RAD51C Germline Mutations in Breast and Ovarian Cancer Cases from High-Risk Families

BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5′ UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001). Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene

Morphogrammata / The lettered Art of Optatian. Figuring Cultural Transformations in the Age of Constantine

This volume explores one of the most complex, multifaceted and momentous of all western cultural transformations: the refashioning of the Roman principate under the emperor Constantine in the early fourth century AD. It does so through the kaleidoscopic lens of one of antiquity’s most fascinating (and maligned) artists, Publilius Optatianus Porfyrius. Optatian’s experiments with word and image are little known among classicists. But, as contributors to this volume argue, his ‘morphogrammatic’ creations uniquely reflect, figure and shape the cultural dynamics of the fourth century. This is the first edited book dedicated to Optatian’s picture-poems and their various historical contexts. By bringing together different disciplinary perspectives (including ancient history, classical philology, art history, theology, philosophy and media studies), the volume demonstrates how Optatian gave form to the various political, intellectual and cultural currents of his age. At the same time, contributors champion Optatian as a uniquely creative artist – and one who anticipated some of our most pressing literary critical, art historical and philosophical concerns today

Approaches to the Writing of Greek in Late Antique Latin Texts

The treatment of Greek words in manuscripts of Augustine and of Ausonius suggests that late Latin writers employed transliteration, rather than writing Greek letters, more often than has been thought, both for familiar loan-words in Latin and for words perceived as still Greek

The Reader And The Poet: The Transformation Of Latin Poetry In The Fourth Century

In Late Antiquity, the figure of the reader came to play a central role in mediating the presence of the text. And, within the tradition of Latin poetry, the fourth century marks a turn towards writing that privileges the reader's involvement in shaping the meaning of the text. Therefore, this dissertation addresses a set of problems related to the aesthetics of Late Antiquity, the reception of Classical Roman poetry, and the relation between author and reader. I begin with a chapter on contemporary methods of reading, in order to show the ways in which Late Antique authors draw attention to their own interpretations of authoritative texts and to their own creation of supplemental meaning. I show how such disparate authors as Jerome, Augustine, Servius, and Macrobius each privileges the work of secondary authorship. The second chapter considers the use of prefaces in Late Antique poetry. The imposition of paratextual borders dramatized the reader's involvement in the text. In the third chapter, I apply Umberto Eco's idea of the open text to the figural poetry of Optatianus Porphyrius, to the Psychomachia of Prudentius, and to the centos from Late Antiquity. These novel forms of poetry are all structurally dependent upon their reader. The fourth chapter turns to a particularly Late Antique form of allusion, in which the poet reproduced the exact words of his source in a different sense. This transpositional mode of allusion is characteristic of the Late Antique creation of a classical past; for it allows the poet to be, in a radical sense, a reader. Because the text's struggle to mean was of central importance in Late Antiquity, poets came to create space for reading. The fragmented surface of a Late Antique poem draws attention to the necessary presence of the reader, and it draws that reader in

Sequential exposure to fibroblast growth factors (FGF) 2, 9 and 18 enhances hMSC chondrogenic differentiation

SummaryObjectiveTo test the effects of sequential exposure to FGF2, 9 and 18 on human Mesenchymal Stem Cells (hMSC) differentiation during in vitro chondrogenesis.DesignControl and FGF2-expanded hMSC were cultured in aggregates in the presence of rhFGF9, rhFGF18 or rhFGFR3-specific signaling FGF variants, starting at different times during the chondroinductive program. Quantitative real time polymerase chain reaction (qRT-PCR) and immunocytochemistry were performed at different stages. The aggregate cultures were switched to a hypertrophy-inducing medium along with rhFGFs and neutralizing antibodies against FGFR1 and FGFR3. Histological/immunohistochemical/biochemical analyses were performed.ResultsFGF2-exposed hMSC during expansion up-regulated Sox9 suggesting an early activation of the chondrogenic machinery. FGF2, FGF9 and 18 modulated the expression profile of FGFR1 and FGFR3 in hMSC during expansion and chondrogenesis. In combination with transforming growth factor-beta (TGF-β), FGF9 and FGF18 inhibited chondrogenesis when added at the beginning of the program (≤d7), while exhibiting an anabolic effect when added later (≥d14), an effect mediated by FGFR3. Finally, FGFR3 signaling induced by either FGF9 or FGF18 delayed the appearance of spontaneous and induced hypertrophy-related changes.ConclusionsThe stage of hMSC-dependent chondrogenesis at which the growth factors are added impacts the progression of the differentiation program: increased cell proliferation and priming (FGF2); stimulated early chondrogenic differentiation (TGF-β, FGF9/FGF18) by shifting the chondrogenic program earlier; augmented extracellular matrix (ECM) production (FGF9/FGF18); and delayed terminal hypertrophy (FGF9/FGF18). Collectively, these factors could be used to optimize pre-implantation conditions of hMSC when used to engineer cartilage grafts

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study

Background: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. Methods: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. Results: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). Conclusions: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence