bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial and Temporal Sequence Learning in Patients with Parkinson's Disease or Cerebellar Lesions
Authors: Shin Jacqueline C. , Ivry Richard B.
Published: December 2003

The functional role of different subcortical areas in sequence learning is not clear. In the current study, Parkinson's patients, patients with cerebellar damage, and age-matched control participants performed a serial reaction time task in which a spatial sequence and a temporal sequence were presented simultaneously. The responses were based on the spatial sequence, and the temporal sequence was incidental to the task. The two sequences were of the same length, and the phase relationship between them was held constant throughout training. Sequence learning was assessed comparing performance when both sequences were present versus when the dimension of interest was randomized. In addition, sequence integration was assessed by introducing phase-shift blocks. A functional dissociation was found between the two patient groups. Whereas the Parkinson's patients learned the spatial and temporal sequences individually, they did not learn the relationship between the two sequences, suggesting the basal ganglia play a functional role in sequence integration. In contrast, the cerebellar patients did not show any evidence of sequence learning at all, suggesting the cerebellum might play a general role in forming sequential associations.
Precise Oculomotor Correlates of Visuospatial Mental Rotation and Circular Motion Imagery
Authors: de'Sperati Claudio
Published: December 2003

Visual imagery is a basic form of cognition central to activities such as problem solving or creative thinking. Phenomena such as mental rotation, in which mental images undergo spatial transformations, and motion imagery, in which we imagine objects in motion, are very elusive. For example, although several aspects of visual imagery and mental rotation have been reconstructed through mental chronometry, their instantaneous evolution has never been directly observed. We paired mental chronometry to eye movement recording in subjects performing a visuospatial mental rotation task and an instructed circular motion imagery task. In both tasks, sequences of spontaneous saccades formed curved trajectories with a regular spatio-temporal evolution. In the visuospatial mental rotation task, saccadic amplitude decreased progressively within each sequence, resulting in an average gaze rotation with a bell-shaped asymmetrical angular velocity profile whose peak and mean increased with the amount of the to-be-performed rotation, as in reaching movements. In the second task, the average gaze rotation reproduced faithfully the to-be-imagined constant-velocity circular motion, thus excluding important distortions in the oculomotor performance. These findings show for the first time the instantaneous spatio-temporal evolution of mental rotation and motion imagery. Moreover, the fact that visuospatial mental rotation is modeled as a reaching act suggests that reaching pertains to the realm of visuospatial thinking, rather than being restricted to the motor domain. This approach based on eye movement recording can be profitably coupled to methods such as event-related potentials, transcranial magnetic stimulation, or functional magnetic resonance to study the precise neuronal dynamics associated with an ongoing mental activity.
Victims and the International Criminal Court: Three major issues
Authors: Garkawe Sam
Published: December 2003

The Statute of the permanent International Criminal Court (the "ICC") agreed to in Rome in 1998 contains many provisions that deal with the specific concerns and rights of victims and survivors of the international crimes that the ICC will have jurisdiction over. It consolidates the work of the two ad hoc international criminal Tribunals (the former Yugoslavia and Rwanda) in this area, but also further enhances the role and rights of victims in a number of innovative ways. These three international criminal Tribunals thus collectively represent an important step forward in the recognition of the suffering and the position of victims and survivors of international crimes. This article will examine three main issues in relation to victims and the ICC. First, after identifying the protective measures for victims allowed at the discretion of the international criminal Tribunal for the former Yugoslavia, it will focus on the most controversial measure (which the ICC can also order) - the non-disclosure to the defence of the identity of witnesses. Does this protective measure violate a defendant's right to a fair trial? The Statute of the ICC also allows, for the first time in international criminal justice, for the right of victims to obtain their own legal representation, subject to the discretion of the ICC. The second issue is how is this going to work in practice in light of the fact that international crimes normally involve hundreds, if not thousands or even tens of thousands, of victims? And finally, while the ICC Statute provides for the possibility of reparations to victims, where will the money come from, and thus what are the chances of victims actually being able to receive compensation?
The doctrine of Res Judicata in International Criminal Law
Authors: Theofanis Rosa
Published: December 2003

Res judicata is well-settled as a general principle of international law. But the rules of res judicata in international criminal procedure are undeveloped. Recent cases from the ad hoc criminal tribunals for the former Yugoslavia and Rwanda have added to the understanding of res judicata in international law - demonstrating the risk that new rules of res judicata will implicitly incorporate either a common-law or civil-law definition of what the "law" is. Analysis of issues considered in recent Tribunal jurisprudence - particularly the questions of review and reconsideration - locates potential hazards in the development of the law and provides guidance for the application of the ICC statute.
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

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

Human 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

The 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

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

Multiple 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

Hyperglycemia 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

In 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<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

Aging 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

It 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.
Final Results of the 94–01 French Head and Neck Oncology and Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma
Authors: Denis Fabrice , Garaud Pascal , Bardet Etienne , Alfonsi Marc , Sire Christian , Germain Thierry , Bergerot Philippe , Rhein Beatrix , Tortochaux Jacques , Calais Gilles
Published: December 2003

Purpose

We report the 5-year survival and late toxicity results of a randomized clinical trial, which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma, using concomitant radiochemotherapy (arm B), compared with standard radiotherapy (arm A).

Patients and Methods

A total of 226 patients were entered onto a phase III multicenter randomized trial comparing radiotherapy alone (70 Gy in 35 fractions; arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil; arm B). Prognostic factors were evaluated by univariate and multivariate analysis. Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity, hearing, taste, mandibula, and teeth damage, and Radiation Therapy Oncology Group toxicity criteria for skin, salivary gland, and mucosa.

Results

Five-year overall survival, specific disease-free survival, and locoregional control rates were 22% and 16% (log-rank P = .05), 27% and 15% (P = .01), and 48% and 25% (P = .002), in arm B and arm A, respectively. Stage IV, hemoglobin level lower than 125 g/L, and standard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis. One or more grade 3 to 4 complications occurred in 56% of the patients in arm B, compared with 30% in arm A (P was not significant).

Conclusion

Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms.
Diurnal Variation in Rat Liver Thyroid Hormone Receptor (TR)-α Messenger Ribonucleic Acid (mRNA) Is Dependent on the Biological Clock in the Suprachiasmatic Nucleus, whereas Diurnal Variation of TRβ1 mRNA Is Modified by Food Intake
Authors: Doulabi B. Zandieh , Schiphorst M. Platvoet-Ter , Kalsbeek A. , Fliers E. , Bakker O. , Wiersinga W. M.
Published: December 2003

Previous studies have shown a diurnal variation of certain isoforms of thyroid hormone receptors (TR) in rat liver. The genesis of these diurnal changes is still unknown. To clarify whether the biological clock, located in the hypothalamic suprachiasmatic nucleus (SCN), is involved, we made selective SCN lesions. Rats with an SCN lesion lost their circadian rhythm of plasma corticosterone and TSH when compared with intact animals. TRα1 and TRα2 mRNA expression of control rats was higher in the light period than in the dark period; changes that were abolished in the rats with SCN lesions. In contrast, liver TRβ1 mRNA of intact rats showed a diurnal variation that failed to reach statistical significance. To evaluate whether these effects could be explained indirectly by the disappearance of rhythmic feeding behavior in rats with SCN lesions, we performed a second experiment in which otherwise intact animals were subjected to a regular feeding (RF) schedule, with one meal every 4 h. When compared with rats with free access to food, RF only affected TRβ1 mRNA expression and had no effect on the diurnal changes in TRα1 and TRα2. We conclude that liver TRβ1 expression is most clearly affected by food intake. Diurnal changes in liver TRα1 and TRα2 are controlled by the biological clock in the SCN but not via changes in the daily rhythm of food intake. The findings may have physiological relevance for diurnal variation of T3-dependent gene expression, which is supported by a diurnal variation in the expression of the 5′-deiodinase gene.
A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage
Authors: Nakayama Naoki , Han Chun-ya E. , Cam Linh , Lee Jae I. , Pretorius Jim , Fisher Seth , Rosenfeld Robert , Scully Sheila , Nishinakamura Ryuichi , Duryea Diane , Van Gwyneth , Bolon Brad , Yokota Takashi , Zhang Ke
Published: December 2003

We have identified a novel chordin-like protein, CHL2, which is structurally most homologous to CHL/neuralin/ventroptin. When injected into Xenopus embryos, CHL2 RNA induced a secondary axis. Recombinant CHL2 protein interacted directly with BMPs in a competitive manner to prevent binding to the type I BMP receptor ectodomain, and inhibited BMP-dependent induction of alkaline phosphatase in C2C12 cells. Thus, CHL2 behaves as a secreted BMP-binding inhibitor. In situ hybridization revealed that CHL2 expression is restricted to chondrocytes of various developing joint cartilage surfaces and connective tissues in reproductive organs. Adult mesenchymal progenitor cells expressed CHL2, and its levels decreased during chondrogenic differentiation. Addition of CHL2 protein to a chondrogenic culture system reduced cartilage matrix deposition. Consistently,CHL2 transcripts were weakly detected in normal adult joint cartilage. However, CHL2 expression was upregulated in middle zone chondrocytes in osteoarthritic joint cartilage (where hypertrophic markers are induced). CHL2 depressed chondrocyte mineralization when added during the hypertrophic differentiation of cultured hyaline cartilage particles. Thus, CHL2 may play negative roles in the (re)generation and maturation of articular chondrocytes in the hyaline cartilage of both developing and degenerated joints.
XenopusMeis3 protein forms a hindbrain-inducing center by activating FGF/MAP kinase and PCP pathways
Authors: Aamar Emil , Frank Dale
Published: December 2003

Knockdown studies in Xenopus demonstrated that the XMeis3gene is required for proper hindbrain formation. An explant assay was developed to distinguish between autonomous and inductive activities of XMeis3 protein. Animal cap explants caudalized by XMeis3 were recombined with explants neuralized by the BMP dominant-negative receptor protein. XMeis3-expressing cells induced convergent extension cell elongations in juxtaposed neuralized explants. Elongated explants expressed hindbrain and primary neuron markers, and anterior neural marker expression was extinguished. Cell elongation was dependent on FGF/MAP-kinase and Wnt-PCP activities. XMeis3 activates FGF/MAP-kinase signaling, which then modulates the PCP pathway. In this manner, XMeis3 protein establishes a hindbrain-inducing center that determines anteroposterior patterning in the brain.
No tail co-operates with non-canonical Wnt signaling to regulate posterior body morphogenesis in zebrafish
Authors: Marlow, Florence , Gonzalez,, Encina M. , Yin Chunyue , Rojo Concepcion , Solnica-Krezel, Lilianna
Published: December 2003

The vertebrate posterior body is formed by a combination of the gastrulation movements that shape the head and anterior trunk and posterior specific cell behaviors. Here, we investigated whether genes that regulate cell movements during gastrulation [no tail(ntl)/brachyury, knypek (kny) and pipetail(ppt)/wnt5] interact to regulate posterior body morphogenesis. Both kny;ntl and ppt;ntl double mutant embryos exhibit synergistic trunk and tail shortening by early segmentation. Gene expression analysis in the compound mutants indicates that anteroposterior germ-layer patterning is largely normal and that the tail elongation defects are not due to failure to specify or maintain posterior tissues. Moreover, ntl interacts with ppt and knyto synergistically regulate the posterior expression of the gene encoding bone morphogenetic protein 4 (bmp4) but not of other known T-box genes,fibroblast growth factor genes or caudal genes. Examination of mitotic and apoptotic cells indicates that impaired tail elongation is not simply due to decreased cell proliferation or increased cell death. Cell tracing in ppt;ntl and kny;ntl mutants demonstrates that the ventral derived posterior tailbud progenitors move into the tailbud. However,gastrulation-like convergence and extension movements and cell movements within the posterior tailbud are impaired. Furthermore, subduction movements of cells into the mesendoderm are reduced in kny;ntl and ppt;ntl mutants. We propose that Ntl and the non-canonical Wnt pathway components Ppt and Kny function in parallel, partially redundant pathways to regulate posterior body development. Our work initiates the genetic dissection of posterior body morphogenesis and links genes to specific tail-forming movements. Moreover, we provide genetic evidence for the notion that tail development entails a continuation of mechanisms regulating gastrulation together with mechanisms unique to the posterior body.
Control of the proliferation versus meiotic development decision in theC. elegansgermline through regulation of GLD-1 protein accumulation
Authors: Hansen Dave , Wilson-Berry Laura , Dang Thanh , Schedl Tim
Published: December 2003

Maintenance of the stem cell population in the C. elegans germline requires GLP-1/Notch signaling. We show that this signaling inhibits the accumulation of the RNA binding protein GLD-1. In a genetic screen to identify other genes involved in regulating GLD-1 activity, we identified mutations in the nos-3 gene, the protein product of which is similar to the Drosophila translational regulator Nanos. Our data demonstrate that nos-3 promotes GLD-1 accumulation redundantly with gld-2,and that nos-3 functions genetically downstream or parallel to fbf, an inhibitor of GLD-1 translation. We show that the GLD-1 accumulation pattern is important in controlling the proliferation versus meiotic development decision, with low GLD-1 levels allowing proliferation and increased levels promoting meiotic entry.
A cell-specific enhancer that specifieslin-3expression in theC. elegansanchor cell for vulval development
Authors: Hwang Byung Joon , Sternberg Paul W.
Published: December 2003

During C. elegans vulval development, the anchor cell (AC) in the somatic gonad expresses lin-3, activating the EGF receptor signaling pathway in vulval precursor cells (VPCs) and thereby inducing and patterning VPCs. Previous studies with lin-3 mutants and transgene expression have revealed that the level of LIN-3 in the AC must be precisely regulated for proper vulval development. To understand how lin-3 expression is achieved in the AC, we identified a 59 bp lin-3 enhancer sufficient to activate lin-3 transcription solely in the AC. The enhancer contains two E-box elements, and one FTZ-F1 nuclear hormone receptor (NHR)binding site that is mutated in a vulvaless mutant, lin-3(e1417). Mutagenesis studies show that both E-boxes and the NHR binding site are necessary to express lin-3 in the AC. In vitro DNA-binding studies and in vivo functional assays indicate that distinct trans-acting factors,including the E-protein/Daughterless homolog HLH-2 and unidentified nuclear hormone receptor(s), are necessary for lin-3 transcription in the AC and thus are involved in vulval development.
Hyaluronan-oligosaccharide-induced transcription of metalloproteases
Authors: Fieber Christina , Baumann Petra , Vallon Rüdiger , Termeer Christian , Simon Jan C. , Hofmann Martin , Angel Peter , Herrlich Peter , Sleeman Jonathan P.
Published: December 2003

Activated dendritic epidermal Langerhans cells and metastatic tumour cells share many properties. Both cell types can invade the surrounding tissue, enter the lymphatic system and travel to regional lymph nodes. We have recently shown that fragments of the extracellular matrix component hyaluronan, which are typically produced at sites of inflammation, can activate dendritic cells. Upon activation, dendritic cells upregulate expression of matrix metalloproteases (MMPs). These observations prompted us to investigate whether exposure to hyaluronan fragments also induces MMP expression in tumour cells. Here, we report that MMP-9, MMP-13 and urokinase plasminogen activator are upregulated in murine 3LL tumour cells after exposure to mixed-size hyaluronan. Similarly upregulated MMP-9 and MMP-13 expression was observed in primary fibroblasts. By using size-fractionated hyaluronan preparations, we show that the enhanced expression of MMP-9 and MMP-13 is only induced by small hyaluronan (HA) fragments. Although our data suggest that HA-fragment-induced MMP-9 and MMP-13 expression is receptor mediated, they rule out an involvement of the hyaluronan receptors CD44, RHAMM/IHAP and TLR-4. Finally, we show that HA fragment-induced MMP-9 transcription is mediated via NF-κB. Our results suggest that the metastasis-associated HA degradation in tumours might promote invasion by inducing MMP expression.
STAT3 is enriched in nuclear bodies
Authors: Herrmann Andreas , Sommer Ulrike , Pranada Albert L. , Giese Bernd , Küster Andrea , Haan Serge , Becker W. , Heinrich Peter C. , Müller-Newen Gerhard
Published: December 2003

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is involved in a variety of biological functions. It is essential for the signal transduction of interleukin-6 (IL-6) and related cytokines. In response to IL-6 stimulation STAT3 becomes phosphorylated and translocates into the nucleus where it binds to enhancer sequences of target genes. We found that activated STAT3 is enriched in dot-like structures within the nucleus, which we termed STAT3 nuclear bodies. To examine the dynamics of STAT3 nuclear body formation, a fusion protein of STAT3 and yellow fluorescent protein (YFP) was constructed. Studies in living cells have shown that the appearance of STAT3 nuclear bodies is transient, correlating with the timecourse of tyrosine-phosphorylation of STAT3. Furthermore, we show by fluorescence recovery after photobleaching (FRAP) analysis that STAT3 within nuclear bodies consists of a highly mobile and an immobile fraction. Colocalization studies provided evidence that these bodies are accompanied with CREB binding protein (CBP) and acetylated histone H4, which are markers for transcriptionally active chromatin. Moreover, STAT3 nuclear bodies in HepG2 cells are not colocalized with promyelocytic leukemia oncoprotein (PML)-containing bodies; neither is a sumoylation of activated STAT3 detectable. Taken together, our data suggest that STAT3 nuclear bodies are either directly involved in active gene transcription or they serve as reservoirs of activated STAT3.
Lamellipodium extension and cadherin adhesion: two cell responses to cadherin activation relying on distinct signalling pathways
Authors: Gavard Julie , Lambert Mireille , Grosheva Inna , Marthiens Véronique , Irinopoulou Theano , Riou Jean-François , Bershadsky Alexander , Mège René-Marc
Published: December 2003

Cell adhesion molecules of the cadherin family contribute to the regulation of cell shape and fate by mediating strong intercellular adhesion through Ca2+-dependent interaction of their ectodomain and association of their cytoplasmic tail to actin. However, the mechanisms co-ordinating cadherinmediated adhesion with the reorganization of the actin cytoskeleton remain elusive. Here, the formation of de novo contacts was dissected by spreading cells on a highly active N-cadherin homophilic ligand. Cells responded to N-cadherin activation by extending lamellipodium and organizing cadherin-catenin complexes and actin filaments in cadherin adhesions. Lamellipodium protrusion, associated with actin polymerization at the leading edge sustained the extension of cadherin contacts through a phosphoinositide 3-kinase (PI 3-kinase)-Rac1 pathway. Cadherin adhesions were formed by PI 3-kinase-independent, Rac1-dependent co-recruitment of adhesion complexes and actin filaments. The expression and localization of p120 at the plasma membrane, associated with an increase in membrane-associated Rac1 was required for both cell responses, consistent with a major role of p120 in signalling pathways initiated by cadherin activation and contributing to Rac1-dependent contact extension and maturation. These results provide additional information on the mechanisms by which cadherin coordinates adhesion with dynamic changes in the cytoskeleton to control cell shape and intercellular junction organization.
Observations on the energy absorption characteristics of a three-spoke steering wheel armature during impact
Authors: Altenhof W , Li Z , Zamani N , Arnold B
Published: December 2003

This research deals with experimental and finite element simulation of impacts occurring between a rigid plate and an aluminium three-spoke steering wheel armature to investigate the energy absorption capabilities of the armature. A limited number of experimental tests were conducted to validate a numerical model of the armature. An acceptable correlation between the experimental testing observations and numerical simulation results was observed for this highly non-linear problem. The numerical model was used to investigate the energy absorption abilities of the armature with variations in the impact location (wheel angle) and orientation of the armature (column angle). The finite element simulations have illustrated that the hub region is the location where most energy due to plastic deformation in the structure is absorbed. These results are very dependent upon the location of impact and the armature orientation. These observations provide an understanding into the characteristics of energy management in crash situations for the steering wheel armature.
Laboratory measurement of rolling resistance in truck tyres under dynamic vertical load
Authors: Popov A A , Cole D J , Winkler C B , Cebon D
Published: December 2003

This paper deals with the rolling resistance of heavy vehicle tyres measured on a large drum under dynamically varying vertical load. The aim is to simulate in the laboratory the dynamic loading conditions arising from interaction of the vehicle with a randomly rough road. A dynamically varying vertical force is generated using a hydraulic actuator. A comprehensive set of experimental data for two different truck tyres is presented, and the influence of dynamic load on the mean rolling resistance is quantified and discussed. The measurements indicate that there is no significant effect of dynamic vertical load on the mean rolling resistance of the two tyres tested.