bluuebunny/crossref_metadata_2025 huggingface dataset:
Accumulation of DNA methylation is associated with tumor stage in gastric cancer
Authors: Oue Naohide , Mitani Yoshitsugu , Motoshita Junichi , Matsumura Shunji , Yoshida Kazuhiro , Kuniyasu Hiroki , Nakayama Hirofumi , Yasui Wataru
Published: February 2006

BACKGROUND

The authors purpose in this study was to clarify the difference in terms of clinicopathologic features between gastric cancer (GC) with high numbers of DNA methylated genes and CpG island methylator phenotype (CIMP)‐positive GC as originally defined.

METHODS

We analyzed DNA methylation of 12 tumor‐related genes (hMLH1, MGMT, p16INK4a, CDH1, RAR‐beta, HLTF, RIZ1, TM, FLNc, LOX, HRASLS, HAND1) in 75 samples of GC from 75 patients, 25 samples of corresponding nonneoplastic mucosa from 25 patients, and 10 samples of normal gastric mucosa from 10 healthy young individuals by methylation‐specific polymerase chain reaction (PCR) and bisulfite PCR. We also investigated CIMP status by examining the methylation of five MINT loci and p53 mutation status by PCR single‐strand conformation polymorphism. We measured levels of expression of mRNAs for these 12 genes by quantitative reverse transcription PCR in 50 GC specimens.

RESULTS

The average number of methylated genes per tumor was 4.83. DNA methylation of each gene was correlated with low expression of the respective mRNA. High methylation (GC with 5 or more methylated genes) was detected in 39 (52.0%) of 75 GCs. Twenty‐nine (37.8%) of 75 GCs were CIMP‐positive. DNA methylation of each of the 12 genes was observed more frequently in the high‐methylation group than in the low‐methylation group. Methylation of 6 specific genes occurred more frequently in CIMP‐positive GC than in CIMP‐negative GC. Methylation of the remaining 6 genes was not correlated with CIMP‐status. High methylation was found more frequently in Stage III/IV GC (26 of 40 cases, 65.0%) than in Stage I/II GC (13 of 35 cases, 37.1%, P = 0.029).

CONLUSIONS.

These findings indicate that GCs with higher numbers of methylated genes have more distinct DNA methylation profiles than the originally defined CIMP‐positive GCs. DNA methylation of tumor‐related genes accumulates in conjunction with tumor progression. Cancer 2006. © 2006 American Cancer Society.
Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR
Authors: Cegelski Lynette , Rice Charles V. , O'Connor Robert D. , Caruano Amy L. , Tochtrop Gregory P. , Cai Zu Yun , Covey Douglas F. , Schaefer Jacob
Published: February 2006

Estrogens are potent antioxidants and neuroprotectants. They have become the focus of drug development efforts aimed at treating and preventing neuronal damage in stroke‐related brain damage, Alzheimer's disease, and Parkinson's disease. 13C{31P} and 13C{19F} rotational‐echo double‐resonance NMR have been used to map the locations of 17β‐estradiol (estradiol), 17β‐estradiol 17‐benzoate (estradiol benzoate), and 17β‐2‐(1‐adamantyl)estradiol (adamantyl estradiol) in 19F‐labeled DPPC phospholipid multilamellar vesicles. Placement of the estrogen molecules in lipid bilayers is correlated with the differences in their neuroprotective potency. Drug Dev. Res. 66:99–102, 2006. © 2006 Wiley‐Liss, Inc.
In Drosophila, don juan and don juan like encode proteins of the spermatid nucleus and the flagellum and both are regulated at the transcriptional level by the TAFII80 cannonball while translational repression is achieved by distinct elements
Authors: Hempel Leonie U. , Rathke Christina , Raja Sunil Jayaramaiah , Renkawitz‐Pohl Renate
Published: February 2006

The genes don juan (dj) and don juan like (djl) encode basic proteins expressed in the male germline. Both proteins show a similar expression pattern being localized in the sperm heads during chromatin condensation and along the flagella. Prematurely expressed Don Juan–eGFP and Myc‐Don Juan Like localize to the cytoplasm of spermatocytes and in mitochondrial derivatives from the nebenkern stage onward suggesting that both proteins associate with the mitochondria along the flagella in elongated spermatids. Premature expression of Myc‐Don Juan Like does not impair spermatogenesis where‐as Don Juan‐eGFP when prematurely expressed causes male sterility as spermatids fail to individualize. In spite of the sequence identity of 72% on the nucleotide level and 42% on the protein level, the presumptive promoter regions and the untranslated regions of the mRNA are diverged. Our in vivo analysis revealed that don juan and don juan like are transcriptionally and translationally controlled by distinct short cis regulatory regions. Transcription of don juan and don juan like depends on the male germ line specific TAFII80, Cannonball (Can). Translational repression elements for both mRNAs are localized in the 5′ UTR and are capable to form distinct secondary structures in close proximity to the translational initiation codon. Developmental Dynamics 235:1053–1064, 2006. © 2006 Wiley‐Liss, Inc.
Inhibins are the major activin ligands expressed during early thymocyte development
Authors: Licona Paula , Chimal‐Monroy Jesús , Soldevila Gloria
Published: February 2006

Activins are members of the transforming growth factor‐beta (TGFβ) superfamily, which regulate cell differentiation processes. Here we report the first quantitative analysis of the expression of Activin/Inhibin ligands, type I and II receptors, as well as Smad proteins in fetal (E14–E16) and adult thymic subpopulations. Our data showed that Alk4, ActRIIA, ActRIIB, and Smads 2, 3, and 4, are expressed in fetal thymus (E14 > E15 > E16) and in thymocytes from adult mice (mostly in the double negative [DN] subpopulation). Ligand expression analysis showed that βA, βB, and α subunits were mainly detected in thymic stromal cells. Interestingly, α subunits were expressed at much higher levels compared to βA and βB subunits, demonstrating for the first time the potential role of Inhibins as important mediators during early T cell development. Our data indicate that Activin/Inhibin signaling could regulate the process of thymus organogenesis and early thymocyte differentiation, as it has been demonstrated for other members of the TGF‐β superfamily. Developmental Dynamics 235:1124–1132, 2006. © 2006 Wiley‐Liss, Inc.
JAK/STAT signalling in Drosophila controls cell motility during germ cell migration
Authors: Brown Stephen , Zeidler Martin P. , Hombría James E. Castelli‐Gair
Published: February 2006

The gonad is formed from two populations of cells originating at different locations: the primordial germ cells (PGCs), giving rise to either sperm or oocytes, and the somatic gonadal mesoderm precursors (SGPs), which support development of the gametes. Following the PGCs' migration during gastrulation, these two populations meet, forming the immature gonad. We present evidence that during embryonic development, the PGCs require the canonical JAK/STAT signalling cascade to migrate efficiently towards the SGPs. Loss of function for any element of the JAK/STAT pathway causes frequent germ cell mislocalisation. We have found that wild‐type germ cells produce filopodia while they migrate through the mesoderm towards the gonad. Our observations suggest that PGCs use filopodia to migrate and to keep contact with each other. Interestingly, activation of the JAK/STAT pathway is required for these filopodia to form, and ectopic JAK/STAT activation enhances their formation. Developmental Dynamics 235:958–966, 2006. © 2006 Wiley‐Liss, Inc.
Cloning and regulation of the vertebrate homologue of lin‐41 that functions as a heterochronic gene in Caenorhabditis elegans
Authors: Kanamoto Takashi , Terada Koji , Yoshikawa Hideki , Furukawa Takahisa
Published: February 2006

The Caenorhabditis elegans gene lin‐41 is the one of the heterochronic genes that regulate the timing of many developmental events. MicroRNA let‐7 negatively regulates the expression of lin‐41 through RNA‐RNA interaction on its 3′ untranslated region (UTR). Here, we report the isolation of chick and mouse homologues of lin‐41 that encode the RBCC‐NHL family protein and their expression patterns. C. elegans lin‐41 is one of the RBCC‐NHL families and the predicted amino acid sequences of isolated two genes encode the same family proteins. Chick and mouse lin‐41 expression was also observed in developing limb buds, branchial arches, and tail buds. The 3′UTRs of the mouse and chick lin‐41 genes contain multiple let‐7 complementary sites. Using luciferase assay, we showed that lin‐41 expression can be regulated through let‐7 complementary sites. Developmental Dynamics 235:1142–1149, 2006. © 2006 Wiley‐Liss, Inc.
Validation of the Spanish version of the Addenbrooke's Cognitive Examination in a rural community in Spain
Authors: García‐Caballero A. , García‐Lado I. , González‐Hermida J. , Recimil MJ. , Area R. , Manes F. , Lamas S. , Berrios GE.
Published: February 2006

Background

The Addenbrooke's Cognitive Examination (ACE) is a brief cognitive test battery designed to detect and differentiate Alzheimer's disease (AD) and frontotemporal dementia (FTD). Translations of this instrument into French and Malayalam have been recently published

Objective

To adapt and validate the ACE into Spanish in a rural population of low‐educational level.

Subjects

A clinical group, composed of 70 patients affected by dementia and 25 patients with memory complaints without dementia, was compared with 72 controls matched for gender, age and educational level

Method

The clinical group was studied with standard neuropsychological instruments, all patients underwent neuroimaging [Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI), and Single Photon Emission Tomography (SPECT) in all cases of suspected FTD], as well as routine neurological examination. Both groups were studied with the ACE and Clinical Dementia Rating scale (CDR). Sensitivity, specificity, area under curve, reliability and Verbal‐Language/ Orientation‐Memory (VLOM) ratio were calculated. Subsequently, the sample was stratified regarding educational level in two groups. Receiver Operating Characteristics (ROC) curves were calculated for these conditions. Different cut‐off points were calculated addressing educational level.

Results

ROC curves demonstrated the superiority of the ACE in the sub sample of patients that finished school at over 14 years old. VLOM ratio confirmed its usefulness for differential diagnosis between AD and FTD

Conclusions

The Spanish version of the ACE is a useful instrument for dementia diagnosis. In our sample VLOM ratio results were useful for differential diagnosis between AD and FTD. Different cut‐off points must be used for different educational levels. Copyright © 2006 John Wiley & Sons, Ltd.
Nursing home institutionalization: a source of eustress or distress for the elderly?
Authors: Scocco Paolo , Rapattoni Monica , Fantoni Giovanna
Published: February 2006

Objective

To investigate why elderly persons moved to a nursing home and detect any change in their psychopathological and cognitive profile, dependency and perceived QOL.

Method

We considered 100 elderly consecutively admitted to a nursing home, within 1 week of admission and 6 months later. Data were collected from medical and nursing records (medical and psychiatric history, ADL), interviews (MMSE, reasons for admission) and self‐report instruments (GDS, BSI, WHOQOL‐brief).

Results

At admission, 68 subjects were able to participate in the survey and agreed to take part. Only 5.9% (n = 4) had moved to the nursing home by their own choice, 26.5% (n = 18) because they were lonely and 36.7% (n = 25) because they had no caregiver available. The reasons for admission reported by the interviewed residents only partly corresponded with the ones noted in their records. Twenty‐six subjects had an MMSE score ≥ 18 and agreed to undertake complete assessment. The scores of 20 of the 26 subjects exceeded the cut‐off on the GDS and five of the nine BSI subscales. During the follow‐up period, 19 of the 68 originally assessed residents died (33 of the entire sample of 100) and one refused to continue to take part in the survey. The mean MMSE and ADL scores of the 48 survivors decreased from 16.87 (SD ± 7.32) to 14.27 (SD ± 7.24; t = 4.89, p < 0.000) and from 8.22 (SD ± 3.55) to 6.39 (SD ± 3.56; t = 5.34, p < 0.000), respectively. The scores achieved on GDI and BSI subscales worsened in 20 survivors with MMSE ≥ 18. The score achieved on the QOL physical health domain also worsened. Comparison of the subjects who died and survived during the follow‐up period showed a significant difference in terms of ADL (6.60 SD ± 4.221 vs 3.64 SD ± 3.773 F = 11.639; p < 0.001).

Conclusion

The 68 original participants expressed feelings of loneliness and marginalization, but these experiences were not noted in their personal records. Most subjects presented psychiatric symptoms and cognitive decline. After 6 months, the clinical condition of the sample, particularly the females, had worsened, with a 33% mortality rate. This suggests that moving to a nursing home did not bring about improvement or stabilization; rather, psychiatric symptoms worsened and quality of life was perceived more poorly. Copyright © 2006 John Wiley & Sons, Ltd.
Association of depression with Alzheimer's disease and vascular dementia in an elderly Arab population of Wadi‐Ara, Israel
Authors: Bowirrat Abdalla , Oscar‐Berman Marlene , Logroscino Giancarlo
Published: February 2006

Objectives

Because dementia and depression share common risk factors, we investigated risk factors for depression in Arab subjects with Alzheimer's disease (AD) and vascular dementia (VaD).

Methods

In a cross‐sectional population‐based study, we conducted a door‐to‐door survey of all adults over age 60 in an Arab community of rural Israel. We conducted interviews, gave questionnaires, and collected DNA blood specimens for determination of ApoE genotype.

Results

Of the 823 individuals in this naturalistic sample, 168 had dementia of Alzheimer's type (DAT) and 49 had VaD. Vascular risk factors, including the ApoE‐ϵ4 allele, were more prevalent among VaD than DAT subjects. Depressive symptoms were present in 57% of DAT patients and 86% of VaD patients. Depressed DAT individuals had a greater history of ischemic cardiovascular or cerebrovascular (CV/CBV) disease than non‐depressed DAT subjects, but depressed DAT subjects were less likely to have the ApoE‐ϵ4 allele. Within the VaD group, there was no difference in the distribution of cardiovascular risk factors in individuals with and without depressive symptoms, and ApoE‐ϵ4 was more prevalent among subjects with depressive symptoms.

Conclusions

Depressive symptomatology is prevalent among subjects with dementias in this Arab community. History of CV/CBV is associated with the presence of depressive symptoms in DAT. Further studies are needed to clarify the role of ApoE in depression onset in different ethnic groups with DAT. Copyright © 2006 John Wiley & Sons, Ltd.
Depressive symptom profile in Parkinson's disease: a comparison with depression in elderly patients without Parkinson's disease
Authors: Ehrt Uwe , Brønnick Kolbjørn , Leentjens Albert F. G. , Larsen Jan Petter , Aarsland Dag
Published: February 2006

Objective

Depression is a common neuropsychiatric syndrome in Parkinson's disease (PD), and may be etiologically related to the neurochemical changes accompanying this disease. It is still unclear whether the disturbances of neurotransmitter activities lead to a specific profile of depressive symptoms, that is characteristic for PD and differs from that in depressed patients without PD.

Method

We compared the individual depressive symptoms of 145 non‐demented depressed patients with PD and 100 depressed patients without PD by comparing item scores on the Montgomery‐Åsberg Depression Rating Scale by way of MANCOVA.

Results

The severity of depression and the level of cognitive functioning in depressed PD patients were comparable with that of depressed control subjects. However, patients with PD showed significant less reported sadness, less anhedonia, less feelings of guilt and, slightly less loss of energy, but more concentration problems than depressed control subjects.

Conclusion

The profile of depressive symptoms in PD differs from that in depressed subjects without PD. This finding is important for the conceptualisation and clinical diagnosis of depression in PD. Copyright © 2006 John Wiley & Sons, Ltd.
The validity and reliability of the Turkish versii̇on of Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) in patients with mild and moderate Alzheimer's disease and normal subjects
Authors: Mavioglu H. , Gedizlioglu M. , Akyel S. , Aslaner T. , Eser E.
Published: February 2006

Objectives

The cognitive subscale of the Alzheimer's Disease Assesment Scale (ADAS‐Cog) is the most widely used test in clinical trials dealing with Alzheimer's disease (AD). The aim of this study was to investigate the validity and reliability of the Turkish version of ADAS‐Cog.

Methods

Twenty‐nine patients with AD, fullfilling NINCDS‐ADRDA criteria of probable AD, who were in stage 3–5 according to the Global Deterioration Scale (GDS), and 27 non‐demented control subjects with similar age, gender and educational status were recruited for the study. The Turkish version of ADAS‐Cog, Standardized Mini Mental Status Examination (MMSE) and Short Orientation‐Memory‐Concentration Test (SOMCT) were applied to both of the groups. Inter‐rater reliability, internal consistency, test–retest reliability; face validity, differential validity and convergent validity were statistically analyzed.

Results

Both MMSE and ADAS‐Cog have significantly differentiated patients with AD and control subjects (p < 0.001). A significant correlation was established between MMSE and ADAS‐Cog scores in AD group (r: −0.739). ADAS‐Cog was also highly significantly correlated with GDS (r: 0.720) and SOMCT (r: 0.738). For the group with AD, control and whole cohort coefficients of internal consistency, Cronbach's α: 0.800, 0.515, 0.873 were found respectively. Inter‐rater reliability for total ADAS‐Cog score was found as ICC: 0.99 and 0.98 and test–retest reliability was found as ICC: 0.91 and 0.95 for demented and nondemented subjects, respectively.

Conclusion

The Turkish version of ADAS‐Cog has been found to be highly reliable and valid in differentiating patients with mild and moderate AD from nondemented subjects. Copyright © 2006 John Wiley & Sons, Ltd.
An open‐label study of escitalopram (Lexapro®) for the treatment of ‘Depression of Alzheimer's disease’ (dAD)
Authors: Rao V. , Spiro J. R. , Rosenberg P. B. , Lee H. B. , Rosenblatt A. , Lyketsos C. G.
Published: February 2006

Background

Depression is a frequent neuropsychiatric complication of Alzheimer's Disease.

Methods

This study investigated the safety and effectiveness of escitalopram (LEXAPRO) for depression in AD (dAD) as defined by the NIMH consensus criteria in an 8‐week, open‐label treatment study.

Conclusion

Escitalopram was efficacious and safe for the treatment of dAD in this study. Larger, controlled studies are warranted to further assess the efficacy for mood and behavioral disturbances in this medically fragile population. Copyright © 2006 John Wiley & Sons, Ltd.
Use of antipsychotic medications among elderly residents in long‐term institutional care: a three‐year follow‐up
Authors: Alanen Hanna‐Mari , Finne‐Soveri Harriet , Noro Anja , Leinonen Esa
Published: February 2006

Objective

To analyse the use of antipsychotic medications, change over time and associated factors in a three‐year follow‐up among elderly residents in long‐term institutional care.

Design

Retrospective study was designed with three identical cross‐sectional samples originating from the same long‐term care facilities, and collected 1 July to 31 December in 2001, 2002 and 2003, in Finland. These were extracted from the Resident Assessment Instrument (RAI) database, based on Minimum Data Set (MDS) assessments.

Setting

Of the data providers 16 were hospital‐based institutions and 25 residential homes.

Participants

Each of the data sets included 3662‐3867 resident assessments.

Results

The prevalence use of one or more antipsychotic decreased from 42% in 2001 to 39% in 2003. The overall confounder‐adjusted decrease in antipsychotic use was not statistically significant. However, the use of antipsychotics decreased among residents who had wandering as a behavioural problem (OR 0.79, 95% CI 0.63–0.99) and increased among residents with concomitant use of anxiolytic medications (OR 1.23, 95% CI 1.03–1.48).

Conclusions

The use of antipsychotic medications among residents in long‐term institutional care was common and the caring patterns were quite stable during the observation period. Adequate indications may not have been achieved in all cases. More attention should be paid to the appropriate use of antipsychotics in this frail population. Copyright © 2006 John Wiley & Sons, Ltd.
Alcohol advertising and alcohol consumption by adolescents
Authors: Saffer Henry , Dave Dhaval
Published: February 2006

This study investigates the effects of alcohol advertising on adolescent alcohol consumption. The theory of an industry response function and evidence from prior studies indicate the importance of maximizing the variance in advertising measures. Monitoring the Future (MTF) and National Longitudinal Survey of Youth 1997 (NLSY97) data are augmented with alcohol advertising, originating on the market level, for five media. The large sample of the MTF allows estimation of race and gender‐specific models. The longitudinal nature of the NLSY97 allows controls for unobserved heterogeneity with state‐level and individual fixed effects. Price and advertising effects are generally larger for females relative to males. Controls for individual heterogeneity yield larger advertising effects, implying that the MTF results may understate the effects of alcohol advertising. Results from the NLSY97 suggest that a 28% reduction in alcohol advertising would reduce adolescent monthly alcohol participation from 25% to between 24 and 21%. For binge participation, the reduction would be from 12% to between 11 and 8%. The past month price–participation elasticity is estimated at −0.26, consistent with prior studies. The results show that reduction of alcohol advertising can produce a modest decline in adolescent alcohol consumption, though effects may vary by race and gender. Copyright © 2006 John Wiley & Sons, Ltd.
Cystic metastasis from head and neck squamous cell cancer: A distinct disease variant?
Authors: Goldenberg David , Sciubba James , Koch Wayne M.
Published: February 2006

Background.

Head and neck squamous cell carcinoma (HNSCC) commonly spreads to regional deep cervical nodes. In most cases, these metastases present as firm, solid masses in the designated lymph node chains. A distinct subset of metastatic nodes present as cystic masses, with most of the volume made up of a liquid center surrounded by a thin solid rim. It has been observed that certain squamous cell carcinoma (SCC) subsites are more likely to produce metastases that are cystic. These sites predominantly include primary tumors of tonsil tissue from Waldeyer's ring. In the past, these cystic cancers often have been erroneously diagnosed as branchiogenic carcinomas, that is, a branchial cleft cyst that has undergone malignant degeneration. Today, most authors have concluded that so‐called branchiogenic carcinomas are actually cystic metastases in the neck probably arising from an oropharyngeal primary SCC. The purpose of this work is to consider the phenomenon of cystic lymph node metastasis in head and neck cancer in depth.

Methods.

A review of the relevant English‐language literature linking cystic metastasis and head and neck cancer was performed.

Results.

These studies indicate that lateral cystic masses in adults often represent an occult primary cancer originating in the epithelium within Waldeyer's ring.

Conclusions.

Adult patients who are initially seen with a lateral cystic neck mass must be presumed to have a cancer until proven otherwise. The mass should be biopsied by fine‐needle aspiration (FNA). However, negative FNA findings may be misleading; therefore, an excisional biopsy and examination under anesthesia with directed biopsies of Waldeyer's ring and bilateral tonsillectomy should be considered a part of the diagnostic workup. © 2006 Wiley Periodicals, Inc. Head Neck, 2006
Clinical curiosity: Cribriform‐morular variant of papillary thyroid carcinoma
Authors: Dalal Kimberly M. , Moraitis Dimitrios , Iwamoto Carlos , Shaha Ashok R. , Patel Snehal G. , Ghossein Ronald A.
Published: February 2006

Background.

There is an increasing awareness of the association of papillary thyroid carcinoma and familial adenomatous polyposis (FAP). Although the incidence is rare, most tend to occur in women. Several authors have described a distinctive histologic variant of papillary thyroid carcinoma, the cribriform‐morular variant, which is associated with FAP but also may be encountered in patients with non‐FAP. This diagnosis may precede the symptoms of colorectal polyposis.

Methods.

A healthy 36‐year‐old woman was seen with a left thyroid nodule, and a 34‐year‐old woman with FAP was seen with a right thyroid nodule; both masses were suspicious for papillary thyroid carcinoma. Both patients underwent total thyroidectomy.

Results.

Pathologic examination of both specimens revealed papillary thyroid carcinoma, cribriform‐morular variant. The first patient subsequently underwent colonoscopy, which was negative for polyposis.

Conclusions.

Patients diagnosed with the cribriform‐morular variant of papillary thyroid cancer should be screened for the presence of FAP. © 2006 Wiley Periodicals, Inc. Head Neck 28: 471–476, 2006
Smoking is associated with a decrease of O6‐alkylguanine‐DNA alkyltransferase activity in bronchial epithelial cells
Authors: Povey Andrew C. , O'Donnell Paul , Barber Phil , Watson Mandy , Margison Geoffrey P. , Koref Mauro F. Santibáñez
Published: February 2006

O6‐alkylguanine‐DNA alkyltransferase (MGMT) represents the first line of defense against the toxic, mutagenic and carcinogenic effects of O6‐alkylguanine adducts in DNA. These adducts mediate the biological activity from a series of alkylating agents, such as the tobacco‐specific nitrosamines, believed to contribute to the carcinogenicity of tobacco smoke. There have been conflicting reports on the effects of smoking on MGMT activity in lung and other tissues. Here, we investigate MGMT activity in peripheral blood mononuclear cells (PBMC) and lung bronchial epithelial cells (BEC), extracted by lung brushings, from smokers and nonsmokers attending a bronchoscopy clinic. MGMT activity was significantly lower in BECs (geometric mean; 95% confidence interval 1.02; 0.86–1.20 fmol/μg DNA) than in PBMCs (7.86; 6.70–9.59 fmol/μg DNA; p < 0.001), suggesting that bronchial epithelia may be particularly sensitive to alkylation damage. More importantly our results indicate that activity in BECs is significantly decreased in samples from current smokers (0.71; 0.54–0.93 fmol/μg DNA) compared to nonsmokers (1.25; 1.03–1.51 fmol/μg DNA; p = 0.002). This could represent an important contribution to the carcinogenicity of tobacco smoke. © 2006 Wiley‐Liss, Inc.
Analysis of fumarate hydratase mutations in a population‐based series of early onset uterine leiomyosarcoma patients
Authors: Ylisaukko‐oja Sanna K. , Kiuru Maija , Lehtonen Heli J. , Lehtonen Rainer , Pukkala Eero , Arola Johanna , Launonen Virpi , Aaltonen Lauri A.
Published: February 2006

Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population‐based series of early onset (≤45 years) ULMSs. Eighty‐one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. © 2006 Wiley‐Liss, Inc.
Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice
Authors: Lacy Jill , Loomis Regina , Grill Susan , Srimatkandada Pavani , Carbone Rocco , Cheng Yung‐Chi
Published: February 2006

Nasopharyngeal carcinoma (NPC) is causally linked to Epstein‐Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP‐1), is expressed in the majority of NPCs. LMP‐1 upregulates antiapoptotic genes, including bcl‐2, and Bcl‐2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl‐2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl‐2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666‐1 line, a stably infected NPC‐derived line that co‐expresses LMP‐1 and Bcl‐2. We have shown that G3139 treatment of C666‐1 in vitro caused sequence‐dependent suppression of Bcl‐2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days × 5 doses) delayed engraftment and significantly inhibited growth of established C666‐1 xenografts in SCID mice compared to control oligo‐treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days × 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real‐time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl‐2 levels were significantly decreased in G3139‐treated animals. Our studies have demonstrated that the Bcl‐2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666‐1, and in combination with CDDP, is curative in C666‐1 NPC xenograft tumors in vivo. The sequence‐dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl‐2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC. © 2006 Wiley‐Liss, Inc.
Rapid induction of apoptosis in B‐cell lymphoma by functionally isolated human antibodies
Authors: Fransson Johan , Tornberg Ulla‐Carin , Borrebaeck Carl A.K. , Carlsson Roland , Frendéus Björn
Published: February 2006

Novel panning and screening methodology was devised to isolate high affinity human recombinant scFv antibody fragments with functionally associated properties in B lymphoma cells. The approach was used to generate a panel of apoptosis‐inducing antibodies specific for antigens differentially expressed in B lymphoma vs. T leukaemia cells. The selections resulted in an antibody pool with near perfect selectivity (>99%) for the B lymphoma target cells. Randomly picked clones (72) revealed 7 unique antibody genotypes. Six of these rapidly induced apoptosis in target cells. Following the conversion to full IgGs, the antibodies were shown to be specific for HLA‐DR/DP, the B‐cell receptor μ chain and for CD54/ICAM‐1. The latter receptor was not previously associated with apoptotic properties in B‐cell lymphomas. Anti‐ICAM‐1 IgG induced apoptosis in a broad range of B lymphoma cell lines and were shown by immunohistochemistry to bind strongly to B lymphoma tissue obtained from 5 different B lymphoma patients. The recombinant IgG antibodies had affinities in the subnanomolar (0.3 nM) to nanomolar (3 nM) range. The described technology is generally applicable for the rapid isolation of high affinity human antibodies with specificity for differentially expressed cell surface receptors with intrinsic negative or positive signalling properties from naïve phage libraries. © 2006 Wiley‐Liss, Inc.
Familial risk of colon and rectal cancer in Iceland: Evidence for different etiologic factors?
Authors: Stefansson Tryggvi , Moller Pall H. , Sigurdsson Fridbjorn , Steingrimsson Eirikur , Eldon Bjarki Jónsson
Published: February 2006

The aim of this study was to characterize the familial risk of colon and rectal cancer using 2 population‐based registries in Iceland, the Icelandic Cancer Registry and a genealogy database. The standardized incidence ratio (SIR) was used to estimate the risk among relatives of colorectal cancer index cases diagnosed in Iceland over a 46‐year period (1955–2000). The 2,770 colorectal cancer patients had 23,272 first‐degree relatives. Among first‐degree relatives, there was an increased risk of both colon (SIR 1.47, 95% confidence interval (CI) 1.34–1.62) and rectal cancer (SIR 1.24, 95% CI 1.04–1.47). An increased risk of colon cancer was observed among siblings of colon cancer patients (SIR 2.03, 95% CI 1.76–2.33), whereas no such increase was observed for parents or offspring. Furthermore, the risk of rectal cancer was only increased among brothers (SIR 2.46 95% CI 1.46–3.89) of rectal cancer patients and not among their sisters (SIR 1.0 95% CI 0.40–2.06). The added risk of colon cancer among first‐degree relatives was independent of site of colon cancer in the proband. Our results confirm that family history of colorectal cancer is a risk factor for the disease. However, family history has a different association with colon cancer than with rectal cancer, suggesting that the 2 cancer types may have different etiologic factors. Our results have implications for colon and rectal cancer screening programs. © 2006 Wiley‐Liss, Inc.
Antiangiogenic combination tumor therapy blocking αv‐integrins and VEGF‐receptor‐2 increases therapeutic effects in vivo
Authors: Strieth Sebastian , Eichhorn Martin E. , Sutter Arne , Jonczyk Alfred , Berghaus Alexander , Dellian Marc
Published: February 2006

Anti‐angiogenesis is a promising strategy for cancer therapy currently evaluated in clinical trials. The aim of the study was to investigate the effects of an antiangiogenic combination therapy inhibiting αv‐integrins by a c(yclic)RGD‐peptide (EMD270179) and blocking VEGFR‐2 by SU5416 on tumor angiogenesis and progression in vivo. Experiments were performed in dorsal skinfold chamber preparations of Syrian golden hamsters (60 ± 5 g) bearing A‐Mel‐3 tumors. From day 3–10 after tumor‐cell implantation, animals (n = 6 per group) were treated by monotherapies using the cRGD‐peptide (114 mg/kg/day; i.p.), the VEGFR‐2 antagonist (6 mg/kg/day; i.p.) or by the combination of both monotherapies. A control group received only the solvent DMSO. Using intravital microscopy parameters of intratumoral microcirculation were analyzed on day 5, 7 and 10. In separate experiments subcutaneous tumor growth and metastasis formation was evaluated starting therapy on day 0. Functional vessel density was significantly reduced by the combination therapy compared to that by all other groups on day 10. Although intratumoral red blood cell velocity and vessel diameters were less affected, blood flow in vessel segments and the microcirculatory perfusion index were lower after combined therapy compared to controls. In addition, we observed a significantly stronger inhibition of subcutaneous tumor growth and metastasis formation using the combination therapy. These data clearly support the concept of antiangiogenic combination therapy and demonstrate that it may especially be effective when scheduled as an early or prophylactic treatment regimen, thus avoiding angiogenesis‐dependent tumor and metastasis initiation or tumor recurrence. © 2006 Wiley‐Liss, Inc.
Expression of Aurora kinases in human thyroid carcinoma cell lines and tissues
Authors: Ulisse Salvatore , Delcros Jean‐Guy , Baldini Enke , Toller Matteo , Curcio Francesco , Giacomelli Laura , Prigent Claude , Ambesi‐Impiombato Francesco S. , D'Armiento Massimino , Arlot‐Bonnemains Yannick
Published: February 2006

The Aurora kinases are involved in the regulation of cell cycle progression, and alterations in their expression have been shown to associate with cell malignant transformation. In the present study, we demonstrated that human thyrocytes express all 3 Aurora kinases (A, B and C) at both protein and mRNA level and this expression is cell cycle‐regulated. An increase in the protein level of the 3 kinases was found, with respect to normal human thyrocytes (HTU5), in the human cell lines derived from follicular (FTC‐133), papillary (B‐CPAP) and anaplastic (8305C) thyroid carcinomas, but not in cells derived from a follicular adenoma (HTU42). These observations were mirrored in RT‐PCR experiments for Aurora‐A and B. In contrast, Aurora‐C mRNA levels were not significantly different among the different cell types analyzed, suggesting that posttranscriptional mechanism(s) modulate its expression. The expression at the protein level of all 3 Aurora kinases was significantly higher in 3 thyroid papillary carcinomas with respect to normal matched tissues obtained from the same patients. Similar modifications, at the mRNA level, could be observed in 7 papillary carcinoma tissues for Aurora‐A and B, but not for Aurora‐C. In conclusion, we demonstrated that normal human thyrocytes express all 3 members of the Aurora kinase family, and their expression is amplified in malignant thyroid cell lines and tissues. These results suggest that the Aurora kinases may play a relevant role in malignant thyroid cancers, and may represent a putative therapeutic target for thyroid neoplasms. © 2006 Wiley‐Liss, Inc.
Predicting 5‐fluorouracil chemosensitivity of liver metastases from colorectal cancer using primary tumor specimens: Three‐gene expression model predicts clinical response
Authors: Matsuyama Ryusei , Togo Shinji , Shimizu Daisuke , Momiyama Nobuyoshi , Ishikawa Takashi , Ichikawa Yasushi , Endo Itaru , Kunisaki Chikara , Suzuki Harukazu , Hayasizaki Yoshihide , Shimada Hiroshi
Published: February 2006

We identified genes related to 5‐fluorouracil (5‐FU) sensitivity in colorectal cancer and utilized these genes for predicting the 5‐FU sensitivity of liver metastases. Eighty‐one candidate genes involved in 5‐FU resistance in gastric and colon cancer cell lines were previously identified using a cDNA microarray. In this study, the mRNA expression levels of these 81 selected genes and the genes of 5‐FU‐related enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT), were measured using real‐time quantitative RT‐PCR assays of surgically resected materials from primary colorectal tumors in 22 patients. Clinical responses were estimated by evaluating the effects of 5‐FU‐based hepatic artery injection (HAI) chemotherapy for synchronous liver metastases. Four genes (TNFRSF1B, SLC35F5, NAG‐1 and OPRT) had significantly different expression profiles in 5‐FU‐nonresponding and responding tumors (p < 0.05). A “Response Index” system using three genes (TNFRSF1B, SLC35F5 and OPRT) was then developed using a discriminate analysis; the results were well correlated with the individual chemosensitivities. Among the 11 cases with positive scores in our response index, 9 achieved a reduction in their liver metastases after 5‐FU‐based chemotherapy, whereas only 1 of the 11 cases with negative scores responded well to chemotherapy. Our “Response Index” system, consisting of TNFRSF1B, SLC35F5 and OPRT, has great potential for predicting the efficacy of 5‐FU‐based chemotherapy against liver metastases from colorectal cancer. © 2006 Wiley‐Liss, Inc.
Enhanced antitumor efficacy of telomerase‐selective oncolytic adenoviral agent OBP‐401 with docetaxel: Preclinical evaluation of chemovirotherapy
Authors: Fujiwara Toshiya , Kagawa Shunsuke , Kishimoto Hiroyuki , Endo Yoshikatsu , Hioki Masayoshi , Ikeda Yoshihiro , Sakai Ryo , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi
Published: February 2006

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase‐specific replication‐competent adenovirus (Telomelysin: OBP‐301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP‐401 (Telomelysin‐GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single‐agent therapy with OBP‐401 as well as of combining OBP‐401 with chemotherapeutic agents. Infection of OBP‐401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP‐401 also inhibited the growth of human cancer cells. Quantitative real‐time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP‐401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP‐401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP‐401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor‐specific oncolytic chemovirotherapies for human cancers. © 2006 Wiley‐Liss, Inc.
Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: A Spanish case‐control study
Authors: Fernández L.P. , Milne R.L. , Barroso E. , Cuadros M. , Arias J.I. , Ruibal A. , Benítez J. , Ribas G.
Published: February 2006

Estrogens, and to a lesser extent progesterones, influence the proliferation, differentiation and physiology of breast tissue as well as the development and progression of breast cancer. Genetic variants in the steroid hormone receptor genes ESR1 and PGR (belonging to the nuclear receptor superfamily) could therefore modify sporadic breast cancer susceptibility. Two studies have shown a protective effect associated with variants in ESR1 in 2 distinct populations. We studied 4 single nucleotide polymorphisms (SNPs) in ESR1 and 4 in PGR in 550 consecutive and unrelated sporadic Spanish breast cancer patients and 564 healthy Spanish controls. We observed a dominant protective effect for the S10S variant in ESR1, with an estimated odds ratio (OR) of 0.75 (95% CI = 0.58–0.97; p = 0.03) although functional studies did not show changes in the RNA stability. A small subset of individuals carried a haplotype combination that corroborates this protection. No other SNP considered in either gene was found to be associated with sporadic breast cancer. Our results obtained in a European population confirm the protective role of the S10S variant in ESR1, previously reported in an Asian and a European–American population. © 2006 Wiley‐Liss, Inc.
The prognostic impact of O6‐Methylguanine‐DNA Methyltransferase (MGMT) promotor hypermethylation in esophageal adenocarcinoma
Authors: Baumann S. , Keller G. , Pühringer F. , Napieralski R. , Feith M. , Langer R. , Höfler H. , Stein H. J. , Sarbia M.
Published: February 2006

Promotor hypermethylation is a common event in human cancer. O6‐Methylguanine‐DNA Methyltransferase (MGMT) is a gene involved in DNA repair, which is methylated in a variety of cancer types. In colorectal cancer and lung cancer, hypermethylation of MGMT has been correlated with p53 mutation. In the present study, 132 samples of esophageal adenocarcinoma and 58 samples of normal esophageal tissue were investigated for MGMT hypermethylation status by methylation‐specific real‐time PCR and results were correlated to clinicopathological parameters, patient's survival, p53 mutation and expression of p53 protein and MGMT protein. In the carcinomas, hypermethylation of MGMT was found in 63.6% of cases and loss of MGMT protein expression in 48.5% of cases. Furthermore, MGMT hypermethylation was found in 5.7% of normal esophageal smooth muscle tissue, in 20.0% of esophageal squamous epithelium and in 61.5% of nonneoplastic Barrett's mucosa. In the carcinomas, hypermethylation of the MGMT gene was correlated with loss MGMT protein expression (p < 0.0001) and with high tumor differentiation (p = 0.0079). In contrast, no correlation between MGMT hypermethylation, Lauren's classification, WHO classification, tumor size, gender, age, pT category and pN category, and p53 status was found. Neither MGMT hypermethylation nor loss of MGMT protein expression was correlated with patient's survival. In conclusion, MGMT hypermethylation in esophageal adenocarcinoma is a frequent event that is associated with loss of MGMT protein expression but not with patient's outcome. © 2006 Wiley‐Liss, Inc.
Enhanced antiangiogenic therapy with antibody‐collagen XVIII NC1 domain fusion proteins engineered to exploit matrix remodeling events
Authors: Sánchez‐Arévalo Lobo Víctor J. , Cuesta Ángel M. , Sanz Laura , Compte Marta , García Pascal , Prieto Jesús , Blanco Francisco J. , Álvarez‐Vallina Luis
Published: February 2006

Antiangiogenic therapy is nowadays one of the most active fields in cancer research. The first strategies, aimed at inhibiting tumor vascularization, included upregulation of endogenous inhibitors and blocking of the signals delivered by angiogenic factors. But interaction between endothelial cells and their surrounding extracellular matrix also plays a critical role in the modulation of the angiogenic process. This study introduces a new concept to enhance the efficacy of antibody‐based antiangiogenic cancer therapy strategies, taking advantage of a key molecular event occurring in the tumor context: the proteolysis of collagen XVIII, which releases the endogenous angiogenesis inhibitor endostatin. By fusing the collagen XVIII NC1 domain to an antiangiogenic single‐chain antibody, a multispecific agent was generated, which was efficiently processed by tumor‐associated proteinases to produce monomeric endostatin and fully functional trimeric antibody fragments. It was demonstrated that the combined production in the tumor area of complementary antiangiogenic agents from a single molecular entity secreted by gene‐modified cells resulted in enhanced antitumor effects. These results indicate that tailoring recombinant antibodies with extracellular matrix‐derived scaffolds is an effective approach to convert tumor progression associated processes into molecular clues for improving antibody‐based therapies. © 2006 Wiley‐Liss, Inc.