bluuebunny/crossref_metadata_2025 huggingface dataset:
In utero complementation of a neural crest‐derived melanocyte defect using cell directed gene transfer
Authors: Dunn Karen J. , Incao Arturo , Watkins‐Chow Dawn , Li Yi , Pavan William J.
Published: August 2002

Summary: This study describes an in utero approach for overexpressing genes in a cell‐type directed manner. It uses an avian leukosis retroviral expression system coupled with a transgenic mouse line expressing the viral receptor tv‐a from a tissue‐specific promoter (RCAS‐TVA system) (Federspiel et al., 1994, and reviewed in Fisher et al., 1999). A transgenic mouse line was generated expressing tv‐a from the Dopachrome tautomerase promoter (DCT‐tv‐a) in embryonic melanocyte precursors (melanoblasts). RCAS virus encoding β‐galactosidase (RCAS‐LacZ) or tyrosinase (RCAS‐Tyr) was injected in utero into embryonic day 12.5 albino (tyrosinase inactive) mouse embryos. Animals were analyzed for β‐galactosidase activity or tyrosinase activity (hair pigmentation). RCAS gene expression was detected in 44% and 25% of the transgenic mice, respectively. We demonstrate the RCAS‐TVA system coupled with the DCT‐tv‐a line of mice can be used for in utero infection. genesis 30:70–76, 2001. © 2001 Wiley‐Liss, Inc.
Evidence for a major gene influence on abdominal fat distribution: The Minnesota breast cancer family study
Authors: Olson J.E. , Atwood L.D. , Grabrick D.M. , Vachon C.M. , Sellers T.A.
Published: August 2002

Abdominal fat has been shown to be an important risk factor for many chronic conditions, including diabetes, heart disease, and breast cancer. The objective of this study was to provide evidence for a major gene influence on the ratio of waist to hip circumference (WHR), a measurement commonly used in large scale studies to indicate the presence of abdominal fat. Segregation analysis was conducted on three subsets of families from the Minnesota Breast Cancer Family Study. One analysis was conducted among families with WHR measurements on all women. Two additional analyses were conducted on subsets of women stratified on menopausal status. Multiple regression analysis was used to identify factors associated with WHR expressed as a continuous trait. Complex segregation analyses were performed on the continuous trait of WHR and the covariates identified in the regression analysis. In the analysis of all women, all hypotheses were rejected. Among premenopausal women, the environmental hypothesis with no heterogeneity between generations fit the data best (P = 0.85). However, among postmenopausal women, the requirements for conclusion of the presence of a major gene were met. All non‐Mendelian hypotheses were rejected (P < 0.0001), but the additive hypothesis was not rejected (P = 0.19) and provided the best fit to the data. The putative major gene identified by this model accounted for 42% of total phenotypic variance in WHR among these postmenopausal women. The allele for high WHR had a frequency of 27%. These findings support the hypothesis that the distribution of abdominal fat in postmenopausal women is under genetic control. Genet. Epidemiol. 20:458–478, 2001. © 2001 Wiley‐Liss, Inc.
Retroviral labeling of Schwann cells: In vitro characterization and in vivo transplantation to improve peripheral nerve regeneration
Authors: Mosahebi Afshin , Woodward Barbara , Wiberg Mikael , Martin Robin , Terenghi Giorgio
Published: August 2002

Transplantation of Schwann cells (SCs) is a promising treatment modality to improve neuronal regeneration. Identification of the transplanted cells is an important step when studying the development of this method. Genetic labeling is the most stable and reliable method of cell identification, but it is still unclear whether it has deleterious effect on SC characteristics. Our aim was to achieve a stable population of SCs transduced with the lacZ gene at a high frequency using a retroviral vector in vitro, and to follow the labeled SC in vitro to assess their viability and phenotypic marker expression. Furthermore, we transplanted lacZ‐labeled SCs in a conduit to repair peripheral nerve to investigate their effect on nerve regeneration in vivo. Rat and human SCs were cultured and transduced with an MFG lacZ nls marker gene, achieving a transduction rate of 80% and 70%, respectively. Rat SCs were kept in culture for 27 weeks and examined every 4 weeks for expression of lacZ, viability, and phenotypic marker expression of GFAP, p75, MHC I and II. Throughout this period, transduced rat SCs remained viable and continued to proliferate. The proportion of cells expressing lacZ dropped only by 10% and the expression of phenotypic markers remained stable. Transduced human SCs were followed up for 4 weeks in culture. They proliferated and continued to express the lacZ gene and phenotypic marker expression of GFAP and p75 was preserved. Primary culture of transduced rat SCs were transplanted, syngeneically, in a conduit to bridge a 10 mm gap in sciatic nerve and the grafts were examined after 3 weeks for the presence and participation of labeled SCs and for axonal regeneration distance. Transplanted transduced rat SCs were clearly identified, taking part in the regeneration process and enhancing the axonal regeneration rate by 100% (at the optimal concentration) compared to conduits without SCs. Thus, retroviral introduction of lacZ gene has no deleterious effect on SCs in vitro and these SCs take part and enhance nerve regeneration in vivo. GLIA 34:8–17, 2001. © 2001 Wiley‐Liss, Inc.
Alzheimer's disease in the UK: comparative evidence on cost of illness and volume of health services research funding
Authors: Lowin Ana , Knapp Martin , McCrone Paul
Published: August 2002

Objective

To review the economic cost of Alzheimer's disease, to determine the level of research expenditure directed at this illness and to make comparisons with cancer, stroke and heart disease.

Method

A literature search of cost‐of‐illness studies was conducted and major funders of research were contacted. Cost‐of‐illness estimates were updated and adjusted to enable comparability across the four disease areas.

Results

The direct costs of Alzheimer's disease were estimated to be between £7.06 billion and £14.93 billion, which was substantially greater than stroke (£3.2 billion), heart disease (£4.05 billion) and cancer (£1.6 billion excluding informal care costs). Research expenditure on Alzheimer's disease was 57% of that on stroke, 10% of that on heart disease and 3% of that on cancer.

Discussion

Alzheimer's disease imposes a high economic burden. However, spending on research is disproportionately low compared with spending on other major illnesses. In the light of these two findings we recommend further discussion of the distribution of public funding for research into this disease. Copyright © 2001 John Wiley & Sons, Ltd.
Facile synthesis of N,N‐dialkylselenoamides from amides
Authors: Koketsu Mamoru , Okayama Yoshihiro , Aoki Hiroshi , Ishihara Hideharu
Published: August 2002

N,N‐Dialkylamides were chlorinated with oxalyl chloride and then allowed to react with LiAlHSeH to afford the corresponding N,N‐dialkyselenoamides in moderate to good yields. The N,N‐dialkylamides bearing bulky substituent groups were not converted into the corresponding selenoamides because of their steric hindrance. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:195–198, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10016
Reactions of sterically congested 1,6‐ and 1,7‐bis(diazo)alkanes with elemental sulfur and selenium: Formation of cyclohexene, 1,2‐dithiocane, 1,2‐diselenocane, and 1,2,3‐triselenecane derivatives
Authors: Ishii Akihiko , Furusawa Ken , Omata Takenori , Nakayama Juzo
Published: August 2002

The reaction of 3,8‐bis(diazo)‐2,2,4,4,7,7,9,9‐octamethyldecane (5) with elemental selenium in 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) at 130°C yielded 1,2‐di‐tert‐butyl‐3,3,6,6‐tetramethylcyclohexene (1) (64%) and trans‐3,8‐di‐tert‐butyl‐4,4,7,7‐tetramethyl‐1,2‐diselenocane (8) (13%), while that of 5 with elemental sulfur in DBU gave trans‐3, 8‐di‐tert‐butyl‐4,4,7,7‐tetramethyl‐1,2‐dithiocane (9) (77%). The reaction of 3,9‐bis(diazo)‐2,2,4,4,8,8,10,10‐octamethylundecane (6) with elemental selenium in DBU at 80°C gave a cyclic triselenide, cis‐4,10‐di‐tert‐butyl‐5,5,9,9‐tetramethyl‐1,2,3‐triselenecane (11), in 15% yield as the only identifiable product. The structures of 9 and 11 were confirmed by X‐ray crystallography. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:351–356, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10046
Photoinduced electron‐transfer reaction of cyclic oligosilanes and polysilanes in solution
Authors: Karatsu Takashi , Kanayama Koji , Takahashi Masakazu , Ishigohoka Noriaki , Fukui Keijiro , Kitamura Akihide
Published: August 2002

Photoinduced electron‐transfer (PET) reactions were investigated for the cyclic oligosilanes and high molecular weight polysilanes in the presence of 9‐cyanoanthracene (CA), 9,10‐dicyanoanthracene (DCA), and triphenylpyrylium tetrafluoroborate (TPP+BF) using chemical and spectroscopic methods in solution. For the cyclic oligosilanes, the pyranyl radical (TPP·) and silane radical cation were observed as direct evidence of the PET from silanes to TPP+BF, and the reaction quantum yields showed that the ring opening of the radical cation of the cyclic oligosilane competed with the nucleophilic attack on the radical cation by the counter ion of the pyrylium salt and a back electron transfer (BET). For the high molecular weight polysilane, the observation of the transient absorptions of TPP· and the radical cation of polysilane is evidence of the PET, and the extremely long lifetime observed for the radical cation indicates the inefficient BET and reactivities. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:269–275, 2001
Indium‐catalyzed reductive coupling of aromatic carbonyl compounds and imines in the presence of aluminum and chlorosilanes
Authors: Ohtaka Seiji , Mori Kenji , Uemura Sakae
Published: August 2002

Reductive homocoupling of aromatic aldehydes, ketones, and imines has been achieved in tetrahydrofuran (THF) at room temperature using a catalytic amount of InCl3 (0.5–3.0 mol %) under a nitrogen atmosphere in the presence of chlorotrimethylsilane (TMSCl) and aluminum metal (Al) to provide the corresponding 1,2‐diols and 1,2‐diamines, respectively, in good to moderate yields. Other indium compounds such as In(NO3)3, cyclopentadienylindium, and indium metal have also been revealed to be effective as catalysts. The catalytic effect of the indium compound is remarkable, and, thus, without it, no reaction occurs in the case of aromatic aldehydes and aldimines, and an induction period is quite long in the case of aromatic ketones. Without either TMSCl or Al, no reaction proceeds even in the presence of the catalyst. Unfortunately, the diastereoselectivity of the products (dl and meso) is not high. Although the precise reaction scheme is not yet clear, we tentatively propose that a redox‐active In‐Al alloy might be formed on the surface of aluminum in the presence of TMSCl, and an electron transfer from the alloy to substrate might occur. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:309–316, 2001
Organizational Models and Facilitators of Change: Providing a Framework for Student and Academic Affairs Collaboration
Authors: Kezar Adrianna
Published: August 2002

The factors affecting the creation of academic and student affairs collaborations display empirical profiles.
Preoperative evaluation of patients with parathyroid adenoma: Role of high‐resolution ultrasonography
Authors: Ulanovski David , Feinmesser Raphael , Cohen Maya , Sulkes Jaqueline , Dudkiewicz Mickey , Shpitzer Thomas
Published: August 2002

Background

Unilateral parathyroid exploration with adenoma removal and identification of a normal parathyroid gland is a controversial surgical approach to the treatment of primary hyperparathyroidism. The aim of this study was to evaluate the ability of high‐resolution ultrasonography to localize adenomas preoperatively and to assess the effect of such localization on operative time.

Methods

One hundred twenty consecutive previously non‐operated patients with primary hyperparathyroidism underwent ultrasonography before surgery, which consisted of unilateral neck exploration. The procedure was changed to bilateral exploration when justified by the surgical findings.

Results

The sensitivity and positive predictive value of the ultrasonographic examinations were 89% and 98%, respectively. These results were obtained regardless of the size of the adenoma. No significant difference was found in the presence of thyroid multinodular disease (p = .2). A positive sonographic examination decreased the operative time to an average of 59 minutes. The average size of the adenomas was 19 mm (range, 4–55 mm). A positive and highly statistically significant correlation was found between adenoma size and both preoperative calcium level (p = .01) and parathyroid hormone level (p = .0001).

Conclusions

In experienced hands, high‐resolution ultrasonography can be a cost‐effective means of localizing parathyroid adenomas when unilateral neck exploration is considered the acceptable surgical approach. © 2002 John Wiley & Sons, Inc. Head Neck 24: 1–5, 2002.
Low expression of p27Kip1 in advanced mucoepidermoid carcinomas of head and neck
Authors: Choi Choong Sik , Choi Geon , Jung Kwang Yoon , Choi Jong Ouck , Chae Yang Seok
Published: August 2002

Background

p27Kip1, a cyclin‐dependent kinase inhibitor, negatively regulates the G1 phase progression of the cell cycle by binding to the cyclin E/cyclin‐dependent kinase 2 complex. This study was done to investigate the expression of p27Kip1 in mucoepidermoid carcinomas and its usefulness as an indicator in tumor progression, aggressiveness, and prognosis.

Methods

Thirty‐one patients with mucoepidermoid carcinomas who had surgical resection were studied retrospectively. Clinicopathologic features, including histologic types, T stage, nodal status, perineural invasion, overall AJCC stage, and survival data, were obtained from medical records. Immunohistochemical staining with monoclonal antibodies against p27Kip1 was performed on the formalin‐fixed, paraffin‐embedded specimens from each patient. The percentage of tumor cells expressing p27Kip1 (labeling index) was evaluated by counting 1000 cells per slide in at least four different areas and comparing with the patients' clinicopathologic features and survival rates.

Results

Significant correlation was found between low p27Kip1 expression and tumors with high‐grade, advanced T stages, positive nodal status, and advanced clinical stages (p = .001 for all) except perineural invasion. Multivariate analysis indicated that p27Kip1 expression (p = .030) was the most significant, and gender (p = .048) was the next significant predictor of overall survival among the variables. Also patients with low p27Kip1 expression showed poor prognosis (p = .002).

Conclusions

We suggest that p27Kip1 is a reliable independent marker of tumor progression, invasiveness, and prognosis in the mucoepidermoid carcinomas. © 2001 John Wiley & Sons, Inc. Head Neck 22: 292–297, 2001.
Unusual T‐ and T/NK‐ cell non‐Hodgkin's lymphoma of the larynx: A diagnostic challenge for clinicians and pathologists
Authors: Mok Johnny S. W. , Pak Martin Wai , Chan K. F. , Chow John , Hasselt C. A. van
Published: August 2002

Background

Lymphomas of T‐cell and T/natural killer (T/NK)‐cell types rarely involve the larynx. Early symptoms are subtle and nonspecific, and confirmation of the diagnosis is often difficult. Because of the rarity of this disease entity, the optimal management remains controversial.

Methods

The case records of patients with the diagnosis of lymphoma involving the larynx were retrospectively reviewed. Details of the pathologic condition, the difficulties in diagnosis, and treatment were presented.

Results

One case of T‐cell lymphoma (Lennert's lymphoma subtype) and two cases of T/NK‐cell lymphomas involving the larynx were presented. The diagnoses were all difficult to establish. All three patients received either multiagent chemotherapy or radiotherapy as the first‐line treatment. They all died of the disease within 32 months of diagnosis.

Conclusions

T‐ and T/NK‐cell non‐Hodgkin's lymphoma of the larynx is a diagnostic challenge for clinicians and pathologists. Conventional chemotherapy or radiotherapy has not been effective. A more aggressive therapy should be considered. © 2001 John Wiley & Sons, Inc. Head Neck 23: 625–628, 2001.
Toward improved employment relations practices of casual employees in the New South Wales registered clubs industry
Authors: Lowry Diannah S. , Simon Alan , Kimberley Nell
Published: August 2002

This research investigated the effects of casual work arrangements on employee job satisfaction and commitment
in a segment of the hospitality sector in Australia. The authors surveyed a total of 454 casual employees: they
interviewed 42 employees in a sample of clubs within the top two hundred registered clubs in the state of New South
Wales (NSW), Australia, and 384 employees returned questionnaires from a sample of different clubs. For
the interviews, the authors selected eighteen clubs using nonproportionate stratified sampling, the strata being
small, medium, and large. The team conducted systematic random sampling of the clubs within each stratum. Using
nonprobability accidental sampling, they then selected individual interviewees at the clubs. For the questionnaire
survey, the sampling procedure was identical, but the team selected eighteen different clubs. Questionnaires were
administered to all two thousand employees at these eighteen clubs. Because of a low response rate to the survey,
the authors questioned an accidental sample of twenty casual employees, who admitted to not responding, in order to
see whether their responses differed from those of the participants. The responses were very similar. Key findings
suggest that casual employees experience varying levels of commitment and satisfaction according to their
perceptions of work context factors such as training, promotion, work scheduling, management practices, and social
integration. The authors encourage employers in highly casualized enterprises to involve and empower their casual
employees, provide continuous feedback as well as behaviorally based formal performance appraisals, address the
issue of training opportunities and program content for casual workers, and consider ways of developing their
career paths.
The role of human resource management: an exploratory study of cross‐country variance
Authors: Bowen David E. , Galang Carmen , Pillai Rajnandini
Published: August 2002

We explore how the role of Human Resource Management (HRM) varies across countries on two
dimensions. One is how the status of HRM departments may vary (e.g., perceptions of its importance and
involvement). Second is whether there is cross‐country strategic HRM (SHRM) in terms of
the conventional contingency approach (linking HRM practices to strategy), as well as a
resource‐based view of the firm (e.g., developing “organizational capability” as
competitive advantage). Results included significant differences in HRM status across countries;
significant correlations between status and “organizational capability”; and in Asian
countries, a slight tendency for HRM practices to be linked more to a “differentiation” strategy,
whereas, in Anglo countries, a strong linkage between HRM practices and “organizational capability.”
© 2002 Wiley Periodicals, Inc.
Converging on IHRM best practices: lessons learned from a globally distributed consortium on theory and practice
Authors: Von Glinow Mary Ann , Drost Ellen A. , Teagarden Mary B.
Published: August 2002

This article captures the results of the “Best Practices” Project and attempts to identify which
IHRM practices are universally embraced in our ten‐country/region sample. Here we present a compelling
argument for understanding cultural contexts by seeking and establishing derived etics. No longer content with
the traditional conduct of cross‐cultural research, we challenge “how” we do research, and
encourage gatekeepers to broaden their research lenses with multiple embedded
contexts—polycontextuality—as they search for answers. We find anomalies, and counterintuitive
findings, and through our “gap analysis,” we discovered several universally embraced etics or best
practices. We believe we have not only made a significant contribution to research, but, in particular, we offer
a solution methodology for conducting globally distributed IHRM research. These findings signal new directions
for all deeply involved in managing within and across different cultures. © 2002 Wiley Periodicals, Inc.
Familial and second esophageal cancers: A nation‐wide epidemiologic study from Sweden
Authors: Hemminki Kari , Jiang Yongwen
Published: August 2002

A few case‐control studies have been published on familial risks in esophageal cancer. Reliable data on familial risks are needed for prevention and clinical decisions. We used the nation‐wide Swedish Family‐Cancer Database on 10.1 million individuals and close to 6000 esophageal cancers to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for esophageal cancer in 0–66‐year‐old offspring by cancers in family members. Additionally, SIRs for second esophageal cancers were analyzed. The SIR for esophageal cancer was 3.91 (95% CI 1.55–7.35) when a parent presented with esophageal cancer and 4.91 (95% CI 1.77–9.62) when a parent presented with squamous cell carcinoma. The sibling risk for esophageal cancer was increased but was based on 1 pair only. The population‐attributable proportion of familial esophageal cancer was 0.70%. Risks for second esophageal cancers were increased after upper aerodigestive tract, esophageal, stomach, larynx, and lung cancers. The data on second cancers suggest that environmental factors are important for esophageal cancer and probably contribute to the familial clustering. However, the high familial risk of 3.91 is unlikely without the involvement of heritable factors. The population‐attributable proportion of familial esophageal cancer is small. © 2001 Wiley‐Liss, Inc.
Correlation between vascular endothelial growth factor‐C expression and invasion phenotype in cervical carcinomas
Authors: Ueda Masatsugu , Terai Yoshito , Yamashita Yoshiki , Kumagai Koji , Ueki Ken , Yamaguchi Hiroyuki , Akise Daisuke , Hung Yao‐Ching , Ueki Minoru
Published: August 2002

The correlation between vascular endothelial growth factor (VEGF)‐C gene expression and in vitro invasive activity and matrix metalloproteinase (MMP)‐2 or 9 gene expression and proteolytic activity in 11 cervical carcinoma cell lines, was investigated. Immunohistochemical expression of VEGF‐C in 52 cervical carcinoma tissues was also correlated with tumor aggressiveness with respect to clinicopathologic features, tumor vascularity, MMP‐2 expression and patient outcome. Expression of VEGF‐C mRNA differed remarkably among the cell lines and there was a statistical correlation between VEGF‐C gene expression and the number of invaded tumor cells (p = 0.0009) and MMP‐2 gene expression and activity (p < 0.05). Anti‐VEGF‐C antibody inhibited the invasive and proteolytic activity of tumor cells in a concentration‐dependent manner. VEGF‐C or MMP‐2 expression in clinical tissue samples was well correlated with depth of myometrial invasion, endometrial invasion, pelvic lymphnode metastasis and tumor vascularity (p < 0.05) and there was a close relation between VEGF‐C and MMP‐2 expression (p < 0.0001) in cervical carcinomas. Overall survival rates for 14 patients with strong VEGF‐C staining tumors were lower than those for 38 patients with weak VEGF‐C staining tumors (p = 0.0132) and VEGF‐C tissue status emerged as an independent prognostic parameter (p = 0.0232). These results suggest that VEGF‐C expression is closely related to invasion phenotype and affects the patient's survival in cervical carcinomas. © 2002 Wiley‐Liss, Inc.
Troglitazione affects survival of human osteosarcoma cells
Authors: Lucarelli Enrico , Sangiorgi Luca , Maini Veronica , Lattanzi Giovanna , Marmiroli Sandra , Reggiani Matteo , Mordenti Marina , Gobbi Giuliana Alessandra , Scrimieri Francesca , Zambon Bertoja Annarosa , Picci Piero
Published: August 2002

Activation of PPARγ, a transcription factor member of the family of peroxisome proliferator‐activated receptors, induces apoptosis in several normal and tumor cell lines. In our study, we investigated whether treatment with troglitazone (TRO), a known PPARγ agonist, induced apoptosis in the human osteosarcoma (OS) cell lines G292, MG63, SAOS and U2OS that express PPARγ. In our experiments, TRO never induced apoptosis of OS cells; on the contrary, TRO increased cell number, based on MTT proliferation assay. Remarkably, the TRO‐induced cell number increase depended on a decrease of apoptosis that naturally occurred in the culture and was not due to an increased cell proliferation rate. TRO also prevented staurosporin‐induced apoptosis. The TRO‐mediated survival effect correlated with the activation of Akt, a well‐known mediator of survival stimuli. Our work describes a new function for TRO and indicates that the Akt survival pathway may be a mediator of TRO‐induced increase of survival. © 2002 Wiley‐Liss, Inc.
Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival
Authors: Farrington Susan M. , McKinley Aileen J. , Carothers Andrew D. , Cunningham Christopher , Bubb Vivien J. , Sharp Linda , Wyllie Andrew H. , Dunlop Malcolm G.
Published: August 2002

It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population‐based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n = 118; non‐age‐selected, n = 181) in the context of clinicopathologic variables. There was a substantial age‐related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p ∼ 0.001) and poorer 5‐year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression. © 2002 Wiley‐Liss, Inc.
Transmission/disequilibrium tests of androgen receptor and glutathione S‐transferase pi variants in prostate cancer families
Authors: Ho Gloria Y.F. , Knapp Michael , Freije Diha , Nelson William G. , Smith Jeffrey R. , Carpten John D. , Bailey‐Wilson Joan E. , Beaty Terri H. , Petersen Gloria , Xu Jianfeng , Kamensky Victor , Walsh Patrick C. , Isaacs William B.
Published: August 2002

Population‐based case‐control studies have found relationships between risk of prostate cancer and genetic polymorphisms in the CAG repeat and GGC repeat of the X‐linked androgen receptor gene (AR) as well as the autosomal gene coding for glutathione S‐transferase pi (GSTP1). This family‐based study utilized the transmission disequilibrium test to examine whether there was evidence that these polymorphisms could account for familial aggregation of prostate cancer. Seventy‐nine North American pedigrees were studied. Most of these families had 3 or more affected first‐degree relatives. Genotype information was obtained on 578 individuals. The reconstruction combined transmission disequilibrium test (RC‐TDT) was used to test for linkage. There was no evidence of linkage to the CAG and GGC repeat sequences in the AR gene or the pentanucleotide (ATAAA) repeat in the GSTP1 gene when each allele was analyzed separately or when alleles were grouped by repeat length. Our findings do not support the hypothesis that familial clustering of prostate cancer in high‐risk families is attributable to these genetic variants. © 2002 Wiley‐Liss, Inc.
Nicotine modulates the effects of retinoids on growth inhibition and RARβ expression in lung cancer cells
Authors: Chen Guo‐quan , Lin Bingzhen , Dawson Marcia I. , Zhang Xiao‐kun
Published: August 2002

Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives, retinoids, are effective agents in preventing the development of tobacco‐associated cancers. Unfortunately, clinical trials of retinoids on cigarette smokers have shown lack of efficacy in preventing lung cancer. In our study, we investigated the effect of nicotine on the anti‐cancer activity of all trans‐retinoic acid (trans‐RA) in human lung cancer cells. Our results demonstrated that nicotine could abrogate the growth inhibitory effect of trans‐RA by suppressing its ability to induce the expression of RA receptor beta (RARβ), a tumor suppressor. The inhibitory effect of nicotine was accompanied with induction of orphan receptor TR3. Inhibition of TR3 expression by overexpression of TR3 anti‐sense RNA in H460 lung cancer cells strongly prevented the suppressive effect of nicotine on trans‐RA activity. Treatment with nicotine or the cotransfection of TR3 expression vector inhibited the induction of RARβ promoter activity by trans‐RA in transient transfection assays. The inhibition of RARβ promoter activity was due to the interaction of TR3 with orphan receptor COUP‐TF, resulting in inhibition of COUP‐TF DNA binding and transactivation on the RARβ promoter. Furthermore, we found that nicotine failed to suppress the effect of a retinoid X receptor (RXR)‐selective retinoid SR11237 on inducing both growth inhibition and RARβ promoter activity, due to the ability of SR11237 to activate the RARβ promoter through the RXR/TR3 heterodimer. Together, our results demonstrate that nicotine suppresses the growth inhibitory effects of trans‐RA by inhibiting RARβ expression through its induction of TR3 expression and suggest that RXR‐selective retinoids may be more effective than classical retinoids for preventing and treating tobacco‐associated cancers. © 2002 Wiley‐Liss, Inc.
Evaluation of cell survival, DNA double strand breaks, and DNA synthesis during concurrent camptothecin and X‐radiation treatments
Authors: Ng Cheng E. , Mazaheri K. , Payant C. , Raaphorst G. Peter
Published: August 2002

We evaluated cell survival, DNA double strand breaks (dsbs), and DNA synthesis following camptothecin (CPT) alone or concurrent CPT and X‐radiation treatments in exponential‐phase cultures of a radioresistant human melanoma cell line. Cell survival was measured by a clonogenic assay. DNA dsbs were measured by pulsed‐field gel electrophoresis. DNA synthesis was measured by incorporation of 3H‐thymidine. We found that (i) concurrent CPT and X‐radiation interacted additively, unlike previous results with plateau‐phase cultures of these cells, which showed synergistic interaction; (ii) there were strong negative correlations (correlation coefficients of at least 0.82) between clonogenic surviving fractions and DNA dsbs following CPT alone or concurrent CPT and radiation treatments; and (iii) concurrent CPT and radiation (10 Gy) treatment did not completely inhibit DNA synthesis, even though addition of radiation to CPT did further decrease DNA synthesis (relative to CPT alone) at CPT concentrations below 20 μM. Our results suggest that during concurrent CPT and radiation treatment residual DNA dsb levels were good indicators of cell killing and that the absence of complete inhibition of DNA synthesis could at least in part explain the additive interaction between CPT and radiation. © 2001 Wiley‐Liss, Inc.
Binary operator design by k‐nearest neighbor learning with application to image resolution increasing
Authors: Kim Hae Yong
Published: August 2002

In a typical office environment, heterogeneous devices and software, each working in a different spatial resolution, must interact. As a result resolution conversion problems arise frequently. This paper addresses the spatial resolution increasing of binary images and documents (e.g., conversion of a 300‐dots per inch [dpi] image into 600 dpi). A new, accurate and efficient solution to this problem is proposed. It makes use of the k‐nearest neighbor learning to design automatically a windowed zoom operator starting from pairs of in‐out sample images. The resulting operator is stored in a look‐up table, which is extremely fast computationally and therefore fit for real‐time applications. It is useful to know a priori the sample complexity (the quantity of training samples needed to get, with probability 1‐δ, an operator with accuracy ε). We use the probably approximately correct (PAC) learning theory to compute sample complexity, for both noise‐free and noisy cases. Because the PAC theory yields an overestimated sample complexity, the statistical estimation is used to estimate, a posteriori, a tight error bound. The statistical estimation is also used to show that the k‐nearest neighbor learning has a good inductive bias that allows reduction of the quantity of training sample images needed. © 2001 John Wiley & Sons, Inc. Int J Imaging Syst Technol, 11, 331–339, 2000
An infant in context: Multiple risks, and a relationship
Authors: Balbernie Robin
Published: August 2002

This article sets out to bring together some of the current thinking on the effect of adverse early experiences on individual development. Although the caregiving relationship is intensely personal, it also reflects a synthesis of surrounding biological and social influences. An exceptional combination of individual characteristics and environmental circumstances may alter the balance between future vulnerability and resilience. These affect the baby via the relationship with the parent. The particular risk factors considered are set within the narrative framework of a single home visit, both to embody them and to emphasize their systemic interrelatedness within a family boundary. ©2002 Michigan Association for Infant Mental Health.
Kojic acid reduces the cytotoxic effects of sulfur mustard on cultures containing human melanoma cells in vitro
Authors: Smith C. N. , Lindsay C. D.
Published: August 2002

In vivo experiments have shown that melanocytes are more sensitive than keratinocytes to the cytotoxic effects of sulfur mustard when it is applied topically to pig skin.1 It has been hypothesized that this is caused by the uncoupling of the melanogenic pathway by depletion of cellular glutathione, resulting in the uncontrolled production of cytotoxic quinone free‐radical species by tyrosinase.2.

In the present study, the feasibility of blocking the melanogenic pathway as a means of reducing the cytotoxicity of sulfur mustard was evaluated using kojic acid. Kojic acid is a topically applied depigmenting agent that exerts its effect by acting as a slow‐binding, competitive inhibitor of tyrosinase.3

Preincubation of G361 pigmented melanoma cells and mixed cultures of G361 cells and SVK keratinocytes with 2.5 mM kojic acid resulted in significant increases in the viability of these cultures as determined by neutral red (NR) and gentian violet (GV) dye binding assays for up to 48 h following exposure to 50 µM sulfur mustard. The highest levels of protection were seen in the G361 cultures, with a 26.8% increase in culture viability (NR assay) compared with the sulfur‐mustard‐only controls at 24 h. Preincubation of SVK cells alone with kojic acid resulted in lower increases in viability (2.5% at 24 h by the NR assay). Inhibition of the melanogenic pathway reduces the sensitivity of cultures containing pigment cells to sulfur mustard. © Crown copyright 2001. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.
Changes in concentrations of type IV collagen and tissue inhibitor of metalloproteinase‐1 in patients with paraquat poisoning
Authors: Nakamura Tsukasa , Ushiyama Chifuyu , Shimada Noriaki , Hayashi Kayo , Ebihara Isao , Suzaki Masataka , Koide Hikaru
Published: August 2002

Respiratory failure is one of the major causes of death in patients with paraquat poisoning. In paraquat‐poisoned lungs, abnormal extracellular matrix regulation occurs. The aim of the present study is to determine whether serum concentrations of type IV collagen and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) are altered during the course of paraquat poisoning and whether haemoperfusion therapy affects these concentrations. Twenty‐one patients were admitted within 3 h after ingestion of paraquat and all patients received direct haemoperfusion therapy. Five out of 21 patients survived and 16 patients died within 28 days. Plasma paraquat concentrations in non‐survivors (5740 ± 380 µg l−1) were not significantly different from those in survivors ( 5920 ± 280 µg l−1) before treatment. Haemoperfusion reduced these concentrations in both non‐survivors (120 ± 7 µg l−1) as well as survivors (136 ± 9 µg l−1) on day 5. Serum concentrations of type IV collagen and TIMP‐1 in survivors showed little change between day 1 (type IV collagen, 90.4 ± 3.6 ng ml−1; TIMP‐1, 172.2 ± 7.0 ng ml−1) and day 5 (type IV collagen, 92.6 ± 4.2 ng ml−1; TIMP‐1, 174.2 ± 7.2 ng ml−1). In contrast, these concentrations in non‐survivors on day 5 (type IV collagen, 143.6 ± 7.8 mg ml−1; TIMP‐1, 246.8 ± 13.6 ng ml−1) were significantly higher than those on day 1 (type IV collagen, 88.4 ± 4.2 ng ml−1, P < 0.01; TIMP‐1, 170.6 ± 9.2 ng ml−1, P < 0.05). These data suggest that serum concentrations of type IV collagen and TIMP‐1 may be useful indicators for the development of respiratory failure in patients with paraquat poisoning. Copyright © 2001 John Wiley & Sons, Ltd.
Chelation in metal intoxication: influence of cysteine or N‐acetyl cysteine on the efficacy of 2,3‐dimercaptopropane‐1‐sulphonate in the treatment of cadmium toxicity
Authors: Tandon Sushil K. , Prasad Satgur , Singh Surendra
Published: August 2002

The influence of cysteine or N‐acetyl cysteine administration on the efficacy of 2,3‐dimercaptopropane‐1‐sulphonate (DMPS) in the treatment of cadmium intoxication was investigated in cadmium‐pre‐exposed rats. Cysteine, N‐acetyl cysteine, DMPS, DMPS + cysteine or DMPS + N‐acetyl cysteine were about equal in effectiveness in mobilizing hepatic cadmium mainly from its supernatant cytosolic fraction (SCF) and both of the combinations were more effective than either of them alone in mobilizing cadmium from its nuclear mitochondrial fraction (NMF). The DMPS was apparently more effective than cysteine or N‐acetyl cysteine in mobilizing renal cadmium from its SCF or NMF and it was more effective than even their combinations in mobilizing cadmium from renal SCF. The treatment with cysteine or N‐acetyl cysteine reduced cadmium‐induced hepatic and renal metallothionein (MT) and the treatment with DMPS reduced renal MT only, probably due to removal of hepatic and renal SCF cadmium by these agents. However, MT levels were high in animals treated with DMPS + cysteine or DMPS + N‐acetyl cysteine, despite lowering of cadmium in these tissues, suggesting a contribution of MT induced by cysteine or N‐acetyl cysteine itself. The cadmium exposure increased hepatic and renal zinc and renal copper levels, probably as a result of cadmium‐induced MT, and some of the levels were normalized considerably by the subsequent treatment with cysteine, DMPS or to a lesser extent N‐acetyl cysteine and their combinations, showing their protective effects against cadmium toxicity. The increase in blood cadmium and the decrease in blood zinc and copper levels due to cadmium exposure also were reversed appreciably by some of these treatments. The results have shown a limited benefit of cysteine or N‐acetyl cysteine administration on the efficacy of DMPS in the treatment of cadmium intoxication. Copyright © 2002 John Wiley & Sons, Ltd.
Effects of DMAEMA and 4‐methoxyphenol on gingival fibroblast growth, metabolism, and response to interleukin‐1
Authors: Lapp Carol A. , Schuster George S.
Published: August 2002

Some components of resins used in restorative dentistry have been shown to alter metabolism in cultured oral epithelial cells. Here we have extended such studies to the underlying supportive tissue, composed of gingival fibroblasts (GF). Primary cultures of human GF were transferred to serum‐free, defined medium and exposed to either 2‐(dimethylamino)ethyl methacrylate (DMAEMA) or 4‐methoxyphenol (MEHQ) for 24–72 h. At a DMAEMA concentration of 6.4 mM, which was well tolerated by epithelial cells, GF numbers, as estimated by crystal violet, and metabolic activity, as indicated by MTT, were reduced at least 60% within 24 h of exposure. Between 1.6 and 6.4 mM, there were dose‐related reductions in cell numbers; however, at lower doses (0.32–0.64 mM), proliferation was stimulated. MEHQ, between 8 and 16 μM, did not stimulate cellular protein production. To examine the capacity of GF to respond to an inflammatory stimulus, interleukin‐6 (IL‐6) production by confluent cells was estimated without or with these compounds. DMAEMA (1.6– 6.4 mM) virtually eliminated the acute IL‐6 response of these cells to an interleukin‐1β challenge; only at 0.32 mM DMAEMA was the response restored. MEHQ (1.6–16 μM) reduced the IL‐6 response by >50%. In summary, both growth and the innate immune responsivity of GF were affected by DMAEMA and MEHQ in vitro; thus, these compounds deserve careful evaluation for biocompatibility. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 60: 30–35, 2002
Interleukin‐4 regulates connective tissue growth factor expression in human lung fibroblasts
Authors: Rishikof David C. , Ricupero Dennis A. , Kuang Ping‐Ping , Liu Hanqiao , Goldstein Ronald H.
Published: August 2002

Transforming growth factor‐β (TGF‐β) and interleukin‐4 (IL‐4) have fibrogenic properties and induce extracellular matrix production in a variety of lung diseases. Connective tissue growth factor (CTGF) is a matrix signaling molecule stimulated by TGF‐β that in part mediates α1(I) collagen mRNA expression. In these studies, the regulation of CTGF expression by IL‐4 in human lung fibroblasts was examined. Following 6 h of stimulation with IL‐4, basal CTGF mRNA levels were unchanged as assessed by Northern blot analysis. However, IL‐4 attenuated the TGF‐β‐stimulated induction of CTGF mRNA expression by 50%. This effect was selective because IL‐4 did not affect fibronectin or α1(I) collagen mRNA expression induced by TGF‐β. Experiments employing the transcriptional inhibitor actinomycin D suggest that IL‐4 did not affect the stability of the CTGF mRNA. Transient transfection assays with 3TP‐Lux, a luciferase gene controlled by a TGF‐β inducible promoter, and with a CTGF promoter construct indicate that IL‐4 interfered with the TGF‐β‐induced transcriptional activation of the CTGF gene. J. Cell. Biochem. 85: 496–504, 2002. © 2002 Wiley‐Liss, Inc.
Evidence for a pre‐restriction point Cdk3 activity
Authors: Keezer Susan M. , Gilbert David M.
Published: August 2002

We have examined the activity of cyclin‐dependent kinase 3 (cdk3) during G1‐phase of the cell cycle in Chinese Hamster Ovary (CHO) fibroblasts. Histone H1 kinase activity associated with anti‐cdk3 immunoprecipitates peaked during a brief window of time, 2–3 h prior to the restriction point. In vitro cdk3 activity was sensitive to roscovitine, a drug previously shown to inhibit cdks 1, 2, and 5, but not cdk4 or 6. Early G1‐phase activation of cdk3 was downregulated by treatment of cells with MG132, an inhibitor of the proteasome, and by the protein synthesis inhibitor cycloheximide. These results provide evidence for a pre‐restriction point cdk3 activity that requires both the synthesis of a regulatory subunit and degradation of an inhibitor. J. Cell. Biochem. 85: 545–552, 2002. © 2002 Wiley‐Liss, Inc.
Utilization of a receptor reserve for effective amplification of mitogenic signaling by an epidermal growth factor mutant deficient in receptor activation***
Authors: Nandagopal Krishnadas , Popp Diana M. , Niyogi Salil K.
Published: August 2002

The idea of a receptor reserve in mediating cellular function is well known but direct biochemical evidence has not been easy to obtain. This study stems from our results showing that L15 of epidermal growth factor (EGF) is important in both EGF receptor (EGFR) binding and activation, and the L15A analog of human EGF (hEGF) partially uncouples EGFR binding from EGFR activation (Nandagopal et al., [1996] Protein Engng 9:781‐788). We address the cellular mechanism of mitogenic signal amplification by EGFR tyrosine kinase in response to L15A hEGF. L15A is partially impaired in receptor dimerization, shown by chemical cross‐linking and allosteric activation of EGFR in a substrate phosphorylation assay. Immunoprecipitation experiments reveal, however, that L15A can induce EGFR autophosphorylation in intact murine keratinocytes by utilizing spare receptors, the ratio of total phosphotyrosine content per receptor being significantly lower than that elicited by wild‐type. This direct biochemical evidence, based on function, of utilization of a receptor reserve for kinase stimulation suggests that an EGF variant can activate varying receptor numbers to generate the same effective response. L15A‐activated receptors can stimulate mitogen‐activated protein kinase (MAPK) that is important for mitogenesis. The lack of linear correlation between levels of receptor dimerization, autophosphorylation, and MAPK activation suggests that signal amplification is mediated by cooperative effects. Flow cytometric analyses show that the percentages of cells which proliferate in response to 1 nM L15A and their rate of entry into S‐phase are both decreased relative to 1 nM wild‐type, indicating that MAPK activation alone is insufficient for maximal stimulation of mitogenesis. Higher concentrations of L15A reverse this effect, indicating that L15A and wild‐type differ in the number of receptors each activates to induce the threshold response, which may be attained by cooperative activation of receptor dimers/oligomers by van der Waal's weak forces of attraction. The maintenance of a receptor reserve underscores an effective strategy in cell survival. J. Cell. Biochem. 83: 326–341, 2001. © 2001 Wiley‐Liss, Inc.