bluuebunny/crossref_metadata_2025 huggingface dataset:
Ribosomal Protein L19 Is a Prognostic Marker for Human Prostate Cancer
Authors: Bee Alix , Ke Youqianq , Forootan Shiva , Lin Ke , Beesley Carol , Forrest Sharon E. , Foster Christopher S.
Published: April 2006

Microquantity differential display analysis of gene expression profiles between benign (PNT2) and malignant (PC3M) human prostate cell lines identified the gene encoding ribosomal protein L19 (RPL19) to be overexpressed in the malignant cells. Northern blot hybridization analysis done on a wide range of human cell lines and tissues confirmed the level of RPL19 mRNA to be 5-fold higher in malignant cell lines and 8-fold higher in malignant tissues, when compared with their benign counterparts. Analysis of RPL19 mRNA expression by in situ hybridization revealed a significant increase of RPL19 expression in a substantial number of prostate cancers. All of the eight normal prostatic tissues were unstained (100%). Of 32 benign prostatic hyperplasia (BPH) tissues, 15 (46.9%) were unstained, 9 (28.1%) stained weakly, and 8 (25%) stained moderately. Among 87 carcinomas, only 7 (8.1%) were unstained, whereas 22 (25.2%) stained weakly, 21 (24.1%) stained moderately, and 37 (42.61%) stained strongly. The intensity of staining of the malignant specimens was significantly higher than that of normal and BPH specimens (χ2: n = 127, P < 0.001). Gleason scores of the carcinomas correlated with RPL19 expression (χ2: n = 87, P < 0.001). Kaplan-Meier survival analysis confirmed increased RPL19 expression to be highly predictive of shorter patient survival (P < 0.05), revealing RPL19 to be a sensitive predictor of prostate cancer progression. Expression of this protein could be a valuable marker in prostate cancer diagnosis and patient management.
Cytokine-Based Therapy and Biochemotherapy for Advanced Melanoma
Authors: Atkins Michael B.
Published: April 2006

A variety of immunotherapeutic approaches have shown activity in patients with metastatic melanoma with the best results being observed with interleukin 2 (IL-2). Follow-up data through 2004 confirm the durability of responses produced by the Food and Drug Administration–approved high-dose IL-2 regimen in this patient population. Efforts to develop more tolerable and/or effective IL-2–based treatment regimens by either prolonged administration of lower doses or the combination of IL-2 with other cytokines, monoclonal antibodies, or vaccines have yet to produce results superior to those seen with high-dose IL-2 alone. Recent investigations have suggested that, in some patients, IL-2 may expand regulatory T-cell populations leading to immune tolerance rather than antitumor immunity. Efforts to shift this balance in favor of immune rejection by reducing the confounding effects of regulatory T cells on IL-2 therapy or the use of novel and potentially more purely immunostimulatory cytokines are ongoing. Despite promising phase 2 data, phase 3 studies have failed to show meaningful clinical benefit for the combination of cytokines with cytotoxic chemotherapy, so-called “biochemotherapy.” Nonetheless, recent investigations with biochemotherapy followed by maintenance immunotherapy suggest that biochemotherapy may still have a role as a “bridge to immunotherapy” in some patients with rapidly progressive disease. Given the low number of patients achieving durable benefit with cytokine-based immunotherapy, considerable recent effort has focused on identifying predictors of therapeutic response. Investigations suggest that immune responsiveness may be predetermined by a tumor microenvironment conducive to immune recognition and the host propensity to develop autoimmunity. Efforts to understand and further define pretreatment predictors of response through the use of gene expression and proteomic techniques are ongoing and raise the potential for eventually limiting cytokine-based immunotherapy to those most likely to benefit.
Pathology of Melanoma
Authors: Elder David E.
Published: April 2006

The purposes of pathologic examination of a lesion suspected of being a malignant melanoma are to provide an accurate diagnosis of melanoma (or not), and to provide prognostic information useful in the clinical management of the patient. In the near future, pathologic attributes will also likely be used to predict responses to therapy, as a guide to the selection of specific therapeutic agents such as “small molecule” inhibitors of signaling pathways.
Use of an Orthotopic Xenograft Model for Assessing the Effect of Epidermal Growth Factor Receptor Amplification on Glioblastoma Radiation Response
Authors: Sarkaria Jann N. , Carlson Brett L. , Schroeder Mark A. , Grogan Patrick , Brown Paul D. , Giannini Caterina , Ballman Karla V. , Kitange Gaspar J. , Guha Abjahit , Pandita Ajay , James C. David
Published: April 2006

Purpose: The influence of epidermal growth factor receptor (EGFR) amplification on glioblastoma patient prognosis following definitive radiotherapy has been extensively investigated in clinical studies, and yet the relationship between EGFR status and radiation response remains unclear. The intent of the current study was to address this relationship using several EGFR-amplified glioblastoma xenografts in an orthotopic athymic mouse model.

Experimental Design: We examined the effect of radiation on the survival of nude mice with intracranial xenografts derived from 13 distinct patient tumors, 7 of which have amplified EGFR. Mice with established intracranial tumors were randomized to sham treatment or 12-Gy radiation in six fractions delivered over 12 days.

Results: For six of the xenografts, radiation of mice with intracranial tumor significantly extended survival, and four of these xenografts had EGFR amplification. For seven other xenografts, radiation treatment did not significantly extend survival, and three of these, including GBM12, had EGFR amplification. Similar to EGFR, the tumor genetic status of p53 or PTEN did not show preferential association with radiation-sensitive or radiation-resistant xenografts whereas hyperphosphorylation of Akt on Ser473 was associated with increased radioresistance. To specifically investigate whether inhibition of EGFR kinase activity influences radiation response, we examined combined radiation and EGFR inhibitor treatment in mice with intracranial GBM12. The combination of oral erlotinib administered concurrently with radiation resulted only in additive survival benefit relative to either agent alone.

Conclusions: Our results indicate that EGFR amplification, as a biomarker, is not singularly predictive of glioblastoma response to radiation therapy, nor does the inhibition of EGFR enhance the intrinsic radiation responsiveness of glioblastoma tumors. However, efficacious EGFR inhibitor and radiation monotherapy regimens can be used in combination to achieve additive antitumor effect against a subset of glioblastoma.
Strategies for the Development of More Effective Adjuvant Therapy of Melanoma: Current and Future Explorations of Antibodies, Cytokines, Vaccines, and Combinations
Authors: Kirkwood John M. , Moschos Stergios , Wang Wenjun
Published: April 2006

Adjuvant trials have evaluated the influence of multiple agents on relapse and mortality for patients with intermediate-risk (stage IIA, American Joint Committee on Cancer staging manual, 6th ed.), high-risk (stage IIB-III), or very high-risk (stage IIIB-IV) operable melanoma. A 25% to 33% reduction of relative relapse risk with high-dose IFN-α2b therapy has been documented in stage groups overall, with survival prolongation in two of these trials. In contrast, no large cooperative group trial has ever shown a significant prolongation of survival for inoperable advanced stage IV melanoma. The basis for the failure of therapies in advanced disease may lie in differences in the immune function of patients with active metastatic stage IV disease. These observations argue for the exploration of promising new therapies in adjuvant settings. Past adjuvant studies have targeted stage IIB-III patients, focusing less on the more advanced but resectable stage IIIB and IV (M1a-b) disease groups. Current chemobiotherapy (S0008) and granulocyte-macrophage colony-stimulating factor plus peptide vaccination (E4697) trials have now evaluated the higher-risk disease groups where trials may soon be expected to yield results. Predictive markers that would allow us to focus treatment on those patients who are most likely to respond would accelerate our development of adjuvant therapy for melanoma. We have recently developed a neoadjuvant approach to high-dose IFN in which the molecular and immunologic effects of IFN have been correlated with clinical antitumor effects of this therapy. In addition, the Hellenic Oncology group has shown that the benefit of high-dose IFN is closely correlated with serologic and clinical manifestations of autoimmunity. These new insights will allow us to develop more efficient approaches to adjuvant therapy of melanoma, focusing on autoimmunity and antitumor immunity with new immunomodulators, such as anti-CTLA4 antibodies and vaccination.
Molecular Targets in Melanoma from Angiogenesis to Apoptosis
Authors: Sosman Jeffrey A. , Puzanov Igor
Published: April 2006

Angiogenesis is a hallmark of melanoma progression. Antiangiogenic agents have been infrequently tested in patients with advanced melanoma. Experience with most other cancers suggests that single-agent application of angiogenic inhibitors is unlikely to have substantial clinical antitumor activity in melanoma. It is more likely that combinations of antiangiogenic agents with either chemotherapy or other targeted therapy will be needed to produce significant clinical benefit. In melanoma, numerous cellular pathways important to cell proliferation, apoptosis, or metastases have recently been shown to be activated. Activation occurs through specific mutations (B-RAF, N-RAS, and PTEN) or changes in expression levels of various proteins (PTEN, BCL-2, NF-κB, CDK2, and cyclin D1). Agents that block these pathways are rapidly entering the clinical setting, including RAF inhibitors (sorafenib), mitogen-activated protein kinase inhibitors (PD0325901), mammalian target of rapamycin inhibitors (CCI-779), and farnesyl transferase inhibitors (R115777) that inhibit N-RAS and proteasome inhibitors (PS-341) that block activation of nuclear factor-κB (NF-κB). It will be a challenge to evaluate these agents alone, in combination with each other, or with chemotherapy in patients with melanoma. Trials with large populations of biologically ill-defined tumors run the risk of missing clinical antitumor activity that is important for a particular yet-to-be-defined subset of patients. To rationally and optimally develop these targeted agents, it will be critical to adequately test for the presence of the presumed cellular target in tumor specimens and the effect of therapy on the proposed target (biological response). Investigators in this field will need to carefully plan these trials so that at the end of the day, we learn from both the failures and successes of targeted therapy.
Progress and Prospects on Melanoma: The Way Forward for Early Detection and Reduced Mortality
Authors: Weinstock Martin A.
Published: April 2006

The public health problem of melanoma is difficult. Recent decades have seen substantial efforts directed at primary prevention, yet the incidence of melanoma continues to increase. Substantial efforts have been devoted to improving treatment, yet melanoma retains a poor prognosis if simple surgical excision is not curative. Early detection has made remarkable progress, however. Five-year relative survival has increased from approximately 80% in 1975 to greater than 90% in 1996. Even so, almost 8,000 Americans are projected to succumb to melanoma in 2005. Because most of these fatal melanomas are visible on the skin surface at a curable phase in their evolution, more can and must be done. To improve the early detection practices of clinicians, we have developed an eight-step Basic Skin Cancer Triage algorithm, which forms the core of a curriculum that we have shown can result in improved skills, attitudes, and practices. We are now in the process of attempting to test a Web-based version of that curriculum in a randomized trial. Skin self-examination also has tremendous potential for contributing to early detection of melanoma. We have tested an intervention to encourage thorough skin self-examination in a randomized trial and found it effective in increasing the performance of this procedure, on increase that is sustained for at least a year, while resulting in only short-term increases in surgical procedures on the skin. Early detection has not yet reached its full potential effect on the public health problem of melanoma and is poised to further reduce melanoma mortality.
Development and Therapeutic Options for the Treatment of Raloxifene-Stimulated Breast Cancer in Athymic Mice
Authors: O'Regan Ruth M. , Osipo Clodia , Ariazi Eric , Lee Eun Sook , Meeke Kathleen , Morris Caroline , Bertucci Anne , Sarker Mohammad A.B. , Grigg Ronald , Jordan V. Craig
Published: April 2006

Purpose: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor α (ERα) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women.

Experimental Design: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance.

Results: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17β-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERα protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERα activity of MCF-7RALT tumors. The coactivator of ERα, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERα in cells derived from the MCF-7RALT tumors.

Conclusions: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERα could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERα activity.
Early-Stage Melanoma: Staging Criteria and Prognostic Modeling
Authors: Ross Merrick I.
Published: April 2006

Accurate risk assessment is central to the process of making rational surgical and systemic treatment recommendations for melanoma patients and in establishing appropriate clinical trial stratification criteria. The current American Joint Commission on Cancer melanoma staging system incorporated relevant prognostic variables to provide a framework for the estimation of risk for recurrence; however, significant prognostic heterogeneity exists within the stage groupings. In the stage I/II group, survival rates range from 40% to 95% as defined by the combination of tumor thickness and ulceration. The use of novel prognostic factors, such as mitotic rate, sentinel node biopsy, and prognostic modeling using a variety of factors, can minimize this prognostic heterogeneity and provide a more accurate and individualized prognostic profile. Recent modifications in the stage III criteria include the number of positive nodes, whether the nodal disease is microscopic or clinically apparent, and the presence of an ulcerated primary. Through these factors, survival estimates can be provided, but like the stage I/II group, wide ranges in prognosis exist. The complexion of the stage III population is in evolution as a result of increasing numbers of patients being diagnosed as having microscopic sentinel node disease. Contemporary efforts are focused on defining the prognosis and natural history of this group. Through prognostic modeling using the number of nodes involved, ulceration status, and a measure of disease burden—disease in the sentinel node—relatively homogeneous subgroups can be identified. Long-term follow-up of patients staged with PCR molecular techniques on sentinel nodes shows conflicting value in assessing prognosis and therefore cannot be routinely used outside a clinical trial. The combination of genomic profiling using microarray analyses and the development of targeted therapy holds the future promise of individualizing prognosis and therapy.
Allogeneic MHC Gene Transfer Enhances Antitumor Activity of Allogeneic Hematopoietic Stem Cell Transplantation without Exacerbating Graft-versus-Host Disease
Authors: Ohashi Masaki , Kobayashi Akihiko , Hara Hidehiko , Miura Yoshiaki , Yoshida Kimiko , Kushida Miwa , Ikarashi Yoshinori , Mandai Masaki , Kitajima Masaki , Yoshida Teruhiko , Aoki Kazunori
Published: April 2006

Enhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen–mismatched alloHSCT (DBA/2→BALB/c: H-2d) recipients, alloMHC gene (H-2Kb) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2Kb gene transfer provides only a limited antitumor effect after syngeneic (BALB/c→BALB/c) HSCT. By contrast, the H-2Kb gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2Kb gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.
Heparins Increase Endothelial Nitric Oxide Bioavailability by Liberating Vessel-Immobilized Myeloperoxidase
Authors: Baldus Stephan , Rudolph Volker , Roiss Mika , Ito Wulf D. , Rudolph Tanja K. , Eiserich Jason P. , Sydow Karsten , Lau Denise , Szöcs Katalin , Klinke Anna , Kubala Lukas , Berglund Lars , Schrepfer Sonja , Deuse Tobias , Haddad Munif , Risius Tim , Klemm Hanno , Reichenspurner Hermann C. , Meinertz Thomas , Heitzer Thomas
Published: April 2006

Background—

Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase (MPO) has emerged as an important mechanistic participant in impaired vasomotor function. MPO binds to and transcytoses endothelial cells in a glycosaminoglycan-dependent manner, and MPO binding to the vessel wall is a prerequisite for MPO-dependent oxidation of endothelium-derived nitric oxide (NO) and impairment of endothelial function in animal models. In the present study, we investigated whether heparin mobilizes MPO from vascular compartments in humans and defined whether this translates into increased vascular NO bioavailability and function.

Methods and Results—

Plasma MPO levels before and after heparin administration were assessed by ELISA in 109 patients undergoing coronary angiography. Whereas baseline plasma MPO levels did not differ between patients with or without angiographically detectable coronary artery disease (CAD), the increase in MPO plasma content on bolus heparin administration was higher in patients with CAD (
P
=0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation (
P
<0.01) and by acetylcholine-induced changes in forearm blood flow (
P
<0.01). The extent of heparin-induced MPO release was correlated with improvement in endothelial function (
r
=0.69,
P
<0.01). Moreover, and consistent with this tenet, ex vivo heparin treatment of extracellular matrix proteins, cultured endothelial cells, and saphenous vein graft specimens from CAD patients decreased MPO burden.

Conclusions—

Mobilization of vessel-associated MPO may represent an important mechanism by which heparins exert antiinflammatory effects and increase vascular NO bioavailability. These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans.
Proarrhythmic Potential of Mesenchymal Stem Cell Transplantation Revealed in an In Vitro Coculture Model
Authors: Chang Marvin G. , Tung Leslie , Sekar Rajesh B. , Chang Connie Y. , Cysyk Josh , Dong Peihong , Marbán Eduardo , Abraham M. Roselle
Published: April 2006

Background—

Mesenchymal stem cells (MSCs) are bone marrow stromal cells that are in phase 1 clinical studies of cellular cardiomyoplasty. However, the electrophysiological effects of MSC transplantation have not been studied. Although improvement of ventricular function would represent a positive outcome of MSC transplantation, focal application of stem cells has the potential downside of creating inhomogeneities that may predispose the heart to reentrant arrhythmias. In the present study we use an MSC and neonatal rat ventricular myocyte (NRVM) coculture system to investigate potential proarrhythmic consequences of MSC transplantation into the heart.

Methods and Results—

Human MSCs were cocultured with NRVMs in ratios of 1:99, 1:9, and 1:4 and optically mapped. We found that conduction velocity was decreased in cocultures compared with controls, but action potential duration (APD
80
) was not affected. Reentrant arrhythmias were induced in 86% of cocultures containing 10% and 20% MSCs (n=36) but not in controls (n=7) or cocultures containing only 1% MSCs (n=4). Immunostaining, Western blot, and dye transfer revealed the presence of functional gap junctions involving MSCs.

Conclusions—

Our results suggest that mixtures of MSCs and NRVMs can produce an arrhythmogenic substrate. The mechanism of reentry is probably increased tissue heterogeneity resulting from electric coupling of inexcitable MSCs with myocytes.
A Tailored Approach to Catheter Ablation of Paroxysmal Atrial Fibrillation
Authors: Oral Hakan , Chugh Aman , Good Eric , Sankaran Sundar , Reich Stephen S. , Igic Petar , Elmouchi Darryl , Tschopp David , Crawford Thomas , Dey Sujoya , Wimmer Alan , Lemola Kristina , Jongnarangsin Krit , Bogun Frank , Pelosi Frank , Morady Fred
Published: April 2006

Background—

Because the genesis of atrial fibrillation (AF) is multifactorial and variable, an ablation strategy that involves pulmonary vein isolation and/or a particular set of ablation lines may not be equally effective or efficient in all patients with AF. A tailored strategy that targets initiators and drivers of AF is a possible alternative to a standardized lesion set.

Methods and Results—

Catheter ablation was performed in 153 consecutive patients (mean age, 56±11 years) with symptomatic paroxysmal AF with the use of an 8-mm tip radiofrequency ablation catheter. The esophagus was visualized with barium. The pulmonary veins and left atrium were mapped during spontaneous or induced AF. Arrhythmogenic pulmonary veins were isolated or encircled. If AF was still present or inducible, complex electrograms in the left atrium, coronary sinus, and superior vena cava were targeted for ablation. The end point of ablation was absence of frequent atrial ectopy and spontaneous AF during isoproterenol infusion and noninducibility of AF. Routine energy applications near the esophagus were avoided. During follow-up, left atrial flutter developed in 19% of patients and was still present in 10% at >12 weeks of follow-up. A repeat ablation procedure was performed in 18% of patients. During a mean follow-up of 11±4 months, 77% of patients were free from AF and/or atrial flutter without antiarrhythmic drug therapy. Pericardial tamponade or transient neurological events occurred in 2% of procedures.

Conclusions—

A tailored ablation strategy that only targets triggers and drivers of AF is feasible and eliminates paroxysmal AF in ≈80% of patients.
Josephus' Rewriting of the Babel Narrative (Gen 11:1-9)
Authors: Inowlocki Sabrina
Published: April 2006

This paper analyzes Josephus' appropriation of the biblical episode of the tower of Babel. It aims to highlight its originality as well as its purposes. Its methodology is two-fold: firstly, it recasts Josephus' passage in the context of the contemporary Jewish literature in general and of Josephus' writings in particular; secondly, it closely examines its language. This analysis reveals that Josephus was inspired by his own experience during the war in Judaea, and therefore presents the episode of Babel as a political-theological myth. In addition, this study explores the manner in which Josephus used the biblical narrative in order to polemicize against the Greeks.
Observed Changes in Cyclone Activity in Canada and Their Relationships to Major Circulation Regimes
Authors: Wang Xiaolan L. , Wan H. , Swail Val R.
Published: April 2006

This study assessed the climate and trend of cyclone activity in Canada using mainly the occurrence frequency of cyclone deepening events and deepening rates, which were derived from hourly mean sea level pressure data observed at 83 Canadian stations for up to 50 years (1953–2002). Trends in the frequency of cyclone activity were estimated by logistic regression analysis, and trends of seasonal extreme cyclone intensity, by linear regression analysis.

The results of trend analysis show that, among the four seasons, winter cyclone activity has shown the most significant trends. It has become significantly more frequent, more durable, and stronger in the lower Canadian Arctic, but less frequent and weaker in the south, especially along the southeast and southwest coasts. Winter cyclone deepening rates have increased in the zone around 60°N but decreased in the Great Lakes area and southern Prairies–British Columbia. However, extreme winter cyclone activity seems to have experienced a weaker increase in northwest-central Canada but a stronger decline in the Great Lakes area and in southern Prairies. The results also show more frequent summer cyclone activity with slower deepening rates on the east coast, as well as less frequent cyclone activity with faster deepening rates in the Great Lakes area in autumn.

Cyclone activity in Canada was found to be closely related to the North Atlantic Oscillation (NAO), the Pacific Decadal Oscillation (PDO), and El Niño–Southern Oscillation (ENSO). Overall, cyclone activity in Canada is most closely related to the NAO. The simultaneous NAO index explains about 44% (41%) of the winter (autumn) cyclone activity variance in the east coast, 31% of winter cyclone activity variance in the 60°–70°N zone, and 17% of autumn cyclone activity variance in the Great Lakes area. Also, in several regions (e.g., the east coast, the southwest, and the 60°–70°N zone) up to 15% of the seasonal cyclone activity variance can be explained by the NAO/PDO/ENSO index one–three seasons earlier, which is useful for seasonal forecasting.
AGCM Precipitation Biases in the Tropical Atlantic
Authors: Biasutti M. , Sobel A. H. , Kushnir Y.
Published: April 2006

Many general circulation models (GCMs) share similar biases in the representation of the intertropical convergence zone (ITCZ) in the Atlantic, even when they are forced with the time series of the observed sea surface temperature (SST). Specifically, they overestimate precipitation in the Southern Hemisphere in boreal spring and in the Caribbean region in boreal summer.

The majority of the models considered here place the rainfall maximum over the SST maximum, although the true precipitation maximum does not occur there. This is the case even though these GCMs accurately place the maximum in surface wind convergence away from the SST maximum, at the location where the observed precipitation maximum lies.

Models that overrespond to SST in this way tend to (i) have fewer heavy-rain events, (ii) rain more for a smaller amount of water vapor in the atmospheric column, and (iii) couple rainfall and surface humidity too strongly and rainfall and humidity above the surface too weakly.
Interannual Tropical Pacific Sea Surface Temperatures and Their Relation to Preceding Sea Level Pressures in the NCAR CCSM2
Authors: Anderson Bruce T. , Maloney Eric
Published: April 2006

This paper describes aspects of tropical interannual ocean/atmosphere variability in the NCAR Community Climate System Model Version 2.0 (CCSM2). The CCSM2 tropical Pacific Ocean/atmosphere system exhibits much stronger biennial variability than is observed. However, a canonical correlation analysis technique decomposes the simulated boreal winter tropical Pacific sea surface temperature (SST) variability into two modes, both of which are related to atmospheric variability during the preceding boreal winter. The first mode of ocean/atmosphere variability is related to the strong biennial oscillation in which La Niña–related sea level pressure (SLP) conditions precede El Niño–like SST conditions the following winter. The second mode of variability indicates that boreal winter tropical Pacific SST anomalies can also be initiated by SLP anomalies over the subtropical central and eastern North Pacific 12 months earlier.

The evolution of both modes is characterized by recharge/discharge within the equatorial subsurface temperature field. For the first mode of variability, this recharge/discharge produces a lag between the basin-average equatorial Pacific isotherm depth anomalies and the isotherm–slope anomalies, equatorial SSTs, and wind stress fields. Significant anomalies are present up to a year before the boreal winter SLP variations and two years prior to the boreal winter ENSO-like events. For the second canonical factor pattern, the recharge/discharge mechanism is induced concurrent with the boreal winter SLP pattern approximately one year prior to the ENSO-like events, when isotherms initially deepen and change their slope across the basin. A rapid deepening of the isotherms in the eastern equatorial Pacific and a warming of the overlying SST anomalies then occurs during the subsequent 12 months.
Rethinking job characteristics in work stress research
Authors: Daniels Kevin
Published: April 2006

In work stress research, consistent relationships between job characteristics and strain have not been established across methods for assessing job characteristics. By examining the methods used to assess job characteristics in work stress research, I argue that this is because different methods are assessing interrelated, yet distinct, facets of job characteristics: latent, perceived and enacted facets. The article discusses the implications for work stress research of differentiating these facets of job characteristics.
The role of networks of practice, value sharing, and operational proximity in knowledge flows between professional groups
Authors: Tagliaventi Maria Rita , Mattarelli Elisa
Published: April 2006

This article investigates the process of knowledge sharing between individuals in different professional groups. Through an ethnographic study in a hospital unit, we examine the individuals’ involvement in networks of practice, their sharing of organizational values, and their operational proximity. Recent attention to networks of practice has led to a view of organizations as crossroads of networks; accordingly, boundary relations between different networks of practice are of core relevance to ensure knowledge diffusion in organizations, but empirical evidence is still lacking. Our grounded theory supports the idea that working side-by-side and having common organizational values are important bases for knowledge transfer between professional groups which belong to different networks of practice. Boundary knowledge transfer evokes new kinds of organizational citizenship behaviours. Professionals who initiate the transfer exhibit extra-role behaviours which, in turn, require the recipient to perform extra-role behaviours as well. Implications of knowledge sharing between professional groups are discussed together with recommendations for managerial action.
Leader framing and follower sensemaking
Authors: Bean Cynthia J. , Hamilton Francis E.
Published: April 2006

Alternative workplaces are increasingly prevalent, combining flexible work practices, open landscape settings and a variety of acceptable working locations, especially for technology-enabled workers. In this article we examine the sensemaking response of technology-enabled, nomadic workers to the firm’s downsizing event at Telenor, Norway’s premier telecom company, in late 2002. We find two opposite interpretations of the firm’s employee database efforts and project-based structure emerge after the downsizing event. Our findings suggest the lack of geosocial boundaries in the organization influences sensemaking. Nomadic workers adopt frames that drive their interpretations and actions idiosyncratically. We suggest further research is needed to understand the influence of alternative work-places on patterns of behavior and human processes.
The dynamics of employee relationships in an ethnically diverse workforce
Authors: Ogbonna Emmanuel , Harris Lloyd C.
Published: April 2006

This article explores and analyses the dynamics of workplace relationships in an organization characterized by a highly ethnically diverse workforce. The specific objectives are: 1) to understand the factors that are contributing to high levels of ethnic diversity; 2) to uncover the ways in which such diversity is manifested in an organizational setting; and 3) to explore the ramifications that this diversity and its manifestations may have for individuals and groups of employees on the one hand and for relations between management and groups of employees on the other. The article concludes by discussing the implications that such ethnic diversity may have for extant research and conceptualization of ethnic minorities in the workplace.
Sixty-six ways to get it wrong
Authors: Whiteman Gail , Cooper William H.
Published: April 2006

Gail Whiteman learned to be a beaver trapper by working in the field with a Cree tallyman in Eastern James Bay, Québec. An account of her managerial experiences and some potential lessons for organizations were reported in Whiteman and Cooper (2000). Central to her managerial experience was the sense of being ecologically embedded – literally being grounded in the local ecology. From that experience we suggested that resources are more likely to be cared for if managers have a strong ecological sense of who and where they are. Banerjee and Linstead (2004) have provided an extensive critique of our article. We itemize the sins with which we are charged and provide responses to the more central criticisms. We close by reiterating the purpose of the original article and what we continue to believe are the virtues of the main points.
Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27
Authors: Bear Harry D. , Anderson Stewart , Smith Roy E. , Geyer Charles E. , Mamounas Eleftherios P. , Fisher Bernard , Brown Ann M. , Robidoux Andre , Margolese Richard , Kahlenberg Morton S. , Paik Soonmyung , Soran Atilla , Wickerham D. Lawrence , Wolmark Norman
Published: April 2006

Purpose

This study was designed to determine the effect of adding docetaxel (T) to preoperative doxorubicin and cyclophosphamide (AC) on breast cancer response rates and disease-free survival (DFS) and overall survival (OS).

Patients and Methods

Women with operable breast cancer (N = 2,411) were randomly assigned to receive preoperative AC followed by surgery, AC followed by T and surgery, or AC followed by surgery and then T. Tamoxifen was initiated concurrently with chemotherapy. Median time on study for 2,404 patients with follow-up was 77.9 months.

Results

Addition of T to AC did not significantly impact DFS or OS. There were trends toward improved DFS with addition of T. The addition of T reduced the incidence of local recurrences as first events (P = .0034). Preoperative T, but not postoperative T, significantly improved DFS in patients who had a clinical partial response after AC (hazard ratio [HR] = 0.71; 95% CI, 0.55 to 0.91; P = .007). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR = 0.33; 95% CI, 0.23 to 0.47; P < .0001). Pathologic nodal status after chemotherapy was a significant predictor of OS (P < .0001).

Conclusion

The addition of preoperative or postoperative T after preoperative AC did not significantly affect OS, slightly improved DFS, and decreased the incidence of local recurrences. The sample size of this study was not sufficient to yield significance for the moderate DFS improvement. Concurrent use of tamoxifen may have limited the impact of adding T.
Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity
Authors: Strauss Sandra J. , Maharaj Lenushka , Hoare Susan , Johnson Peter W. , Radford John A. , Vinnecombe Sarah , Millard Lynda , Rohatiner Ama , Boral Anthony , Trehu Elizabeth , Schenkein David , Balkwill Frances , Joel Simon P. , Lister T. Andrew
Published: April 2006

Purpose

To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.

Patients and Methods

Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-α) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture.

Results

Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-α of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07).

Conclusion

Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-α and in vitro sensitivity in a small number of patients.
Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis
Authors: Kawanishi Shosuke , Hiraku Yusuke , Pinlaor Somchai , Ma Ning
Published: April 2006

Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis.
Cancer-preventive anti-oxidants that attenuate free radical generation by inflammatory cells
Authors: Murakami Akira , Ohigashi Hajime
Published: April 2006

Active inflammatory leukocytes are a major endogenous source of reactive oxygen and nitrogen oxide species (RONS). We have recently established novel bioassay systems, in which either phorbol ester-stimulated, differentiated HL-60 human leukemia cells or lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages were co-cultured with AS52 Chinese hamster ovary cells. Extensive screening of extracts from Asian vegetables and fruits led to the identification of 1′-acetoxychavicol acetate (ACA), auraptene, nobiletin, and zerumbone, all of which were found to be highly anti-mutagenic in the above co-culture systems. Pretreatment of RAW264.7 macrophages with LPS led to the activation of mitogen-activated protein kinases (MAPKs) and Akt, together with the degradation of IκB-α protein, and the resultant activation of the AP-1, NF-κB, and CREB transcription factors. ACA abrogated ERK1/2 and JNK1/2, but not p38 activation, as well as the activation and transcriptional activation of NF-κB and CREB, whereas nobiletin allowed phosphorylation of these MAPKs, while it suppressed AP-1, NF-κB, and CREB activation. Interestingly, zerumbone did not have any effects on the latter transcription factors, although it did attenuate iNOS mRNA expression. In addition, auraptene suppressed iNOS protein production, but not mRNA expression, implying that it targets the translation step. Our model systems may be useful for identifying potentially anti-carcinogenic inhibitors of RONS generation.
Role of the kinin B1 receptor in insulin homeostasis and pancreatic islet function
Authors: Araújo Ronaldo C. , Mori Marcelo A. , Merino Vanessa F. , Bascands Jean-Loup , Schanstra Joost P. , Zollner Ricardo L. , Villela Conceição A. , Nakaie Clovis R. , Paiva Antonio C.M. , Pesquero Jorge L. , Bader Michael , Pesquero João B.
Published: April 2006

Kinins are potent vasoactive peptides generated in blood and tissues by the kallikrein serine proteases. Two distinct kinin receptors have been described, one constitutive (subtype B2) and one inducible (subtype B1), and many physiological functions have been attributed to these receptors, including glucose homeostasis and control of vascular permeability. In this study we show that mice lacking the kinin B1 receptor (B1
-/- mice) have lower fasting plasma glucose concentrations but exhibit higher glycemia after feeding when compared to wild-type mice. B1
-/- mice also present pancreas abnormalities, characterized by fewer pancreatic islets and lower insulin content, which leads to hypoinsulinemia and reduced insulin release after a glucose load. Nevertheless, an insulin tolerance test indicated higher sensitivity in B1
-/- mice. In line with this phenotype, pancreatic vascular permeability was shown to be reduced in B1 receptor-ablated mice. The B1 agonist desArg9bradykinin injected intravenously can induce the release of insulin into serum, and this effect was not observed in the B1
-/- mice or in isolated islets. Our data demonstrate the importance of the kinin B1 receptor in the control of pancreatic vascular homeostasis and insulin release, highlighting a new role for this receptor in the pathogenesis of diabetes and related diseases.
Herpes Simplex Virus Central Nervous System Relapse During Treatment of Infantile Spasms With Corticotropin
Authors: Bonkowsky Joshua L. , Filloux Francis M. , Byington Carrie L.
Published: April 2006

Here we report an infant who had herpes simplex virus (HSV) encephalitis and sustained severe bilateral damage to the posterior frontal lobes, postcentral gyri, and the thalami despite intravenous acyclovir treatment. At 7 months of age, the patient developed infantile spasms and was treated with corticotropin injections. After 10 days of corticotropin treatment, she developed lethargy, fever, and opisthotonic posturing. Her cerebrospinal fluid again was positive for HSV DNA, indicating recurrent HSV encephalitis, and repeat MRI revealed new lesions of the right frontal, parietal, temporal, and occipital lobes. Immunosuppression by corticotropin may have led to the reactivation of the HSV encephalitis. Corticotropin should be relatively contraindicated for use when a patient has a history of HSV infection, or intravenous acyclovir should be administered concurrently.
Pneumonia and Empyema Caused by Penicillin-Resistant Neisseria meningitidis: A Case Report and Literature Review
Authors: Glikman Daniel , Matushek Scott M. , Kahana Madelyn D. , Daum Robert S.
Published: April 2006

Pneumonia is an uncommon manifestation of Neisseria meningitidis infection, and empyema is rarely reported. Uniform penicillin susceptibility has been assumed for meningococcal infections for many years, but decreased penicillin susceptibility has been recognized recently with increasing frequency. Breakpoints to define different categories of susceptibility were published recently by the Clinical and Laboratory Standards Institute. We report the case of a teenage girl with sepsis and extensive bilateral pneumonia with empyema caused by an N meningitidis isolate that was resistant to penicillin. Her protracted clinical course suggested that penicillin resistance contributed to her delayed recovery. Our experience with this patient suggests that susceptibility testing should be performed in every case of N meningitidis isolation, and treatment with a third-generation cephalosporin should be provided until the susceptibility results are known. Clinical suspicion of N meningitidis as a possible cause of respiratory symptoms accompanied by hypotension, even in the absence of a rash, may aid in diagnosis and therefore in the treatment and provision of prophylaxis to contacts of patients with meningococcal disease.