bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke
Authors: Li Zhaohui , Sun Li , Zhang Hongye , Liao Yuhua , Wang Daowen , Zhao Bingrang , Zhu Zhiming , Zhao Jizong , Ma Aiqun , Han Yu , Wang Yibo , Shi Yi , Ye Jue , Hui Rutai
Published: August 2003

Background and Purpose—

It is still controversial whether elevated plasma homocysteine and the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene are risk factors for stroke. The aim of the present study was to investigate the association between the 2 factors and stroke in Chinese in a large case-control study.

Methods—

We recruited 1823 stroke patients (807 cerebral thrombosis, 513 lacunar infarction, 503 intracerebral hemorrhage) and 1832 controls. Total plasma homocysteine was determined by high-performance liquid chromatography. C677T polymorphism was genotyped by polymerase chain reaction and
Hin
fI digestion.

Results—

Total plasma homocysteine levels were significantly higher in cases than controls (median, 14.7 versus 12.8 μmol/L;
P
<0.001) and associated with an increased risk of 1.87-fold (95% confidence interval [CI], 1.58 to 2.22) for overall stroke, 1.72-fold (95% CI, 1.39 to 2.12) for cerebral thrombosis, 1.89-fold (95% CI, 1.50 to 2.40) for lacunar infarction, and 1.94-fold (95% CI, 1.48 to 2.55) for intracerebral hemorrhage. The C677T mutation of the MTHFR gene was positively correlated with plasma homocysteine levels in both controls (β=0.250,
P
<0.001) and cases (β=0.272,
P
<0.001) and more frequently in cases than in controls (47.0% versus 44.2%,
P
=0.017). The TT genotype was associated with an increased risk for overall stroke (odds ratio, 1.27; 95% CI, 1.04 to 1.56) and thrombotic stroke (odds ratio, 1.37; 95% CI, 1.06 to 1.78).

Conclusions—

The C677T polymorphism of the MTHFR gene was associated with increased risk of cerebral thrombotic stroke in Chinese. Total plasma homocysteine was correlated with both ischemic and hemorrhagic stroke, suggesting potential initiation of homocysteine-lowering therapy in this population.
Proportion of Different Subtypes of Stroke in China
Authors: Zhang Lin-Feng , Yang Jun , Hong Zhen , Yuan Guang-Gu , Zhou Bei-Fan , Zhao Lian-Cheng , Huang Yi-Ning , Chen Jie , Wu Yang-Feng
Published: August 2003

Background and Purpose—

The goal of this article is to clarify the proportion of stroke subtypes in China, where stoke is the most common cause of death.

Methods—

A total of 16 031 first-ever strokes in subjects ≥25 years of age were identified in 1991 to 2000 from 17 Chinese populations through a community-based cardiovascular disease surveillance program in the China Multicenter Collaborative Study of Cardiovascular Epidemiology. World Health Organization diagnosis criteria were used for classification of stroke subtypes.

Results—

CT scan rate of stroke cases reached a satisfactorily high level only after 1996 in the study populations. In 8268 first-ever stroke events from 10 populations with CT scan rate >75% in 1996 to 2000, 1.8% were subarachnoid hemorrhage, 27.5% were intracerebral hemorrhage, 62.4% were cerebral infarction, and 8.3% were undetermined stroke. The proportion of intracerebral hemorrhage varied from 17.1% to 39.4% and that for cerebral infarction varied from 45.5% to 75.9% from population to population. The ratio of ischemic to hemorrhagic stroke ranged from 1.1 to 3.9 and averaged 2.0). The 28-day fatality rate was 33.3% for subarachnoid hemorrhage, 49.4% for intracerebral hemorrhage, 16.9% for cerebral infarction, and 64.6% for undetermined stroke.

Conclusions—

In our study, ischemic stroke was more frequent and its proportion was higher than hemorrhagic stroke in Chinese populations. Although hemorrhagic stroke was more frequent in Chinese than in Western populations, the variation in the proportion of stroke subtypes among Chinese populations could be as large as or larger than that between Chinese and Western populations.
Hyperglycemia Exacerbates Brain Edema and Perihematomal Cell Death After Intracerebral Hemorrhage
Authors: Song Eun-Chol , Chu Kon , Jeong Sang-Wuk , Jung Keun-Hwa , Kim Seong-Hoon , Kim Manho , Yoon Byung-Woo
Published: August 2003

Background and Purpose—

Hyperglycemia has a deleterious effect on brain ischemia. However, the effect of hyperglycemia in intracerebral hemorrhage (ICH) is not well known. We investigated the effect of hyperglycemia on the development of brain edema and perihematomal cell death in ICH.

Methods—

Hyperglycemia was induced by intraperitoneal injection of streptozotocin (60 mg/kg) in adult Sprague-Dawley male rats. ICH was induced by stereotaxic infusion of 0.23 U of collagenase into the left striatum. Seventy-two hours after ICH, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was performed for perihematomal cell death. We also measured brain water content to evaluate edema formation.

Results—

The serum glucose level of the hyperglycemic group was 394.0±180.3 mg/dL (n=31), and that of the normoglycemic group was 97.5±27.4 mg/dL (n=31). The size of hemorrhage was similar between groups, without any significant difference (n=8 in each group). The brain water content of hyperglycemic rats (n=17) increased in both lesioned (81.0±0.5%) and nonlesioned hemispheres (78.7±0.6%) compared with the normoglycemic group (n=17; lesioned: 78.9±0.8%; nonlesioned: 77.3±1.1%). In the hyperglycemic group, more TUNEL-positive cells were found in the perihematomal regions (n=6).

Conclusions—

Hyperglycemia caused more profound brain edema and perihematomal cell death in experimental ICH.
Profiles of Matrix Metalloproteinases, Their Inhibitors, and Laminin in Stroke Patients
Authors: Horstmann Solveig , Kalb Pamela , Koziol James , Gardner Humphrey , Wagner Simone
Published: August 2003

Background and Purpose—

The goal of this study was to determine the temporal profile of several matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and laminin (an MMP substrate) in human stroke under different treatment paradigms, including thrombolysis and hypothermia.

Methods—

We serially measured the serum levels of MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, and laminin in 50 patients with acute ischemic stroke using zymography or enzyme-linked immunosorbent assay. Patients were treated with heparin, therapeutic thrombolysis, or hypothermia. Scandinavian Stroke Scale scores were obtained at baseline. Infarct volume was measured with CT scanning on day 4 after stroke onset. Healthy persons were used as control subjects.

Results—

MMP-2 and MMP-9 increased during the course of ischemia, whereas intact laminin and TIMP-2 decreased significantly (
P
<0.05). MMP-9 and laminin levels varied significantly by infarct size (
P
=0.001) and therapy (
P
=0.0005). MMP-9 levels were significantly higher in patients treated with tissue plasminogen activator (tPA) compared with patients treated with hypothermia. The cleaved form of MMP-9 was found solely in 4 patients treated with tPA. Intact laminin levels were significantly lower in the tPA group than in the hypothermia group.

Conclusions—

Selected MMPs and TIMPs are involved in the pathophysiology of acute stroke. This is also reflected by changes in laminin. Treatment paradigms differentially influence levels of MMP-9 and laminin. Combination therapies explicitly involving MMP inhibition could be of value in future treatment strategies.
Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graft-versus-host disease and with the graft-versus-leukemia effect
Authors: Sakaida Emiko , Nakaseko Chiaki , Harima Akane , Yokota Akira , Cho Ryuko , Saito Yasushi , Nishimura Miki
Published: August 2003

Late-onset noninfectious pulmonary complications (LONIPCs) occurring beyond 3 months after allogeneic stem cell transplantation (allo-SCT) have become recognized as life-threatening complications, and they reduce the recipient's quality of life. However, the pathogenesis and optimal treatment for LONIPCs are still unclear. In this study, we retrospectively analyzed the incidence and outcome of LONIPCs among allo-SCT recipients. Between October 1993 and September 2001, 96 patients underwent allo-SCT and 76 patients who survived and were free of disease for more than 3 months after SCT were enrolled. Among the 76 patients, 18 patients (23.7%) developed LONIPCs at a median interval of 227 days after allo-SCT (range, 91-1105 days). The patients with LONIPCs were subclassified into those with bronchiolitis obliterans (BO) (6 patients), with interstitial pneumonia (IP) (11 patients), or with both BO and IP (1 patient). The presence of extensive chronic graft-versus-host disease (GVHD) was significantly associated with the development of LONIPCs (P = .0008). Liver or skin involvement in chronic GVHD was not associated, but sicca syndrome was significantly associated with the development of LONIPCs (P < .0001). Most of the IP patients (58.3%) responded well to immunosuppressive treatment, while BO patients did not respond to the therapy. Eight of the 18 patients with LONIPCs died. The major cause of death was respiratory failure (62.5%). The relapse rate of primary malignant disease in the LONIPC patients was significantly lower than that of non-LONIPC patients (1 of 17 [5.9%] versus 16 of 52 [30.8%]; P = .0387). These results indicate that the development of LONIPCs was strongly associated with chronic GVHD and especially with sicca syndrome and the graft-versus-leukemia (GVL) effect. (Blood. 2003;102:4236-4242)
Chemokine stimulation of human peripheral blood T lymphocytes induces rapid dephosphorylation of ERM proteins, which facilitates loss of microvilli and polarization
Authors: Brown Martin J. , Nijhara Ruchika , Hallam John A. , Gignac Michelle , Yamada Kenneth M. , Erlandsen Stanley L. , Delon Jérôme , Kruhlak Michael , Shaw Stephen
Published: August 2003

Lymphocyte microvilli mediate initial rolling-adhesion along endothelium but are lost during transmigration from circulation to tissue. However, the mechanism for resorption of lymphocyte microvilli remains unexplored. We show that chemokine stimulation of human peripheral blood T (PBT) cells is sufficient to induce rapid resorption of microvilli. Microvilli in other cells are regulated by ezrin/radixin/moesin (ERM) proteins, which link the plasma membrane to the cortical F-actin cytoskeleton; maintenance of these linkages requires ERM activation, reflected by phosphorylation at a specific carboxy-terminal threonine residue. Carboxyphosphorylated-ERM (cpERM) proteins in resting PBT cells show a punctate peripheral distribution consistent with localization to microvilli. cpERM dephosphorylation begins within seconds of stimulation by chemokines (stromal derived factor 1α [SDF-1α] or secondary lymphoid tissue cytokine), and ERM proteins lose their punctate distribution with kinetics paralleling the loss of microvilli. The cpERM proteins are preferentially associated with the cytoskeleton at rest and this association is lost with chemokine-induced dephosphorylation. Transfection studies show that a dominant-negative ERM construct destroys microvilli, whereas a construct mimicking cpERM facilitates formation of microvilli, retards chemokine-induced loss of microvilli, and markedly impairs chemokine-induced polarization. Thus, chemokine induces rapid dephosphorylation and inactivation of cpERM, which may in turn facilitate 2 aspects of cytoskeletal reorganization involved in lymphocyte recruitment: loss of microvilli and polarization.
Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII
Authors: Scallan Ciaran D. , Liu Tongyao , Parker Amy E. , Patarroyo-White Susannah L. , Chen Haifeng , Jiang Haiyan , Vargas Joseph , Nagy Dea , Powell Sharon K. , Wright J. Fraser , Sarkar Rita , Kazazian Haig H. , McClelland Alan , Couto Linda B.
Published: August 2003

Using separate adeno-associated viral 2 (AAV2) vectors to deliver the heavy and light chains of factor VIII (FVIII) we have overcome the packaging limitations of AAV, achieving phenotypic correction of hemophilia A in mice. AAV vectors were constructed that use a liver-specific promoter and the cDNA sequences of either the human or canine heavy and light chains of FVIII. After intraportal vein injection of these vectors in hemophilia-A mice, therapeutic to superphysiologic levels of active FVIII were achieved in plasma in a dose-dependent manner. Phenotypic correction of the bleeding diathesis was demonstrated by survival of all treated mice after tail clipping. Biochemical analysis demonstrated lower levels of heavy-chain (25- to 100-fold) compared with light-chain protein in the plasma of treated animals. Differences in gene transfer and transcription did not account for the differences in protein expression. We hypothesize that improvements in FVIII activity could be achieved by improvements in FVIII heavy-chain expression. This work demonstrates that cotransduction of liver with AAV vectors expressing the heavy and light chains of FVIII corrects hemophilia A in vivo, providing an alternative approach to the use of a single vector. This strategy may potentially be useful for other large therapeutic proteins that contain functionally distinct domains.
T-cell interaction with ICAM-1/ICAM-2 double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells
Authors: Lyck Ruth , Reiss Yvonne , Gerwin Nicole , Greenwood John , Adamson Peter , Engelhardt Britta
Published: August 2003

Endothelial intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 are both involved in lymphocyte extravasation during immunosurveillance and inflammation. To define their exact role during T-cell extravasation, we used mouse T cells and ICAM-1-/-ICAM-2-/- brain endothelioma cells. ICAM-1-/-ICAM-2-/- brain endothelioma cells did not support transendothelial migration (TEM) of T cells in vitro. Re-expression of different ICAM-1 mutants in the ICAM-1-/-ICAM-2-/- endothelioma line bEndI1/2.1 or in the ICAM-1-/- endothelioma line bEndI1.1 demonstrated that the extracellular domain of ICAM-1 suffices to support T-cell adhesion while the presence of the cytoplasmic tail was strictly required for TEM. Surprisingly, tyrosine phosphorylation of endothelial ICAM-1 was not necessary for TEM of T cells or for Rho guanosine triphosphatase (RhoGTPase) activation. Furthermore, cytoplasmic deletion mutants of ICAM-1 were unable to mediate RhoGTPase activation. Thus, our data demonstrate that the cytoplasmic tail of endothelial ICAM-1—independently from tyrosine phosphorylation—is essential for supporting TEM of T lymphocytes, while Rho signaling is involved in endothelial cells. (Blood. 2003;102:3675-3683)
Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin
Authors: de Saint-Vis Blandine , Bouchet Caroline , Gautier Grégory , Valladeau Jenny , Caux Christophe , Garrone Pierre
Published: August 2003

Eph receptor tyrosine kinases and their ligands, the ephrins, have been primarily described in the nervous system for their roles in axon guidance, development, and cell intermingling. Here we address whether Eph receptors may also regulate dendritic cell (DC) trafficking. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that DCs derived from CD34+ progenitors, but not from monocytes, expressed several receptors, in particular EphA2, EphA4, EphA7, EphB1, and EphB3 mRNA. EphB3 was specifically expressed by Langerhans cells, and EphA2 and EphA7 were expressed by both Langerhans- and interstitial-type DCs. EphA and EphB protein expression on DCs generated in vitro was confirmed by staining with ephrin-A3-Fc and ephrin-B3-Fc fusion proteins that bind to different Eph members, in particular EphA2 and EphB3. Immunostaining with anti-EphA2 antibodies demonstrated the expression of EphA2 by immature DCs and by skin Langerhans cells isolated ex vivo. Interestingly, ephrin expression was detected in epidermal keratinocytes and also in DCs. Adhesion of CD34+-derived DCs to fibronectin, but not to poly-l-lysine, was increased in the presence of ephrin-A3-Fc, a ligand of EphA2, through a β1 integrin activation pathway. As such, EphA2/ephrin-A3 interactions may play a role in the localization and network of Langerhans cells in the epithelium and in the regulation of their trafficking. (Blood. 2003;102:4431-4440)
Interleukin-21 inhibits dendritic cell activation and maturation
Authors: Brandt Katja , Bulfone-Paus Silvia , Foster Donald C. , Rückert René
Published: August 2003

Interleukin 21 (IL-21) is a newly described cytokine with homology to IL-4 and IL-15. They belong to a cytokine family that uses the common γ chain for signaling but also have their private high-affinity receptors. Since it is well known that IL-4 modulates differentiation and activation of dendritic cells (DCs), we analyzed effects of IL-21 compared with IL-15 on DC differentiation, maturation, and function. Here we show that DCs generated with granulocyte-macrophage colony-stimulating factor (GMCSF) in the presence of IL-21 (IL-21DCs) differentiated into phenotypically and functionally altered DCs characterized by reduced major histocompatibility complex class II (MHCII) expression, high antigen uptake, and low stimulatory capacity for T-cell activation in vitro. Additionally, IL-21DCs completely failed to induce antigen (Ag)-specific T-cell mediated contact hypersensitivity. Furthermore, IL-21 blocked lipopolysaccharide (LPS)-induced activation and maturation of DCs, which was not mediated by release of the anti-inflammatory cytokine IL-10. In contrast, when supplementing GMCSF with IL-15, DCs differentiated into mature antigen-presenting cells (APCs) with low antigen uptake and highly significant increased capacities to stimulate T cells in vitro and in vivo. Taken together, these results identify a dichotomous action of these structurally related cytokines on DCs, establishing IL-21 as inhibitory cytokine on DC activation and IL-15 as potent stimulator of DC function, making both cytokines interesting targets for therapeutic manipulation of DC-induced immune reactions. (Blood. 2003;102: 4090-4098)
Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro–aged or –injured mouse platelets
Authors: Bergmeier Wolfgang , Burger Peter C. , Piffath Crystal L. , Hoffmeister Karin M. , Hartwig John H. , Nieswandt Bernhard , Wagner Denisa D.
Published: August 2003

Platelet transfusions are a crucial component of support for patients with severe thrombocytopenia. Storage of platelet concentrates, however, is associated with a reduction in platelet posttransfusion recovery and hemostatic function. In this study, we established a model of mitochondrial injury that resembles platelet storage lesion. Mitochondrial injury, provoked by incubation of platelets with carbonyl cyanide m-chlorophenylhydrazone (CCCP), led to reduced posttransfusion recovery in mice, an effect that directly correlated with the duration of treatment. Damaged platelets were characterized by shape change, disruption of membrane asymmetry, surface expression of P-selectin, and profound proteolysis of GPIbα. Using our model, we identified a key role for endogenous metalloproteinase(s) in platelet clearance, as their inhibition markedly improved posttransfusion recovery of both the mitochondria-injured and in vitro-aged mouse platelets. Metalloproteinase inhibition also prevented proteolysis of GPIbα on damaged platelets, thereby improving the hemostatic function of these cells in vivo. We propose that inhibition of metalloproteinase activity during storage could significantly improve the effectiveness of platelet transfusions. Surface expression of GPIbα might be a powerful marker to determine the quality of platelet concentrates, because it reflects metalloproteinase activity in vitro. (Blood. 2003;102: 4229-4235)
CD4+CD25+ regulatory T cells inhibit immune-mediated transgene rejection
Authors: Gross David-Alexandre , Leboeuf Marylène , Gjata Bernard , Danos Olivier , Davoust Jean
Published: August 2003

Like cellular transplantation, gene therapy is often limited by immune rejection of the newly expressed antigen. In a model of gene transfer in muscle, delivery of the influenza hemagglutinin (HA) membrane protein by adeno-associated virus (AAV) is impaired by a strong immune response that leads to a rapid rejection of the transduced fibers. We show here that injection of HA-specific CD4+CD25+ T cells from T-cell receptor (TCR)-transgenic animals, concomitant with gene transfer, down-regulates the anti-HA cytotoxic and B-lymphocyte responses and enables persistent HA expression in muscle. This demonstrates for the first time that adoptive transfer of antigen-specific CD4+CD25+ regulatory T cells can be used to induce sustained transgene engraftment in solid tissues. (Blood. 2003;102:4326-4328)
Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease
Authors: Saunthararajah Yogen , Hillery Cheryl A. , Lavelle Don , Molokie Robert , Dorn Louise , Bressler Linda , Gavazova Stefana , Chen Yi-Hsiang , Hoffman Ronald , DeSimone Joseph
Published: August 2003

Fetal hemoglobin (HbF) decreases polymerization of sickle hemoglobin (HbS) and improves outcomes in sickle cell disease (SSD). Therefore, a therapeutic goal in SSD is pharmacologic reactivation of HbF. Silencing of the γ-globin (HbF) gene is associated with DNA methylation. The cytosine analog 5-aza-2′-deoxycytidine (decitabine) hypomethylates DNA by inhibiting DNA methyltransferase. We examined if subcutaneous decitabine could increase HbF levels and improve SSD pathophysiology without cytotoxicity. Eight symptomatic SSD patients resistant or intolerant of standard treatment with hydroxyurea received decitabine 0.2 mg/kg subcutaneously 1 to 3 times per week in 2 cycles of 6-week duration. Treatment decreased neutrophils and increased mean HbF (6.5% to 20.4%, P < .0001) and mean total hemoglobin (76 to 96 g/L [7.6 to 9.6 g/dL], P < .001). Features of vaso-occlusive crisis pathophysiology such as red cell adhesion, endothelial damage, and coagulation pathway activity significantly improved. γ-Globin gene promoter methylation decreased, and platelets and the proportion of megakaryocytes and erythroid cells in the marrow increased without a decrease in marrow cellularity, consistent with a DNA hypomethylating, noncytotoxic mechanism of action. Weekly subcutaneous decitabine produces cumulative increases in HbF and total hemoglobin through a noncytotoxic mechanism of action. Chronic dosing and sustained increases in hemoglobin F and total hemoglobin levels may be possible. Further studies in SSD and thalassemia are indicated.
Thallium-201 Single-Photon Emission Computed Tomography As an Early Predictor of Outcome in Recurrent Glioma
Authors: Vos Maaike J. , Hoekstra Otto S. , Barkhof Frederik , Berkhof Johannes , Heimans Jan J. , van Groeningen Cees J. , Vandertop W. Peter , Slotman Ben J. , Postma Tjeerd J.
Published: August 2003

Purpose: With limited response rates and potential toxicity of chemotherapeutic treatment in patients with recurrent glioma, reliable response assessment is essential. Currently, the assessment of treatment response in glioma patients is based on the combination of radiologic and clinical findings. However, response monitoring with computed tomography (CT) or magnetic resonance imaging (MRI) is hampered by several pitfalls and is prone to interobserver variability. The aim of this study was to establish the value of thallium-201 single-photon emission computed tomography (201Tl-SPECT) as a predictor of overall survival and response to chemotherapy in recurrent glioma, and to compare the value of 201Tl-SPECT with that of CT and MRI.

Patients and Methods: We studied patients who underwent CT or MRI and 201Tl-SPECT before chemotherapy (n = 57), and patients who also had undergone CT or MRI and 201Tl-SPECT after two courses of chemotherapy (n = 44). The value of the radiologic variables (CT-MRI tumor size, 201Tl-SPECT tumor size, and maximal tumor intensity) at baseline and at follow-up in predicting overall survival, and the percentage of patients alive and progression-free at 6 months (APF6) were examined using Cox regression and logistic regression analysis.

Results: Both at baseline and at follow-up, 201Tl-SPECT maximal tumor intensity was the strongest predictive variable and was inversely related to overall survival and APF6. In particular, progression of maximal tumor intensity after two courses of chemotherapy was a powerful predictor of poor outcome.

Conclusion: 201Tl-SPECT is superior to conventional CT-MRI in the early prediction of overall survival and response to chemotherapy in patients with recurrent glioma.
Undertreatment Strongly Decreases Prognosis of Breast Cancer in Elderly Women
Authors: Bouchardy Christine , Rapiti Elisabetta , Fioretta Gérald , Laissue Paul , Neyroud-Caspar Isabelle , Schäfer Peter , Kurtz John , Sappino André-Pascal , Vlastos Georges
Published: August 2003

Purpose: No consensus exists on therapy of elderly cancer patients. Treatments are influenced by unclear standards and are usually less aggressive. This study aims to evaluate determinants and effect of treatment choice on breast cancer prognosis among elderly patients.

Patients and Methods: We reviewed clinical files of 407 breast cancer patients aged ≥ 80 years recorded at the Geneva Cancer Registry between 1989 and 1999. Patient and tumor characteristics, general health status, comorbidity, treatment, and cause of death were considered. We evaluated determinants of treatment by logistic regression and effect of treatment on mortality by Cox model, accounting for prognostic factors.

Results: Age was independently linked to the type of treatment. Overall, 12% of women (n = 48) had no treatment, 32% (n = 132) received tamoxifen only, 7% (n = 28) had breast-conserving surgery only, 33% (n = 133) had mastectomy, 14% (n = 57) had breast-conserving surgery plus adjuvant therapy, and 2% (n = 9) received miscellaneous treatments. Five-year specific breast cancer survival was 46%, 51%, 82%, and 90% for women with no treatment, tamoxifen alone, mastectomy, and breast-conserving surgery plus adjuvant treatment, respectively. Compared with the nontreated group, the adjusted hazard ratio of breast cancer mortality was 0.4 (95% CI, 0.2 to 0.7) for tamoxifen alone, 0.4 (95% CI, 0.1 to 1.4) for breast-conserving surgery alone, 0.2 (95% CI, 0.1 to 0.7) for mastectomy, and 0.1 (95% CI, 0.03 to 0.4) for breast-conserving surgery plus adjuvant treatment.

Conclusion: Half of elderly patients with breast cancer are undertreated, with strongly decreased specific survival as a consequence. Treatments need to be adapted to the patient’s health status, but also should offer the best chance of cure.
The Addition of Interleukin-6 Soluble Receptor and Transforming Growth Factor Beta1 Improves a Preoperative Nomogram for Predicting Biochemical Progression in Patients With Clinically Localized Prostate Cancer
Authors: Kattan Michael W. , Shariat Shahrokh F. , Andrews Ben , Zhu Kuichun , Canto Eduardo , Matsumoto Kazumasa , Muramoto Masatoshi , Scardino Peter T. , Ohori Makoto , Wheeler Thomas M. , Slawin Kevin M.
Published: August 2003

Purpose: Several preoperative prostate cancer nomograms have been developed that predict risk of progression using pretreatment prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason grade. We describe the development and performance of a new nomogram. The nomogram adds new markers to the standard clinical predictors that reflect the biologic behavior of prostate cancer: pretreatment plasma levels of interleukin-6 soluble receptor (IL6SR) and transforming growth factor beta1 (TGF-β1).

Patients and Methods: Between November 7, 1994 and December 22, 1997, 714 patients with stage cT1c to cT3a prostate cancer and no prior therapy were treated with radical prostatectomy at the Methodist Hospital, Houston TX. Plasma levels of IL6SR and TGF-β1 were measured in banked preoperative plasma. With these data, a nomogram was developed to predict the probability of PSA progression within 5 years of surgery. The nomogram was validated with bootstrapping to assess its discrimination and calibration performance.

Results: In the multivariable Cox model, PSA (P = .004), IL6SR (P < .001), TGF-β1 (P < .001), primary Gleason grade (P < .002), and secondary Gleason grade (P = .029) were associated with PSA progression, whereas clinical stage (P = .696) was not. The nomogram seemed to be well calibrated and had a bootstrap-corrected area under the receiver operating characteristic curve (ie, concordance index) of 0.83. For comparison, a nomogram that omitted IL6SR and TGF-β1 achieved a concordance index of only 0.75.

Conclusion: We found that pretreatment plasma levels of IL6SR and TGF-β1 improved the ability to predict biochemical progression by a prognostically substantial margin. A nomogram including the pretreatment levels of these molecular markers, along with standard clinical markers, has been developed and internally validated.
Elevated Steroidogenesis, Defective Reproductive Organs, and Infertility in Transgenic Male Mice Overexpressing Human Chorionic Gonadotropin
Authors: Rulli Susana B. , Ahtiainen Petteri , Mäkelä Sari , Toppari Jorma , Poutanen Matti , Huhtaniemi Ilpo
Published: August 2003

We previously developed a transgenic (TG) mouse model that overexpresses the human chorionic gonadotropin (hCG) β-subunit under the universal human ubiquitin C promoter, displaying in males a modest 3-fold increase in circulating levels of LH/hCG bioactivity. The males were fertile and presented with a mild reproductive phenotype. To achieve higher levels of hCG, a double TG model was generated by cross-breeding the hCGβ-expressing mice with another TG line harboring a ubiquitin C/common α-subunit fusion gene. The double-TG mice expressed excessive levels of dimeric hCG, with 2000-fold elevated circulating LH/hCG bioactivity. These male mice were infertile, primarily due to inability to copulate, and they showed enhanced testicular androgen production despite clear down-regulation of LH/hCG receptors. Their intratesticular inhibin B was unaltered, but serum FSH was markedly reduced. Apparently the chronic hCG hyperstimulation led to focal Leydig cell proliferation/hypertrophy at 6 months of age, but failed to promote testicular tumors. Even though full spermatogenesis occurred in most of the seminiferous tubules, progressive tubule degeneration was apparent as the males grew older. The prostate and seminal vesicles were enlarged by distension of glandular lumina. Functional urethral obstruction was indicated by distension and sperm accumulation in distal vas deferens as well as by dilated urinary bladder and enlarged kidneys. The abnormal function of accessory sex glands and/or lower urinary tract as a consequence of the disturbed sex hormone balance or direct action of hCG may be the main cause of infertility in this model. The present study provides in vivo evidence that exposure of male mice to chronically elevated levels of hCG severely affects their urogenital tract function at multiple sites and causes infertility, but, unlike in LH/hCG overexpressing female mice, it is not tumorigenic.
Compromised Reproductive Function in Adult Female Mice Selectively Expressing Mutant ErbB-1 Tyrosine Kinase Receptors in Astroglia
Authors: Li Biao , Yang Zhihui , Hou Jingwen , McCracken April , Jennings M. Anita , Ma Mark Y. J.
Published: August 2003

The ErbB-1 tyrosine kinase receptor plays critical roles in regulating physiological functions. This receptor-mediated signaling in astroglia has been implicated in controlling female sexual development via activating neurons that release LH-releasing hormone (LHRH), the neuropeptide required for the secretion of LH. It remains unknown whether astroglial ErbB-1 receptors are necessary for maintaining normal adult reproductive function. Here we provide genetic evidence that astroglia-specific and time-controlled disruption of ErbB-1 receptor signaling by expressing mutant ErbB-1 receptors leads to compromised reproduction due to alteration in LHRH neuron-controlled secretion of LH in adult female mice. Therefore, astroglial ErbB-1 receptors are required for controlling LHRH neuronal function and thus maintaining adult reproduction, suggesting that compromised astroglial ErbB-1 signaling may also contribute to reproductive abnormalities in aging females.
Bcl-2 expression decreases cadherin-mediated cell-cell adhesion
Authors: Li Laiji , Backer Jody , Wong Annisa S. K. , Schwanke Erin L. , Stewart Brian G. , Pasdar Manijeh
Published: August 2003

Bcl-2, a member of the apoptosis-regulating family of proteins confers a survival advantage on cells by inhibiting apoptosis. Bcl-2 expression is estrogen-responsive and high in various tumors. Overexpression of Bcl-2 has been associated with the loss of contact inhibition, unregulated growth and foci formation in culture.

In this study, we have examined the effects of bcl-2 overexpression and expression on cell-cell adhesion in MCF-7 and MDCK epithelial cell lines respectively. Overexpression of Bcl-2 in estrogen receptor-positive MCF-7 mammary carcinoma cells led to decreased cell surface E-cadherin and the disruption of junctional complexes concurrent with intracellular redistribution of their components. Particularly noticeable, was the partial nuclear localization of the tight junction-associated protein ZO-1 which coincided with upregulation of ErbB2. The expression of this EGF co-receptor is regulated by the ZO-1-associated transcription factor ZONAB. Growth in estrogen-depleted media led to downregulation of Bcl-2 expression and upregulation and membrane localization of all junctional proteins. Similar disruption in junctions, accompanied by decreased transepithelial resistance, was observed when Bcl-2 was expressed in MDCK cells.

These results strongly suggest that Bcl-2 expression decreases the level of functional E-cadherin thereby interfering with junction formation. The inhibition of junction formation decreases cell-cell adhesion leading to the loss of contact inhibition, which, in vivo, can lead to unregulated growth and tumorigenesis.
Endothelial expression of the α6β4 integrin is negatively regulated during angiogenesis
Authors: Hiran Tejindervir S. , Mazurkiewicz Joseph E. , Kreienberg Paul , Rice Frank L. , LaFlamme Susan E.
Published: August 2003

Development and homeostasis of the vascular system requires integrin-facilitated cellular adhesion, migration, proliferation and survival. A specific role for the α6β4 integrin in the vasculature, however, has not been identified. Using immunohistochemistry, we observed α6β4 expression on the dermal microvasculature of human foreskin. Analysis of individual cells isolated from trypsin-disrupted foreskin tissue indicated that α6β4 was expressed by a subset of epithelial and endothelial cells, and not by smooth muscle cells. Expression of α6β4 was also analyzed during new vessel growth using explants of human saphenous vein cultured in fibrinogen gels. The results indicate that α6β4 is not expressed by outgrowing endothelial cells, and is downregulated by the original α6β4-positive endothelial cells of the explant. To determine whether α6β4 is expressed during angiogenesis in vivo, the expression of the β4 subunit was analyzed during the development of the mouse mystacial (whisker) pad. Immunohistochemical staining of the whisker pad indicates that β4 is expressed by the adult vasculature. To identify when and where β4 is turned on in the vasculature, we examined the whisker pads from the developing embryo (E19.5 pc), and from postnatal days zero (P0), three (P3) and seven (P7) pups. The expression of α6β4 was found to be turned on spatially and temporally from caudal to rostral regions and from the deep to superficial vasculature, correlating with the maturation of the whisker pad and its corresponding vasculature. Together, these findings suggest a potential role for α6β4 as a negative component of the angiogenic switch, whereas expression of α6β4 on the adult vasculature may indicate regions requiring additional adhesive mechanisms.
Barrier-to-autointegration factor plays crucial roles in cell cycle progression and nuclear organization inDrosophila
Authors: Furukawa Kazuhiro , Sugiyama Shin , Osouda Shinichi , Goto Hidemasa , Inagaki Masaki , Horigome Tsuneyoshi , Omata Saburo , McConnell Maeve , Fisher Paul A. , Nishida Yasuyoshi
Published: August 2003

Barrier-to-autointegration factor (BAF) is potentially a DNA-bridging protein, which directly associates with inner nuclear membrane proteins carrying LEM domains. These features point to a key role in regulation of nuclear function and organization, dependent on interactions between the nuclear envelope and chromatin. To understand the functions of BAF in vivo, Drosophila baf null mutants generated by P-element-mediated imprecise excision were analyzed. Homozygous null mutants showed a typical mitotic mutant phenotype: lethality at the larval-pupal transition with small brains and missing imaginal discs. Mitotic figures were decreased but a defined anaphase defect as reported for C. elegans RNAi experiments was not observed in these small brains, suggesting a different phase or phases of cell cycle arrest. Specific abnormalities in interphase nuclear structure were frequently found upon electron microscopic examination of baf null mutants, with partial clumping of chromatin and convolution of nuclear shape. At the light microscopic level, grossly aberrant nuclear lamina structure and B-type lamin distribution correlated well with the loss of detectable amounts of BAF protein from nuclei. Together, these data represent evidence of BAF's anticipated function in mediating interactions between the nuclear envelope and interphase chromosomes. We thus conclude that BAF plays essential roles in nuclear organization and that these BAF functions are required in both M phase and interphase of the cell cycle.
Suprabasal α6β4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFβ signalling
Authors: Owens David M. , Romero M. Rosario , Gardner Clare , Watt Fiona M.
Published: August 2003

Inappropriate α6β4 integrin expression correlates with a high risk of tumour progression in stratified squamous epithelia. Targeted expression of α6β4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the β4 cytoplasmic domain. Suprabasal α6β4 also perturbed transforming growth factor β (TGFβ) signalling as demonstrated by decreased nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes, suprabasal α6β4 relieved TGFβ-mediated growth inhibition and blocked nuclear translocation of activated Smad2/3. Responsiveness to TGFβ could be restored by inhibiting cadherin-mediated cell-cell adhesion or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting mitogen-activated protein kinase (MAPK) activity. These data suggest that suprabasal α6β4 promotes tumourigenesis by preventing TGFβ from suppressing clonal expansion of initiated cells in the epidermal basal layer.
Preparation and Magnetic Property of Sm2Fe17Nx Fine Powders Sorbed by Zinc Vapor
Authors: Noguchi Kenji , Nishimura Masashi , Machida Ken-ichi , Adachi Gin-ya
Published: August 2003

Finely ground powders of Sm2Fe17Nx were uniformly sorbed with the Zn vapor formed at 623-673 K in evacuated glass tubings, so that coercivity (Hcj) values and oxidation resistance of the resulting Zn/Sm2Fe17Nx powders were considerably improved to a practical use level as bonded magnet materials compared with those of the untreated powder.
X-ray Structural Characterization of Molybdate-tripeptide Complex, [Mo4O12(glycylglycylglycine)2]·9H2O
Authors: Yamase Toshihiro , Inoue Miyao , Naruke Haruo , Fukaya Keisuke
Published: August 2003

The first isolated polyoxomolybdate-tripeptide complex, [Mo4O12(glycylglycylglycine)2], is an infinite centrosymmetric complex of the Mo4O12 unit in which a pair of Mo atoms is singly bridged by a glycylglycylglycine carboxylate group as a bidentate ligand resulted in four edge-shared MoO6 octahedral linkage. [Mo4O12]n exhibits a corrugated sheet-belt structure of four co-planar Mo atoms linked by four triply-bridging O atoms with cis-configurated two terminal O atoms for each Mo atom.
Preparation and Characterization of Carbosilane Dendrimers Carrying Mesogens with Chiral Substituent
Authors: Terunuma Daiyo , Nishio Rei , Aoki Yoshio , Nohira Hiroyuki , Matsuoka Koji , Kuzuhara Hiroyoshi
Published: August 2003

A series of new carbosilane dendrimers carrying a mesogenic group, 5-((+)-2-fluorooctyloxy)-2-phenylpyrimidine derivative, were prepared successfully. Although the dendrimers did not show any clear Sc* phases, it was found that all the dendrimers prepared were operative as chiral dopants.
New Findings in Photochemistry of p-Nitrophenyl Azide in the Presence of an Amine: Generation and Trapping of Enamines
Authors: Murata Shigeru , Mori Yoko , Satoh Youji , Yoshidome Ryuichi , Tomioka Hideo
Published: August 2003

4,5-Dihydro-5-diethylamino-1-(p-nitrophenyl)-1,2,3-triazole (3) was obtained in the photolysis of p-nitrophenyl azide (1) in triethylamine (TEA), for which the structure was determined by X-ray crystallographic analysis. The formation of the triazoline 3 is reasonably explained in terms of trapping of N,N-diethylvinylamine (5) generated in situ with the starting azide 1. The reaction sequence involving a single electron transfer from TEA to the electronically excited azide is proposed for the formation of the enamine 5.
Effect of Acidity and Additives on the Potential Oscillations during the Reduction of IO3−
Authors: Li Zelin , Chen Ke , Zeng Yue , Cai Jiale , Zhou Shaomin
Published: August 2003

Unlike in alkaline solutions, totally different oscillatory behavior has been observed during the reduction of IO3− in an acidic solution, and the addition of some organic substances in the alkaline solution varies the current range where the potential oscillations occur to remarkably different extent, depending on the electric charge, length of chain, and concentration of the additive. Some explanation is given for these new observations.
Iridium-Catalyzed Regioselective Reaction of 1-Naphthols with Alkynes at the peri-Position
Authors: Satoh Tetsuya , Nishinaka Yuko , Miura Masahiro , Nomura Masakatsu
Published: August 2003

1-Naphthols efficiently couple with internal alkynes in the presence of an iridium catalyst to selectively afford the corresponding 8-substituted 1-naphthol derivatives.
Importance of Product Desorption in Enantioselective Hydrogenation of (E)-α-Phenylcinnamic Acid with a Cinchonidine-Modified Pd/TiO2 Catalyst: Effect of Additives
Authors: Nitta Yuriko
Published: August 2003

Addition of amines, especially benzylamine, to the reaction mixture of (E)-α-phenylcinnamic acid with a cinchonidine-modified palladium catalyst resulted in much enhanced activities and fairly increased enantioselectivities. The preferential acceleration of the selective reaction is attributable to the effective desorption, assisted by the added base, of the hydrogenated molecules from the modified sites.
New Pyridine-modified Macrocycle and Its Ability to Encapsulate Four Divalent Metal Ions [Nickel(II), Manganese(II), and Zinc(II)] into the Ring
Authors: Asato Eiji , Furutachi Hideki , Tamanaha Chikahiro , Matsudaira Hideo , Ohba Masaaki , Okawa Hisashi , Mikuriya Masahiro
Published: August 2003

A large phenol- and polyether chain-based macrocycle H2Lpy possessing four pyridylmethyl groups as pendant donors was prepared and its ability to encapsulate four divalent metal ions [Ni(II), Mn(II), and Zn(II)] was confirmed by IR and NMR spectroscopy and X-ray crystallography.
Photochromism of a Chiral Cyclohexane Having Two Diarylethene Chromophores. A Large Optical Rotation Change
Authors: Yamaguchi Tadatsugu , Nakazumi Hiroyuki , Uchida Kingo , Irie Masahiro
Published: August 2003

A chiral cyclohexane having two diarylethene chromophores was synthesized in an attempt to construct a molecule which shows a large optical rotation change by photoirradiation. Circular dichroism (CD) and optical rotation were found to change dramatically upon photoirradiation.
Effect of Molecular Weight on Polymer Monolayer Formation
Authors: Fan Fengqiu , Miyashita Tokuji
Published: August 2003

Monolayer behavior of poly(N-dodecylacrylamide) (PDDA) with various molecular weights on water surface was investigated. The surface - area isotherms changed drastically with the molecular weight. The monolayer becomes more stable and more condensed form with increasing molecular weight. We discuss various factors influencing the monolayer formation of polymeric compounds.
Element Effect Revisited. Variable and Inverse Element Effect in the SNAr Reaction of Picryl Halide and 2,4-Dimethoxyaniline
Authors: Sugiyama Naoki , Hayami Jun-ichi
Published: August 2003

Kinetic studies were made of the SNAr reaction of picryl halides (PicX, X = F, Cl) with 2,4-dimethoxyaniline in organic solvents. The element effect, kΨPicF/kΨPicCl, was found to be well-known large value at high [DMA], however, diminished continuously as the decrease of [DMA], and an inverse element effect was observed in CH3CN. Variable/inverse element effect has not been suggested for SNAr reaction and clearly shows that care must be exercised in using as the probe of reaction mechanism.
Highly Active, Thermally Robust V-based New Olefin Polymerization Catalyst System
Authors: Nakayama Yasushi , Bando Hideki , Sonobe Yoshiho , Suzuki Yasuhiko , Fujita Terunori
Published: August 2003

A new ethylene polymerization catalyst system containing a phenoxy-imine ligated V complex and a MgCl2-based compound has been discovered. Unlike ordinary V-based catalysts, the system exhibits higher activities at elevated temperatures, and the activity reached a very high value of 65100 kg-PE/mol-cat/h at 75 °C, representing the first example of a highly active, thermally robust V-based ethylene polymerization catalyst system.
Hydrothermal Synthesis of Fine MoS2 Crystals from Na2MoO4 and KSCN
Authors: Tian Ye , He Yu , Zhu Yongfa
Published: August 2003

A fine crystal MoS2 has been synthesized by hydrothermal method in a clean and efficient system consisting of Na2MoO4 and KSCN in a short time (24 h). The product is characterized by XRD and TEM, and the ED pattern reveals a hexagonal crystal. The mechanism of this reaction is also put forward. Thus this method provides us a new routine to synthesize other transition metal sulfides.
Red Luminescent Squarylium Dyes for Noncovalent HSA Labeling
Authors: Nakazumi Hiroyuki , Colyer Chista L , Kaihara Koji , Yagi Shigeyuki , Hyodo Yutaka
Published: August 2003

Asymmetric squarylium fluorophores with 618–680 nm emissions exhibit significantly enhanced fluorescence and increased quantum yield (maximum 97%) by the formation of 1:1 dye–protein complexes when bound as non-covalent labeling probes to human serum albumin (HSA).
Reversible Change in Optical Rotation by Phtochromism of Diarylethenes in the Stretched DNA–Quaternary Ammonium Ion Complex Films
Authors: Saito Masako , Yokoyama Yayoi , Yokoyama Yasushi
Published: August 2003

Transparent stretched films of DNA–dimethyldioctadecylammonium ion complex incorporating a photochromic diarylethene exhibited large change in optical rotation by its photochromic reactions. As the stretched films at the photostationary state of UV-irradiation showed the dichroism, it was suggested that the diarylethene molecules are partly intercalated between the DNA base pairs.