bluuebunny/crossref_metadata_2025_split huggingface dataset:
G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses
Authors: Zhu Quan-Sheng , Robinson Lisa J. , Roginskaya Vera , Corey Seth J. 
Published: December 2003

Abstract
The granulocyte colony-stimulating factor receptor (G-CSFR) transduces intracellular signals for myeloid cell proliferation, survival, and differentiation through the recruitment of nonreceptor protein tyrosine kinases Lyn and janus kinase 2 (Jak2). This results in the tyrosine phosphorylation of a small set of positive and negative adapters and effectors. Grb2-associated binder-2 (Gab2) is a newly described adapter molecule, preferentially expressed in hematopoietic cells and associated with phosphatidylinositol 3 (PI3) kinase. Studies suggest that Gab2 plays both positive and negative roles in cytokine receptor signaling. To investigate the role Gab2 plays in G-CSF receptor-mediated signaling, we have analyzed its activation state and correlated that with wild-type and mutant G-CSF receptors stably expressed in the murine factor-dependent Ba/F3 cell lines. G-CSF-induced tyrosine phosphorylation of Gab2 occurred in the wild-type and single Y-to-F mutants (Y704F, Y729F, and Y744F), but not in the ADA and W650R loss-of-function mutants. Cells expressing truncated proximal G-CSFR, the tyrosine-null (Y4F) G-CSFR, or Y764F mutant receptors had decreased phosphorylation of Gab2. Specific inhibitors of Src kinase (PD173 and PP1) but not Jak2 kinase (AG490) blocked Gab2 phosphorylation. Phosphorylation of Gab2 occurred in wild-type, but not Lyn-deficient, G-CSFR-transfected DT40 B cells. These data propose that Lyn, not Jak2, phosphorylates Gab2 and that maximal phosphorylation of Gab2 requires Y764, a Grb2-binding site. Serine phosphorylation of Akt, a marker of PI3-kinase activity, was detected in both wild-type and truncated proximal domain receptors, but not in the ADA and W650R mutants. Levels of phospho-Akt and phospho-extracellular signal-regulated kinase (phospho-ERK) were greater in proximal truncated than in wild-type G-CSFR cells, suggesting that Gab2 is dissociated from PI3 kinase or ERK activities. Overexpression of Gab2 enhanced the phosphorylation state of Akt, but not of ERK. This inhibited the proliferation of wild-type and truncated G-CSFR-transfected Ba/F3 cells and enhanced their myeloid differentiation. All together, these data indicate that G-CSF treatment leads to Lyn-mediated tyrosine phosphorylation of Gab2, which may serve as an important intermediate of enhanced Akt activity and myeloid differentiation, not growth/survival response. (Blood. 2004; 103:3305-3312)
Identification and in vitro expansion of CD4+ and CD8+ T cells specific for human neutrophil elastase
Authors: Fujiwara Hiroshi , El Ouriaghli Frank , Grube Matthias , Price David A. , Rezvani Katayoun , Gostick Emma , Sconocchia Giuseppe , Melenhorst Jos , Hensel Nancy , Douek Daniel C. , Barrett A. John 
Published: December 2003

AbstractHuman neutrophil elastase (HNE) and proteinase 3 (PRO3) are myeloid tissue-restricted serine proteases, aberrantly expressed by myeloid leukemia cells. PRO3 and HNE share the PR1 peptide sequence that induces HLA-A*0201–restricted cytotoxic T cells (CTLs) with antileukemia reactivity. We studied the entire HNE protein for its ability to induce CTLs. In an 18-hour culture, HNE-loaded monocytes stimulated significant intracellular interferon γ (IFN-γ) production by CD4+ and CD8+ T cells in 12 of 20 and 8 of 20 healthy individuals, respectively. Lymphocytes from 2 HNE responders were pulsed weekly for 4 weeks to generate HNE-specific CTLs. One of 2 HLA-A*0201–negative individuals inhibited the colony formation of HLA-identical chronic myelogenous leukemia progenitor cells (73% inhibition at 50:1 effector-target [E/T] ratio), indicating that peptides other than PR1 can induce leukemia-reactive CTLs. Repetitive stimulations with HNE in 2 of 5 HLA-A*0201+ individuals increased PR1 tetramer-positive CD8+ T-cell frequencies from 0.1% to 0.29% and 0.02% to 0.55%, respectively. These CTLs recognized PR1 peptide or killed HNE-loaded targets. These results indicate that exogenously processed HNE is a source of PR1 peptide as well as other peptide sequences capable of inducing leukemia-specific CD8+ and CD4+ T cells. HNE could, therefore, be used in an HLA-unrestricted manner to induce leukemia-reactive CTLs for adoptive immunotherapy. (Blood. 2004; 103:3076-3083)
Vδ2-Jα rearrangements are frequent in precursor-B–acute lymphoblastic leukemia but rare in normal lymphoid cells
Authors: Szczepański Tomasz , van der Velden Vincent H. J. , Hoogeveen Patricia G. , de Bie Maaike , Jacobs Daniëlle C. H. , van Wering Elisabeth R. , van Dongen Jacques J. M. 
Published: December 2003

AbstractThe frequently occurring T-cell receptor delta (TCRD) deletions in precursor-B–acute lymphoblastic leukemia (precursor-B–ALL) are assumed to be mainly caused by Vδ2-Jα rearrangements. We designed a multiplex polymerase chain reaction tified clonal Vδ2-Jα rearrangements in 141 of 339 (41%) childhood and 8 of 22 (36%) adult precursor-B–ALL. A significant proportion (44%) of Vδ2-Jα rearrangements in childhood precursor-B–ALL were oligoclonal. Sequence analysis showed preferential usage of the Jα29 gene segment in 54% of rearrangements. The remaining Vδ2-Jα rearrangements used 26 other Jα segments, which included 2 additional clusters, one involv ing the most upstream Jα segments (ie, Jα48 to Jα61; 23%) and the second cluster located around the Jα9 gene segment (7%). Real-time quantitative PCR studies of normal lymphoid cells showed that Vδ2 rearrangements to upstream Jα segments occurred at low levels in the thymus (10–2 to 10–3) and were rare (generally below 10–3) in B-cell precursors and mature T cells. Vδ2-Jα29 rearrangements were virtually absent in normal lymphoid cells. The monoclonal Vδ2-Jα rearrangements in precursor-B–ALL may serve as patient-specific targets for detection of minimal residual disease, because they show high sensitivity (10–4 or less in most cases) and good stability (88% of rearrangements preserved at relapse).
Bcl-XL down-regulation suppresses the tumorigenic potential of NPM/ALK in vitro and in vivo
Authors: Coluccia Addolorata Maria Luce , Perego Silvia , Cleris Loredana , Gunby Rosalind Helen , Passoni Lorena , Marchesi Edoardo , Formelli Franca , Gambacorti-Passerini Carlo 
Published: December 2003

Abstract
Deregulated apoptosis is a common finding in tumorigenesis. The oncogenic tyrosine kinase nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) delivers a strong survival signal in anaplastic large cell lymphomas (ALCLs). Although NPM/ALK activates multiple antiapoptotic pathways, the biologic relevance and therapeutic potential of more downstream apoptotic effectors are mostly unknown. In this report, the NPM/ALK-mediated induction of Bcl-XL (but not of Bcl-2) was identified in human ALCL-derived cells. NPM/ALK kinase activity was required to promote Bcl-XL expression and its protective effect on mitochondrial homeostasis. Down-regulation of Bcl-XL significantly reduced the antiapoptotic potential of NPM/ALK in both transformed murine Ba/F3 pro-B cells and human ALCL-derived KARPAS-299 cells. To elucidate the role of Bcl-XL in vivo, Ba/F3-NPM/ALK+ cells expressing a doxycycline (Dox)-inducible Bcl-XL antisense transgene (pTet-ON) were injected into nude mice. Doxycycline administration prevented a fatal systemic disease in 15 of 15 intravenously injected mice and the appearance of subcutaneous tumor xenografts in 9 of 12 mice; in vivo down-regulation of Bcl-XL was also documented. Our results show a pivotal role for Bcl-XL in ALK-mediated oncogenicity; a single protein placed downstream of a known oncogene can be crucial for the survival of neoplastic cells both in vitro and in vivo. Bcl-XL deserves further investigation as a possible therapeutic target in ALK+ ALCLs. (Blood. 2004;103:2787-2794)
Targeted overexpression of Bcl-XL in B-lymphoid cells results in lymphoproliferative disease and plasma cell malignancies
Authors: Linden Michael , Kirchhof Nicole , Carlson Cathy , Van Ness Brian 
Published: December 2003

AbstractMultiple myeloma is an incurable malignancy, and there is currently no mouse model that fully recapitulates the development and progression of the disease. We now describe a transgenic mouse that expresses a Bcl-XL transgene under the control of the 3′κ immunoglobulin light chain enhancer, which is most active in murine B cells in late developmental stages. These mice developed nonmalignant plasma cell foci in the bone marrow and soft tissues and hyaline tubular casts in the kidneys. Median survival of the 3′KE/Bcl-XL mice was similar to littermate controls. When the 3′KE/Bcl-XL mouse was crossed to an Eμ/c-Myc transgenic mouse, median survival of double transgenic progeny was 5.5 weeks. Peripheral blood and soft tissues were infiltrated with immature/mature B cells, and plasma cell lesions were identified in the bone marrow of all mice coexpressing Bcl-XL and c-Myc. These B- and plasma cell lesions demonstrated features consistent with malignancy. These results indicate that the 3′κ immunoglobulin light chain enhancer can effectively target expression of Bcl-XL to B cells in late developmental stages, and they provide direct evidence that Bcl-XL can contribute to plasmacytomagenesis. Furthermore, this murine model serves as an important step in developing a novel genetically induced mouse model of plasma cell malignancies exhibiting bone marrow involvement. (Blood. 2004;103:2779-2786)
The roles of insulin and hyperglycemia in sepsis pathogenesis
Authors: Andersen Soren Kaeseler , Gjedsted Jakob , Christiansen Christian , Tønnesen Else 
Published: December 2003

AbstractHyperglycemia is a risk marker of morbidity and mortality in acute critical illness, and insulin therapy seems to be beneficial in this patient group. Whether this is true for a population of sepsis patients, as such, has not been investigated in clinical trials, but evidence from in vitro studies and experimental sepsis suggests that this may be the case. The endocrinology of septic patients is characterized by a shift in the balance between insulin and its counter-regulatory hormones favoring the latter. This leads to prominent metabolic derangements composed of high release and low use of glucose, amino acids, and free fatty acids (FFA), resulting in increased blood levels of these substrates. Circulating, proinflammatory mediators further enhance this state of global catabolism. Increased levels of glucose and FFA have distinct effects on inflammatory signaling leading to additional release of proinflammatory mediators and endothelial and neutrophil dysfunction. Insulin has the inherent capability to counteract the metabolic changes observed in septic patients. Concomitantly, insulin therapy may act as a modulator of inflammatory pathways inhibiting the unspecific, inflammatory activation caused by metabolic substrates. Given these properties, insulin could conceivably be serving a dual purpose for the benefit of septic patients.
Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN
Authors: Di Filippo Clara , Rossi Francesco , Rossi Settimio , D’Amico Michele 
Published: December 2003

AbstractIn this study, we have assessed the activation of the cannabinoid CB2 receptor (CB2-R) in a model of mouse myocardial ischemia/reperfusion (I/R). The results show that treatment of animals with WIN55212-2, a CB1/CB2-R agonist, given 30 min before induction of I/R, significantly reduced the extent of infarct size (IS) in the area at risk, as measured 2.5 h later, with almost a 51% inhibition observed at the dose tested of 3.5 mg/kg intraperitoneally (i.p.). The protective effect of WIN55212-2 was almost abolished by the selective CB2-R antagonist AM630 (1 mg/kg i.p.) and not affected by the selective CB1-R antagonist AM251 (3 mg/kg i.p.). The CB2-R antagonist administered alone produced a slight but significant (P&lt;0.05) increase in IS compared with vehicle alone. The protection afforded by WIN55212-2 was paralleled by lower values of myeloperoxidase activity and interleukin-1β and of the CXC chemokine ligand 8 into the injured tissue. In conclusion, we demonstrate for the first time that exogenous and endogenous CB2-R activation reduces the leukocyte-dependent myocardial damage associated with an I/R procedure.
Age-associated alterations in the recruitment of signal-transduction proteins to lipid rafts in human T lymphocytes
Authors: Larbi Anis , Douziech Nadine , Dupuis Gilles , Khalil Abdelouahed , Pelletier Hugues , Guerard Karl-Philippe , Fülöp Tamàs 
Published: December 2003

AbstractAging is associated with a decline in T cell activation and proliferation, but the underlying mechanisms are not fully understood. Recent findings suggest that lipid rafts act as a platform in the initiation of T cell activation by selectively recruiting signaling proteins associated with formation of the initial complex of signal transduction. We tested the hypothesis that lipid raft properties are altered in T lymphocytes from elderly, healthy individuals in comparison with young subjects. Results showed that the cholesterol content of lipid rafts derived from these cells was consistently higher in the case of elderly donors and that membrane fluidity was decreased. In addition, lipid rafts coalescence to the site of T cell receptor engagement was impaired in T cells from elderly donors. The recruitment of p56lck, linker of activated T cells, and their tyrosine-phosphorylated forms to lipid rafts was decreased in activated T cells from aged individuals. CD45 was not recruited to the lipid raft fractions in either group of subjects. Our data suggest that some properties of lipid rafts are altered in aging, and this finding may be part of the causes for the decline in T cell functions that are observed in elderly individuals.
The significance of carbohydrates on G-CSF: differential sensitivity of G-CSFs to human neutrophil elastase degradation
Authors: Carter Clive R D , Whitmore Katie M , Thorpe Robin 
Published: December 2003

AbstractIt has been reported recently that granulocyte-colony stimulating factor (G-CSF) is degraded upon exposure to human neutrophil elastase (HNE), and this has a negative effect on the ability of the cytokine to promote the in vitro proliferation and maturation of CD34+ cells. This has important implications on the possible in vivo role of elastase in providing negative feedback to granulopoiesis by the direct antagonism of G-CSF. The cytokine used in that study was expressed in Escherichia coli [and was nonglycosylated (NG)], unlike the naturally occurring cytokine, which is an O-linked glycoprotein. As a Chinese hamster ovary-derived (glycosylated) cytokine is available, we compared the susceptibility of NG and glycosylated G-CSF to elastase degradation by incubating the cytokines with HNE and assessing its impact by sodium dodecyl sulfate gel electrophoresis and bioassay. We confirmed the ability of elastase to degrade NG G-CSF in a time- and concentration-dependent manner and found this was associated with a reduction in biological activity of the cytokine. Glycosylated G-CSF, however, was more resistant to elastase degradation, although prolonged exposure did lead to degradation and decreased biological activity. The significance of sugar residues on glycosylated G-CSF in providing protection against the effects of elastase was investigated using enzymatically deglycosylated G-CSF and a mutated form of the G-CSF molecule that was expressed in yeast but was NG. The possible role of HNE in serum-induced inactivation of NG G-CSF was also considered.
Are Older Cancer Patients Being Referred to Oncologists? A Mail Questionnaire of Ontario Primary Care Practitioners to Evaluate Their Referral Patterns
Authors: Townsley Carol A. , Naidoo Kendra , Pond Gregory R. , Melnick Wendy , Straus Sharon E. , Siu Lillian L. 
Published: December 2003

Purpose: Understanding why older patients are frequently underrepresented in cancer services use and clinical research may help to increase their participation in clinical trials and eventually result in better cancer care for this vulnerable population. Methods: To identify potential barriers that may prevent older cancer patients from being referred from a primary care physician (PCP) to an oncology specialist, a self-administered questionnaire was mailed to 9,312 PCPs throughout Ontario. Results: With a one-time mailing, 2,240 questionnaires were returned (response rate, 24%) of which 2,089 (93%) were assessable. Although 86% of respondents would refer most older patients with early-stage, potentially curable cancers to oncologists, only 65% would refer those with advanced-stage, potentially incurable cancers. The factors that most influence referral decisions of PCPs are patient’s desire to be referred (69%), type (54%) and stage (49%) of cancer, and severity of cancer symptoms (49%). Other factors including age do not seem to influence the referral decision. Approximately 9% of respondents found it difficult to refer older cancer patients to oncology specialists, with the most commonly cited barriers being the length of waiting lists, mandatory tissue diagnosis before referral, and the belief that oncologists seldom relate to PCPs. Conclusion: Most PCPs stated that they would refer all elderly patients with cancer to oncologists and that referral decisions were based mainly on patients’ wishes. Continued efforts are needed to overcome barriers in the referral process and to understand the perspectives of elderly patients to enhance their cancer care.
Surgery Plus Chemotherapy Compared With Surgery Alone for Localized Squamous Cell Carcinoma of the Thoracic Esophagus: A Japan Clinical Oncology Group Study—JCOG9204
Authors: Ando Nobutoshi , Iizuka Toshifumi , Ide Hiroko , Ishida Kaoru , Shinoda Masayuki , Nishimaki Tadashi , Takiyama Wataru , Watanabe Hiroshi , Isono Kaichi , Aoyama Norio , Makuuchi Hiroyasu , Tanaka Otsuo , Yamana Hideaki , Ikeuchi Shunji , Kabuto Toshiyuki , Nagai Kagami , Shimada Yutaka , Kinjo Yoshihide , Fukuda Haruhiko 
Published: December 2003

Purpose: We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery. Patients and Methods: Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area × 1 day) and fluorouracil (800 mg/m2 × 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival. Results: Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P = .037). The 5-year overall survival rate was 52% and 61%, respectively (P = .13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis. Conclusion: Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.
Interaction of Splenectomy and Perioperative Blood Transfusions on Prognosis of Patients With Proximal Gastric and Gastroesophageal Junction Cancer
Authors: Weitz Jürgen , D’Angelica Michael , Gonen Mithat , Klimstra David , Coit Daniel G. , Brennan Murray F. , Karpeh Martin S. 
Published: December 2003

Purpose: To assess the interaction of splenectomy and perioperative allogeneic blood transfusions on the prognosis of patients undergoing a potentially curative resection of proximal gastric and gastroesophageal junction (GEJ) cancer, because reports from the transplantation literature demonstrated that the immunosuppressive effects of transfusions are dependent on the presence of an intact spleen.Patients and Methods: Between July 1, 1985, and July 30, 2001, 240 patients underwent complete resection (R0) of a proximal gastric or GEJ cancer (Siewert type II or III). Clinical and pathologic factors were collected in a prospective database. The survival data were modeled using the method of Kaplan and Meier and analyzed by the log-rank test and Cox regression.Results: The median follow-up of the patients was 25 months (40 months for survivors). The median relapse-free survival was 30 months, and the median disease-specific survival was 45 months. Univariate analysis suggested an interaction of splenectomy and perioperative transfusion in their effect on relapse-free survival. Patients who received a perioperative transfusion but did not undergo splenectomy demonstrated the worst prognosis on multivariate analysis independent of other prognostic factors. In patients who underwent splenectomy, perioperative transfusion had no effect on relapse-free survival on multivariate analysis.Conclusion: Our study suggests an interaction of blood transfusion and splenectomy in their effect on survival paralleling the findings in the transplantation literature. The adverse effect of allogeneic blood transfusion on prognosis in patients with gastric cancer seems to be associated with the presence of an intact spleen and is abrogated by its absence.
Consolidation Radiation After Complete Remission in Hodgkin's Disease Following Six Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Chemotherapy: Is There a Need?
Authors: Laskar S. , Gupta T. , Vimal S. , Muckaden M.A. , Saikia T.K. , Pai S.K. , Naresh K.N. , Dinshaw K.A. 
Published: December 2003

Purpose Combined modality treatment using multidrug chemotherapy (CTh) and radiotherapy (RT) is currently considered the standard of care in early stage Hodgkin's disease. Its role in advanced stages, however, continues to be debated. This study was aimed at evaluating the role of consolidation radiation in patients achieving a complete remission after six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy using event-free survival (EFS) and overall survival (OS) as primary end points. Patients and Methods Two hundred and fifty-one patients with Hodgkin's disease attending the lymphoma clinic at the Tata Memorial Hospital (Mumbai, India) from 1993 to 1996 received induction chemotherapy with six cycles of ABVD after initial staging evaluation. A total of 179 of 251 patients (71%) achieved a complete remission after six cycles of ABVD chemotherapy and constituted the randomized population. Patients were randomly assigned to receive either consolidation radiation or no further therapy. Results With a median follow-up of 63 months, the 8-year EFS and OS in the CTh-alone arm were 76% and 89%, respectively, as compared with 88% and 100% in the CTh+RT arm (P = .01; P = .002). Addition of RT improved EFS and OS in patients with age < 15 years (P = .02; P = .04), B symptoms (P = .03; P = .006), advanced stage (P = .03; P = .006), and bulky disease (P = .04; P = .19). Conclusion Our study suggests that the addition of consolidation radiation helps improve the EFS and OS in patients achieving a complete remission after six cycles of ABVD chemotherapy, particularly in the younger age group and in patients with B symptoms and bulky and advanced disease.