1,721,198 research outputs found
Efficacy of second line agents for the treatment of metastatic castration-resistant prostate cancer progressing after docetaxel: Systematic review and meta-analysis.
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The cellular response to different radiation qualities in relation to breast cancer screening and treatment
Get PDFVariations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Polymorphisms in DNA double-strand break repair genes: link with breast cancer susceptibility and in vitro chromosomal radiosensitivity.
No full textBreast cancer is one of the most common types of neoplasia in females in Western industrialised countries. In Belgium, breast cancer is the leading cause of death by cancer in females and the risk of being diagnosed with breast cancer before the age of 75 years in Belgium is 11.5 %. One of the strongest risk factors is a family history of the disease, indicating a genetic predisposition to breast cancer. However, only 6% of all breast cancer cases can be linked to monogenic, germline mutations in the breast cancer predisposing genes BRCA1, BRCA2, ATM, CHK2, PTEN and TP53. Epidemiological analyses suggest that the remaining breast cancer cases can be explained by a polygenic model that states that the combined effect of many individual weak genetic variants is responsible for an enhanced breast cancer risk. As enhanced in vitro chromosomal radiosensitivity is a hallmark for breast cancer and results from non‐ or misrepaired double strand breaks (DSBs), single nucleotide polymorphisms (SNPs) in DSB repair genes, could be involved in in vitro chromosomal radiosensitivity and genetic predisposition to breast cancer. Several population based case‐control studies have already shown a link between SNPs in DSB repair genes and breast cancer risk. Moreover, the breast is a selected micro‐environment, vulnerable to endogenous oxidative stress through hormone exposure. Especially oestrogen has attracted considerable attention, as it induces DSBs during its metabolism and may act as a complete carcinogen. In the studies presented in this thesis, we investigated whether SNPs in the core repair genes of DSBs are associated with an enhanced breast cancer susceptibility and/or in vitro chromosomal radiosensitivity. Genes from the two main DSB repair pathways were studied: Ku70, Ku80 and DNAPKCS of the non homologous end‐joining (NHEJ) pathway and RAD51, XRCC3, BRCA1 and BRCA2 of the homologous recombination (HR) pathway.
The results demonstrate that the c.‐1310C>G SNP in the promoter region of Ku70 is significantly associated with breast cancer risk in an unselected patient population, comprising mainly of sporadic patients. Additionally, the combination of the variant “G” allele of this polymorphism with a hormonal breast cancer risk factor, reflecting susceptibility to oestrogen exposure, is associated with a more pronounced increase in breast cancer risk. The c.2099‐2408G>A SNP in Ku80 shows a positive association with breast cancer risk in a group of patients with a known or putative genetic predisposition to the disease. Both the c.‐1310C>G (Ku70) and c.2099‐2408G>A (Ku80) point‐variations can be considered risk alleles for breast cancer and they also show a positive association with chromosomal radiosensitivity. The combination of 2 or 4 putative high‐risk genotypes in RAD51 and XRCC3 resulted in a significant association with breast cancer risk in a patient population selected for a genetic predisposition, which is in agreement with the polygenic model for breast cancer initiation. Our results are also indicative of a modifying effect of SNPs in RAD51, XRCC3, BRCA1 and BRCA2 on breast cancer penetrance and phenotype in patients carrying a pathological mutation in BRCA1 or BRCA2. We also showed that the c.190T>C variation in the BRCA1 RING finger domain may induce modifications of the protein structure which could disrupt the BRCA1‐BARD1 interaction and hence predispose to breast cancer. The studies performed in the frame of this thesis contribute to the ongoing research concerning the genetic profiles associated with an enhanced breast cancer risk. A better understanding of the underlying genetic factors, responsible for breast cancer predisposition will improve our understanding of the mechanisms underlying breast cancer aetiology and this will influence the approach to breast cancer prevention and treatment
Analysis of radiosensitivity in South African cervical and breast cancer patients
Get PDFIntroduction: Ionising radiation can cause DNA double strand breaks (DSB), that result in chromosomal aberrations if un- or mis-repaired. Individuals with compromised DNA damage repair mechanisms display increased chromosomal radiosensitivity. The G0-micronucleus assay (MN assay) and the γ-H2AX assay are two assays used in radiobiology to study DNA DSB and repair.
Breast cancer is the leading cancer amongst South African women, with a lifetime risk of 1 in 34. Since most cancer patients in South Africa present with late-stage disease, chemotherapy and radiotherapy are commonly-used treatments. Several international studies have shown breast cancer patients to be more chromosomally radiosensitive than healthy controls. These studies have not been confirmed on a cancer population living in South Africa.
Cervical cancer is the second most common cancer in South Africa; however, it is the leading cancer amongst black women with a lifetime risk of 1/35 compared to 1/82 in white women. Studies show a genetic link to cervical cancer susceptibility and DNA damage repair genes. International studies on radiation-induced DNA damage in lymphocytes of cervical cancer patients remain inconclusive and have never been performed on a South African population. Cervical cancer is caused by infection with the Human Papilloma Virus (HPV). Human Immunodeficiency Virus (HIV), HPV and cervical cancer are epidemiologically linked. Due to the high rate of HIV in South Africa, a significant proportion of cervical cancer patients receiving radiotherapy treatment will be HIV-positive. Studies show an effect of HIV on chromosomal radiosensitivity, however this has not been confirmed on a cancer population. The MN assay on the biopsies and exfoliated cervical cells of cervical cancer patients could be used as a predictive test for response to radiotherapy. The overall aim was to study chromosomal radiosensitivity in South African cervical and breast cancer patients.
Materials and methods: Chromosomal radiosensitivity of lymphocytes of cervical and breast cancer patients was examined using the MN assay with the Metafer 4 of Metasystems. Different scoring methods for the Metafer system were compared to each other. The effect of HIV, HPV, ethnicity, clinical parameters and age on micronuclei (MN) values in lymphocytes was investigated. The MN assay was attempted on cells from cervical biopsies and exfoliated cervical cells. The γ-H2AX was performed on the lymphocytes of a group of cervical cancer patients.
Results: A new scoring method for the Metafer 4 system that is more reliable in patients with late-stage disease was introduced. Cervical cancer patients had significantly higher MN values with HIV patients having the highest values. HPV, clinical parameters and age had a limited effect on MN values. The MN assay was unsuccessful on biopsies and exfoliated cervical cells of cervical cancer patients. There was no difference in double strand break induction and repair between cervical cancer patients and controls. In breast cancer patients, ethnicity had an effect on MN values, with only white breast cancer patients having significantly higher MN counts.
Conclusion: The study showed increased chromosomal radiosensitivity in cervical cancer and white breast cancer patients. Results highlight how such studies are important within the South African context, where factors like HIV, disease stage and ethnicity can have an effect on chromosomal radiosensitivity and where unique genes/polymorphisms may play a role in cancer risk
From human genetics to radiobiology : in vitro radiosensitivity in individuals with a germline defect in DNA damage response genes
Get PDFAll currently known high to intermediate risk “breast cancer genes”, including BRCA1 and BRCA2, are involved in the DNA damage response pathway. Heterozygous germline mutations in these genes predispose to breast and ovarian cancer. In addition, such mutations may also result in enhanced radiosensitivity mediated by chromosomal instability after exposure to ionizing radiation, leading to a higher risk to develop radiation-induced breast cancer. However, results of currently available clinical studies evaluating carcinogenesis and in vitro studies comparing chromosomal radiosensitivity in mutation carriers and non-carriers are inconclusive. Nevertheless, insights into the radiosensitive phenotype of healthy tissues of mutation carriers is of the utmost importance for the safe use of ionizing radiation for
diagnostic purposes or radiotherapy treatment. In this thesis, we evaluated in vitro radiosensitivity in carriers of a mutation in DNA damage response genes by means of two different assays.
The first assay, the G2 micronucleus assay, is a cytogenetic assay in which MN are analyzed in cells irradiated in the G2 phase of the cell cycle. This assay was developed to evaluate radiosensitivity in cells with a heterozygous BRCA1 or BRCA2 mutation. BRCA1 and BRCA2 have a function in homologous recombination (HR), the main DNA double strand break repair pathway activated in late S and G2 phase of the cell cycle. Furthermore, BRCA1 is also involved in the G2/M cell cycle checkpoint. The G2 micronucleus assay allows evaluation of both functions by means of two distinct endpoints: (1) the radiation-induced micronucleus yield, which reflects DNA double strand break repair capacity and (2) the G2/M checkpoint efficiency ratio, which allows evaluation of the G2 arrest capacity.
Before applying the G2 micronucleus assay on BRCA mutation carriers, the assay was validated in a patient with Ataxia Telangiectasia (AT). AT patients are characterized by a manifest increased radiosensitivity. AT patients show biallelic inactivation of ATM, involved in both DNA double strand break repair by means of HR and G2/M checkpoint activation. We demonstrated a severely increased radiosensitivity with both endpoints when applying the G2 micronucleus assay in lymphocytes of this AT patient. In lymphocytes of healthy relatives with a heterozygous ATM mutation the radiosensitivity observed with this assay was intermediate between the AT patient and the control cohort.
When applying the G2 micronucleus assay on lymphocytes of healthy BRCA1/2 mutation carriers, we demonstrated significantly enhanced radiation-induced MN yields in both BRCA1 and BRCA2 germline mutation carriers, pointing to an impaired DNA double strand break repair capacity in both groups. Furthermore, an impaired G2 arrest capacity was observed in BRCA1 mutation carriers. In healthy relatives who did not inherit the familial mutation, no enhanced radiosensitivity was observed. Although a significantly enhanced radiosensitivity was demonstrated for the cohort of BRCA1 and BRCA2 mutation carriers compared to the control cohort, individual radiosensitivity evaluation was less straightforward due to overlap in micronucleus yields between both cohorts. Therefore, a scoring system to evaluate individual radiosensitivity was implemented.
As both BRCA1 and BRCA2 are involved in HR, we evaluated if the accumulation of RAD51, a key protein involved in this pathway, at the double strand break site can be used to assess HR functionality and radiosensitivity. To this end, a radiation-induced RAD51 foci assay was optimized in a breast epithelial cell line (MCF10A) expressing ±50% reduced BRCA1 and BRCA2 protein levels, obtained by RNA interference. RAD51 foci were analyzed in cells synchronized in S phase by aphidicolin as HR is upregulated during this phase of the cell cycle. We demonstrated significantly reduced RAD51 foci formation, and thus impaired HR capacity, in response to the induction of radiation-induced double strand breaks in the BRCA knockdown cells compared to control cells. As no overlap in RAD51 foci distribution is observed between knockdown and control cells, we think that this assay could better differentiate between normal cells and cells with a heterozygous BRCA1 or BRCA2 mutation than the G2 micronucleus assay. This will be further explored in synchronized lymphocytes of heterozygous germline mutation carriers.
In addition to the detection of unequivocal deleterious mutations in BRCA1 and BRCA2, variants of unknown clinical significance (VUS) are detected during diagnostic screening. The associated breast cancer risk is unknown, which creates a challenge for genetic counselling. mRNA analysis to assess variants that might impair proper RNA splicing, a highly regulated process, are widely used. We evaluated the outcome at cDNA level of 21 putative splicing variants in BRCA1 and BRCA2 and demonstrated aberrant splicing for 12 variants, suggesting that these are likely pathogenic. Furthermore, we demonstrated that in silico prediction tools might assist in the evaluation of these putative splicing variants. However, further optimization is warranted to allow reliable application outside the highly conserved consensus splice sites.
The results obtained in this thesis may indicate that care should be taken when applying ionizing radiation for diagnostic or therapeutic purposes in individuals with a germline mutation in BRCA1 or BRCA2 as they may be at higher risk of developing radiation-induced breast cancer
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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