bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the response to imatinib in chronic myeloid leukemia patients – comparison between the FISH, multiplex and RT‐PCR methods
Authors: Raanani Pia , Ben‐Bassat Isaac , Gan Shlomit , Trakhtenbrot Luba , Mark Ziva , Ashur‐Fabian Osnat , Itskovich Svetlana , Brok‐Simoni Frida , Rechavi Gideon , Amariglio Ninette , Nagler Arnon 
Published: September 2004

Abstract:  Objective: The objective of this study was to evaluate the kinetics of molecular response in chronic myeloid leukemia (CML) patients treated with imatinib and to compare between the fluorescent in situ hybridization (FISH), multiplex and real‐time quantitative RT‐PCR (RQ‐PCR) methods with this respect. Methods: Molecular follow‐up was carried out on 24 CML patients treated with imatinib. FISH analysis was performed according to the standard protocol. For RT‐PCR the multiplex and RQ‐PCR methods were used. Results: Sixty‐three percent and 52% of the patients achieved complete remission according to FISH and multiplex RT‐PCR analyses, respectively. Seventy‐five percent of the patients achieved remission within the first year of treatment. In 83% of the cases the FISH and RT‐PCR results were concordant. RQ‐PCR analysis was carried out on 32 of the 41 samples negative by multiplex RT‐PCR but only nine were negative. All samples with a BCR–ABL/ABL ratio below 2% were also negative by FISH. There was an excellent correlation between the RQ‐PCR and the FISH tests. Conclusions: Molecular remission according to FISH and multiplex RT‐PCR can be achieved by imatinib within 1 yr of therapy. There is a good correlation between the FISH, multiplex and RQ‐PCR results in terms of the kinetics of disappearance of the BCR–ABL transcript and the predictability of each method for the other. Although RQ‐PCR is the most sensitive method for molecular follow‐up, FISH and multiplex RT‐PCR can be used as complementary tools, at least during the early period of treatment.
Development of packaging cell lines for generation of adeno‐associated virus vectors by lentiviral gene transfer of trans‐complementary components
Authors: Nakamura Satoki , Nakamura Reiko , Shibata Kiyoshi , Kobayashi Miki , Sahara Naohi , Shigeno Kazuyuki , Shinjo Kaori , Naito Kensuke , Ohnishi Kazunori , Kasahara Noriyuki , Iwaki Yuichi 
Published: September 2004

Abstract:  Adeno‐associated virus (AAV) vector system has several useful advantages with regard to in vitro and in vivo gene transfer. However, their usages have been limited by cumbersome and labor‐intensive vector production in the traditional method. To overcome limitations in AAV production, in this report, we explored the possibility of generating AAV packaging cell line, 293T R/C.VA.E2A.E4. cells, by using lentivirus‐mediated transduction of Rep/Cap gene of AAV‐2, VA RNA, E2A, and E4 genes of Ad5 into 293T cells. In packaging cell lines, it is important that supply of the AAV vector can be stably performed for long time. We showed that the 293T R/C.VA.E2A.E4. cells have stably maintained the transduced components after more than 10 passages and yielded high‐titer AAV vectors, and the titer of AAV vectors did not decline even if culture of the packaging cells was continued for long time. The Rep/Cap and E4 gene products caused no remarkable cytotoxicity. The 293T R/C.VA.E2A.E4. cells might be able to tolerate the Rep/Cap and E4 gene products, or have less copy numbers of the Rep/Cap and E4 genes than the traditional method. Moreover, we showed that the AAV vectors derived from 293T R/C.VA.E2A.E4. cells infected the primary human CD34+ haematopoietic progenitor cells with high efficiency (50–70%). In the 293T R/C.VA.E2A.E4. cells, the AAV vectors can be generated by the transfection of one AAV vector plasmid, and large‐scale AAV production can be easily achieved. It is important that cumbersome, variable, and costly transfection is avoided.
Diagnostic characteristics of pulpal blood flow levels associated with adverse outcomes of luxated permanent maxillary incisors
Authors: Emshoff R. , Emshoff I. , Moschen I. , Strobl H. 
Published: September 2004

Abstract –  Laser Doppler flowmetry (LDF) is a non‐invasive method to assess pulpal blood flow (PBF). Dental injury has been associated with significant PBF reduction. The purpose of this study was (i) to describe PBF characteristics of teeth with specific clinical outcomes, and (ii) to demonstrate diagnostic characteristics for different threshold PBF values for detection of specific multiple adverse outcomes. In 80 trauma patients, a single maxillary incisor treated by repositioning and splinting, and the respective contralateral homologous control tooth were investigated by LDF to assess local PBF values. Perfusion units (PU) were taken in two sessions, on the day of splint removal (session I), and 12 weeks after splint removal (session II). The ability of session II‐related PBF measurements at 2.9, 6.4 and 9.9 PU levels to identify adverse outcomes occurring 36 weeks after splint removal was investigated. Adverse outcomes were classified as type I (loss of sensitivity), type II (periapical radiolucency), type III (grey discolouration), type IV (loss of sensitivity and periapical radiolucency), and type V (loss of sensitivity, periapical radiolucency and grey discolouration of crown). Receiver–operator characteristic (ROC) curves were used to evaluate the sensitivity and specificity of PBF assessments. There was a significant increase in PBF values from session I to session II (P = 0.0001) for teeth without an adverse outcome, while teeth affected by a type II–V outcome showed a significant decrease in PBF values (P < 0.05). PBF measurements did not change over time for the contralateral incisors (P > 0.05). A type IV and V outcome occurred in 21 and 24% of the instances, respectively. The PBF of 2.9 PU demonstrated a sensitivity of 70% and a specificity of 93% for type V outcomes. The best likelihood ratio was found for the PBF 2.9 PU level and incisors associated with a type V outcome. The data suggest that the LDF test to be a valuable diagnostic adjunct for luxated teeth showing signs of adverse outcomes including grey discolouration or a combination of other signs. However, it may also become necessary to apply clinical decision‐making methods in order to correctly evaluate the value of information gathered. The clinical implication is that LDF may become useful in the prediction of adverse outcomes at a much earlier time period than may be accomplished by standard sensitivity tests.
Temporal relation between depression and cognitive impairment in old age: prospective population based study
Authors: Vinkers David J , Gussekloo Jacobijn , Stek Max L , Westendorp Rudi G J , Mast Roos C van der 
Published: September 2004

Abstract

Objective
To examine the temporal relation between depression and cognitive impairment in old age.

Design
Prospective, population based study with four years of follow up.

Setting
City of Leiden, the Netherlands.

Participants
500 people aged 85 years at recruitment.

Main outcome measures
Annual assessments of depressive symptoms (15 item geriatric depression scale), global cognitive function (mini-mental state examination), attention (Stroop test), processing speed (letter digit coding test), and immediate and delayed recall (12 word learning test).

Results
At 85 years old, participants' depressive symptoms and cognitive impairment were highly significantly correlated (P < 0.001). During follow up, an accelerated annual increase of depressive symptoms was associated with impaired attention (0.08 points (95% confidence interval 0.01 to 0.16)), immediate recall (0.17 points (0.09 to 0.25)), and delayed recall (0.10 points (0.02 to 0.18)) at baseline. In contrast, depressive symptoms at baseline were not related to an accelerated cognitive decline during follow up (P > 0.05).

Conclusion
Caregivers should be aware of the development of depressive symptoms when cognitive impairment is present. However, the presence of depression only does not increase the risk of cognitive decline.
Asynchronous Shear Stress and Circumferential Strain Reduces Endothelial NO Synthase and Cyclooxygenase-2 but Induces Endothelin-1 Gene Expression in Endothelial Cells
Authors: Dancu Michael B. , Berardi Danielle E. , Vanden Heuvel John P. , Tarbell John M. 
Published: September 2004

Objective—Endothelium-derived vasoactive agents NO, endothelin-1 (ET-1), and prostacyclin (PGI2) not only regulate vascular tone but also influence atherogenic processes, including smooth muscle migration and proliferation, as well as monocyte and platelet adhesion. Complex hemodynamics characterized by the temporal phase angle between mechanical factors circumferential strain and wall shear stress (stress phase angle [SPA]) have been implicated in regions prone to pathologic development, such as atherosclerosis and intimal hyperplasia, in coronary and peripheral arteries where the mechanical forces are highly asynchronous (SPA=−180°). We determined the gene expression of endothelial NO synthase (eNOS), ET-1, and cyclooxygenase-2 (COX-2) affected by asynchronous hemodynamics (SPA=−180°) relative to normal hemodynamics (SPA=0°) in bovine aortic endothelial cells.Methods and Results—Quantitative competitive RT-PCR analysis showed that eNOS production (at 5 and 12 hours) and COX-2 production (at 5 hours) were reduced at the gene expression level by asynchronous hemodynamics (SPA=−180°) compared with synchronous hemodynamics (SPA=0°), whereas ET-1 exhibited an opposite trend (at 5 and 12 hours). NO, ET-1, and PGI2secretion followed their respective gene expression profiles after 5 and 12 hours.Conclusion—Together, these data suggest that highly asynchronous mechanical force patterns (SPA=−180°) can elicit proatherogenic vasoactive responses in endothelial cells at the gene expression level, indicating a novel mechanism that induces cardiovascular pathology.
Genetic Influence on Inflammation Variables in the Elderly
Authors: de Maat Moniek P.M. , Bladbjerg Else Marie , von Bornemann Hjelmborg Jacob , Bathum Lise , Jespersen Jørgen , Christensen Kaare 
Published: September 2004

Background—Inflammation variables (C-reactive protein [CRP], fibrinogen, and soluble intercellular adhesion molecule-1 [sICAM-1]) have been identified as risk factors for cardiovascular disease. It is still not known how much the regulation of inflammatory risk factors is determined by genetic factors, and the aim of this study was to determine the heritability of these inflammation variables and of the acute phase regulating cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) at older ages.Methods and Results—The heritability of CRP, fibrinogen, sICAM-1, IL-6, and TNF-α was determined in a twin study consisting of 129 monozygotic twin pairs and 153 dizygotic same-sex twins aged 73 to 94 years who participated in the Longitudinal Study of Aging of Danish Twins. Furthermore, we determined the influence of selected genetic polymorphisms on the plasma level variations. Genetic factors accounted for 20% to 55% of the variation in plasma levels of the inflammation variables. The highest heritability was found for sICAM-1. The genetic polymorphisms we studied explained only a small, insignificant part of the heritability.Conclusions—This study in elderly twins provides evidence for a substantial genetic component of inflammatory cardiovascular risk factors among the elderly.
Inhibition of Tumor Necrosis Factor-α Reduces Atherosclerosis in Apolipoprotein E Knockout Mice
Authors: Brånén Lena , Hovgaard Lars , Nitulescu Mihaela , Bengtsson Eva , Nilsson Jan , Jovinge Stefan 
Published: September 2004

Objective—Inflammation plays an important role in atherosclerosis. One of the most potent pro-inflammatory cytokines is tumor necrosis factor-α (TNF-α), a cytokine identified to have a pathogenic role in chronic inflammatory diseases such as rheumatoid arthritis (RA). The aim of the study was to evaluate the importance of TNF-α in atherogenesis.Methods and Results—Mice deficient in both apolipoprotein E (apoE) and TNF-α were compared regarding their atherosclerotic burden. Mice were fed a Western-style diet (WD) or normal chow. Mice deficient in both apoE and TNF-α exhibited a 50% (P=0.035) reduction of relative lesion size after 10 weeks of WD. Bone marrow transplantation ofapoEomice withapoEotnf-αobone marrow resulted in a 83% (P=0.021) reduction after 25 weeks on WD. InapoEknockout mice treated with recombinant soluble TNF receptor I releasing pellets, there was a reduction in relative lesion size after 25 weeks of 75% (P=0.018).Conclusions—These findings demonstrate that TNF-α is actively involved in the progression of atherosclerosis. Accordingly, TNF-α represents a possible target for prevention of atherosclerosis. This may be of particular importance in rheumatoid arthritis because these patients have an increased risk for cardiovascular disease.
The adaptor protein 3BP2 associates with VAV guanine nucleotide exchange factors to regulate NFAT activation by the B-cell antigen receptor
Authors: Foucault Isabelle , Le Bras Séverine , Charvet Céline , Moon Chéol , Altman Amnon , Deckert Marcel 
Published: September 2004

Abstract
Engagement of the B-cell antigen receptor (BCR) activates kinases of the Src and Syk families and signaling complexes assembled by adaptor proteins, which dictate B-cell fate and function. The adaptor 3BP2/SH3BP2, an Abl Src homology domain 3 (SH3)–binding and Syk-kinases interacting protein, exhibits positive regulatory roles in T, natural killer (NK), and basophilic cells. However, its involvement in BCR signaling is completely unknown. Here we show that 3BP2 is tyrosine phosphorylated following BCR aggregation on B lymphoma cells, and that 3BP2 is a substrate for Syk and Fyn, but not Btk. To further explore the function of 3BP2 in B cells, we screened a yeast 2-hybrid B-lymphocyte library and found 3BP2 as a binding partner of Vav proteins. The interaction between 3BP2 and Vav proteins involved both constitutive and inducible mechanisms. 3BP2 also interacted with other components of the BCR signaling pathway, including Syk and phospholipase C γ (PLC-γ). Furthermore, overexpression and RNAi blocking experiments showed that 3BP2 regulated BCR-mediated activation of nuclear factor of activated T cells (NFATs). Finally, evidence was provided that 3BP2 functionally cooperates with Vav proteins and Rho GTPases to activate NFATs. Our results show that 3BP2 may regulate BCR-mediated gene activation through Vav proteins.
Interleukin-15 induces IL-12 receptor β1 gene expression through PU.1 and IRF 3 by targeting chromatin remodeling
Authors: Musikacharoen Tipayaratn , Oguma Asako , Yoshikai Yasunobu , Chiba Norika , Masuda Akio , Matsuguchi Tetsuya 
Published: September 2004

AbstractInterleukin-12 receptor β1 (IL12RB1) is expressed on a variety of immune cells, including T and natural killer (NK) cells and macrophages, and is involved in innate and adaptive immune responses. Levels of IL12RB1 mRNA are dynamically regulated by various cytokines, including interferon-γ (IFN-γ) and IL-15. To reveal the regulatory mechanisms governing IL12RB1 gene expression, we analyzed the transcriptional regulatory region of the mouse IL12RB1 gene. Promoter analyses in a mouse macrophage cell line, RAW264.7, revealed that the 2508-bp region upstream of the transcriptional start site is sufficient for the full transcriptional activation of the IL12RB1 gene by IFN-γ or IL-15. Analyses of the deletion mutants revealed critical roles of IRE/ISRE and ETS/PU.1 elements, to which IRF3 and PU.1, respectively, bound. Notably, chromatin immunoprecipitation (ChIP) assays revealed IL-15 rapidly induced histone H3 acetylation at the IL12RB1 promoter. Consistently, IL-15, as a histone deacetylase inhibitor, synergistically enhanced IL12RB1 gene expression and promoter activation by IFN-γ through increased protein binding to ETS/PU.1 and IRE/ISRE sites. Additionally, IL12RB1 promoter activation by IFN-γ was enhanced by the coexpression of a coactivator protein, CBP. Thus, IL-15 induces chromatin remodeling of the IL12RB1 gene promoter, increasing IL12RB1 mRNA expression in synergy with IFN-γ through the recruitment of PU.1 and IRF3.
Stromal cell–derived factor-1α/CXCL12–induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1
Authors: Okabe Seiichi , Fukuda Seiji , Kim Young-June , Niki Masaru , Pelus Louis M. , Ohyashiki Kazuma , Pandolfi Pier Paolo , Broxmeyer Hal E. 
Published: September 2004

AbstractEvents mediating stromal cell–derived factor-1 (SDF-1α/CXCL12) chemotaxis of lymphocytes are not completely known. We evaluated intracellular signaling through RasGAP-associated protein p62Dok-1 (downstream of tyrosine kinase [Dok-1]) and associated proteins. SDF-1α/CXCL12 stimulated Dok-1 tyrosine phosphorylation and association with RasGAP, adaptor protein p46Nck, and Crk-L in Jurkat T cells. The phosphorylation of Dok-1 was blocked by pretreatment of cells with the src kinase inhibitor PP2. Src kinase family member Lck was implicated. SDF-1α/CXCL12 did not phosphorylate Dok-1 in J.CaM1.6 cells, a Jurkat derivative not expressing Lck, but did phosphorylate Dok-1 in J.CaM1.6 cells expressing Lck. SDF-1α/CXCL12 induced the tyrosine phosphorylation of Pyk2 and the association of Pyk2 with zeta chain–associated protein-70 kilodaltons (Zap-70) and Vav. SDF-1α/CXCL12 enhanced the association of RasGAP with Pyk2. CXCR4–expressing NIH3T3 and Baf3 cells transfected with full-length Dok-1 cDNA were suppressed in their responses to SDF-1α/CXCL12–induced chemotaxis; mitogen-activated protein (MAP) kinase activity was also decreased. Chemotaxis to SDF-1/CXCL12 was significantly enhanced in Dok-1–/– CD4+ and CD8+ splenic T cells. These results implicate Dok-1, Nck, Crk-L, and Src kinases—especially Lck, Pyk2, Zap-70, Vav, and Ras-GAP—in intracellular signaling by SDF-1α/CXCL12, and they suggest that Dok-1 plays an important role in SDF-1α/CXCL12–induced chemotaxis in T cells.
Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis
Authors: Kawabata Hiroshi , Fleming Robert E. , Gui Dorina , Moon Seo Y. , Saitoh Takayuki , O'Kelly James , Umehara Yutaka , Wano Yuji , Said Jonathan W. , Koeffler H. Phillip 
Published: September 2004

Abstract
Transferrin receptor 2 (TfR2) is a membrane glycoprotein that mediates cellular iron uptake from holotransferrin. Homozygous mutations of this gene cause one form of hereditary hemochromatosis in humans. We recently reported that homozygous TfR2(Y245X) mutant mice, which correspond to the TfR2(Y250X) mutation in humans, showed a phenotype similar to hereditary hemochromatosis. In this study, we further analyzed the phenotype as well as iron-related gene expression in these mice by comparing the TfR2-mutant and wild-type siblings. Northern blot analyses showed that the levels of expression of hepcidin mRNA in the liver were generally lower, whereas those of duodenal DMT1, the main transporter for uptake of dietary iron, were higher in the TfR2-mutant mice as compared to the wild-type siblings. Expression of hepcidin mRNA in the TfR2 mutant mice remained low even after intraperitoneal iron loading. In isolated hepatocytes from both wild-type and TfR2 mutant mice, interleukin-6 and lipopolysaccharide each induced expression of hepcidin mRNA. These results suggest that up-regulation of hepcidin expression by inflammatory stimuli is independent of TfR2 and that TfR2 is upstream of hepcidin in the regulatory pathway of body iron homeostasis. (Blood. 2005;105:376-381)
Vascular endothelial growth factor regulation of Weibel-Palade–body exocytosis
Authors: Matsushita Kenji , Yamakuchi Munekazu , Morrell Craig N. , Ozaki Michitaka , O'Rourke Brian , Irani Kaikobad , Lowenstein Charles J. 
Published: September 2004

AbstractVascular endothelial growth factor (VEGF) not only regulates angiogenesis, vascular permeability, and vasodilation but also promotes vascular inflammation. However, the molecular basis for the proinflammatory effects of VEGF is not understood. We now show that VEGF activates endothelial cell exocytosis of Weibel-Palade bodies, releasing vasoactive substances capable of causing vascular thrombosis and inflammation. VEGF triggers endothelial exocytosis in part through calcium and phospholipase C-γ (PLC-γ) signal transduction. However, VEGF also modulates endothelial cell exocytosis by activating endothelial nitric oxide synthase (eNOS) production of nitric oxide (NO), which nitrosylates N-ethylmaleimide sensitive factor (NSF) and inhibits exocytosis. Thus, VEGF plays a dual role in regulating endothelial exocytosis, triggering pathways that both promote and inhibit endothelial exocytosis. Regulation of endothelial exocytosis may explain part of the proinflammatory effects of VEGF.
CD1d-unrestricted human NKT cells release chemokines upon Fas engagement
Authors: Giroux Martin , Denis François 
Published: September 2004

AbstractAttempts at inducing allograft immune privilege by enforced Fas ligand expression have shown accelerated rejection mediated by neutrophils. While it has been proposed that Fas ligand was directly chemotactic toward neutrophils, several lines of evidence argue for an indirect recruitment mechanism. This question was addressed by using in vitro migration assays that used highly purified human leukocyte subsets. Granulocytes did not migrate in response to Fas engagement and required the presence of T cells expressing several natural killer (NK) cell markers. These rare CD8 memory T cells expressed T and NK cell markers and were not restricted to CD1d, showing that they are distinct from conventional natural killer T (NKT) cells. These cells were able to kill both NK-sensitive and -insensitive targets and secreted several CC and CXC chemokines active toward granulocytes, monocytes, and NK cells upon Fas engagement. Chemotactic factor release depended on caspase activity, in the absence of NKT cell apoptosis. The ability of CD1d-unrestricted NKT cells to recruit innate immune system cells might play a role in cancer cell eradication and contribute to inflammatory diseases.
Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy
Authors: Powell Daniel J. , Dudley Mark E. , Robbins Paul F. , Rosenberg Steven A. 
Published: September 2004

AbstractIn humans, the pathways of memory T-cell differentiation remain poorly defined. Recently, adoptive cell transfer (ACT) of tumor-reactive T lymphocytes to metastatic melanoma patients after nonmyeloablative chemotherapy has resulted in persistence of functional, tumor-reactive lymphocytes, regression of disease, and induction of melanocyte-directed autoimmunity in some responding patients. In the current study, longitudinal phenotypic analysis was performed on melanoma antigen-specific CD8+ T cells during their transition from in vitro cultured effector cells to long-term persistent memory cells following ACT to 6 responding patients. Tumor-reactive T cells used for therapy were generally late-stage effector cells with a CD27Lo CD28Lo CD45RA- CD62 ligand- (CD62L-) CC chemokine receptor 7- (CCR7-) interleukin-7 receptor αLo (IL-7RαLo) phenotype. After transfer, rapid up-regulation and continued expression of IL-7Rα in vivo suggested an important role for IL-7R in immediate and long-term T-cell survival. Although the tumor antigen-specific T-cell population contracted between 1 and 4 weeks after transfer, stable numbers of CD27+ CD28+ tumor-reactive T cells were maintained, demonstrating their contribution to the development of long-term, melanoma-reactive memory CD8+ T cells in vivo. At 2 months after transfer, melanoma-reactive T cells persisted at high levels and displayed an effector memory phenotype, including a CD27+ CD28+ CD62L- CCR7- profile, which may explain in part their ability to mediate tumor destruction. (Blood. 2005;105:241-250)