bluuebunny/crossref_metadata_2025_split huggingface dataset:
A CONTINUOUS-TIME REEXAMINATION OF DOLLAR-COST AVERAGING
Authors: MILEVSKY MOSHE A. , POSNER STEVEN E. 
Published: March 2003

The widespread practice of dollar-cost averaging (DCA) amongst the investing public, has puzzled most financial economists, ever since Constantinides [2] demonstrated the dynamic inefficiency of this strategy under very general conditions. This enduring phenomena has forced researchers, such as Statman [12], to suggest behavioral explanations for DCA's popularity, predicated on the prospect theory of Kahneman and Tversky [4]. In this paper we reexamine the payoff structure of DCA via continuous-time financial mathematics and then ask the question: Is it possible to reconcile the theory and practice of dollar-cost averaging? To answer this question, we take a slightly different approach to the issue by using the tools of stochastic calculus and Brownian bridges. We demonstrate that engaging in a dollar-cost averaging strategy is akin to purchasing a zero strike arithmetic Asian option on the underlying security. In other words, people who engage in dollar-cost averaging are implicitly purchasing a path-dependent contingent claim. We then prove that the expected return from this exotic option — i.e. the DCA strategy — conditional on knowing the final value of the security will uniformly exceed the return from the underlying security for all sufficiently large volatilities. This leads us to argue that investors may be dollar-cost averaging because they have "target prices" for the underlying asset price. The strategy of dollar-cost averaging would then exceed the returns from lump-sum investing, based on their subjective conditional expectation. In fact, the more volatile the underlying security, the greater is the benefit to dollar-cost averaging — conditional on knowing the final value — which is consistent with common practice.
THE INTERRUPTION OF MYTH: A NANCIAN READING OF BLANCHOT AND AL-BAYATI
Authors: Salama Mohammad Ramadan 
Published: March 2003

AbstractJean-Luc Nancy's provocative second chapter of The Inoperative Community, "Myth Interrupted," sets to redefine the relationship between myth and literature. This paper puts Nancy's new perspective to test through juxtaposing Abd al-Wahhab al-Bayati's myth of Orpheus with Maurice Blanchot's. The assumption is that when literature stages myth and presents it from various perspectives, it does so not to invoke or allegorize its content through the letter, but rather to interrupt it. This new discovery of the "untraceability" of myth leaves us with a different perspective of literature as that language which cuts across myth and exposes its limit and as a language that inhabits myth only to interrupt it. Blanchot's interest in Orpheus, as it is articulated in his novel/story Thomas l'obscur (the 1950 New Version) and in his chapter on "Orpheus's Gaze" in The Space of Literature, and al-Bayati's reference to Orpheus in his poetic collections He Who Comes and Does Not Come, Death in Life, and Writing on the Mud thematize this playful staging of the myth of Orpheus. Both seem to follow a different path with the same myth. Blanchot disregards the ending of the Orpheus story, and al-Bayati disregards the gaze. However, it is not just selection, but modification that is at work here: both shape their chosen materials in conformity to a specific need. The logic that binds the two writers together in relation to myth and literature expresses itself not only in the choice of the same myth, but they also have in common the shared debt to this classical material and more importantly in their (re)definition of this material. The point of departure between the two of them in their treatment (reinterpretation) of Orpheus is that Blanchot is looking at the effect of death on writing, while al-Bayati is exploring the effect of writing on death.
Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α-chain
Authors: Odeberg Jenny , Plachter Bodo , Brandén Lars , Söderberg-Nauclér Cecilia 
Published: March 2003

AbstractHuman cytomegalovirus (HCMV) has developed multiple strategies to escape immune recognition. Here, we demonstrate that HCMV down-regulates HLA-DR expression in infected interferon γ (IFN-γ)–stimulated fibroblasts at 1 day after infection. Decreased HLA-DR expression was not observed on cells infected with an HCMV strain lacking the pp65 gene (RVAD65), but was observed on cells transfected with the pp65 gene. HLA-DR expression accumulated in vacuoles near the nucleus in HCMV-infected, but not in uninfected or RVAD65-infected cells. In addition, the HLA-DR α-chain, but not the β-chain or HLA-DM, was degraded in HCMV-infected but not in RVAD65-infected cells. Thus, the HCMV protein pp65 mediates decreased expression of HLA-DR, by mediating an accumulation of HLA class II molecules in lysosomes that results in degradation of the HLA-DR α-chain.
A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease
Authors: Orchard Jenny , Garand Richard , Davis Zadie , Babbage Gavin , Sahota Surinder , Matutes Estella , Catovsky Daniel , Thomas Peter W. , Avet-Loiseau Hervé , Oscier David 
Published: March 2003

AbstractWe analyzed lymphocyte morphology, histology, immunophenotype, immunoglobulin heavy chain (IgVH) gene mutations, and clinical course in 80 unselected patients presenting with circulating t(11;14) lymphocytes. Of the 80 patients, 43 had peripheral lymphadenopathy (nodal group), and histology confirmed mantle cell lymphoma (MCL) in all. There were 37 patients with no lymphadenopathy (nonnodal group); 13 of 37 had histology, all showing MCL. IgVH genes were unmutated in 28 (90%) of 31 nodal and 15 (44%) of 34 nonnodal cases (P = .0001); CD38 was positive in 32 (94%) of 34 nodal and 16 (48%) of 33 nonnodal cases (P &lt; .001); 41 (95%) of 43 nodal patients required immediate treatment compared with 18 (49%) of 37 nonnodal patients who had indolent disease (P &lt; .0001). Median survival (95% confidence interval) was 30 months (10-50) in the nodal group and 79 months (22-136) in the nonnodal group (P = .005). Mutation status did not statistically affect survival, but of 6 long-term survivors (&gt; 90 months) all were nonnodal and 5 of 5 had mutated IgVH genes. Lymphocyte morphology was heterogeneous in both groups: typical MCL in 56 cases (34 nodal, 22 nonnodal), blastoid MCL in 8 cases (3 nodal, 5 nonnodal), and small-cell MCL in 16 cases (6 nodal, 10 nonnodal, P = .12). Matutes immunophenotyping score was 1 in 65 cases and 2 in 15 (8 nodal, 7 nonnodal). We find no evidence against a diagnosis of MCL in the nonnodal group and suggest that mutated IgVH genes may help identify patients with indolent disease.
Induction of apoptosis in IL-3–dependent hematopoietic cell lines by guanine nucleotide depletion
Authors: Gu Jing Jin , Gathy Karen , Santiago Lalaine , Chen Eric , Huang Min , Graves Lee M. , Mitchell Beverly S. 
Published: March 2003

AbstractInosine 5′-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch point of purine nucleotide biosynthesis, leading to the generation of guanine nucleotides. Inhibition of IMPDH results in the depletion of guanine nucleotides, prevents cell growth by G1 arrest, and induces cell differentiation in a cell-type–specific manner. The molecular and sensing mechanisms underlying these effects are not clear. We have examined the induction of apoptosis by mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 (IL-3)–dependent murine hematopoietic cell lines. MPA treatment, at clinically relevant doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 pre-B cells in the ongoing presence of IL-3. Apoptosis was completely prevented by the addition of guanosine at time points up to 12 hours, after which caspase 3 activity increased and apoptosis was not reversible. MPA treatment caused marked down-regulation of the MAP kinase kinase/extracellular regulatory kinase (MEK/Erk) pathway at 3 hours while simultaneously increasing the phosphorylation of c-Jun kinase. In addition, MPA strongly down-regulated the mammalian target of rapamcyin (mTOR) pathway, as indicated by the decreased phosphorylation of p70 S6 kinase and of 4EBP1. Inhibition of either the mitogen-activated protein kinase (MAPK) or the mTOR pathway alone by standard pharmacologic inhibitors did not induce apoptosis in IL-3–dependent cells, whereas inhibition of both pathways simulated the effects of MPA treatment. These results indicate that IMPDH inhibitors may be effective in modulating signal transduction pathways in hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for hematologic malignancies.
Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis
Authors: Nutku Esra , Aizawa Hideyuki , Hudson Sherry A. , Bochner Bruce S. 
Published: March 2003

AbstractSialic acid binding immunoglobulin-like lectin 8 (Siglec-8), which exists in 2 isoforms including one possessing cytoplasmic tyrosine motifs, is expressed only on human eosinophils, basophils, and mast cells. Until now, its function was unknown. Here we define a novel function of Siglec-8 on eosinophils. Siglec-8 cross-linking with antibodies rapidly generated caspase-3–like activity and reduced eosinophil viability through induction of apoptosis. The pancaspase inhibitor benzyloxycarbonyl (Cbz)–Val-Ala-Asp-(Ome)-fluoromethyl ketone (zVAD-FMK) completely blocked this response, implicating caspases in Siglec-8 cross-linking–induced apoptosis. Eosinophil survival-promoting cytokines such as interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) failed to block apoptosis and instead enhanced the sensitivity of eosinophils to undergo apoptosis in response to Siglec-8 antibody. Siglec-8 activation may provide a useful therapeutic approach to reduce numbers of eosinophils (and perhaps basophils and mast cells) in disease states where these cells are important.
Generation of low-toxicity interleukin-2 fusion proteins devoid of vasopermeability activity
Authors: Hu Peisheng , Mizokami Myra , Ruoff Gina , Khawli Leslie A. , Epstein Alan L. 
Published: March 2003

AbstractBecause of its key role in immunity, interleukin-2 (IL-2) has been studied extensively for the adoptive immunotherapy of cancer. Although systemic administration of IL-2 has been shown to stimulate antitumor responses in vivo, its efficacy in the clinic has been limited by the development of serious side effects, including the induction of vascular leak syndrome. Previously, we have identified a small peptide fragment of IL-2 that was found to contain the entire vasopermeability activity of the cytokine. The identification of the location of this potentially undesirable property of IL-2 enabled us to focus on the generation of mutant derivatives that might be lacking vasopermeability activity but that retain cytokine functionality. In addition to this discovery, our laboratory has constructed monoclonal antibody/IL-2 fusion proteins that can target this potent cytokine directly to tumor for the immunotherapy of both solid and lymphoid malignancies. Using this fusion protein technology, we have constructed a series of point mutations in the newly identified vasopermeability region of IL-2 for the purpose of deleting this activity. Fusion proteins showing reduced or deleted vasopermeability activity were then tested for their cytokine potency by several methods, including their binding to IL-2 receptors, T-cell proliferation assays, the induction of secondary cytokines, dose-escalating toxicity, and finally their ability to treat established solid tumors in syngeneic immunocompetent mice. The results of these studies clearly show that the vasopermeability activity of IL-2 can be substantially deleted by single point mutations such as Arg38Trp without grossly affecting the immune function of the cytokine.
CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities
Authors: Yanagawa Yoshiki , Onoé Kazunori 
Published: March 2003

AbstractAlthough chemokines are well known to function in chemotaxis, additional roles for these molecules in the immune system are not well understood. Dendritic cells (DCs) developmentally regulate the expression of chemokine receptors to facilitate their migration from the peripheral tissues to regional lymph nodes. Expressions of CCR1 and CCR5 on immature DCs are down-regulated on maturation, whereas CCR7 is selectively expressed on mature DCs. In the present study, we examined the effects of CCL19 and CCL21, 2 CCR7 ligands, on endocytosis of fluorescein isothiocyanate (FITC)–dextran by murine DCs. Both CCL19 and CCL21 markedly induced rapid uptake of FITC-dextran by mature DCs but not immature DCs. In contrast, CCL3, a ligand of CCR1 and CCR5, induced rapid uptake of FITC-dextran by immature DCs but not mature DCs. CCL19-induced endocytosis could be completely blocked by Clostridium difficile toxin B, which inhibits the Rho guanosine triphosphatase proteins, Rho, Rac, and Cdc42. This process was not abrogated by Y-27632, a specific inhibitor of Rho-associated kinase. In addition, CCL19 rapidly enhanced Cdc42 and Rac activity in mature DCs. These findings demonstrate that certain chemokines induce rapid endocytosis in each relevant DC population. It is suggested that CCR7 ligands activate Cdc42 and Rac, thereby inducing the endocytosis in mature DCs.
Platelet factor 4 enhances generation of activated protein C in vitro and in vivo
Authors: Slungaard Arne , Fernandez Jose A. , Griffin John H. , Key Nigel S. , Long Janel R. , Piegors Donald J. , Lentz Steven R. 
Published: March 2003

AbstractPlatelet factor 4 (PF4), an abundant platelet α-granule protein, accelerates in vitro generation of activated protein C (APC) by soluble thrombin/thrombomodulin (TM) complexes up to 25-fold. To test the hypothesis that PF4 similarly stimulates endothelium-associated TM, we assessed the influence of human PF4 on thrombin-dependent APC generation by cultured endothelial monolayers. APC generated in the presence of 1 to 100 μg PF4 was up to 5-fold higher than baseline for human umbilical vein endothelial cells, 10-fold higher for microvascular endothelial cells, and unaltered for blood outgrowth endothelial cells. In an in vivo model, cynomolgus monkeys (n = 6, each serving as its own control) were infused with either PF4 (7.5 mg/kg) or vehicle buffer, then with human thrombin (1.0 μg/kg/min) for 10 minutes. Circulating APC levels (baseline 3 ng/mL) peaked at 10 minutes, when PF4-treated and vehicle-treated animals had APC levels of 67 ± 5 ng/mL and 39 ± 2 ng/mL, respectively (P &lt; .001). The activated partial thromboplastin time (APTT; baseline, 28 seconds) increased maximally by 27 ± 6 seconds in PF4-treated animals and by 9 ± 1 seconds in control animals at 30 minutes (P &lt; .001). PF4-dependent increases in circulating APC and APTT persisted more than 2-fold greater than that of control's from 10 through 120 minutes (P ≤ .04). All APTT prolongations were essentially reversed by monoclonal antibody C3, which blocks APC activity. Thus, physiologically relevant concentrations of PF4 stimulate thrombin-dependent APC generation both in vitro by cultured endothelial cells and in vivo in a primate thrombin infusion model. These findings suggest that PF4 may play a previously unsuspected physiologic role in enhancing APC generation. (Blood. 2003;102:146-151)
Highly effective treatment of acquired immunodeficiency syndrome–related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology
Authors: Little Richard F. , Pittaluga Stefania , Grant Nicole , Steinberg Seth M. , Kavlick Mark F. , Mitsuya Hiroaki , Franchini Genoveffa , Gutierrez Martin , Raffeld Mark , Jaffe Elaine S. , Shearer Gene , Yarchoan Robert , Wilson Wyndham H. 
Published: March 2003

AbstractThe outcome of acquired immunodeficiency syndrome–related lymphomas (ARLs) has improved since the era of highly active antiretroviral therapy, but median survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral therapy in 39 newly diagnosed ARLs and examined protein expression profiles associated with drug resistance and histogenesis, patient immunity, and HIV dynamics and mutations. The expression profiles from a subset of ARL cases were also compared with a matched group of similarly treated HIV-negative cases. Complete remission was achieved in 74% of patients, and at 53 months median follow-up, disease-free and overall survival are 92% and 60%, respectively. Following reinstitution of antiretroviral therapy after chemotherapy, the CD4+ cells recovered by 12 months and the viral loads decreased below baseline by 3 months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and higher CD10 expression, consistent with a germinal center origin and good prognosis, but were more likely to be highly proliferative and to express p53, adverse features with standard chemotherapy. Unlike HIV-negative cases, p53 overexpression was not associated with a poor outcome, suggesting different pathogenesis. High tumor proliferation did not correlate with poor outcome and may partially explain the high activity of dose-adjusted EPOCH. The results suggest that the improved immune function associated with highly active antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from lymphomas of post–germinal center origin, which have a poor prognosis. These results suggest that tumor pathogenesis is responsible for the improved outcome of ARLs in the era of HAART.
Profound difference in pharmacokinetics between morin and its isomer quercetin in rats
Authors: Hou Y C , Chao P D L , Ho H J , Wen C C , Hsiu S L 
Published: March 2003

Abstract
Morin and quercetin are isomeric antioxidant flavonols widely distributed in plant foods and herbs. The pharmacokinetics of both flavonols at two doses were investigated and compared in rats. Parent forms and their glucuronides and sulfates in serum were determined by HPLC before and after enzymatic hydrolysis, respectively. After oral dosing of morin, both the parent form, morin, and its glucuronides and sulfates were present in the bloodstream. The conjugated metabolites predominated at the dose of 25 mg kg−1, whereas the parent form was predominant at the dose of 50 mg kg−1. Moreover, the AUC of morin parent form increased by a factor of 37 when the dose doubled, indicating that morin showed nonlinear pharmacokinetics. On the other hand, quercetin presented only as glucuronides and sulfates in the blood, indicating negligible bioavailability of quercetin, and the metabolites showed linear pharmacokinetics at the two doses studied. When considering the total AUC of parent form with conjugated metabolites, the extent of absorption of morin was 3 fold that of quercetin at the dose of 50 mg kg−1. The results indicated that the difference in hydroxylation pattern on B-ring of flavonol markedly affected their fates in rats.
Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu-To, a traditional Chinese medicine, to rats
Authors: Yasuda Takaaki , Takasawa Akie , Nakazawa Takahiro , Ueda Joji , Ohsawa Keisuke 
Published: March 2003

Abstract
Shimotsu-To, which consists of four herbal extracts, has been used clinically for improving abnormal blood coagulation, fibrinolysis, atherosclerosis and chronic inflammation in Japan and China. We have investigated the pharmacological relationship between the effects and chemical components of Shimotsu-To after oral administration to rats. The urinary constituents were separated and identified by three dimensional (3D-) HPLC equipped with a photodiode array detector as a new tool and the chemical structures were determined by spectroscopic methods to be trans-ferulic acid-3-O-sulfate (1), vanillic acid (2), m-hydroxyphenylpropionic acid (3), trans-ferulic acid (4) and cis-ferulic acid (5). Of these compounds, 2–5 strongly inhibited platelet aggregation induced by ADP and arachidonic acid. Compound 1, the sulfate conjugate of 4, did not show any inhibitory effect, which suggested that the inhibitory effect on platelet aggregation was inactivated by sulfate conjugation. These results indicated that compounds 2–5 partly contributed to the anti-Oketsu effect of Shimotsu-To through the inhibition of platelet aggregation.
Targeted immunotherapy of cancer: development of antibody-induced cellular immunity
Authors: Lu Yingjuan , Low Philip S 
Published: March 2003

Abstract
Although immunotherapy of cancer encompasses a large variety of distinct protocols, virtually all therapeutic strategies require the enabling/training of the immune system to distinguish tumour tissue from healthy tissue. In the case of antibody-based therapies, specificity obviously arises from the selectivity of the antibodies for tumour antigens, and tumour cell death derives from either direct cytotoxicity of the antibody or antibody-dependent cellular cytotoxicity. However, even when both of the above killing mechanisms are simultaneously active, we suggest that antibody-based immunotherapies may fall far short of their full potential. In this editorial, we first summarize the mechanisms by which current antibody-based therapies mediate cancer cell removal, and then propose two strategies by which this class of immunotherapies might be further improved. These suggested improvements involve the decoration of tumour cell surfaces with foreign haptens against which an endogenous humoral immune response can be mounted and the recruitment of the cellular arm of the immune system in an antibody-dependent process.
Adherens junctions and tight junctions are regulated via different pathways by progastrin in epithelial cells
Authors: Hollande Frédéric , Lee Debra J. , Choquet Armelle , Roche Serge , Baldwin Graham S. 
Published: March 2003

Adhesion between neighbouring epithelial cells is a crucial and tightly controlled process. In the gastrointestinal tract, the integrity of cell-cell contacts is essential for the regulation of electrolyte absorption and for the prevention of tumour metastasis. We recently showed that migration of the gastric epithelial cell line IMGE-5 is stimulated by the nonamidated form of the hormone gastrin17. Here, we examine the effect on cell-cell adhesion of the prohormone progastrin, the concentration of which is increased in the plasma of patients with colorectal carcinoma.Progastrin induced the dissociation of both tight junction (TJ) and adherens junction (AJ) complexes in IMGE-5 cells. In progastrin-secreting DLD-1 human colorectal carcinoma cells, expression of an antisense gastrin construct restored membrane localisation of zonula occludens-1 (ZO-1),occludin, β-catenin and E-cadherin. This restoration was reversed by treatment with exogenous progastrin. Endogenous or exogenous progastrin also increased the paracellular flux of mannitol, and induced cell migration of several gastrointestinal cell lines. In addition, progastrin enhanced Src tyrosine kinase activity and induced a spatial delocalisation of protein kinase Cα. Using dominant-negative mutants and pharmacological inhibitors, we showed that the stimulation of Src kinase activity was essential for the regulation of TJs. By contrast, the dissociation of AJs involved phosphatidylinositol 3-kinase, partly through the formation of a complex with protein kinase Cα. We conclude that separate pathways mediate the disruption of AJs and TJs by progastrin. Either pathway may contribute to the co-carcinogenic role of this prohormone in colorectal carcinoma.