bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of polyunsaturated fatty acids on hibernation and torpor: a review and hypothesis
Authors: Ruf Thomas , Arnold Walter
Published: January 2008

Polyunsaturated fatty acids (PUFAs) can have strong effects on hibernation and daily torpor in mammals. High dietary PUFA contents were found to increase proneness for torpor, decrease body temperatures, prolong torpor bout duration, and attenuate hibernation mass loss. The mechanism by which PUFAs enhance torpor and hibernation is unknown, however. On the basis of a review of the literature, and on reexamining our own data on alpine marmots, we propose that effects on hibernation are not due to PUFAs in general, but to shifts in the ratio of n-6 PUFAs to n-3 PUFAs in membrane phospholipids. Specifically, high ratios of n-6 to n-3 PUFAs increase the activity of the Ca2+-Mg2+pump in the sarcoplasmic reticulum of the heart (SERCA) and counteract Q10effects on SERCA activity at low tissue temperatures. Therefore, high n-6 to n-3 PUFA ratios in cardiac myocyte membranes appear to protect the hibernating heart from arrhythmia, which in hypothermic nonhibernators is caused by massive increases in cytosolic Ca2+. The resulting reduced risk of cardiac arrest during hypothermia may explain why increased dietary uptake of n-6 PUFAs, but not of n-3 PUFAs, can strongly enhance the propensity for hibernation, and allows heterotherms to reach lower body temperatures, with associated increased energy savings. Therefore, at least for herbivorous hibernators, such as marmots, linoleic acid (C18:2 n-6)—the dietary source of all n-6 PUFAs—appears to represent a crucial and limited resource in natural environments.
Targeted disruption of the meprin metalloproteinase β gene protects against renal ischemia-reperfusion injury in mice
Authors: Bylander John , Li Qing , Ramesh Ganesan , Zhang Binzhi , Reeves W. Brian , Bond Judith S.
Published: January 2008

Meprins are membrane-bound and secreted metalloproteinases consisting of α- and/or β-subunits that are highly expressed in mouse kidney proximal tubules. Previous studies have implied that the meprin α/β-isoform is deleterious when renal tissue is subjected to ischemia-reperfusion (I/R). To delineate the roles of the meprin isoforms in renal disease, we subjected mice deficient in meprin-β (KO) and their wild-type (WT) counterparts to I/R. WT mice were markedly more susceptible to renal injury after I/R than the meprin-β KO mice as determined by blood urea nitrogen levels. Urinary levels of inflammatory cytokines IL-6 and KC (CXCL1) were significantly higher in WT compared with meprin-β KO mice by 6 h post-I/R. At 96 h postischemia, kidney mRNA expression levels for tumor necrosis factor-α, transforming growth factor-β, inducible nitric oxide synthase, and heat shock protein-27 were significantly higher in the WT than meprin-β KO mice. For WT mice subjected to I/R, there was a rapid (3 h) redistribution of meprin β-subunits in cells in S3 segments of proximal tubules, followed by shedding of apical cell membrane and detachment of cells. These studies indicate that meprin-β is important in the pathogenesis of renal injury following I/R and that the redistribution of active meprin-α/β is a major contributor to renal injury and subsequent inflammation.
Role of calcium-independent phospholipase A2in complement-mediated glomerular epithelial cell injury
Authors: Cohen Daniel , Papillon Joan , Aoudjit Lamine , Li Hongping , Cybulsky Andrey V. , Takano Tomoko
Published: January 2008

In experimental membranous nephropathy, complement C5b-9-induced glomerular epithelial cell (GEC) injury leads to morphological changes in GEC and proteinuria, in association with phospholipase A2(PLA2) activation. The present study addresses the role of calcium-independent PLA2(iPLA2) in GEC injury. iPLA2β short and iPLA2γ were expressed in cultured rat GEC and normal rat glomeruli. To determine whether iPLA2is involved in complement-mediated arachidonic acid (AA) release, GEC were stably transfected with iPLA2γ or iPLA2β cDNAs (GEC-iPLA2γ; GEC-iPLA2β). Compared with control cells (GEC-Neo), GEC-iPLA2γ and GEC-iPLA2β demonstrated greater expression of iPLA2proteins and activities. Complement-mediated release of [3H]AA was augmented significantly in GEC-iPLA2γ compared with GEC-Neo, and the augmented [3H]AA release was inhibited by the iPLA2-directed inhibitor bromoenol lactone (BEL). For comparison, overexpression of iPLA2γ also amplified [3H]AA release after incubation of GEC with H2O2, or chemical anoxia followed by reexposure to glucose (in vitro ischemia-reperfusion injury). In parallel with release of [3H]AA, complement-mediated production of prostaglandin E2was amplified in GEC-iPLA2γ. Complement-mediated cytotoxicity was attenuated significantly in GEC-iPLA2γ compared with GEC-Neo, and the cytoprotective effect of iPLA2γ was reversed by BEL, and in part by indomethacin. Overexpression of iPLA2β did not amplify complement-dependent [3H]AA release, but nonetheless attenuated complement-mediated cytotoxicity. Thus iPLA2γ may be involved in complement-mediated release of AA. Expression of iPLA2γ or iPLA2β induces cytoprotection against complement-dependent GEC injury. Modulation of iPLA2activity may prove to be a novel approach to reducing GEC injury.
Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1
Authors: Wang Wei , Zolty Einath , Falk Sandor , Summer Sandra , Zhou Zhu , Gengaro Patricia , Faubel Sarah , Alp Nicholas , Channon Keith , Schrier Robert
Published: January 2008

Endotoxin-related acute kidney injury has been shown to profoundly induce nitric oxide (NO), which activates sympathetic and renin-angiotensin system, resulting in renal vasoconstriction. While vascular muscle cells are known to upregulate inducible NO synthase (iNOS), less is known about the endothelium as a source of NO during endotoxemia. Studies were, therefore, undertaken both in vitro in mouse microvascular endothelial cells and in vivo in transgenic mice with overexpression of endothelial GTP cyclohydrolase, the rate-limiting enzyme for tetrahydrobiopterin, a cofactor for NO synthase. LPS significantly induced endothelial cell iNOS expression and NO concentration in the culture media, with no change in endothelial NO synthase expression. GTP cyclohydrolase-1 transgenic (Tg) mice demonstrated a significant increase in baseline urine NO-to-creatinine ratio and a more significant increase in renal iNOS expression and serum NO levels with LPS treatment compared with the wild-type (WT) mice. Glomerular filtration rate and renal blood flow decreased significantly in Tg mice with 1.0 mg/kg LPS, while no changes were observed in WT with the same dose of LPS. Serum IL-6 levels were significantly higher in Tg compared with WT mice during endotoxemia. The antioxidant tempol improved the glomerular filtration rate in the Tg mice. Thus endothelium can be an important source of iNOS and serum NO concentration during endotoxemia, thereby increasing the sensitivity to AKI. Reactive oxygen species appear to be involved in this acute renal injury in Tg mice during endotoxemia.
Warning Signals Induce Automatic EMG Activations and Proactive Volitional Inhibition: Evidence From Analysis of Error Distribution in Simple RT
Authors: Boulinguez Philippe , Jaffard Magali , Granjon Lionel , Benraiss Abdelrhani
Published: January 2008

Typical simple reaction-time (RT) paradigms usually include a warning signal followed by a variable foreperiod before the presentation of a reaction stimulus. Most current interpretations suggest that the warning stimulus alerts the organism and so results in faster processing of either the sensory or motor components of the task. In this study, electromyography (EMG) was used to detect both covert and overt motor errors in a simple warned RT task. Results show that warning signals may trigger automatic motor activations that are likely to cause false alarms. Distribution analysis reveals that 77% of all errors detected with EMG are erroneous responses to the warning signal. Accordingly, we propose that movement triggering needs to be temporarily inhibited before the stimulus to prevent premature responses during the foreperiod. This proactive inhibition would be responsible for a paradoxical increase in RT for conditions with short foreperiods compared with control conditions in which no warning signal is presented. These results call for a reassessment of the theoretical framework used to interpret the effects of warning signals.
Analysis of the QTL for sleep homeostasis in mice:Homer1ais a likely candidate
Authors: Mackiewicz M. , Paigen B. , Naidoo N. , Pack A. I.
Published: January 2008

Electroencephalographic oscillations in the frequency range of 0.5–4 Hz, characteristic of slow-wave sleep (SWS), are often referred to as the delta oscillation or delta power. Delta power reflects sleep intensity and correlates with the homeostatic response to sleep loss. A published survey of inbred strains of mice demonstrated that the time course of accumulation of delta power varied among inbred strains, and the segregation of the rebound of delta power in BxD recombinant inbred strains identified a genomic region on chromosome 13 referred to as the delta power in SWS (or Dps1). The quantitative trait locus (QTL) contains genes that modify the accumulation of delta power after sleep deprivation. Here, we narrow the QTL using interval-specific haplotype analysis and present a comprehensive annotation of the remaining genes in the Dps1 region with sequence comparisons to identify polymorphisms within the coding and regulatory regions. We established the expression pattern of selected genes located in the Dps1 interval in sleep and wakefulness in B6 and D2 parental strains. Taken together, these steps reduced the number of potential candidate genes that may underlie the accumulation of delta power after sleep deprivation and explain the Dps1 QTL. The strongest candidate gene is Homer1a, which is supported by expression differences between sleep and wakefulness and the SNP polymorphism in the upstream regulatory regions.
Distinctive MicroRNA Profiles Relating to Patient Survival in Esophageal Squamous Cell Carcinoma
Authors: Guo Yong , Chen Zhaoli , Zhang Liang , Zhou Fang , Shi Susheng , Feng Xiaoli , Li Baozhong , Meng Xin , Ma Xi , Luo Mingyong , Shao Kang , Li Ning , Qiu Bin , Mitchelson Keith , Cheng Jing , He Jie
Published: January 2008

Esophageal cancer is the sixth leading cause of death from cancer and one of the least studied cancers worldwide. The global microRNA expression profile of esophageal cancer has not been reported previously. Here, for the first time, we have investigated expressed microRNAs in cryopreserved esophageal cancer tissues using advanced microRNA microarray techniques. Our microarray analyses identified seven microRNAs that could distinguish malignant esophageal cancer lesions from adjacent normal tissues. Some microRNAs could be correlated with the different clinicopathologic classifications. High expression of hsa-miR-103/107 correlated with poor survival by univariate analysis as well as by multivariate analysis. These results indicate that microRNA expression profiles are important diagnostic and prognostic markers of esophageal cancer, which might be analyzed simply using economical approaches such as reverse transcription-PCR. [Cancer Res 2008;68(1):26–33]
A Vascular Targeted Pan Phosphoinositide 3-Kinase Inhibitor Prodrug, SF1126, with Antitumor and Antiangiogenic Activity
Authors: Garlich Joseph R. , De Pradip , Dey Nandini , Su Jing Dong , Peng Xiaodong , Miller Antoinette , Murali Ravoori , Lu Yiling , Mills Gordon B. , Kundra Vikas , Shu H-K. , Peng Qiong , Durden Donald L.
Published: January 2008

PTEN and the pan phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1benzopyran-4-one (LY294002) exert significant control over tumor-induced angiogenesis and tumor growth in vivo. The LY294002 compound is not a viable drug candidate due to poor pharmacologic variables of insolubility and short half-life. Herein, we describe the development and antitumor activity of a novel RGDS-conjugated LY294002 prodrug, termed SF1126, which is designed to exhibit increased solubility and bind to specific integrins within the tumor compartment, resulting in enhanced delivery of the active compound to the tumor vasculature and tumor. SF1126 is water soluble, has favorable pharmacokinetics, and is well tolerated in murine systems. The capacity of SF1126 to inhibit U87MG and PC3 tumor growth was enhanced by the RGDS integrin (αvβ3/α5β1) binding component, exhibiting increased activity compared with a false RADS-targeted prodrug, SF1326. Antitumor activity of SF1126 was associated with the pharmacokinetic accumulation of SF1126 in tumor tissue and the pharmacodynamic knockdown of phosphorylated AKT in vivo. Furthermore, SF1126 seems to exhibit both antitumor and antiangiogenic activity. The results support SF1126 as a viable pan PI3K inhibitor for phase I clinical trials in cancer and provide support for a new paradigm, the application of pan PI3K inhibitory prodrugs for the treatment of cancer. [Cancer Res 2008;68(1):206–15]
DNA Protein Kinase–Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells
Authors: Arlander Sonnet J.H. , Greene Bryan T. , Innes Cynthia L. , Paules Richard S.
Published: January 2008

Members of the phosphatidylinositol 3-kinase–related kinase family, in particular the ataxia-telangiectasia mutated (ATM) kinase and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), regulate cellular responses to DNA double-strand breaks. Increased sensitivity to ionizing radiation (IR) in DNA-PKcs– or ATM-deficient cells emphasizes their important roles in maintaining genome stability. Furthermore, combined knockout of both kinases is synthetically lethal, suggesting functional complementarity. In the current study, using human mammary epithelial cells with ATM levels stably knocked down by >90%, we observed an IR-induced G2 checkpoint that was only slightly attenuated. In marked contrast, this G2 checkpoint was significantly attenuated with either DNA-PK inhibitor treatment or RNA interference knockdown of DNA-PKcs, the catalytic subunit of DNA-PK, indicating that DNA-PK contributes to the G2 checkpoint in these cells. Furthermore, in agreement with the checkpoint attenuation, DNA-PK inhibition in ATM-knockdown cells resulted in reduced signaling of the checkpoint kinase CHK1 as evidenced by reduced CHK1 phosphorylation. Taken together, these results show a DNA-PK–dependent component to the IR-induced G2 checkpoint, in addition to the well-defined ATM-dependent component. This may have important implications for chemotherapeutic strategies for breast cancers. [Cancer Res 2008;68(1):89–97]
Arsenic Trioxide Sensitizes Human Glioma Cells, but not Normal Astrocytes, to TRAIL-Induced Apoptosis via CCAAT/Enhancer-Binding Protein Homologous Protein–Dependent DR5 Up-regulation
Authors: Kim Eun Hee , Yoon Mi Jin , Kim Seung U. , Kwon Taeg Kyu , Sohn Seonghyang , Choi Kyeong Sook
Published: January 2008

The current study shows that treatment of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–resistant glioma cells with a combination of TRAIL and subtoxic doses of arsenic trioxide (As2O3) induces rapid apoptosis. Whereas TRAIL-mediated proteolytic processing of procaspase-3 was partially blocked in glioma cells, treatment with As2O3 efficiently recovered TRAIL-induced activation of caspases. We also found that As2O3 treatment of glioma cells significantly up-regulated DR5, a death receptor of TRAIL. Furthermore, suppression of DR5 expression by small interfering RNA (siRNA) inhibited As2O3/TRAIL-induced apoptosis of U87MG glioma cells, suggesting that DR5 up-regulation is critical for As2O3-induced sensitization of glioma cells to TRAIL-mediated apoptosis. Our results also indicate that an increase in CCAAT/enhancer binding protein homologous protein (CHOP) protein levels precedes As2O3-induced DR5 up-regulation. The involvement of CHOP in this process was confirmed by siRNA-mediated CHOP suppression, which not only attenuated As2O3-induced DR5 up-regulation but also inhibited the As2O3-stimulated TRAIL-induced apoptosis. These results therefore suggest that the CHOP-mediated DR5 up-regulation, brought about by As2O3, stimulates the TRAIL-mediated signaling pathway. This in turn leads to complete proteolytic processing of caspase-3, which is partially primed by TRAIL in glioma cells. In contrast to human glioma cells, astrocytes were very resistant to the combined administration of As2O3 and TRAIL, demonstrating the safety of this treatment. In addition, As2O3-mediated up-regulation of CHOP and DR5, as well as partial proteolytic processing of procaspase-3 by TRAIL, was not induced in astrocytes. Taken together, the present results suggest that the combined treatment of glioma cells with As2O3 plus TRAIL may provide an effective and selective therapeutic strategy. [Cancer Res 2008;68(1):266–75]
Capsiate, a Nonpungent Capsaicin-Like Compound, Inhibits Angiogenesis and Vascular Permeability via a Direct Inhibition of Src Kinase Activity
Authors: Pyun Bo-Jeong , Choi Sun , Lee Yoonji , Kim Tae-Woong , Min Jeong-Ki , Kim Yonghak , Kim Byung-Dong , Kim Jeong-Han , Kim Tae-Yoon , Kim Young-Myeong , Kwon Young-Guen
Published: January 2008

Capsiate, a nonpungent capsaicin analogue, and its dihydroderivative dihydrocapsiate are the major capsaicinoids of the nonpungent red pepper cultivar CH-19 Sweet. In this study, we report the biological actions and underlying molecular mechanisms of capsiate on angiogenesis and vascular permeability. In vitro, capsiate and dihydrocapsiate inhibited vascular endothelial growth factor (VEGF)–induced proliferation, chemotactic motility, and capillary-like tube formation of primary cultured human endothelial cells. They also inhibited sprouting of endothelial cells in the rat aorta and formation of new blood vessels in the mouse Matrigel plug assay in response to VEGF. Moreover, both compounds blocked VEGF-induced endothelial permeability and loss of vascular endothelial (VE)–cadherin–facilitated endothelial cell-cell junctions. Importantly, capsiate suppressed VEGF-induced activation of Src kinase and phosphorylation of its downstream substrates, such as p125FAK and VE-cadherin, without affecting autophosphorylation of the VEGF receptor KDR/Flk-1. In vitro kinase assay and molecular modeling studies revealed that capsiate inhibits Src kinase activity via its preferential docking to the ATP-binding site of Src kinase. Taken together, these results suggest that capsiate could be useful for blocking pathologic angiogenesis and vascular permeability caused by VEGF. [Cancer Res 2008;68(1):227–35]
Transcription Factor Stat5 Synergizes with Androgen Receptor in Prostate Cancer Cells
Authors: Tan Shyh-Han , Dagvadorj Ayush , Shen Feng , Gu Lei , Liao Zhiyong , Abdulghani Junaid , Zhang Ying , Gelmann Edward P. , Zellweger Tobias , Culig Zoran , Visakorpi Tapio , Bubendorf Lukas , Kirken Robert A. , Karras James , Nevalainen Marja T.
Published: January 2008

The molecular mechanisms underlying progression of prostate cancer to the hormone-independent state are poorly understood. Signal transducer and activator of transcription 5a and 5b (Stat5a/b) is critical for the viability of human prostate cancer cells. We have previously shown that Stat5a/b is constitutively active in high-grade human prostate cancer, but not in normal prostate epithelium. Furthermore, activation of Stat5a/b in primary human prostate cancer predicted early disease recurrence. We show here that transcription factor Stat5a/b is active in 95% of clinical hormone-refractory human prostate cancers. We show for the first time that Stat5a/b synergizes with androgen receptor (AR) in prostate cancer cells. Specifically, active Stat5a/b increases transcriptional activity of AR, and AR, in turn, increases transcriptional activity of Stat5a/b. Liganded AR and active Stat5a/b physically interact in prostate cancer cells and, importantly, enhance nuclear localization of each other. The work presented here provides the first evidence of synergy between AR and the prolactin signaling protein Stat5a/b in human prostate cancer cells. [Cancer Res 2008;68(1):236–48]
Two Distinct Local Relapse Subtypes in Invasive Breast Cancer: Effect on their Prognostic Impact
Authors: Casalini Patrizia , Carcangiu Maria Luisa , Tammi Raija , Auvinen Päivi , Kosma Veli-Matti , Valagussa Pinuccia , Greco Marco , Balsari Andrea , Ménard Sylvie , Tagliabue Elda
Published: January 2008

Purpose: Local relapse (LR) remains an important concern in breast cancer surveillance. Given the unique opportunity to study local recurrences in the breast in the absence of irradiation, we tested the possibility of identifying a particular tumor feature that might account for LR.

Experimental Design: Archival specimens from 235 patients belonging to the control arm (no radiotherapy) of the Milan 3 Trial were retrieved and included in this study. H&E-stained histologic slides were reviewed for diagnostic reassessment. A panel of biological variables was assessed by immunohistochemical/cytochemical staining.

Results: Onset of LR was significantly linked only to patient's age, with a hazard ratio (HR) to relapse reduced by 60% in patients >50 years of age (P = 0.002). Univariate and multivariate Cox analyses in women ≤50 years of age indicated that only expression of hyaluronan in tumor cells was associated with LR risk (HR, 2.48; P = 0.0364 and HR, 2.34; P = 0.0580, respectively). In patients >50 years of age, lymph node and estrogen receptor status were significantly predictive of LR (HR, 3.34; P = 0.0113 and HR, 0.39; P = 0.0424, respectively). Multivariate analysis indicated that apart from lymph node positivity (HR, 3.48; P = 0.0120), none of the variables associated with LR in univariate analysis displayed an independent LR-predictive power. LR had a strong prognostic impact on distant metastasis in patients >50 years of age, whereas in younger women, LR did not affect the risk of metastasis.

Conclusions: These results support the notion that LR arises from two distinct mechanisms, one that is more frequent in young patients, associated with host characteristics, and is not linked with prognosis, and another that is less frequent, but is associated with tumor aggressiveness which represents a peculiar and distinct marker of breast tumor malignancy.
Stem Cell Marker CD133 Affects Clinical Outcome in Glioma Patients
Authors: Zeppernick Felix , Ahmadi Rezvan , Campos Benito , Dictus Christine , Helmke Burkhard M. , Becker Natalia , Lichter Peter , Unterberg Andreas , Radlwimmer Bernhard , Herold-Mende Christel C.
Published: January 2008

Purpose: The CD133 antigen has been identified as a putative stem cell marker in normal and malignant brain tissues. In gliomas, it is used to enrich a subpopulation of highly tumorigenic cancer cells. According to the cancer stem cell hypothesis, CD133-positive cells determine long-term tumor growth and, therefore, are suspected to influence clinical outcome. To date, a correlation between CD133 expression in primary tumor tissues and patients' prognosis has not been reported.

Experimental Design: To address this question, we analyzed the expression of the CD133 stem cell antigen in a series of 95 gliomas of various grade and histology by immunohistochemistry on cryostat sections. Staining data were correlated with patient outcome.

Results: By multivariate survival analysis, we found that both the proportion of CD133-positive cells and their topological organization in clusters were significant (P < 0.001) prognostic factors for adverse progression-free survival and overall survival independent of tumor grade, extent of resection, or patient age. Furthermore, proportion of CD133-positive cells was an independent risk factor for tumor regrowth and time to malignant progression in WHO grade 2 and 3 tumors.

Conclusions: These findings constitute the first conclusive evidence that CD133 stem cell antigen expression correlates with patient survival in gliomas, lending support to the current cancer stem cell hypothesis.
Cardiac Toxicity in Breast Cancer Survivors: Review of Potential Cardiac Problems
Authors: Bird Brian R.J. Healey , Swain Sandra M.
Published: January 2008

As breast cancer survival is increased by the diagnosis of earlier-stage disease and treatments improve, the side effects of cancer treatments, such as cardiotoxicity, remain clinically important. Although physicians have known for 30 years that anthracyclines cause acute and chronic cardiotoxicity, the cardiotoxic effects of radiation therapy, hormonal therapy (including tamoxifen and the aromatase inhibitors), and chemotherapy with taxanes and trastuzumab treatment have emerged more recently. This review examines the cardiac toxicity of adjuvant therapy, monitoring for early changes and existing guidelines for monitoring cardiac function in patients with breast cancer.
Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents
Authors: Leoni Lorenzo M. , Bailey Brandi , Reifert Jack , Bendall Heather H. , Zeller Robert W. , Corbeil Jacques , Elliott Gary , Niemeyer Christina C.
Published: January 2008

Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds.

Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard.

Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism.

Conclusion: These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
Using Pharmacokinetic and Pharmacodynamic Modeling and Simulation to Evaluate Importance of Schedule in Topotecan Therapy for Pediatric Neuroblastoma
Authors: Panetta John C. , Schaiquevich Paula , Santana Victor M. , Stewart Clinton F.
Published: January 2008

Purpose: The study aims to use mathematical modeling and simulation to assess the relative contribution of topotecan systemic exposure and scheduling in the activity and myelosuppression of topotecan in pediatric patients with neuroblastoma.

Experimental Design: Pharmacokinetic and pharmacodynamic data were obtained from a phase II study for pediatric patients with high-risk neuroblastoma. The topotecan dosage was individualized to attain a topotecan lactone area under the plasma concentration-time curve between 80 and 120 ng/mL h and given over a protracted schedule (i.e., 10 days). Four mathematical models describing topotecan pharmacokinetics, tumor growth, and neutrophil and platelet dynamics were developed. The models were combined to simulate and compare different topotecan treatment strategies with respect to systemic exposure and schedule.

Results: The median change in tumor volume was significantly different between schedules (5% increase for D × 5 versus 60% decrease for D × 5 × 2; P < 0.0001) when administering the same total systemic exposure. Whereas protracted schedules showed increased neutropenia (median of 7 versus 12 days below an absolute neutrophil count of 500/μL; P < 0.0001) and thrombocytopenia (median of 3 versus 10 days below a platelet count of 20,000/μL; P < 0.00001), simulations showed that delays in topotecan therapy would not be required. Simulations showed that an increase in topotecan exposure on the D × 5 schedule by 2.4-fold resulted in a modest decrease in tumor volume (i.e., median percentage change tumor volume of 24% versus 3%).

Conclusions: The present mathematical model gave an innovative approach to determining relevant topotecan schedules for possible evaluation in the clinic, which could lead to improved tumor response with minimized toxicities.
A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer
Authors: Dahut William L. , Scripture Charity , Posadas Edwin , Jain Lokesh , Gulley James L. , Arlen Philip M. , Wright John J. , Yu Yunkai , Cao Liang , Steinberg Seth M. , Aragon-Ching Jeanny B. , Venitz Jürgen , Jones Elizabeth , Chen Clara C. , Figg William D.
Published: January 2008

Purpose: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC).

Experimental Design: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles.

Results: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimenn. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0-12) and maximum concentration (Cmax) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (tmax) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively.

Conclusions: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.
Forkhead Transcription Factors and Cardiovascular Biology
Authors: Papanicolaou Kyriakos N. , Izumiya Yasuhiro , Walsh Kenneth
Published: January 2008

The Forkhead family of transcription factors modulates a wide variety of cellular functions in cardiovascular tissues. In this review article, we discuss recent advances in our understanding of regulation provided by the forkhead factors in cardiac myocytes and vascular cells.
Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease
Authors: Tonelli Marcello , Sacks Frank , Arnold Malcolm , Moye Lemuel , Davis Barry , Pfeffer Marc
Published: January 2008

Background—

Higher levels of red blood cell distribution width (RDW) may be associated with adverse outcomes in patients with heart failure. We examined the association between RDW and the risk of all-cause mortality and adverse cardiovascular outcomes in a population of people with coronary disease who were free of heart failure at baseline.

Methods and Results—

We performed a post hoc analysis of data from the Cholesterol and Recurrent Events study. Baseline RDW was measured in 4111 participants who were randomized to receive pravastatin 40 mg daily or placebo and followed for a median of 59.7 months. We used Cox proportional hazards models to examine the association between RDW and adverse clinical outcomes. During nearly 60 months of follow-up, 376 participants died. A significant association was noted between baseline RDW level and the adjusted risk of all-cause mortality (hazard ratio per percent increase in RDW, 1.14; 95% confidence interval, 1.05 to 1.24). After categorization based on quartile of baseline RDW and further adjustment for hematocrit and other cardiovascular risk factors, a graded independent relation between RDW and death was observed (
P
for trend=0.001). For instance, participants with RDW in the highest quartile had an adjusted hazard ratio for death of 1.78 (95% confidence interval, 1.28 to 2.47) compared with those in the lowest quartile. Higher levels of RDW were also associated with increased risk of coronary death/nonfatal myocardial infarction, new symptomatic heart failure, and stroke.

Conclusions—

We found a graded independent relation between higher levels of RDW and the risk of death and cardiovascular events in people with prior myocardial infarction but no symptomatic heart failure at baseline.
Effects of Salt Compensation on the Climate Model Response in Simulations of Large Changes of the Atlantic Meridional Overturning Circulation*
Authors: Stocker Thomas F. , Timmermann Axel , Renold Manuel , Timm Oliver
Published: January 2008

Freshwater hosing experiments with a comprehensive coupled climate model and a coupled model of intermediate complexity are performed with and without global salt compensation in order to investigate the robustness of the bipolar seesaw. In both cases, a strong reduction of the Atlantic meridional overturning circulation is induced, and a warming in the South Atlantic results. When a globally uniform salt flux is applied at the surface in order to keep the global mean salinity constant, this causes additional widespread warming in the Southern Ocean. It is shown that this warming is mainly due to heat transport anomalies that are induced by the specific parameterization in ocean models to represent eddy mixing. Surface salt fluxes tend to move outcropping isopycnals equatorward. As the density perturbation originates at the surface, changes in isopycnal slopes are generated that lead to anomalies in the bolus velocity field. The associated bolus heat flux convergence creates a warming enhancing the bipolar seesaw response, particularly in the Southern Ocean. The importance of this mechanism is illustrated in coupled model simulations in which this parameterization in the ocean model component is switched on or off. Additional experiments in which the same total amount of freshwater is delivered at rates 10 times smaller show that the effect of the global salt compensation is not important in this case, but that the eddy-mixing parameterization is still responsible for a substantial temperature response in the Southern Ocean.
The Granular Sea Ice Model in Spherical Coordinates and Its Application to a Global Climate Model
Authors: Sedlacek Jan , Lemieux Jean-François , Mysak Lawrence A. , Tremblay L. Bruno , Holland David M.
Published: January 2008

The granular sea ice model (GRAN) from Tremblay and Mysak is converted from Cartesian to spherical coordinates. In this conversion, the metric terms in the divergence of the deviatoric stress and in the strain rates are included. As an application, the GRAN is coupled to the global Earth System Climate Model from the University of Victoria. The sea ice model is validated against standard datasets. The sea ice volume and area exported through Fram Strait agree well with values obtained from in situ and satellite-derived estimates. The sea ice velocity in the interior Arctic agrees well with buoy drift data. The thermodynamic behavior of the sea ice model over a seasonal cycle at one location in the Beaufort Sea is validated against the Surface Heat Budget of the Arctic Ocean (SHEBA) datasets. The thermodynamic growth rate in the model is almost twice as large as the observed growth rate, and the melt rate is 25% lower than observed. The larger growth rate is due to thinner ice at the beginning of the SHEBA period and the absence of internal heat storage in the ice layer in the model. The simulated lower summer melt is due to the smaller-than-observed surface melt.
Connection between Spring Conditions and Peak Summer Monsoon Rainfall in South America: Role of Soil Moisture, Surface Temperature, and Topography in Eastern Brazil
Authors: Grimm Alice M. , Pal Jeremy S. , Giorgi Filippo
Published: January 2008

A link between peak summer monsoon rainfall in central-east Brazil, composing part of the South American monsoon core region, and antecedent conditions in spring is disclosed. Rainfall in this region during part of spring holds a significant inverse correlation with rainfall in peak summer, especially during ENSO years. A surface–atmosphere feedback hypothesis is proposed to explain this relationship: low spring precipitation leads to low spring soil moisture and high late spring surface temperature; this induces a topographically enhanced low-level anomalous convergence and cyclonic circulation over southeast Brazil that enhances the moisture flux from northern and central South America into central-east Brazil, setting up favorable conditions for excess rainfall. Antecedent wet conditions in spring lead to opposite anomalies. The main links in this hypothesis are confirmed through correlation analysis of observed data: spring precipitation is negatively correlated to late spring surface temperature in central-east Brazil, and surface temperature in southeast Brazil is positively correlated with peak summer monsoon precipitation in central-east Brazil. The intermediary links of the surface–atmosphere feedback are tested in sensitivity experiments with the regional climate model version 3 (RegCM3). These experiments confirm that the proposed links are possible: the reduced soil moisture in central-east Brazil is shown to increase the surface temperature and produce a cyclonic anomaly over southeast Brazil, as well as increased precipitation in central-east Brazil. A crucial role of the mountains of southeast Brazil in anchoring the patterns of intraseasonal variability, and sustaining the “dipolelike” precipitation mode observed over South America, is suggested. The low predictability of monsoon rainfall anomalies in central-east Brazil during the austral summer might be partially ascribed to the fact that the models do not well reproduce the topographical features and the land–atmosphere interactions that are important for the variability in that region.
Heterogeneous Distribution of Rainfall and Discharge Regimes in the Ecuadorian Amazon Basin
Authors: Laraque A. , Ronchail J. , Cochonneau G. , Pombosa R. , Guyot J. L.
Published: January 2008

The hydrology of the Ecuadorian Amazon basin is still poorly documented. The research developed between the Institute for Research and Development (IRD) and the National Institute of Meteorology and Hydrology (INAMHI) of Ecuador takes advantage of a newly available rainfall and discharge dataset to explore spatial distribution and regimes in this region (135 600 km2). Forty-seven rainfall and 27 discharge stations were retained over a 30-yr period (1965–94). A new annual isoyets map is proposed for the Amazon basin of Ecuador. The most striking result is a high spatial regime variability, to the extent that out-of-phase regimes are found in nearby stations. Indeed, in high intra-Andean basins there is a marked bimodal rainfall regime, with maxima in March–April and in October and a minimum from June to August. On the contrary, as moisture transport reaches a maximum in June, a rainfall peak can also be observed at the same time on slopes to the east due to the moist easterlies. In the lowlands, a bimodal regime is observed as in the intra-Andean basin; as water vapor is abundant, seasonal variability is not as strong as in the Andes. Discharge regimes are related to rainfall regimes. However, even if no delay is observed between maximum rainfall and maximum discharge in the inner Andean basins, a delay varying from one to two months is observed in larger basins. Soil conditions also affect the discharge regime in the upper and inner Andes: paramo soils (a kind of tundra formation) release water, in particular after the March–April rainfall peak, and sustain the dry season runoff.
Flash Flood Forecasting for Small Urban Watersheds in the Baltimore Metropolitan Region
Authors: Javier Julie Rose N. , Smith James A. , Meierdiercks Katherine L. , Baeck Mary Lynn , Miller Andrew J.
Published: January 2008

The utility of distributed hydrologic models in combination with high-resolution Weather Surveillance Radar-1988 Doppler (WSR-88D) rainfall estimates for flash flood forecasting in urban drainage basins is examined through model simulations of 10 flood events in the 14.3 km2 Dead Run watershed of Baltimore County, Maryland. The hydrologic model consists of a simple infiltration model and a geomorphological instantaneous unit hydrograph–based representation of hillslope and channel response. Analyses are based on high-resolution radar rainfall estimates from the Sterling, Virginia, WSR-88D and observations from a nested network of 6 stream gauges in the Dead Run watershed and a network of 17 rain gauge stations in Dead Run. For the three largest flood peaks in Dead Run, including the record flood on 7 July 2004, hydrologic model forecasts do not capture the pronounced attenuation of flood peaks. Hydraulic controls imposed by valley bottom constrictions associated with bridges and bridge abutments are a dominant element of the extreme flood response of small urban watersheds. Model analyses suggest that a major limitation on the accuracy of flash flood forecasting in urban watersheds is imposed by storm water management infrastructure. Model analyses also suggest that there is potential for improving model forecasts through the utilization of information on initial soil moisture storage. Errors in the rainfall field, especially those linked to bias correction, are the largest source of uncertainty in quantitative flash flood forecasting. Bias correction of radar rainfall estimates is an important element of flash flood forecasting systems.
A Practical Approach to Sequential Estimation of Systematic Error on Near-Surface Mesoscale Grids
Authors: Hacker Joshua P. , Rife Daran L.
Published: January 2008

Statistical analysis arguments are used to construct an estimation algorithm for systematic error of near-surface temperatures on a mesoscale grid. The systematic error is defined as the observed running-mean error, and an averaging length of 7 days is shown to be acceptable. Those errors are spread over a numerical weather prediction model grid via the statistical analysis equation. Two covariance models are examined: 1) a stationary, isotropic function tuned with the observed running-mean errors and 2) dynamic estimates derived from a recent history of running-mean forecasts. Prediction of error is possible with a diurnal persistence model, where the error at one time of day can be estimated from data with lags of 24-h multiples. The approach is tested on 6 months of 6-h forecasts with the fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5) over New Mexico. Results show that for a quantity such as 2-m temperature, the systematic component of error can be effectively predicted on the grid. The gridded estimates fit the observed running-mean errors well. Cross validation shows that predictions of systematic error result in a substantial error reduction where observations are not available. The error estimates show a diurnal evolution, and are not strictly functions of terrain elevation. Observation error covariances, localization operators, and covariance functions in the isotropic case must be tuned for a specific forecast system and observing network, but the process is straightforward. Taken together, the results suggest an effective method for systematic error estimation on near-surface mesoscale grids in the absence of a useful ensemble. Correction for those errors may provide benefits to forecast users.
The Intersections of Work, Health, Diversity, and Social Justice
Authors: Werth James L. , Borges Nicole J. , McNally Christopher J. , Maguire Colleen P. , Britton Paula J.
Published: January 2008

Although counseling psychology has discussed vocational issues, health concerns, diversity, and social justice, discussion of these topics has typically been narrowly focused. This article uses the example of persons with HIV (PWHIV) to demonstrate how these areas can be intertwined. The counseling psychology literature is also examined to determine the degree to which direction has been provided regarding clients facing health concerns, disabilities, confusion regarding career issues, or possible discrimination. Because HIV is now considered to be a chronic illness for many people, there is an increased likelihood that PWHIV will be faced with employment issues, as well as significant barriers to beginning work, returning to work, or keeping a job. After highlighting characteristics of PWHIV, we review the degree to which the vocational literature addresses the needs and issues of PWHIV. We also examine the role of social justice in relation to PWHIV who are considering work.
Improving of Cell Structure of Microcellular Foams Based on Polypropylene/High-density Polyethylene Blends
Authors: Huang Han-Xiong , Wang Jian-Kang , Sun Xiao-Hui
Published: January 2008

Polypropylene/high-density polyethylene (PP/HDPE) blends and their nanocomposites are melt compounded using twin-screw extruder. The as-extruded samples are then batch foamed with supercritical carbon dioxide. It is demonstrated that the blend with a viscosity ratio close to unity produces a microcellular foam with very uniformly distributed finer cell structure, whereas nonuniformly distributed cells may be obtained in the foamed blend with a viscosity ratio greater than unity. Then three methods are tried to improve the cellular structure of the latter. The results show that the increase of HDPE content improves the uniformity of cellular size and distribution, but results in the increase of cell diameter and the decrease of cell density. Properly lowering the foaming temperature reduces the cell diameter and improves the cellular distribution. Incorporating nanoparticles, including nano-calcium carbonate and nanoclay, into the blend leads to a significantly smaller cell size and more homogeneous cell distribution. A critical content of nanoparticles exists to obtain dramatically improved cell structure. Moreover, the results show that most cells in foamed blends are nearly reticulated. So open-celled foams are achieved in this work.