunction with T-cell receptor engagement, up-regulates transcription of several cytokines, including interleukin-2 (IL-2), through transcriptional activation of the RE/AP composite element. Although CD28 is not normally expressed on B cells or plasma cells, more than 90% of extramedullary myelomas (a late stage B-cell neoplasm) express CD28. The functional significance of this is unknown. The results of this study demonstrate that CD28 stimulates transcriptional activation of RE/AP-based reporters in B cells and myeloma cells. However, CD28 stimulation does not up-regulate IL-2 production in myeloma cell lines, demonstrating that the IL-2 promoter may not be a relevant RE/AP-containing target of CD28 in myelomas. Instead, an RE/AP composite element has been identified within the promoter of the IL-8 gene, a chemokine that promotes angiogenesis. Furthermore, stimulation of endogenous CD28 expressed by 3 myeloma cell lines increased IL-8 production. Therefore, the study demonstrates that CD28 is functional in myelomas to up-regulate transcription of endogenous genes, includingIL-8. The proposal is made that aberrant expression of CD28 may play a role in the progression of multiple myeloma.
Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine
Authors: Stone Richard M. , Berg Deborah T. , George Stephen L. , Dodge Richard K. , Paciucci Paolo A. , Schulman Philip P. , Lee Edward J. , Moore Joseph O. , Powell Bayard L. , Baer Maria R. , Bloomfield Clara D. , Schiffer Charles A. 
Published: July 2002

AbstractThe treatment of older patients with acute myeloid leukemia (AML) remains unsatisfactory, with complete remission (CR) achieved in only approximately 50% and long-term disease-free survival in 10% to 20%. Three hundred eighty-eight patients (60 years of age and older) with newly diagnosed de novo AML were randomly assigned to receive placebo (P) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM in a double-blind manner, beginning 1 day after the completion of 3 days of daunorubicin and 7 days of cytarabine therapy. No differences were found in the rates of leukemic regrowth, CR, or infectious complications in either arm. Of 205 patients who achieved CR, 169 were medically well and were randomized to receive cytarabine alone or a combination of cytarabine and mitoxantrone. With a median follow-up of 7.7 years, the median disease-free survival times were 11 months and 10 months for those randomized to cytarabine or cytarabine/mitoxantrone, respectively. Rates of relapse, excluding deaths in CR, were 77% for cytarabine and 82% for cytarabine/mitoxantrone. Induction randomization had no effect on leukemic relapse rate or remission duration in either postremission arm. Because cytarabine/mitoxantrone was more toxic and no more effective than cytarabine, it was concluded that this higher-dose therapy had no benefit in the postremission management of older patients with de novo AML. These results suggest the need to develop novel therapeutic strategies for these patients.
Differentiation of cytomegalovirus-specific CD8+ T cells in healthy and immunosuppressed virus carriers
Authors: Gamadia Laila E. , Rentenaar Rob J. , Baars Paul A. , Remmerswaal Ester B. M. , Surachno Sugianto , Weel Jan F. L. , Toebes Mireille , Schumacher Ton N. M. , ten Berge Ineke J. M. , van Lier René A. W. 
Published: July 2002

AbstractDuring immunosuppression, cytomegalovirus (CMV) can reactivate and cause serious clinical problems. Normally, abundant virus replication is suppressed by immune effector mechanisms. To study the interaction between CD8+ T cells and persisting viruses, frequencies and phenotypes of CMV-specific CD8+ T cells were determined in healthy individuals and compared to those in renal transplant recipients. In healthy donors, function of circulating virus-specific CD8+ T cells, as measured by peptide-induced interferon γ (IFN-γ) production, but not the number of virus-specific T cells enumerated by binding of specific tetrameric peptide/HLA complexes, correlated with the number of CMV-specific IFN-γ–secreting CD4+ helper T cells. Circulating CMV- specific CD8+ T cells did not express CCR7 and may therefore not be able to recirculate through peripheral lymph nodes. Based on coexpression of CD27 and CD45R0 most CMV-specific T cells in healthy donors appeared to be memory-type cells. Remarkably, frequencies of CMV-specific CD8+ T cells were significantly higher in immunosuppressed individuals than in healthy donors. In these patients CMV-specific cells predominantly had an effector phenotype, that is, CD45R0+CD27−CCR7− or CD45RA+CD27−CCR7− and contained both granzyme B and perforin. Our data show that in response to immunosuppressive medication quantitative and qualitative changes occur in the CD8+ T-cell compartment. These adaptations may be instrumental to maintain CMV latency.
No difference in graft-versus-host disease, relapse, and survival comparing peripheral stem cells to bone marrow using unrelated donors
Authors: Remberger Mats , Ringdén Oolle , Blau Igor-Wolfgang , Ottinger Hellmut , Kremens Bernhard , Kiehl Micheil G. , Aschan Johan , Beelen Dietrich W. , Basara Nadezda , Kumlien Gunilla , Fauser Axel A. , Runde Volker 
Published: July 2002

AbstractThe clinical results in 107 patients receiving a peripheral blood stem cell (PBSC) graft mobilized by granulocyte colony-stimulating factor (G-CSF) from HLA-A, -B, and -DR–compatible unrelated donors were compared to 107 matched controls receiving unrelated bone marrow (BM) transplants. Engraftment was achieved in 94% of the patients in both groups. The PBSC graft contained significantly more nucleated cells, CD34+, CD3+, and CD56+ cells (P &lt; .001), and resulted in a significantly shorter time-to-neutrophil (15 versus 19 days) and platelet engraftment (20 versus 27 days), compared to the BM control group (P &lt; .001). Probabilities of acute graft-versus-host disease (GVHD) grades II to IV were 35% and 32% (not significant [NS]) and of chronic GVHD 61% and 76% (NS) in the PBSC and BM groups, respectively. There was no difference between the 2 groups in bacteremia, cytomegalovirus reactivation or disease, and fungal infection. The 3-year transplant-related mortality (TRM) rates were 42% in the PBSC group and 31% in the BM controls (P = .7) and the survival rates were 46% and 51%, respectively. The probability of relapse was 25% and 31% in both groups (NS), resulting in disease-free survival rates of 43% in the PBSC group and 46% in the BM controls (NS). In the multivariate analysis, early disease, acute GVHD grade 0 to I, and presence of chronic GVHD were independent factors associated with a better disease-free survival in this study. PBSC from HLA-compatible unrelated donors can be used safely as an alternative to BM for stem cell transplantation.
Multipotent hematopoietic cell lines derived from C/EBPα(−/−) knockout mice display granulocyte macrophage–colony-stimulating factor, granulocyte– colony-stimulating factor, and retinoic acid–induced granulocytic differentiation
Authors: Collins Steven J. , Ulmer Jon , Purton Louise E. , Darlington Gretchen 
Published: July 2002

Abstract
The transcription factor C/EBPα is an important mediator of granulocyte differentiation and regulates the expression of multiple granulocyte-specific genes including the granulocyte–colony-stimulating factor (G-CSF) receptor, neutrophil elastase, and myeloperoxidase. Indeed C/EBPα knockout mice display a profound block in granulocyte differentiation. To study this block in granulocytic differentiation in more detail, retroviral vector-mediated transduction of a dominant-negative retinoic acid receptor was used to establish hematopoietic growth factor–dependent, lympho-myeloid progenitor cell lines from the fetal livers of both the C/EBPα knockout animals (C/EBPα(−/−)) and their heterozygous littermates (C/EBPα(+/−)). Surprisingly, the C/EBPα(−/−) cell lines displayed significant spontaneous granulocytic differentiation, and this differentiation was markedly enhanced when the cells were stimulated with granulocyte macrophage (GM)–CSF. This GM-CSF–mediated differentiation was associated with the up-regulation of G-CSF receptor mRNA, and the combination of GM-CSF and G-CSF generated more than 95% mature neutrophils in the C/EBPα(−/−) cultures. The addition of all-transretinoic acid also enhanced this granulocytic differentiation of the cultured C/EBPα(−/−) cells, indicating that the activated retinoic acid receptors can enhance granulocytic differentiation through a molecular pathway that is independent of C/EBPα. These studies clearly indicate that terminal granulocytic differentiation associated with the up-regulation of C/EBPα-responsive genes can occur in the absence of C/EBPα, and they indicate the existence of multiple independent molecular pathways potentially used by primitive hematopoietic precursors that can lead to the development of mature granulocytes.
Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease
Authors: Ancliff Phil J. , Gale Rosemary E. , Liesner Ri , Hann Ian M. , Linch David C. 
Published: July 2002

AbstractSevere congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.
Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8+CD57+CD28− compartment
Authors: Sze Daniel M.-Y. , Giesajtis Gillian , Brown Ross D. , Raitakari Maria , Gibson John , Ho Joy , Baxter Alan G. , Fazekas de St Groth Barbara , Basten Antony , Joshua Douglas E. 
Published: July 2002

AbstractThe occurrence of clonal T cells in multiple myeloma (MM), as defined by the presence of rearrangements in the T-cell receptor (TCR)–β chains detected on Southern blotting, is associated with an improved prognosis. Recently, with the use of specific anti–TCR-variable-β (anti–TCRVβ) antibodies, the presence in MM patients of expanded populations of T cells expressing particular Vβ regions was reported. The majority of these T-cell expansions have the phenotype of cytotoxic T cells (CD8+CD57+ and perforin positive). Since Vβ expansions can result from either a true clonal population or a polyclonal response, the clonality of CD8+TCRVβ+ T cells was tested by TCRVβ complementarity-determining region 3 length analysis and DNA sequencing of the variable region of the TCR. In this report, the CD57+ and CD57− subpopulations within expanded TCRVβ+CD8+ cell populations are compared, and it is demonstrated that the CD57+ subpopulations are generally monoclonal or biclonal, whereas the corresponding CD57− cells are frequently polyclonal. The oligoclonality of CD57+ expanded CD8+ T cells but not their CD57− counterparts was also observed in age-matched controls, in which the T-cell expansions were mainly CD8−. The CD8+CD57+ clonal T cells had a low rate of turnover and expressed relatively lower levels of the apoptotic marker CD95 than their CD57− counterparts. Taken together, these findings demonstrate that MM is associated with CD57+CD8+ T-cell clones, raising the possibility that the expansion and accumulation of activated clonal CD8+ T cells in MM may be the result of persistent stimulation by tumor-associated antigens, combined with a reduced cellular death rate secondary to reduced expression of the apoptosis-related molecule CD95.
Evaluation of impulse oscillation system: comparison with forced oscillation technique and body plethysmography
Authors: Hellinckx J. , Cauberghs M. , De Boeck K. , Demedts M. 
Published: July 2002

The impulse oscillation system (IOS) has been developed recently to measure respiratory system resistance (Rrs) and reactance (Xrs) at different frequencies up to ≥25 Hz. IOS has, however, not been validated against established techniques.This study compared IOS with the classical pseudorandom noise forced oscillation technique (FOT) and body plethysmographic airway resistance (Raw) in 49 subjects with a variety of lung disorders and a wide range ofRaw(0.10–1.28 kPa·L−1·s).Rrs,IOSwas slightly greater thanRrs,FOT, especially at lower frequencies, with a mean±sd difference at 5–6 Hz of 0.14±0.09 kPa·L−1·s. Comparisons with the wave-tube technique applied on two analogues indicated an overestimation by IOS.Xrs,IOSandXrs,FOTwere very similar, with a slightly higher resonant frequency with IOS than with FOT (mean difference±sd 1.35±3.40 Hz).Rawwas only moderately correlated withRrs-FOTandRrs-IOS; although the mean differences were small (0.04±0.14 kPa·L−1·s forRrs6,FOTand −0.10±0.14 kPa·L−1·s forRrs5,IOS), IOS and FOT markedly underestimated high resistance values.In conclusion, the impulse oscillation system yields respiratory system resistance and reactance values similar, but not identical to those provided by the forced oscillation technique.
Sarcoidosis severity and socioeconomic status
Authors: Rabin D.L. , Richardson M.S.A. , Stein S.R. , Yeager H. 
Published: July 2002

Several chronic diseases are more severe in persons who are Black, of low socioeconomic status (SES), and underinsured. The authors ask if this is true for sarcoidosis. Associations among sarcoidosis disease severity, SES, insurance coverage, and functional limitations were analysed.Back and White sarcoidosis patients (n=110) of a municipal and university hospital sarcoidosis registry were interviewed by telephone. Data on disease severity were abstracted from patient charts.Most patients reported good or excellent health by demographic characteristics. Low SES and no or public insurance were associated with worse health status and more severe dyspnoea. More advanced radiographic stage was associated with lower income, and forced vital capacity impairment with less education. Physical and social activity limitations due to physical and emotional disability were related to no or public insurance and lower income, but not education.Sarcoidosis severity is associated with socioeconomic status and insurance indicators; no or public insurance and low income are associated with functional limitations. Sarcoidosis-associated limitations are substantial, emphasizing the social significance of sarcoidosis. Lack of private insurance may inhibit the use of medical care, contributing to disease severity and impairment.