bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole
Authors: Kamdem Landry K. , Liu Yong , Stearns Vered , Kadlubar Susan A. , Ramirez Jacqueline , Jeter Stacie , Shahverdi Karineh , Ward Bryan A. , Ogburn Evan , Ratain Mark J. , Flockhart David A. , Desta Zeruesenay 
Published: August 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Anastrozole is primarily cleared by hepatic metabolism via oxidative and conjugating enzymes. WHAT THIS STUDY ADDS • Anastrozole is oxidized to hydroxyanastrozole mainly by CYP3A4/5 and glucuronidated to anastrozole glucuronide predominantly by UGT1A4 in vitro.• Hydroxyanastrozole glucuronide and hydroxyanastrozole were quantified as the major metabolites of anastrozole in plasma of breast cancer patients.• This study describes for the first time anastrozole metabolic pathways and the enzymes involved, which may serve as the scientific basis for pharmacogenetic and drug‐interaction assessments.AIMSLittle information is available regarding the metabolic routes of anastrozole and the specific enzymes involved. We characterized anastrozole oxidative and conjugation metabolism in vitro and in vivo.METHODSA sensitive LC‐MS/MS method was developed to measure anastrozole and its metabolites in vitro and in vivo. Anastrozole metabolism was characterized using human liver microsomes (HLMs), expressed cytochrome P450s (CYPs) and UDP‐glucuronosyltransferases (UGTs).RESULTSHydroxyanastrozole and anastrozole glucuronide were identified as the main oxidative and conjugated metabolites of anastrozole in vitro, respectively. Formation of hydroxyanastrozole from anastrozole was markedly inhibited by CYP3A selective chemical inhibitors (by >90%) and significantly correlated with CYP3A activity in a panel of HLMs (r= 0.96, P= 0.0005) and mainly catalyzed by expressed CYP3A4 and CYP3A5. The Km values obtained from HLMs were also close to those from CYP3A4 and CYP3A5. Formation of anastrozole glucuronide in a bank of HLMs was correlated strongly with imipramine N‐glucuronide, a marker of UGT1A4 (r= 0.72, P < 0.0001), while expressed UGT1A4 catalyzed its formation at the highest rate. Hydroxyanastrozole (mainly as a glucuronide) and anastrozole were quantified in plasma of breast cancer patients taking anastrozole (1 mg day−1); anastrozole glucuronide was less apparent.CONCLUSIONAnastrozole is oxidized to hydroxyanastrozole mainly by CYP3A4 (and to some extent by CYP3A5 and CYP2C8). Once formed, this metabolite undergoes glucuronidation. Variable activity of CYP3A4 (and probably UGT1A4), possibly due to genetic polymorphisms and drug interactions, may alter anastrozole disposition and its effects in vivo.
Targeting paediatric acute lymphoblastic leukaemia: novel therapies currently in development
Authors: Lee‐Sherick Alisa B. , Linger Rachel M. A. , Gore Lia , Keating Amy K. , Graham Douglas K. 
Published: August 2010

SummaryModifications to the treatment of acute lymphoblastic leukaemia (ALL) in children have led to a dramatic increase in survival in the past 40 years. Despite this success, a significant subset of paediatric leukaemia patients either relapse or fail to ever achieve a complete remission. Additionally, some patients necessitate treatment with intensified chemotherapy regimens due to clinical or laboratory findings which identify them as high risk. These patients are unlikely to respond to further minor adjustments to the dosing or timing of administration of the same chemotherapy medications. Many novel targeted therapies for the treatment of childhood ALL provide potential mechanisms to further improve cure rates, and provide the possibility of minimizing toxicity to non‐malignant cells, given their specificity to malignant cell phenotypes. This article explores many of the potential targeted therapies in varying stages of development, from those currently in clinical trials to those still being refined in the research laboratory.
Desmoplakin and KIF20B as target antigens in patients with paroxysmal nocturnal haemoglobinuria
Authors: Alahmad Adnan , Preuss Klaus‐Dieter , Schenk Joachim , Füreder Wolfgang , Schrezenmeier Hubert , Müller‐Lantzsch Nikolaus , Schubert Jörg , Pfreundschuh Michael 
Published: August 2010

SummaryAt least two hypotheses have been proposed to explain the mechanism of clonal expansion of mutant cells in paroxysmal nocturnal haemoglobinuria (PNH). One hypothesis assumes an immune escape mechanism and another proposes an intrinsic second mutational event within clonal cells. We hypothesised that autoantibodies detected in PNH patients could identify antigens that might play a role in the pathophysiology of this disease and screened a human fetal liver cDNA library for serological reactivity against haematopoietic stem/progenitor cells antigens using the SEREX approach. Two antigens were identified that are constitutively expressed in CD34+ cells. Three and four of 10 PNH patients showed antibody responses against kinesin family member 20B (KIF20B) (previously termed M‐phase phosphoprotein 1, MPP1) and desmoplakin (DSP) respectively. We also found an antibody response in one of 20 healthy volunteers against desmoplakin, yet at a much lower titre than in PNH patients. No response to KIF20B or desmoplakin was detected in five patients with aplastic anaemia without a glycosyl phosphatidyl inositol ‐deficient clone. We conclude that KIF20B and desmoplakin have been shown to be the first known auto‐antigens to be recognised by the immune system of patients with PNH. The analysis of the mechanisms underlying the autoimmune response might contribute to our understanding of the clonal expansion in PNH.
Silencing of ROR1 and FMOD with siRNA results in apoptosis of CLL cells
Authors: Choudhury Aniruddha , Derkow Katja , Daneshmanesh Amir Hossein , Mikaelsson Eva , Kiaii Shahryar , Kokhaei Parviz , Österborg Anders , Mellstedt Håkan 
Published: August 2010

SummaryWe have previously demonstrated that ROR1 and FMOD (fibromodulin) are two genes upregulated in chronic lymphocytic leukaemia (CLL) cells compared to normal blood B cells. In this study, siRNAs were used to specifically silence ROR1 and FMOD expression in CLL cells, healthy B cells and human fibroblast cell lines. siRNA treatment induced a specific reduction (75–95%) in FMOD and ROR1 mRNA. Western blot analysis with specific antibodies for FMOD and ROR1 demonstrated that the proteins were significantly downregulated 48 h after siRNA treatment. Silencing of FMOD and ROR1 resulted in statistically significant (P ≤ 0·05–0·001) apoptosis of CLL cells but not of B cells from normal donors. Human fibroblast cell lines treated with FMOD and ROR1 siRNA did not undergo apoptosis. This is the first report demonstrating that ROR1 and FMOD may be involved in the survival of CLL cells. ROR1 in particular is further explored as potential target for therapy in CLL.
The relationship between liver disease stage and liver fibrosis: a tangled web
Authors: Germani Giacomo , Burroughs Andrew K , Dhillon Amar P 
Published: August 2010

Germani G, Burroughs A K & Dhillon A P  (2010) Histopathology57, 773–784 The relationship between liver disease stage and liver fibrosis: a tangled web The structural consequences of chronic liver disease are described as a series of liver disease ‘stages’ with scarring and architectural change that eventually destroys and replaces the normal lobular structure of the liver. Fibrosis (‘excess collagen’) and stage have been confused in histological staging systems. Fibrosis is part of increasing liver disease stage, but fibrosis and stage are different. Staging liver disease is important in routine histopathological assessment. Measurement of liver fibrosis is another process. The collagenous proportion of a liver biopsy [collagen proportionate area (CPA)] correlates with hepatic venous pressure gradient (HVPG), which is of recognized prognostic value. CPA at 1 year post‐transplantation in hepatitis C virus‐infected patients predicts subsequent clinical decompensation. CPA in cirrhotic patients predicts decompensation more accurately than staging or HVPG. The ‘cirrhosis’ stage category has poor prognostic power, and CPA effectively substages cirrhosis. CPA improves the description of liver disease stage. Proper validation of antifibrotic treatments and ‘non‐invasive markers of liver fibrosis’ requires measurement of liver fibrosis (and not liver biopsy stage scores). It is unacceptable for the words ‘fibrosis’ and ‘score’ to remain next to each other. There are benefits to properly understanding liver fibrosis and liver disease stage and properly assessing each of them.
Methylation profiles of hereditary and sporadic ovarian cancer
Authors: Bol Guus M , Suijkerbuijk Karijn P M , Bart Joost , Vooijs Marc , Van Der Wall Elsken , Van Diest Paul J 
Published: August 2010

Bol G M, Suijkerbuijk K P M, Bart J, Vooijs M, van der Wall E & van Diest P J (2010) Histopathology 57, 363–370 Methylation profiles of hereditary and sporadic ovarian cancerAims:  Tumour suppressor gene silencing through promoter hypermethylation plays an important role in oncogenesis. Carcinogenesis of hereditary cancers usually differs from that of their sporadic counterparts, but methylation has hardly been studied in hereditary ovarian cancer. The aim of this study was to investigate promoter methylation of a set of common tumour suppressor genes in BRCA1‐related ovarian cancer in comparison with sporadic ovarian cancer.Methods and results:  Methylation‐specific multiplex ligation‐dependent probe amplification was used to assess the extent of promoter methylation of 24 different tumour suppressor genes in BRCA1‐associated (n = 25) and matched sporadic ovarian tumours (n = 50). A cumulative methylation index (CMI) was calculated and differences between individual genes were analysed. There was no significant difference in cumulative methylation between BRCA1‐associated and sporadic ovarian carcinomas (median CMI 108; CMI 110; P = 0.86). Also, methylation patterns of individual genes did not show distinct differences after correction for multiple comparisons. CDH13, GSTP1 and RASSF1 were frequently methylated in both sporadic and hereditary ovarian cancers. BRCA1 methylation occurred in 14% of sporadic tumours, but was not detected in BRCA1‐associated tumours.Conclusions:  CDH13, GSTP1 and RASSF1 are frequently methylated in both sporadic and BRCA1‐associated ovarian cancers. Interestingly, methylation of BRCA1, while frequent in sporadic ovarian cancer, never occurred in the hereditary group. BRCA1‐associated ovarian cancers mimic their sporadic counterparts in extent and pattern of promoter methylation of several common tumour suppressor genes. This finding could have implications for future chemotherapy regimens based on epigenetic changes.
Homogeneous EGFR amplification defines a subset of aggressive Barrett’s adenocarcinomas with poor prognosis
Authors: Marx Andreas H , Zielinski Margarete , Kowitz Charlotte‐Marie , Dancau Ana‐Maria , Thieltges Sabrina , Simon Ronald , Choschzick Matthias , Yekebas Emre , Kaifi Jussuf T , Mirlacher Martina , Atanackovic Djordje , Brümmendorf Tim H , Fiedler Walter , Bokemeyer Carsten , Izbicki Jakob R , Sauter Guido 
Published: August 2010

Marx A H, Zielinski M, Kowitz C‐M, Dancau A‐M, Thieltges S, Simon R, Choschzick M, Yekebas E, Kaifi J T, Mirlacher M, Atanackovic D, Brümmendorf T H, Fiedler W, Bokemeyer C, Izbicki J R & Sauter G (2010) Histopathology 57, 418–426 Homogeneous EGFR amplification defines a subset of aggressive Barrett’s adenocarcinomas with poor prognosisAims:  The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) involved in the tumour progression of many cancer types and may serve as an important therapeutic target (erlotinib, cetuximab). Heterogeneity of EGFR amplification and expression could represent a major drawback for anti‐EGFR therapy. The aim of this study was performed to determine the potential impact of tumour heterogeneity on anti‐EGFR therapy in Barrett’s adenocarcinoma (BAC).Methods and results:  Tissue microarray (TMA) sections of 112 BAC and 45 lymph node metastases were analysed for EGFR amplification and expression using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). A subset of 20 samples was also sequenced for EGFR exons 18–21 and Kirsten rat sarcoma viral oncogene homologue (KRAS) exons 2–3 mutations. EGFR amplification was seen in seven (6.25%) of 112 interpretable BAC and typically high‐level with more than 10–20 EGFR copies per tumour cell (EGFR/centromere 7 ratio >3). EGFR amplification was associated with high pT, pN and poor prognosis (P = 0.0004). Identical EGFR amplification status was found in 29 primary tumours and 29 matched lymph node metastases. Moreover, FISH analysis of three to 16 large sections from all amplified BAC and corresponding lymph node metastases did not reveal any heterogeneity of EGFR amplification. No EGFR mutation but one KRAS mutation was found.Conclusion:  The high level and homogeneity of EGFR amplification in primary tumours and metastases suggests the potential therapeutic utility of anti‐EGFR drugs in BAC.
Next‐generation small RNA sequencing for microRNAs profiling in the honey bee Apis mellifera
Authors: Chen X. , Yu X. , Cai Y. , Zheng H. , Yu D. , Liu G. , Zhou Q. , Hu S. , Hu F. 
Published: August 2010

AbstractMicroRNAs (miRNAs) are key regulators in various physiological and pathological processes via post‐transcriptional regulation of gene expression. The honey bee (Apis mellifera) is a key model for highly social species, and its complex social behaviour can be interpreted theoretically as changes in gene regulation, in which miRNAs are thought to be involved. We used the SOLiD sequencing system to identify the repertoire of miRNAs in the honey bee by sequencing a mixed small RNA library from different developmental stages. We obtained a total of 36 796 459 raw sequences; of which 5 491 100 short sequences were fragments of mRNA and other noncoding RNAs (ncRNA), and 1 759 346 reads mapped to the known miRNAs. We predicted 267 novel honey bee miRNAs representing 380 182 short reads, including eight miRNAs of other insects in 14 107 583 genome‐mapped sequences. We verified 50 of them using stem‐loop reverse‐transcription PCR (RT‐PCR), in which 35 yielded PCR products. Cross‐species analyses showed 81 novel miRNAs with homologues in other insects, suggesting that they were authentic miRNAs and have similar functions. The results of this study provide a basis for studies of the miRNA‐modulating networks in development and some intriguing phenomena such as caste differentiation in A. mellifera.
Effect of bioaggregate on differentiation of human periodontal ligament fibroblasts
Authors: Yan P. , Yuan Z. , Jiang H. , Peng B. , Bian Z. 
Published: August 2010

Yan P, Yuan Z, Jiang H, Peng B, Bian Z. Effect of bioaggregate on differentiation of human periodontal ligament fibroblasts. International Endodontic Journal.AbstractAim  To investigate the cytotoxicity of bioaggregate (BA; Innovative Bioceramix, Vancouver, BC, Canada) to human periodontal ligament (PDL) fibroblasts and its effect on differentiation of human PDL fibroblasts and to compare its performance to that of mineral trioxide aggregate (MTA; Dentsply, Tulsa, OK, USA).Methodology  Cytotoxicity was assessed by 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay on days 1, 2, and 3 after incubation with BA or MTA. The influence of BA and MTA on differentiation of human PDL fibroblasts on days 3, 5, and 7 was evaluated by gene expression of alkaline phosphatase (ALP) and collagen type I (COLI) via quantitative real‐time polymerase chain reaction (PCR). The data were analysed by one‐way analysis of variance followed by Tukey’s test.Results  Cell numbers in the BA group were similar to that of the control group throughout the culture period, whereas MTA suppressed the proliferation of fibroblasts. ALP expression was significantly increased in the BA group on day 7, whilst it was enhanced by MTA on day 3. Gene expression of COLI was induced by both BA and MTA compared to the control group.Conclusions  Bioaggregate was nontoxic to human PDL fibroblasts and appeared to induce the differentiation of human PDL fibroblasts.
Microcalcifications in atherosclerotic lesion of apolipoprotein E‐deficient mouse
Authors: Debernardi Nicola , Roijers Ruben B. , Krams Rob , De Crom Rini , Mutsaers Peter H.A. , Van Der Vusse Ger J. 
Published: August 2010

SummaryEvidence is accumulating that calcium‐rich microdeposits in the vascular wall might play a crucial role in the onset and progression of atherosclerosis. Here we investigated an atherosclerotic lesion of the carotid artery in an established murine model, i.e. the apolipoprotein E‐deficient (APOE−/−) mouse to identify (i) the presence of microcalcifications, if any, (ii) the elemental composition of microcalcifications with special reference to calcium/phosphorus mass ratio and (iii) co‐localization of increased concentrations of iron and zinc with microcalcifications. Atherosclerosis was induced by a flow‐divider placed around the carotid artery resulting in low and high shear‐stress regions. Element composition was assessed with a proton microprobe. Microcalcifications, predominantly present in the thickened intima of the low shear‐stress region, were surrounded by areas with normal calcium levels, indicating that calcium‐precipitation is a local event. The diameter of intimal microcalcifications varied from 6 to 70 μm. Calcium/phosphorus ratios of microcalcifications varied from 0.3 to 4.8, mainly corresponding to the ratio of amorphous calcium‐phosphate. Increased iron and zinc concentrations commonly co‐localized with microcalcifications. Our findings indicate that the atherosclerotic process in the murine carotid artery is associated with locally accumulated calcium, iron and zinc. The calcium‐rich deposits resemble amorphous calcium phosphate rather than pure hydroxyapatite. We propose that the APOE−/− mouse, in which atherosclerosis was evoked by a flow‐divider, offers a useful model to investigate the pathophysiological significance of accumulation of elements such as calcium, iron and zinc.
Erythropoietin is involved in angiogenesis in human primary melanoma
Authors: Ribatti Domenico , Nico Beatrice , Perra Maria Teresa , Longo Vito , Maxia Cristina , Annese Tiziana , Piras Franca , Murtas Daniela , Sirigu Paola 
Published: August 2010

SummaryIn this study, the extent of angiogenesis, evaluated as microvascular volume density, immunoreactivity of tumour cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human primary melanoma specimens. Results showed that Epo/EpoR expression correlate with angiogenesis and tumour thickness. These findings suggest that Epo is secreted by tumour cells and it affects vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner, playing an important role in melanoma angiogenesis.
Strong facilitation in mild environments: the stress gradient hypothesis revisited
Authors: Holmgren Milena , Scheffer Marten 
Published: August 2010

Summary 1. The idea that the role of facilitative interactions increases as environmental conditions become more stressful has become a ruling paradigm in ecology. Here, we review three reasons why positive interactions may actually be more prominent than generally thought under moderately stressful rather than under extreme conditions. 2. First, there is evidence that in some communities the net effect of amelioration of shortage of a limiting resource, such as water under the canopy of nurse plants, may be beneficial under moderate conditions whereas it can be overruled by increased competition for the same resource in very harsh environments. 3. Secondly, we show that even in situations where the relative role of facilitation increases monotonically with stress, the absolute effect should as a rule be largest at intermediately stressful conditions. This is because under the harshest conditions, facilitative amelioration of conditions is insufficient to allow growth altogether. Therefore, while facilitation will expand the range of conditions where an organism may occur, the largest absolute effects on biomass will always occur under less stressful conditions. 4. A third reason why facilitation may be more important under moderate conditions than previously thought is that in any ecosystem, the suite of organisms is adapted to local conditions. This implies that even under conditions that appear benign, facilitation may play an unexpectedly large role as organisms are simply more sensitive than those found under harsher overall conditions. 5. Synthesis. We argue that while facilitation will extend the range of conditions where an organism can occur, it should also boost performance of the species well into the more moderate range of conditions. Broadening our search image for facilitative effects towards milder environments will reveal wider than expected prevalence of positive interactions and their effects on stability and diversity in nature.
Environment‐enhanced self‐fertilization: implications for niche shifts in adjacent populations
Authors: Levin Donald A. 
Published: August 2010

Summary1. Pollen‐mediated gene flow from ecological core populations may hamper the ability of populations to invade new, closely adjacent habitats. The potential for the invasion of a new habitat is enhanced when selection against immigrants is augmented by the elevation of self‐fertilization. This shift imparts a measure of reproductive isolation to the invader.2. Whereas genetically mediated changes in selfing often accompany niche shifts in plants, the elevation of self‐fertilization by plastic responses to novel, stressful, environments has not been explored. Here I will show that invaders of novel habitats may have elevated levels of self‐fertility mediated by alterations in floral form and self‐compatibility.3. Heightened selfing facilitates the evolution of local adaptation by increasing the additive genetic variance for tolerance to the new habitat. Heightened selfing also facilitates local adaptation by increasing reproductive assurance.4. Elevated levels of selfing based on developmental responses are immediate, as opposed to that obtained by multigenerational selection.5. Synthesis. The likelihood of a niche shift will be substantially enhanced if the invader is protected from the swamping effect of gene flow from a nearby core population. This protection may be afforded by an environment‐induced elevation of self‐fertility. The likelihood of a niche shift also is enhanced by an increase in reproductive assurance which may be vital to the survival of an invading population whose reproductive success is density‐dependent.