bluuebunny/crossref_metadata_2025 huggingface dataset:
Front-line Bevacizumab in combination with Oxaliplatin, Leucovorin and 5-Fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study
Authors: Emmanouilides Christos , Sfakiotaki Georgia , Androulakis Nikolaos , Kalbakis Kostas , Christophylakis Charalambos , Kalykaki Antonia , Vamvakas Lambros , Kotsakis Athanasios , Agelaki Sofia , Diamandidou Eleni , Touroutoglou Nikolaos , Chatzidakis Adam , Georgoulias Vassilis , Mavroudis Dimitris , Souglakos John
Published: May 2007

Purpose

To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC).

Patients and Methods

Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d1), oxaliplatin (85 mg/m2 on d1), leucovorin (200 mg/m2) on days 1 and 2 and 5-Fluorouracil (400 mg/m2 as i.v. bolus and 600 mg/m2 as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks.

Results

Fifty three patients (46 with a PS 0–1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%–92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3–4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle.

Conclusion

The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.
Differences in the quality of primary medical care for CVD and diabetes across the NHS: evidence from the quality and outcomes framework
Authors: McLean Gary , Guthrie Bruce , Sutton Matt
Published: May 2007

Background

Health policy in the UK has rapidly diverged since devolution in 1999. However, there is relatively little comparative data available to examine the impact of this natural experiment in the four UK countries. The Quality and Outcomes Framework of the 2004 General Medical Services Contract provides a new and potentially rich source of comparable clinical quality data through which we compare quality of primary medical care for coronary heart disease (CHD), stroke, hypertension and diabetes across the four UK countries.

Methods

A cross-sectional analysis was undertaken involving 10,064 general practices in England, Scotland, Wales and Northern Ireland. The main outcome measures were prevalence rates for CHD, stroke, hypertension and diabetes. Achievement on 14 simple process, 3 complex process, 9 intermediate outcome and 5 treatment indicators for the four clinical areas.

Results

Prevalence varies by up to 28% between the four UK countries, which is not reflected in resource distribution between countries, and penalises practices in the high prevalence countries (Wales and Scotland). Differences in simple process measures across countries are small. Larger differences are found for complex process, intermediate outcome and treatment measures, most notably for Wales, which has consistently lower quality of care. Scotland has generally higher quality than England and Northern Ireland is most consistently the highest quality.

Conclusion

Previously identified weaknesses in Wales related to waiting times appear to reflect a more general quality problem within NHS Wales. Identifying explanations for the observed differences is limited by the lack of comparable data on practice resources and organisation. Maximising the value of cross-jurisdictional comparisons of the ongoing natural experiment of health policy divergence within the UK requires more detailed examination of resource and organisational differences.
Case control study of the geographic variability of exposure to disinfectant byproducts and risk for rectal cancer
Authors: Bove Gerald E , Rogerson Peter A , Vena John E
Published: May 2007

Background

Levels of byproducts that result from the disinfection of drinking water vary within a water distribution system. This prompted us to question whether the risk for rectal cancer also varies, depending upon one's long term geographic location within the system. Such a geographic distribution in rectal cancer risk would follow naturally from an association between level of byproduct and rectal cancer risk. We assess the effects of estimated geographic variability in exposure to some of the components of the trihalomethane group of disinfectant byproducts (DBPs) on the odds ratios and probabilities for rectal cancer in white males in a case control study of 128 cases and 253 controls, conducted in Monroe County, Western New York State, U.S.A. The study was designed around health data initially collected at the University at Buffalo (Department of Social and Preventative Medicine) as part of the Upstate New York Diet Study, and trihalomethane (THM) data collected from a separate independent study of THMs conducted by Monroe County Department of Health. Case participants were chosen from hospital pathology records. The controls are disease-free white males between 35–90 years old, living in Monroe County, and chosen from control groups for studies from cancer of five other (unrelated) sites. Using a combination of case control methodology and spatial analysis, the spatial patterns of THMs and individual measures of tap water consumption provide estimates of the effects of ingestion of specific amounts of some DBPs on rectal cancer risk. Trihalomethane (THM) data were used to spatially interpolate levels at the taps of cases and controls, and odds ratios were estimated using logistic regression to assess the effects of estimated THM exposure dose on cancer risk, adjusting for alcohol, dietary beta carotene intake, tap water intake, and total caloric intake.

Results

Trihalomethane levels varied spatially within the county; although risk for rectal cancer did not increase with total level of trihalomethanes, increasing levels of the component bromoform (measured in ug/day) did correspond with an increase in odds ratios (OR = 1.85; 95% CI = 1.25 – 2.74) for rectal cancer. The highest quartiles of estimated consumption of bromoform (1.69–15.43 ug/day) led to increased risk for rectal cancer (OR = 2.32; 95% CI = 1.22–4.39). Two other THMs were marginally associated with an increase in risk – chlorodibromomethane (OR = 1.78, 95% CI = 1.00–3.19) and bromodichloromethane (OR = 1.15; 95% CI = 1.00–1.32).

Conclusion

Levels of THMs in the water distribution system exhibited spatial variation that was partially due to variation in water age. We also observed a geographic pattern of increased risk of rectal cancer in areas with the highest levels of bromoform in the county.
Developmental expression of DAX1 in the European sea bass, Dicentrarchus labrax: lack of evidence for sexual dimorphism during sex differentiation
Authors: Martins Rute ST , Deloffre Laurence AM , Mylonas Constantinos C , Power Deborah M , Canário Adelino VM
Published: May 2007

Background

DAX1 (NR0B1), a member of the nuclear receptors super family, has been shown to be involved in the genetic sex determination and in gonadal differentiation in several vertebrate species. In the aquaculture fish European sea bass, Dicentrarchus labrax, and in the generality of fish species, the mechanisms of sex determination and differentiation have not been elucidated. The present study aimed at characterizing the European DAX1 gene and its developmental expression at the mRNA level.

Methods

A full length European sea bass DAX1 cDNA (sbDAX1) was isolated by screening a testis cDNA library. The structure of the DAX1 gene was determined by PCR and Southern blot. Multisequence alignments and phylogenetic analysis were used to compare the translated sbDAX1 product to that of other vertebrates. sbDAX1 expression was analysed by Northern blot and relative RT-PCR in adult tissues. Developmental expression of mRNA levels was analysed in groups of larvae grown either at 15°C or 20°C (masculinising temperature) during the first 60 days, or two groups of fish selected for fast (mostly females) and slow growth.

Results

The sbDAX1 is expressed as a single transcript in testis and ovary encoding a predicted protein of 301 amino acids. A polyglutamine stretch of variable length in different DAX1 proteins is present in the DNA binding domain. The sbDAX1 gene is composed of two exons, separated by a single 283 bp intron with conserved splice sites in same region of the ligand binding domain as other DAX1 genes. sbDAX1 mRNA is not restricted to the brain-pituitary-gonadal axis and is also detected in the gut, heart, gills, muscle and kidney. sbDAX1 mRNA was detected as early as 4 days post hatching (dph) and expression was not affected by incubation temperature. Throughout gonadal sex differentiation (60–300 dph) no dimorphic pattern of expression was observed.

Conclusion

The sbDAX1 gene and putative protein coding region is highly conserved and has a wide pattern of tissue expression. Although gene expression data suggests sbDAX1 to be important for the development and differentiation of the gonads, it is apparently not sex specific.
Association of TP53codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients
Authors: Toyama Tatsuya , Zhang Zhenhuan , Nishio Mariko , Hamaguchi Maho , Kondo Naoto , Iwase Hirotaka , Iwata Hiroji , Takahashi Satoru , Yamashita Hiroko , Fujii Yoshitaka
Published: May 2007

Introduction

Single-nucleotide polymorphisms (SNPs) in codon 72 of the TP53 (also known as p53) gene (rs1042522) and in the promoter region of the MDM2 gene (SNP309; rs2279744) have been suggested to play roles in many cancers. We investigated whether these SNPs were associated with patient outcome and the effect of adjuvant systemic therapy.

Methods

The genotypes of TP53 codon 72 and MDM2 SNP309 were defined among 557 primary Japanese breast cancer patients (median follow-up, 61.7 months). The effects of several variables on survival were tested by Cox's proportional hazards regression analysis.

Results

We showed that the Pro/Pro genotype of TP53 codon 72 was associated with poorer disease-free survival (DFS) than other genotypes by Kaplan-Meier analysis (P = 0.049) and multivariate Cox's proportional hazards regression analysis (P = 0.047, risk ratio of recurrence = 1.67), whereas MDM2 SNP309 status was not associated with DFS. The association of the Pro/Pro TP53 genotype with poorer DFS was especially significant in patients who received adjuvant chemotherapy (P = 0.009). In contrast, among the patients who had received adjuvant hormonal therapy or no adjuvant systemic therapy, TP53 codon 72 genotype was not associated with DFS.

Conclusion

The Pro/Pro genotype of TP53 codon 72 appears to be an independent prognostic marker in breast cancer patients.
Expression and translocation of fluorescent-tagged p21-activated kinase-binding domain and PH domain of protein kinase B during murine neutrophil chemotaxis
Authors: Magalhães Marco A O , Zhu Fei , Sarantis Helen , Gray-Owen Scott D , Ellen Richard P , Glogauer Michael
Published: May 2007

Neutrophils are key cells of the innate immune system; they are terminally differentiated and therefore difficult to genetically manipulate and study in vitro. In the present study, we describe a protocol to transiently express two fluorescent markers, the PH domain of protein kinase B fused to red fluorescent protein and the p21-activated kinase-binding domain fused to a yellow fluorescent protein, in primary neutrophils. Using this approach, we are able to achieve a transfection efficiency of ∼30%. The expression of the transfected probes occurred within 2 h and allowed for real-time monitoring of intermediates in key neutrophil activation pathways at the leading edge of migrating cells. We describe here a transfection protocol for primary neutrophils, which preserves fMLP-mediated cell polarization and cytoskeleton reorganization with simultaneous accumulation of PI-3K products and active Rac at the leading edge. The visualization and analysis of transfected fluorescent markers in primary neutrophils are a powerful technique to monitor chemotaxis signaling pathways in real time.
Phase I/II Trial of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group Study
Authors: Siu Lillian L. , Soulieres Denis , Chen Eric X. , Pond Gregory R. , Chin Soo F. , Francis Peggy , Harvey Luc , Klein Meri , Zhang Wenjiang , Dancey Janet , Eisenhauer Elizabeth A. , Winquist Eric
Published: May 2007

Purpose

To determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC).

Patients and Methods

HNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate.

Results

A total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m2IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% CI, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% CI, 33% to 65%). Median progression-free survival was 3.3 months (95% CI, 2.7 to 4.8 months) and median overall survival was 7.9 (95% CI, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P = .034).

Conclusion

This schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens.
Predictive and Pharmacodynamic Biomarker Studies in Tumor and Skin Tissue Samples of Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Treated With Erlotinib
Authors: Agulnik Mark , da Cunha Santos Gilda , Hedley David , Nicklee Trudey , dos Reis Patricia Pintor , Ho James , Pond Gregory R. , Chen Heidi , Chen Shuo , Shyr Yu , Winquist Eric , Soulieres Denis , Chen Eric X. , Squire Jeremy A. , Marrano Paula , Kamel-Reid Suzanne , Dancey Janet , Siu Lillian L. , Tsao Ming S.
Published: May 2007

Purpose

Pharmacodynamic tissue studies were conducted on a phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream signaling components, and markers of angiogenesis and apoptosis were evaluated to determine the relationship between correlative end points and clinical outcomes.

Patients and Methods

Pretreatment and during-treatment tumor and skin biopsies, and archival tumor specimens were evaluated for EGFR, phosphorylated (p) -EGFR, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-Akt, Ki67, p27, p-nuclear factor kappa B (NFκB), p-signal transducer and activator of transcription 3 (STAT3), and EGFR gene copy number.

Results

On 37 archival samples, response to therapy was evident in two of four (50%) patients with high EGFR gene copy number tumors and in four of 27 (15%) patients with low gene copy number tumors. On nine paired tumor biopsies, elevated pretreatment levels of p27 and p-STAT3 predicted for prolonged time to progression (TTP) and overall survival (OS; P ≤ .03). With treatment, a decrease in p-EGFR, p-NFκB, and p27 correlated with increased TTP, OS, or both TTP and OS, respectively (P ≤ .04). Multidimensional scaling (MDS) models revealed clustering profiles of tumor markers by immunofluorescence could predict response. On 32 paired skin biopsies, suppression of p-EGFR with therapy correlated with increased OS (P = .045).

Conclusion

High EGFR gene copy in tumor specimens may predict which patients have an increased likelihood of response to erlotinib, and decreased p-EGFR level in skin biopsies during therapy may represent a potential surrogate marker for improved clinical outcome. MDS represents a novel way to evaluate the relationships between molecular markers and clinical outcome. Additional biomarker studies with larger sample sizes are required to elucidate HNSCC patients who may benefit from this targeted therapy.
Assessment of Care by Breast Cancer Patients Participating or Not Participating in a Randomized Controlled Trial: A Report With the Patients' Committee for Clinical Trials of the Ligue Nationale Contre le Cancer
Authors: Julian-Reynier Claire , Genève Jean , Dalenc Florence , Genre Dominique , Monnier Alain , Kerbrat Pierre , Largillier Rémy , Serin Daniel , Rios Maria , Roché Henri , Jimenez Marta , Tarpin Carole , Maraninchi Dominique
Published: May 2007

Purpose

Cancer patients participating in randomized controlled trials (RCTs) have not been found to have better clinical outcomes than other patients. Our objective was to assess the impact of RCTs on patients' satisfaction with care.

Patients and Methods

A prospective study was carried out in a cohort of women with breast cancer (N = 455) divided into those invited to participate in an RCT (201 acceptances, 66 refusals) and a comparable control group not invited to participate (n = 188). All the patients underwent the same treatment (fluorouracil, epirubicin, and cyclophosphamide 100 mg/m2 for six cycles). One and 7 months after the beginning of chemotherapy, self-administered satisfaction scores were used to compare the women's assessment of their care (Comprehensive Assessment of Satisfaction with Care validated scale).

Results

At the beginning of chemotherapy, women to whom RCT had been proposed rated the doctors' availability (average ± standard deviation [SD]: RCT acceptance group, 3.60 ± 0.78; RCT refusal group, 3.68 ± 0.87; control group, 3.41 ± 0.82; P ≤ .02) and the doctors' communication (average ± SD: RCT acceptance group, 3.56 ± 0.88; RCT refusal group, 3.67 ± 0.88; control group, 3.39 ± 0.84; P ≤ .05) higher than those to whom the trial was not proposed. After the treatment, participants in the RCT felt that their doctor was more supportive (average ± SD: RCT acceptance group, 3.04 ± 0.92; control group, 2.77 ± 0.85; P = .005) and more informative about their illness and treatment (average ± SD: RCT acceptance group, 3.34 ± 0.88; control group, 3.08 ± 0.92; P = .006) than those in the control group. The general level of satisfaction was also higher in the RCT acceptance group.

Conclusion

Women participating in an RCT have a more positive picture of their doctors' care than others, probably because of the structural effects of the informed consent and data collection processes.
Economic Analysis of NCIC CTG JBR.10: A Randomized Trial of Adjuvant Vinorelbine Plus Cisplatin Compared With Observation in Early Stage Non–Small-Cell Lung Cancer—A Report of the Working Group on Economic Analysis, and the Lung Disease Site Group, National Cancer Institute of Canada Clinical Trials Group
Authors: Ng Raymond , Hasan Baktiar , Mittmann Nicole , Florescu Marie , Shepherd Frances A. , Ding Keyue , Butts Charles Andrew , Cormier Yvon , Darling Gail , Goss Glenwood D. , Inculet Richard , Seymour Lesley , Winton Timothy L. , Evans William K. , Leighl Natasha B.
Published: May 2007

Purpose

National Cancer Institute of Canada Clinical Trials Group JBR.10 study is among the landmark trials that have established third generation platinum-based adjuvant chemotherapy as the standard of care after resection of stages IB-II NSCLC, improving absolute 5-year survival by 15% and median survival by 21 months. This cost-effectiveness analysis of adjuvant chemotherapy from the perspective of Canada's public health care system was undertaken based on the JBR.10 study population.

Patients and Methods

The primary outcome of the study was the incremental cost effectiveness ratio (ICER) expressed in dollars per life-year gained (LYG). Direct medical resource utilization data were collected retrospectively from trial data and medical records of patients enrolled in the JBR.10 study at the five largest accruing Canadian centers, from the time of random assignment until death or study closure (April 2004). Survival and available costs (2005 Canadian dollars [$CAD]) are presented both with and without discounting at 5% per year.

Results

Utilization data were collected from 172 Canadian patients (36% of the trial population), 85 randomly assigned to observation and 87 randomly assigned to chemotherapy. The mean costs of treatment per patient in the observation and adjuvant chemotherapy arms were $23,878 and $31,319, respectively, with an ICER of CAD$7,175/LYG discounted (95% CI, −$3,463 to $41,565), and $10,096/LYG undiscounted (95% CI, −$819 to $55,651).

Conclusion

Adjuvant vinorelbine plus cisplatin is a highly cost effective treatment that compares very favorably with other standard health care interventions.
Predominant Treatment Failure in Postprostatectomy Patients Is Local: Analysis of Patterns of Treatment Failure in SWOG 8794
Authors: Swanson Gregory P. , Hussey Michael A. , Tangen Catherine M. , Chin Joseph , Messing Edward , Canby-Hagino Edith , Forman Jeffrey D. , Thompson Ian M. , Crawford E. David
Published: May 2007

Purpose

Southwest Oncology Group (SWOG) trial 8794 demonstrated that adjuvant radiation reduces the risk of biochemical (prostate-specific antigen [PSA]) treatment failure by 50% over radical prostatectomy alone. In this analysis, we stratified patients as to their preradiation PSA levels and correlated it with outcomes such as PSA treatment failure, local recurrence, and distant failure, to serve as guidelines for future research.

Patients and Methods

Four hundred thirty-one subjects with pathologically advanced prostate cancer (extraprostatic extension, positive surgical margins, or seminal vesicle invasion) were randomly assigned to adjuvant radiotherapy or observation.

Results

Three hundred seventy-four eligible patients had immediate postprostatectomy and follow-up PSA data. Median follow-up was 10.2 years. For patients with a postsurgical PSA of ≤ 0.2 ng/mL, radiation was associated with reductions in the 10-year risk of biochemical treatment failure (72% to 42%), local failures (20% to 7%), and distant failures (12% to 4%). For patients with a postsurgical PSA between higher than 0.2 and ≤ 1.0 ng/mL, reductions in the 10-year risk of biochemical failure (80% to 73%), local failures (25% to 9%), and distant failures (16% to 12%) were realized. In patients with postsurgical PSA higher than 1.0, the respective findings were 94% versus 100%, 28% versus 9%, and 44% versus 18%.

Conclusion

The pattern of treatment failure in high-risk patients is predominantly local with a surprisingly low incidence of metastatic failure. Adjuvant radiation to the prostate bed reduces the risk of metastatic disease and biochemical failure at all postsurgical PSA levels. Further improvement in reducing local treatment failure is likely to have the greatest impact on outcome in high-risk patients after prostatectomy.
Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check
Authors: Muldoon Leslie L. , Soussain Carole , Jahnke Kristoph , Johanson Conrad , Siegal Tali , Smith Quentin R. , Hall Walter A. , Hynynen Kullervo , Senter Peter D. , Peereboom David M. , Neuwelt Edward A.
Published: May 2007

Purpose

This review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006.

Results

Chemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking.

Conclusion

In this article, we review drug delivery across the BBB, as well as blood-tumor and –cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.
Increased Permeability of the Blood-Brain Barrier to Chemotherapy in Metastatic Brain Tumors: Establishing a Treatment Paradigm
Authors: Gerstner Elizabeth R. , Fine Robert L.
Published: May 2007

There is no accepted standard of care for the chemotherapy treatment of metastatic brain tumors, which has been generally limited to lipophilic alkylators, which may not have efficacy against the tumor that metastasized to the brain. More than 50% of chemotherapy agents are natural product drugs, which are rarely used in the treatment of metastatic brain tumors because they are thought to not cross the blood-brain barrier (BBB). A major protein constituent in the BBB is P-glycoprotein (P-gp), which pumps natural product chemotherapy drugs and toxins out of the CNS. However, P-gp expression in the neovasculature of metastatic brain tumors is similar to the P-gp expression in the neovasculature of the primary, extracranial tumor. In contrast, gliomas have higher P-gp expression in their neovasculature, similar to the greater intrinsic expression of P-gp in normal brain vasculature. This decreased immunohistochemical expression of P-gp in the neovasculature of metastatic tumors, as well as our recent pharmacologic demonstration of increased tissue concentrations of paclitaxel in metastatic brain tumors compared with gliomas, support the idea that the choice of chemotherapy agents should be based on the histologic origin of the metastatic brain tumor and not on the lipophilicity of the drug. Our hypothesis is that metastatic brain tumors from tumors with intrinsically low P-gp expression (eg, lung, melanoma, and untreated breast) may be more permeable to natural product chemotherapy drugs than gliomas. This information could lead to a paradigm shift in the use of natural product drugs for metastatic brain tumors.
Brain White Matter Expansion in Human Obesity and the Recovering Effect of Dieting
Authors: Haltia Lauri T. , Viljanen Antti , Parkkola Riitta , Kemppainen Nina , Rinne Juha O. , Nuutila Pirjo , Kaasinen Valtteri
Published: May 2007

Context and Objective: Obesity is associated with several metabolic abnormalities. Recent studies suggest that obesity also affects brain function and is a risk factor for some degenerative brain diseases. The objective of this study was to examine the effects of weight gain and weight loss on brain gray and white matter structure. We hypothesized that possible differences seen in the brains of obese subjects would disappear or diminish after an intensive dieting period.

Methods: In part I of the study, we scanned with magnetic resonance imaging 16 lean (mean body mass index, 22 kg/m2) and 30 obese (mean body mass index, 33 kg/m2) healthy subjects. In part II, 16 obese subjects continued with a very low-calorie diet for 6 wk, after which they were scanned again. Regional brain white and gray matter volumes were calculated using voxel-based morphometry.

Results: White matter volumes were greater in obese subjects, compared with lean subjects in several basal brain regions, and obese individuals showed a positive correlation between white matter volume in basal brain structures and waist to hip ratio. The detected white matter expansion was partially reversed by dieting. Regional gray matter volumes did not differ significantly in obese and lean subjects, and dieting did not affect gray matter.

Conclusions: The precise mechanism for the discovered white matter changes remains unclear, but the present study demonstrates that obesity and dieting are associated with opposite changes in brain structure. It is not excluded that white matter expansion in obesity has a role in the neuropathogenesis of degenerative brain diseases.
Follicle-Stimulating Hormone Induces Multiple Signaling Cascades: Evidence that Activation of Rous Sarcoma Oncogene, RAS, and the Epidermal Growth Factor Receptor Are Critical for Granulosa Cell Differentiation
Authors: Wayne Chad M. , Fan Heng-Yu , Cheng Xiaodong , Richards JoAnne S.
Published: May 2007

FSH regulates ovarian granulosa cell differentiation not only by activating adenylyl cyclase and protein kinase A (PKA) but also by other complex mechanisms. Using primary rat granulosa cell cultures, we provide novel evidence that FSH rapidly activates two small GTP-binding proteins RAP1 and RAS. FSH activation of RAP1 requires cAMP-mediated activation of exchange factor activated by cAMP/RAPGEF3 whereas FSH activation of RAS and downstream signaling cascades involves multiple factors. Specifically, FSH activation of RAS required Rous sarcoma oncogene (SRC) family tyrosine kinase (SFK) and epidermal growth factor receptor (EGFR) tyrosine kinase activities but not PKA. FSH-induced phosphorylation of ERK1/2 was blocked by dominant-negative RAS as well as by inhibitors of EGFR tyrosine kinase, metalloproteinases involved in growth factor shedding, and SFKs. In contrast, FSH-induced phosphorylation of protein kinase B (PKB/AKT) and the Forkhead transcription factor, FOXO1a occurred by SFK-dependent but RAS-independent mechanisms. The SFKs, c-SRC and FYN, and the SRC-related tyrosine kinase ABL were present and phosphorylated rapidly in response to FSH. Lastly, the EGF-like factor amphiregulin (AREG) activated RAS and ERK1/2 phosphorylation in granulosa cells by mechanisms that were selectively blocked by an EGFR antagonist but not by an SFK antagonist. However, AREG-mediated phosphorylation of PKB and FOXO1a required both EGFR and SFK activation. Moreover, we show that FSH induces AREG and that activation of the EGFR impacts granulosa cell differentiation and the expression of genes characteristic of the luteal cell phenotype. Thus, FSH orchestrates the coordinate activation of three diverse membrane-associated signaling cascades (adenylyl cyclase, RAS, and SFKs) that converge downstream to activate specific kinases (PKA, ERK1/2, and PKB/FOXO1a) that control granulosa cell function and differentiation.
Wnt signaling is a key mediator ofCdx1expression in vivo
Authors: Pilon Nicolas , Oh Karen , Sylvestre Jean-René , Savory Joanne G. A. , Lohnes David
Published: May 2007

In the mouse, Cdx1 is essential for normal anteroposterior vertebral patterning through regulation of a subset of Hox genes. Retinoic acid (RA) and certain Wnts have also been implicated in vertebral patterning, although the relationship between these signaling pathways and the regulation of mesodermal Hox gene expression is not fully understood. Prior work has shown that Cdx1 is a direct target of both Wnt and retinoid signaling pathways,and might therefore act to relay these signals to the Hox genes. Wnt and RA are believed to impact on Cdx1 through an atypical RA-response element (RARE) and Lef/Tcf-response elements (LRE), respectively, in the proximal promoter. To address the roles of these regulatory motifs and pathways, we derived mice mutated for the LRE or the LRE plus the RARE. In contrast to RARE-null mutants, which exhibit limited vertebral defects,LRE-null and LRE+RARE-null mutants exhibited vertebral malformations affecting the entire cervical region that closely phenocopied the malformations seen in Cdx1-null mutants. Mutation of the LRE also greatly reduced induction of Cdx1 by RA, demonstrating a requirement for Wnt signaling in the regulation of this gene by retinoids. LRE and LRE+RARE mutants also exhibited vertebral fusions, suggesting a defect in somitogenesis. As Wnt signaling is implicated in somitogenesis upstream of the Notch pathway, it is conceivable that Cdx1 might play a role in this process. However, none of the Notch pathway genes assessed was overtly affected.
Crk-associated substrate (Cas) signaling protein functions with integrins to specify axon guidance during development
Authors: Huang Zhiyu , Yazdani Umar , Thompson-Peer Katherine L. , Kolodkin Alex L. , Terman Jonathan R.
Published: May 2007

Members of the Cas family of Src homology 3 (SH3)-domain-containing cytosolic signaling proteins are crucial regulators of actin cytoskeletal dynamics in non-neuronal cells; however, their neuronal functions are poorly understood. Here, we identify a Drosophila Cas (DCas), find that Cas proteins are highly expressed in neurons and show that DCas is required for correct axon guidance during development. Functional analyses reveal that Cas specifies axon guidance by regulating the degree of fasciculation among axons. These guidance defects are similar to those observed in integrin mutants, and genetic analysis shows that integrins function together with Cas to facilitate axonal defasciculation. These results strongly support Cas proteins working together with integrins in vivo to direct axon guidance events.
Endocardium is necessary for cardiomyocyte movement during heart tube assembly
Authors: Holtzman Nathalia Glickman , Schoenebeck Jeffrey J. , Tsai Huai-Jen , Yelon Deborah
Published: May 2007

Embryonic heart formation requires the union of bilateral populations of cardiomyocytes and their reorganization into a simple tube. Little is known about the morphogenetic mechanisms that coordinate assembly of the heart tube and determine its dimensions. Using time-lapse confocal microscopy to track individual cardiomyocyte movements in the zebrafish embryo, we identify two morphologically and genetically separable phases of cell movement that coordinate heart tube assembly. First, all cardiomyocytes undergo coherent medial movement. Next, peripherally located cardiomyocytes change their direction of movement, angling toward the endocardial precursors and thereby establishing the initial circumference of the nascent heart tube. These two phases of cardiomyocyte behavior are independently regulated. Furthermore, we find that myocardial-endocardial interactions influence the second phase by regulating the induction, direction and duration of cardiomyocyte movement. Thus, the endocardium plays a crucial early role in cardiac morphogenesis,organizing cardiomyocytes into a configuration appropriate for heart tube assembly. Together, our data reveal a dynamic cellular mechanism by which tissue interactions establish organ architecture.
Characterization of NIP2/centrobin, a novel substrate of Nek2, and its potential role in microtubule stabilization
Authors: Jeong Yeontae , Lee Jungmin , Kim Kyeongmi , Yoo Jae Cheal , Rhee Kunsoo
Published: May 2007

Nek2 is a mitotic kinase whose activity varies during the cell cycle. It is well known that Nek2 is involved in centrosome splitting, and a number of studies have indicated that Nek2 is crucial for maintaining the integrity of centrosomal structure and microtubule nucleation activity. In the present study, we report that NIP2, previously identified as centrobin, is a novel substrate of Nek2. NIP2 was daughter-centriole-specific, but was also found in association with a stable microtubule network of cytoplasm. Ectopic NIP2 formed aggregates but was dissolved by Nek2 into small pieces and eventually associated with microtubules. Knockdown of NIP2 showed significant reduction of microtubule organizing activity, cell shrinkage, defects in spindle assembly and abnormal nuclear morphology. Based on our results, we propose that NIP2 has a role in stabilizing the microtubule structure. Phosphorylation may be crucial for mobilization of the protein to a new microtubule and stabilizing it.
Uterine involvement in guineapig salmonellosis
Authors: Okewole P. A. , Uche E. M. I. , Oyetunde I. L. , Odeyemi P. S. , Dawul P. B.
Published: May 2007

Of 334 mature breeding guineapigs, 53 (15·9%) died in a disease outbreak involving Salmonella typhimurium serotypes 1, 4, 5 and 12 : i : 1,2. The uterus was consistently involved.

Nine other Salmonella-free mature female guineapigs when inoculated with a pure isolate from the outbreak, using the subcutaneous, intramuscular or per os route, succumbed to salmonellosis, reproducing signs and lesions observed during the outbreak.

Abortion was not recorded during the outbreak despite many pregnant sows being affected.

The isolate was sensitive to gentamicin, tetracycline, ampicillin and cefuroxime but resistant to co-trimoxazole, erythromycin and penicillin.
A method for intratracheal instillation of endotoxin into the lungs of mice
Authors: Starcher B. , Williams I.
Published: May 2007

A detailed method is presented for the intratracheal instillation of fluids into the lungs of mice. Using 125I-albumen it was determined that 25-50 µl of volume gave almost equal distribution to all lobes of the mouse lung. Extremely low levels of endotoxin given intratracheally (12·5-25 ng) resulted in a dramatic increase in the neutrophil content of the lung. The increase started in less than 4 h, reaching levels of 7 × 105 by 18 h and was maintained at elevated levels for at least 48 h. This neutrophil count represented more than 90% of the cell population of the lung.
Squamous-cell carcinoma and oral, pharyngeal and nasal lesions caused by foreign bodies in feed. Cases from a long-term study in rats
Authors: Madsen C.
Published: May 2007

In a carcinogenicity study 443 out of 956 rats had chaff from oat and barley in the mouth between the molars and the gingiva. These foreign bodies caused chronic irritation and inflammation. In 173 animals disruption of tissue caused by the foreign bodies led to pathological communication between the mouth, pharynx and nose. Carcinomas in the oral, pharyngeal or nasal cavity were found in 101 of the 443 animals. Twenty-two animals died and 96 were killed because of intestinal gaseous distension. The intestinal distension was related significantly to the pathological communication between the mouth and pharynx/nose. The study shows that the foreign body-induced chronic irritation and inflammation in the epithelium of the mouth, pharynx and nose can lead to formation of squamous-cell carcinomas. The pathogenesis of the intestinal distension is discussed.
Probe Molecule-Dependent Particle Density and its Effect on the Supercritical Gas Adsorption Isotherm of Nanoporous Cu Complex Crystals
Authors: Noguchi Hiroshi , Kondo Atsushi , Kajiro Hiroshi , Kanoh Hirofumi , Kaneko Katsumi
Published: May 2007

Accurate particle densities of the Cu-based metal organic framework [Cu(4,4'-bipyridine)2(BF4)2] for He, N2 and CH4 molecules using the high-pressure buoyancy method have been determined. A smaller probe molecule gave a larger particle density (1.70 g/ml from He, 1.66 g/ml from N2, 1.60 g/ml from CH4). The effect of particle density on the evaluation of the surface excess mass for supercritical gas adsorption was examined; the above particle density difference gave rise to a 2–4% difference in the surface excess mass.
Formation of Ultra-Thin Nanotubular Chrysotile Particles and Their Thermal Properties
Authors: Kittaka Shigeharu , Matsuda Tomoko , Yamaguchi Keisuke , Yamashita Akio
Published: May 2007

A simple method of forming ultra-thin chrysotile nanotubes was developed. A solution of MgCl2 and NaOH was treated hydrothermally in the presence of silica or silicate glasses. The thinnest tubular particles, containing pores with an inner diameter of 8–10 nm, an outer diameter of ca. 15 nm and length ca. 150 nm, were formed in the Mg-rich systems. As the NaOH content in the system was increased, the wall thickness increased while the outer diameter was unchanged, i.e. the inner pore size decreased. Newly formed chrysotile decomposed at ca. 500°C, i.e. between the corresponding temperatures for Mg(OH)2 (350°C) and natural chrysotile (600°C). The mesoporosity of the nanotubes was confirmed by the appearance of hysteresis loops in both nitrogen adsorption and water vapour adsorption measurements. Heat treatment led to a narrowing of the pore edges and brought about the sealing of the tube ends. Nitrogen and water adsorption measurements were also performed to analyze the effect of heat treatment on the porous structure and the condensed phases in the pores.
The Adsorption of the Water-Soluble Dye X-BR onto Three Types of Resin: Behaviour and Mechanism
Authors: Yang Weiben , Fan Jun , Li Aimin , Ge Junjie , Zhang Quanxing
Published: May 2007

The adsorption of the water-soluble Reactive dye Brilliant Blue X-BR onto three different types of resins was investigated. The study focused on the static equilibrium adsorption behaviours and other factors influencing the adsorption process. The three resins exhibited different adsorption behaviours and mechanisms for the adsorption of X-BR from aqueous solution. The adsorption isotherms associated with the acrylic ester resin YWB-50 could be well fitted by the Langmuir equation, while those of the resins NDA-150 and D-301 could be well fitted by the Freundlich equation. The adsorption dynamics and desorption process were also investigated as a means of further exploring the difference between the adsorption behaviours and mechanisms on the three resin types.
Loss Rates for Lévy Processes with Two Reflecting Barriers
Authors: Asmussen Søren , Pihlsgård Mats
Published: May 2007

We consider a Lévy process that is reflected at 0 and at K < 0. The reflected process is obtained by adding the difference between the local time at 0 and the local time at K to the sum of the feeding Lévy process and an initial condition. We define the loss rate to be the expectation of the local time at K at time 1 under stationary conditions. The main result of the paper is the identification of the loss rate in terms of the stationary measure of the reflected process and the characteristic triplet of the Lévy process. We also derive asymptotics of the loss rate as K ← ∞ when the drift of the feeding process is negative and the Lévy measure is light tailed. Finally, we extend the results for Lévy processes to hold for Markov-modulated Lévy processes.
A Multiperiod Newsvendor Problem with Partially Observed Demand
Authors: Bensoussan Alain , Çakanyıldırım Metin , Sethi Suresh P.
Published: May 2007

We consider a newsvendor problem with partially observed Markovian demand. Demand is observed if it is less than the inventory. Otherwise, only the event that it is larger than or equal to the inventory is observed. These observations are used to update the demand distribution from one period to the next. The state of the resulting dynamic programming equation is the current demand distribution, which is generally infinite dimensional. We use unnormalized probabilities to convert the nonlinear state transition equation to a linear one. This helps in proving the existence of an optimal feedback ordering policy. So as to learn more about the demand, the optimal order is set to exceed the myopic optimal order. The optimal cost decreases as the demand distribution decreases in the hazard rate order. In a special case with finitely many demand values, we characterize a near-optimal solution by establishing that the value function is piecewise linear.
Mathematical Programs with Complementarity Constraints: Convergence Properties of a Smoothing Method
Authors: Bouza Gemayqzel , Still Georg
Published: May 2007

In this paper, optimization problems P with complementarity constraints are considered. Characterizations for local minimizers \bar{x} of P of Orders 1 and 2 are presented. We analyze a parametric smoothing approach for solving these programs in which P is replaced by a perturbed problem P_{\tau} depending on a (small) parameter \tau. We are interested in the convergence behavior of the feasible set \cal{F}_{\tau} and the convergence of the solutions \bar{x}_{\tau} of P_{\tau} for \tau\to 0. In particular, it is shown that, under generic assumptions, the solutions \bar{x}_{\tau} are unique and converge to a solution \bar{x} of P with a rate \cal{O}(\sqrt{\tau}). Moreover, the convergence for the Hausdorff distance d(\cal{F}_{\tau}, \cal{F}) between the feasible sets of P_{\tau} and P is of order \cal{O}(\sqrt{\tau}).
Secret Correlation in Repeated Games with Imperfect Monitoring
Authors: Gossner Olivier , Tomala Tristan
Published: May 2007

We characterize the maximum payoff that a team can guarantee against another in a class of repeated games with imperfect monitoring. Our result relies on the optimal tradeoff for the team between optimization of stage payoffs and generation of signals for future correlation.
Preemptive Therapy in Nonneutropenic Patients with Candida Infection Using the Japanese Guidelines
Authors: Tsuruta Ryosuke , Mizuno Hidekazu , Kaneko Tadashi , Oda Yasutaka , Kaneda Kotaro , Fujita Motoki , Inoue Takeshi , Kasaoka Shunji , Maekawa Tsuyoshi
Published: May 2007

Background:

The Japanese Guidelines for the Diagnosis and Treatment of Deep-Seated Mycosis were established in 2003. Proven Candida infection (CI) is defined as at least one positive blood culture yielding a Candida species. Clinically documented CI requires documentation of more than 2 sites of colonization and a positive plasma β-O-glucan test. Possible CI is diagnosed by one of the above criteria in febrile, nonneutropenic critically ill patients.

Objective:

To assess the use of definitions of clinically documented and possible CI for guiding preemptive antifungal therapy in critically ill patients.

Methods:

The patients treated in our intensive care unit (ICU) for at least 48 hours between 2000 and 2004 were investigated. The administration of antifungal agents and ICU mortality were compared among proven, clinically documented, and possible CI groups for age, sex, APACHE II score, diagnosis, length of ICU stay, treatment, number of colonization sites, and plasma β-D-glucan level.

Results:

Six patients were diagnosed with proven CI, 25 were diagnosed with clinically documented CI, and 104 with possible CI. The patients with clinically documented CI were compared with those with possible CI, and statistically significant differences were found in the following variables: APACHE II score (p = 0.018), length of ICU stay (p < 0.01), use of ventilator (p = 0.027), tracheotomy (p = 0.027), number of colonization sites (p < 0.001), plasma β-D-glucan level (p < 0.001), and administration of antifungal agents (p < 0.001); incidence of mortality was not statistically significant (p = 0.33). The shorter length of ICU stay, use of ventilator, and continuous hemodiafiltration were risk factors for death after adjusting for APACHE II score, admission before/after 2003, antifungal therapy, and other factors. Although the frequency of the administration of preemptive antifungal therapy was higher after 2003 than before, the mortality rate did not differ significantly,

Conclusions:

The use of the definitions of clinically documented and possible CI may be beneficial for determining when it is appropriate to initiate preemptive antifungal therapy. However, use of the guidelines did not lead to prevention of possible CI proceeding to clinically documented CI or to improved mortality.