bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Type of Hepatitis B Virus Mutation: Replacement Mutation Involving a Hepatocyte Nuclear Factor 1 Binding Site Tandem Repeat in Chronic Hepatitis B Virus Genotype E
Authors: Fujiwara Kei , Tanaka Yasuhito , Paulon Emma , Orito Etsuro , Sugiyama Masaya , Ito Kiyoaki , Ueda Ryuzo , Mizokami Masashi , Naoumov Nikolai V. 
Published: October 2005

ABSTRACT
The genetic diversity of hepatitis B virus (HBV) strains has evolved through mutations such as point mutations, deletions or insertions, and recombination. We identified and characterized a novel type of mutation which is a complex of external insertion, deletion, and internal duplication in sequences from one of six patients with chronic hepatitis B virus genotype E (HBV/E). We provisionally named this mutation a “replacement mutation”; the core promoter upstream regulatory sequence/basic core promoter was replaced with a part of the S1 promoter covering the hepatocyte nuclear factor 1 (HNF1) binding site, followed by a tandem repeat of the HNF1 site. A longitudinal analysis of the HBV population over 6 years showed the clonal change from wild-type HBV/E to replacement-mutant type, resulting in a lower hepatitis B (HB) e antigen titer, a high HBV DNA level in serum, and progression of liver fibrosis. In an in vitro study using a replication model, the replacement-mutant HBV showed higher replication levels than the wild-type HBV/E replicon, probably mediated by altered transcription factor binding. Additionally, this HNF1 site replacement mutation was associated with excessive HB nucleocapsid protein expression in hepatocytes, in both in vivo and in vitro studies. This novel mutation may be specific to HBV genotype E, and its prevalence requires further investigation.
Intracellular Interference of Infectious Bursal Disease Virus
Authors: González Dolores , Rodríguez Jose Francisco , Abaitua Fernando 
Published: October 2005

ABSTRACT
A search for dominant-negative mutant polypeptides hampering infectious bursal disease virus (IBDV) replication has been undertaken. We have found that expression of a mutant version of the VP3 structural polypeptide known as VP3/M3, partially lacking the domain responsible for the interaction with the virus-encoded RNA polymerase, efficiently interferes with the IBDV replication cycle. Transformed cells stably expressing VP3/M3 show a significant reduction (up to 96%) in their ability to support IBDV growth. Our findings provide a new tool for the characterization of the IBDV replication cycle and might facilitate the generation of genetically modified chicken lines with a reduced susceptibility to IBDV infection.
An N-Linked Glycoprotein with α(2,3)-Linked Sialic Acid Is a Receptor for BK Virus
Authors: Dugan Aisling S. , Eash Sylvia , Atwood Walter J. 
Published: October 2005

ABSTRACT
BK virus (BKV) is a common human polyomavirus infecting >80% of the population worldwide. Infection with BKV is asymptomatic, but reactivation in renal transplant recipients can lead to polyomavirus-associated nephropathy. In this report, we show that enzymatic removal of α(2,3)-linked sialic acid from cells inhibited BKV infection. Reconstitution of asialo cells with α(2,3)-specific sialyltransferase restored susceptibility to infection. Inhibition of N-linked glycosylation with tunicamycin reduced infection, but inhibition of O-linked glycosylation did not. An O-linked-specific α(2,3)-sialyltransferase was unable to restore infection in asialo cells. Taken together, these data indicate that an N-linked glycoprotein containing α(2,3)-linked sialic acid is a critical component of the cellular receptor for BKV.
Murine Coronavirus with an Extended Host Range Uses Heparan Sulfate as an Entry Receptor
Authors: de Haan Cornelis A. M. , Li Zhen , te Lintelo Eddie , Bosch Berend Jan , Haijema Bert Jan , Rottier Peter J. M. 
Published: October 2005

ABSTRACTOnly a relatively few mutations in its spike protein allow the murine coronavirus to switch from a murine-restricted tropism to an extended host range by being passaged in vitro. One such virus that we studied had acquired two putative heparan sulfate-binding sites while preserving another site in the furin-cleavage motif. The adaptation of the virus through the use of heparan sulfate as an attachment/entry receptor was demonstrated by increased heparin binding as well as by inhibition of infection through treatment of cells and the virus with heparinase and heparin, respectively.
Alveolar adenoma of the lung: a clinicopathological description of a case of this very unusual tumour
Authors: Halldorsson A , Dissanaike S , Kaye K S 
Published: October 2005

Alveolar adenomas are extremely rare, and are probably benign lung tumours of unknown histogenesis. This report describes a case of alveolar adenoma in a 43 year old white man, who presented with pleuritic chest pain. A chestx ray and computerised tomography scan demonstrated a solitary left lower lobe lung nodule. Although a positron emission tomography scan seemed to document the benign nature of the lesion, a thoracoscopic wedge resection was performed to alleviate the symptoms and verify the diagnosis. Histologically, the lesion was well demarcated, dominated by large and small cysts with no normal lung parenchyma. The interstitial cellular component consisted of both epithelioid and vaguely spindle shaped cells. The cystic cell linings were mostly indistinct, although areas of cuboidal epithelial cells were seen. Multiple histochemical and immunohistochemical tests were performed. There were no histological signs of malignancy and the patient is doing well one and a half years postoperatively.
Activation of the extracellular signal regulated kinase (ERK) pathway in human melanoma
Authors: Zhuang L , Lee C S , Scolyer R A , McCarthy S W , Palmer A A , Zhang X D , Thompson J F , Bron L P , Hersey P 
Published: October 2005

Background:Several studies suggest that melanoma may be resistant to treatment because of resistance to apoptosis and that this may be the result of activation of the extracellular signal regulated kinase (ERK1/2) pathway.Aims:To test this hypothesis by examining the expression of ERK1/2 and its activated form in histological sections of melanoma and its relation to known prognostic features of the disease.Materials/Methods:Immunohistochemistry with antibodies to ERK1/2 and phosphorylated ERK (p-ERK) was performed on formalin fixed sections from 42 primary melanomas, 38 metastases, and 20 naevi. Fourteen of the primary melanomas were in the radial and 28 in the vertical growth phase.Results:ERK1/2 was widely expressed (100%) in all the (pigmented) lesions studied. p-ERK1/2 expression was much lower in compound (32.4%) and dysplastic (54.5%) naevi than in primary melanoma (nodular 78.8%, superficial spreading 67%) and subcutaneous metastases (76.3%). p-ERK expression was much lower in lymph node metastases (48.5%), suggesting that the microenvironment may influence the activation of ERK. There was a (non-significant) trend for p-ERK expression to be higher in thick (>1.0 mm) versus thin (⩽1.0 mm) melanoma (p = 0.23). There was a trend for overall survival to be related to p-ERK expression in patients with melanoma over 1 mm in thickness.Conclusions:Expression of activated ERK1/2 in melanocytic lesions appears to be related to malignant potential so that activation of ERK1/2 may be important in melanoma progression. These results provide important histological support for the proposal that inhibition of this signalling pathway may be useful in treatment of melanoma.
Evidence based criteria for the histopathological diagnosis of toxoplasmic lymphadenopathy
Authors: Eapen M , Mathew C F , Aravindan K P 
Published: October 2005

Aims:To formulate evidence based histopathological criteria for the diagnosis of acquired toxoplasmic lymphadenitis, in an area of high tuberculosis prevalence.Methods:Multiple histopathological parameters were assessed in a consecutive sample of biopsies from 68 patients presenting with lymphadenopathy with a duration of less than six months. Serum IgM enzyme linked immunosorbent assay was used as the standard reference test for the diagnosis of toxoplasmic lymphadenitis. The sensitivity, specificity, and likelihood ratios of various histological parameters were estimated.Results:The presence of microgranulomas (p < 0.0001), paracortical widening (p  =  0.006), paracortical hyperplasia (p  =  0.02), monocytoid B cells in sinuses (p  =  0.007), lower than grade 2 macrogranuloma (p  =  0.002), and the absence of giant cells (p  =  0.05) were found to discriminate between IgM positive cases and IgM negative controls. Using a composite criterion—(1) presence of microgranulomas, (2) lower than grade 2 macrogranuloma, (3) absence of giant cells, and (4) follicular hyperplasia—toxoplasmic lymphadenitis can be diagnosed with a high degree of sensitivity (100%), specificity (96.6%), and positive likelihood ratio (29).Conclusion:Toxoplasma lymphadenitis can be diagnosed with a high degree of confidence using the specific histopathological criteria identified here.
Grading melanocytic dysplasia in paraffin wax embedded tissue by the nucleic acid index
Authors: Berman D M , Wincovitch S , Garfield S , Romeo M J 
Published: October 2005

Background:Although nucleic acid derangements are the hallmark of melanocytic dysplasia, the gold standard for its diagnosis remains the microscopic evaluation of haematoxylin and eosin stained slides. However, light microscopy is subjective and crucial genomic changes do not always show as changes in histology.Aims:To introduce the nucleic acid index (NAI) as a means of analysing nucleic acid derangements in histological sections at the level of the individual cell and within the context of its microenvironment.Methods:Confocal laser scanning microscopy was performed on melanocytic lesions stained with acridine orange (AO), a fluorescent stain for DNA and RNA. The NAI, calculated by measuring the fluorescence intensities of AO in nuclei relative to the surrounding cytoplasm, reflects the concentration of DNA relative to RNA.Results:When applied to benign naevi, dysplastic naevi, and melanoma, a very strong significant association was seen between lower NAI and malignant potential (p < 0.0001). Strong inverse correlations were found between NAI and both mitotic index and Breslow thickness. Interestingly, the NAI for dysplastic naevi is between that of melanoma and most benign naevi, consistent with their intermediate biological behaviour and histological appearance.Conclusion:By providing a quantitative measure for melanocytic neoplasia, the NAI may improve the diagnosis of melanocytic lesions and the selection of treatment.
Interobserver reproducibility of histological features in cutaneous malignant melanoma
Authors: Urso C , Rongioletti F , Innocenzi D , Saieva C , Batolo D , Chimenti S , Filotico R , Gianotti R , Lentini M , Tomasini C , Rebora A , Pippione M 
Published: October 2005

Aims:To assess the interobserver reproducibility of certain histological features proposed for the diagnosis of melanoma.Methods:In a series of melanomas, 13 histological parameters were analysed: dimension > 6 mm, asymmetry, poor circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, asymmetrical melanin, melanin in deep cells, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis.Results:The agreement (reproducibility) between the nine observers was excellent (κ > 0.75) for 10 of the 13 examined features (dimension > 6 mm, poor circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, asymmetrical melanin, melanin in deep cells, mitoses, and necrosis). The agreement for asymmetry was very close to excellence (κ  =  0.74), and that for cytological atypia (κ  =  0.65) and dermal lymphocytic infiltrate (κ  =  0.47) was slightly lower, but in the fair to good agreement range. The κ values obtained by comparison with the majority diagnosis were generally high (⩾ 0.85); the mean value of κ was lower (0.70) for only one parameter (dermal lymphocytic infiltrate).Conclusions:The parameters investigated showed an overall good reproducibility.
CD44s is useful in the differentiation of benign and malignant papillary lesions of the breast
Authors: Tse G M K , Tan P-H , Ma T K F , Gilks C B , Poon C S P , Law B K B 
Published: October 2005

Background/Aims:CD44s, the standard form of CD44, has been shown to be downregulated during malignant transformation of breast cancers. It has also been reported recently to be a useful marker in differentiating between benign and malignant papillary lesions of the breast, with high expression in the former. CD44s expression in benign and malignant papillary lesions was evaluated.Methods:CD44s expression was assessed by immunohistochemistry in 101 benign papillomas and 59 papillary carcinomas (seven invasive papillary carcinomas, 41 papillary ductal carcinomas in situ, and 11 ductal carcinomas involving papillomas).Results:Patients’ age and tumour size were significantly different between the papilloma and papillary carcinoma groups (p < 0.0001). CD44s showed positive staining in 45 papillomas (45%) and five papillary carcinomas (8%), and the difference was significant (p < 0.0001). The myoepithelial cells, when present, were also positive for CD44s in both groups, with no observable differences. Using CD44s positive staining to differentiate between benign and malignant papillary lesions gives a sensitivity, specificity, and accuracy of 45%, 92%, and 62%, respectively.Conclusions:CD44s may be useful as an adjunct in the evaluation of morphologically problematic cases of papillary lesion of the breast.
Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial
Authors: Jirström K , Rydén L , Anagnostaki L , Nordenskjöld B , Stål O , Thorstenson S , Chebil G , Jönsson P-E , Fernö M , Landberg G 
Published: October 2005

Background:Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.Aims:To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.Materials/methods:Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.Results:Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.Conclusions:Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
Role of mesangial fibrinogen deposition in the pathogenesis of crescentic Henoch-Schönlein nephritis in children
Authors: Shin J I , Park J M , Shin Y H , Lee J S , Jeong H J 
Published: October 2005

Aims:To clarify the role of mesangial fibrinogen deposition in crescentic Henoch-Schönlein nephritis (HSN).Methods:A retrospective analysis of 21 children with HSN treated with immunosuppressants. Serial renal biopsies were performed before and after treatment. They were divided into two groups according to the immunofluorescent course of fibrinogen deposition: group I (n = 9), no or decreased deposition; group II (n = 12), persistent or increased deposition.Results:There were no differences between the two groups in renal manifestations or laboratory and histological findings at presentation. However, the activity index after immunosuppressive treatment was significantly decreased in group I (mean, 7.9 (SEM, 0.7)v2.9 (0.4); p = 0.008) and unchanged in group II (mean, 6.8 (SEM, 0.3)v6.0 (2.1)). The chronicity index was unchanged in group I, but increased in group II (mean, 0.8 (SEM, 0.3)v1.8 (0.3); p = 0.02). Univariate analysis revealed that the only factor significantly related to persistent or increased fibrinogen deposition was age more than 9 years (p = 0.03). Furthermore, the intensity of fibrinogen deposition at the second biopsy correlated positively with the age at onset (R2 = 0.306; p = 0.009) and changes in the percentage of crescents (post-treatment crescents (%) minus pretreatment crescents (%)) correlated positively with the intensity of fibrinogen deposition at the second biopsy (R2 = 0.193; p = 0.046).Conclusions:This study indicates that fibrinogen deposition has an important role to play in renal injury of crescentic HSN and reflects persistent severe histological activity.
EVOLUTIONARY DYNAMICS IN CARCINOGENESIS
Authors: GATENBY ROBERT A. , VINCENT THOMAS L. , GILLIES ROBERT J. 
Published: October 2005

We have previously demonstrated intra- and extra-cellular factors that govern somatic evolution of the malignant phenotype can be modeled through evolutionary game theory, a mathematical approach that analyzes phenotypic adaptation to in-vivo environmental selection forces. Here we examine the global evolutionary dynamics that control evolutionary dynamics explicitly addressing conflicting data and hypothesis regarding the relative importance of the mutator phenotype and microenvironment controls. We find evolution of invasive cancer follows a biphasic pattern. The first phase occurs within normal tissue, which possesses a remarkable adaptive landscape that permits non-competitive coexistence of multiple cellular populations but renders it vulnerable to invasion. When random genetic mutations produce a fitter phenotype, self-limited clonal expansion is observed — equivalent to a polyp or nevus. This step corresponds to tumor initiation in classical skin carcinogenesis experiments because the mutant population deforms the adaptive landscape resulting in the emergence of unoccupied fitness peaks — a premalignant configuration because, over time, extant cellular populations will tend to evolve toward available fitness maxima forming an invasive cancer. We demonstrate that this phase is governed by intracellular processes, such as the mutation rate, that promote phenotypic diversity and environmental factors that control cellular selection and population growth. These results provide an integrative model of carcinogenesis that incorporates cell-centric approaches such as the mutator phenotype hypothesis with the critical role of the environmental demonstrated by Bissell and others. The biphasic dynamics of carcinogenesis give a quantitative framework of understanding for the empirically observed initiation and promotion/progression stages in skin carcinogenesis experimental models.
Fractionated Low-Dose Radiation Exposure Leads to Accumulation of DNA Damage and Profound Alterations in DNA and Histone Methylation in the Murine Thymus
Authors: Pogribny Igor , Koturbash Igor , Tryndyak Volodymyr , Hudson Darryl , Stevenson Sandie M.L. , Sedelnikova Olga , Bonner William , Kovalchuk Olga 
Published: October 2005

Abstract
Thymus, an important component of hematopoietic tissue, is a well-documented “target” of radiation carcinogenesis. Both acute and fractionated irradiation result in a high risk of leukemia and thymic lymphoma. However, the exact mechanisms underlying radiation-induced predisposition to leukemia and lymphoma are still unknown, and the contributions of genetic and epigenetic mechanisms in particular have yet to be defined. Global DNA hypomethylation is a well-known characteristic of cancer cells. Recent studies have also shown that tumor cells undergo prominent changes in histone methylation, particularly a substantial loss of trimethylation of histone H4-Lys20 and demethylation of genomic DNA. These losses are considered a universal marker of malignant transformation. In the present study, we investigated the effect of low-dose radiation exposure on the accumulation of DNA lesions and alterations of DNA methylation and histone H4-Lys20 trimethylation in the thymus tissue using an in vivo murine model. For the first time, we show that fractionated whole-body application of 0.5 Gy X-ray leads to decrease in histone H4-Lys20 trimethylation in the thymus. The loss of histone H4-Lys20 trimethylation was accompanied by a significant decrease in global DNA methylation as well as the accumulation of DNA damage as monitored by persistence of histone γH2AX foci in the thymus tissue of mice exposed to fractionated irradiation. Altered DNA methylation was associated with reduced expression of maintenance (DNMT1) and, to a lesser extent, de novo DNA methyltransferase DNMT3a in exposed animals. Expression of another de novo DNA methyltransferase DNMT3b was decreased only in males. Irradiation also resulted in ∼20% reduction in the levels of methyl-binding proteins MeCP2 and MBD2. Our results show the involvement of epigenetic alterations in radiation-induced responses in vivo. These changes may play a role in genome destabilization that ultimately leads to cancer.
A Mechanism of COOH–Terminal Binding Protein–Mediated Repression
Authors: Meloni Alison R. , Lai Chun-Hsiang , Yao Tso-Pang , Nevins Joseph R. 
Published: October 2005

Abstract
The E2F4 and E2F5 proteins specifically associate with the Rb-related p130 protein in quiescent cells to repress transcription of various genes encoding proteins important for cell growth. A series of reports has provided evidence that Rb-mediated repression involves both histone deacetylase (HDAC)–dependent and HDAC-independent events. Our previous results suggest that one such mechanism for Rb-mediated repression, independent of recruitment of HDAC, involves the recruitment of the COOH-terminal binding protein (CtBP) corepressor, a protein now recognized to play a widespread role in transcriptional repression. We now find that CtBP can interact with the histone acetyltransferase, cyclic AMP–responsive element–binding protein (CREB) binding protein, and inhibit its ability to acetylate histone. This inhibition is dependent on a NH2-terminal region of CtBP that is also required for transcription repression. These results thus suggest two complementary mechanisms for E2F/p130-mediated repression that have in common the control of histone acetylation at target promoters.