276 research outputs found
Overcoming the Fear of Difference
No full textThe Nineteenth Jacoby-Lunin Humanitarian Lecture underwritten by the Frank Jacoby Foundation in collaboration with the Carl and Dorothy Bennett Center for Judaic Studies and Open VISIONS Forum present… Timothy P. Shriver, Activist, author and Chairman of Special Olympics.https://digitalcommons.fairfield.edu/bennettcenter-posters/1341/thumbnail.jp
Abstract P4-07-01: Assessment of the hereditary component in 94 cancer predisposition genes to triple negative breast cancer
No full textAbstract
Background: In women with triple negative breast cancer (TNBC) unselected for age or family history, 8-14% and 5% of patients harbor germline mutations in BRCA1 and BRCA2, respectively. Diagnosis of TNBC <60 years of age is one of the NCCN criterion for genetic testing of BRCA1 and BRCA2. The contribution of germline mutations in other cancer predisposition genes to TNBC, is, however, not well-studied.
Methods: TNBC was classified as tumors with <1% positively staining cells for ER and PR and HER2 = 0+, 1+ or 2+/not amplified. Genomic DNA was isolated from blood samples and targeted sequencing was performed using the TruSight Cancer panel (Illumina). Pathogenic mutations were identified using VariantStudio and classified as pathogenic, uncertain significance (VUS) or benign using ClinVar.
Results: 196 female patients diagnosed with TNBC 2001-2014 had genomic DNA available. Average age at diagnosis was 52.8 years (range 34.1-83.4 years). The majority of patients were of European (66%) or African (31%) American ancestry; 26% had a family history and 13% had died of disease with an average time to death of 2.81 years. Twenty-three (12%) of women with TNBC had pathogenic mutations in breast cancer genes BRCA1 (n=14), BRCA2 (n=5), PALB2 (n=1) and CHEK2 (n=3), two women had mutations in the colon cancer genes MUTYH, one had a mutation in the ovarian cancer gene BRIP1, and an additional three women had pathogenic mutations in cancer predisposition genes FANCD2, SDHB and XPC. An additional 42 women had VUS in 20 genes, including one in BRCA1 and 5 in BRCA2.
Discussion: Although the majority of pathogenic mutations in this cohort of women with TNBC were in the BRCA1 and BRCA2 genes (10%), panel testing allowed for the detection of mutations in other breast (2%), colon (1%), ovarian (1%) and other cancer (2%) predisposition genes. Panel testing thus identifies genes other than BRCA1/2 associated with increased risk of TNBC and may incidentally identify women who would benefit from enhanced surveillance for other cancers.
The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences or any other agency of the U.S. Government.
Citation Format: Ellsworth RE, Lovejoy LA, Shriver CD. Assessment of the hereditary component in 94 cancer predisposition genes to triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-07-01.</jats:p
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IIFET 2000 Author Index
No full textThis alphabetical listing of authors was linked to the papers on the original CD version of the proceedings
Abstract P3-08-11: Contribution of germline mutations in cancer predisposition genes to tumor etiology in women diagnosed with invasive breast cancer before 40 years
No full textAbstract
Background: Although breast cancer in young women (YW) accounts for &lt;10% of diagnoses annually, tumors in young patients have more aggressive characteristics and higher mortality rates. The cost of breast cancer, including treatment costs, physical and psychosocial effects, and lost productivity, is higher in YW than older patients. Improved understanding of etiology of breast cancer in YW is critical to developing effective prevention strategies.
Methods: All patients diagnosed before 40 years were identified. Family history was classified as average (No first or second degree relatives with breast or ovarian cancer or 1 second degree relative with breast cancer diagnosed &gt;50 years), moderate (1 first degree relative with breast cancer, 2 first or second degree relatives with breast cancer diagnosed &gt;50 years or 1 first or second degree relative with ovarian cancer) or strong (&gt;1 first or second degree relative with bilateral breast cancer, breast and ovarian cancer or male breast cancer, &gt;2 first or second degree relatives with breast cancer before age 50, breast and ovarian cancer in different relatives, ovarian cancer at any age or &gt;3 first or second degree relatives with breast cancer at any age). Genomic DNA was isolated from blood samples and targeted sequencing was performed using the TruSight Cancer panel (Illumina). Pathogenic mutations were identified using VariantStudio.
Results: Seven percent (132/1950) of patients enrolled in the CBCP were diagnosed &lt;40 years. Of these, 7% had a strong family history). TruSight sequencing was completed for 63 women for whom genomic DNA was available: five patients had pathogenic BRCA2 mutations (1813dupA, 5849del4, 999del5, Q2491X, Y3098X), all ER+ tumors, and seven patients had BRCA1 mutations (187delAG, 448insA, 943ins10, E84X, Q1313X, E1535X) all in triple negative breast cancers (TNBC). A pathogenic CHEK2 I157T was detected in an African American woman with TNBC. Variants of unknown significant were also detected in APC, ATM, BRCA1, BRCA2, CHEK2, CDH1, ERCC4, FANCA and PMS2 and heterozygote mutations detected in autosomal recessive genes BLM and RECQL4.
Discussion: Pathogenic mutations were found in 21% of young women with breast cancer with an additional 22% harboring potentially pathogenic mutations. BRCA1 mutations were associated with triple negative breast tumors in individuals with moderate to strong family history and BRCA2 mutations were associated with ER+ tumors in young women without strong family histories. These data demonstrate that although genetic predisposition may account for 21-43% of tumors, &gt;50% of tumors in young women are not attributable to genetic causes, and identification of those non-genetic factors is critical to reduce the burden of breast cancer in this population.
Citation Format: Ellsworth RE, Rummel SK, Shriver CD. Contribution of germline mutations in cancer predisposition genes to tumor etiology in women diagnosed with invasive breast cancer before 40 years [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-11.</jats:p
The potential for circular dichroism as an additional facile and sensitive method of monitoring low-molecular-weight heparins and heparinoids
No full textThe ultraviolet circular dichroism (CD) spectra of commercial low-molecular-weight heparins, heparinoids and other anticoagulant preparations have been recorded between 180 and 260 nm. Principal component analysis of the spectra allowed their differentiation into a number of groups related to the means of their production reflecting the structural changes introduced by each process. The findings suggest that CD provides a complementary technique for the rapid analysis of heparin preparations
Alive but Cancelled: The Public’s Response to the Controversial Author
No full textThis thesis explores how the public has responded to authors J.K. Rowling and Lionel Shriver, who have become the subject of public controversy, and what this response tells us about the current conceptions about the author. Academics like Wenche Ommundsen and English & Frow have established that authors are no longer the faceless names they once were, and several of them have reached a proper celebrity status. Especially now, in a time in which social media exerts great influence on how the general public views celebrities and concepts like “wokeness” and social justice become increasingly relevant topics, celebrities and celebrity authors are often expected to display socially just behaviour and reprimanded when they do not. By analysing the online responses to the controversies caused by these two prominent authors, this thesis argues that the public perceives a strong relationship between authors and their work and generally attributes a great deal of responsibility to popular authors with vast platforms.
Keywords: Lionel Shriver; J.K. Rowling; literary celebrity; wokeness; cancel culture; Death of the Author; transphobia; cultural appropriatio
The cave: A search for the mother’s story in narrative literature
No full textThe mother’s voice is underrepresented in literature. The mother has been a silent figure, always present, often near, featuring in the story of another, but rarely the focus of the story. She has been spoken for, about and around, but rarely empowered to speak for herself.
In this thesis I argue that the mother’s story, in narrative fiction and memoir, should be available, and culturally valued. Since the diversity of women’s experiences of mothering cannot be explained by any single theory or ideology, narrative may articulate the complexities and ambiguities experienced in motherhood in ways that scholarly discourses do not always allow.
This thesis includes a creative component—a collection of related fictional stories narrated by one mother, and entitled “The Cave”. Adopting the concept of the cave, as a metaphor for the transformative potential of mothering, the fiction draws on the mundane, everyday experiences of a life that is centred on caring for children. The exegesis that follows is based on three approaches to mothering narratives: their research, reading and writing. It explores the emergence of the mother’s story within theoretical discourses around motherhood, and its more recent appearances in fiction and non-fiction narratives. It suggests reasons for the absence of the mother’s subjective voice, argues that women have been disadvantaged by this silence, and seeks new possibilities for representing the complexity of mothering experiences
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IIFET 2000 Proceedings Cover
No full textOmnipress produced the CD of the conference proceedings. This is the cover of that CD along with the copyright statement concerning the packaging of the proceedings
Abstract P5-05-02: NEDD9 promotes breast cancer metastasis by regulating mitochondrial functions
No full textAbstract
NEDD9 has been characterized as a metastasis-promoting gene in various cancer cells including breast. We previously reported that NEDD9 promotes malignant phenotypes of breast cancer cells through distinct and non-overlapped domains. For example, the FAT (Focal Adhesion Targeting) domain of NEDD9 promotes cancer cell growth, while the SH-domain facilitates cell migration. These results suggest that NEDD9 promotes tumor metastasis by enhancing dissemination and growth in the tumor-host microenvironments through distinct and non-overlapped domains. Thus, targeting functions of NEDD9 is a promising approach for breast cancer therapies.
In order to further characterize NEDD9-mediated breast cancer growth, we performed yeast-two hybrid (Y2H) screening to identify proteins that associate with the FAT domain of NEDD9. Using the FAT domain constructed in pGBKKT7 (Clonetech, CA) as a bait to screen library of human fibroblast (Clonetech, CA), we identified several proteins that associate with the domain. They are small GTPases (i.e. RAB11a and ARF4), cytoskeletal proteins (i.e. Nexilin), and cytosolic proteins (i.e. HAX-1). Among of these potential partner proteins, we focused on the interaction between NEDD9 and HAX-1 in breast cancer cells. Co-immunoprecipitation assays confirm the molecular complex of NEDD9-HAX-1 in both SK-Br3 and SUM149 cells. Importantly, p130cas, which harbors similar domain structures with NEDD9, was not precipitated with NEDD9, suggesting a specific interaction between NEDD9 and HAX-1. Given the fact of NEDD9 as a key metastasis promoting gene, these results suggest that NEDD9-HAX-1 plays a key role breast cancer metastasis by facilitating growth in microenvironments.
While the biological function are not clear at present, previous studies demonstrated that HAX-1 localizes in mitochondria in breast cancer cells, Indeed, we demonstrated that NEDD9 was found in both cytosol and mitochondria fractions in malignant breast cancer cell MDA-MB-231, but not non-metastatic HCC38. These results suggest the presence of NEDD9-HAX1 complex in mitochondria and this complex may facilitate breast cancer metastasis. In addition to HAX-1, several mitochondrial proteins such as EFG1, DCTN6, and MMADHC were found in the Y2H screening system as described above. These results suggest that NEDD9 facilitates breast cancer metastasis through regulating multiple pathways including signaling pathways and mitochondrial functions, thus serving as a promising therapeutic target for cancer patients including breast.
The view expressed in this article are those of the author and do not reflect the official policy of the Department of Defense, or U.S.Government.
Citation Format: Iida J, Dorchak J, Slavik J, Clancy R, Cutler ML, Shriver CD. NEDD9 promotes breast cancer metastasis by regulating mitochondrial functions [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-05-02.</jats:p
Abstract P2-06-04: Use of principal component analyses to select ER-balanced subset for gene centering in PAM50 subtyping
No full textAbstract
Background: PAM (Prediction Analysis of Microarray) 50 is an established gene expression-based algorithm to classify breast tumors into basal-like, HER2-enriched, luminal A (LA), and luminal B (LB) subtypes. Clinical subtyping is mainly based on immunohistochemistry (IHC) assays of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2) and Ki67 classifying tumors into triple-negative (ER-/PR-/Her2-), Her2+ (ER-/PR-/Her2+), LA (ER+/Her2-/Ki67-), LB1 (ER+/Her2-/Ki67+) and LB2 (ER+/Her2+). These two subtyping methods do not completely match even on comparable subtypes. Nevertheless, the ER-balanced subset for gene-centering in PAM50 subtyping was selected based on clinical status. Here we explored the possibility of using principal component analyses and iterative PAM50 call to refine the selection of an ER balance subset to improve consistency between these methods focusing on LB calls which is more aggressive than LA tumors.
Methods: Normalized gene expression data was obtained from TCGA research network for 712 primary tumors which had IHC status available for ER, PR and Her2. Since Ki67 status was not available LA and LB was discriminated for ER+ cases with Her2- and Her2+ respectively. In house RNA-Seq dataset had 118 primary tumors and were drawn from the Clinical Breast Care Project where breast cancer patients were consented using an IRB-approved protocol. Tumors were selected and processed by laser microdissection. RNA was extracted from tissues using the Illustra triplePrep kit (GE Healthcare). Paired-end mRNA sequencing was performed using the Illumina HiSeq platform. Sequenced reads were processed using PERL based pipeline utilizing PRINSEQ, GSNAP and HTSeq. Principal component analysis (PCA) was done using R. Wilcoxon rank sum test was used for statistical significance (p&lt;0.05).
Results: In both datasets, the PCA map grouping of cases does not perfectly reflect the clinical subtypes. This motivated us to select ER balance subset based on the PC1 separation and IHC subtype. The resulting PAM50 subtypes on PCA map distinguished Basal and LA as two well separated components. Using all of Basal and equal number of LA cases for ER balance subset for PAM50 resulted in increased LB call and a better consistency with IHC LB calls. Among 712 cases in TCGA LB numbers increased from 142 in initial PAM50 call to 203 in ER balanced refined PAM50 call. We noticed that there was significantly higher (p-value = 4.414e-11) MKI67 expression for the 39 cases switch from LA to LB between PAM50 calls. Similar trend was observed in our in-house dataset where majority of the IHC-LB1 cases was called as LB in PAM50. The new method increased LB call from 22 to 27 which in-turn increased consistency between molecular and clinical subtypes from 73 to 79 out of the total of 118 cases.
Conclusion: We show that an iterative PAM50 call coupled with PCA for selection of ER balance set potentially enhanced the consistency of the LB calls with clinical subtyping and that the tumors switched from LA to LB have high MKI67 expression.
The views expressed in this article are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, the Department of Defense, or U.S. Government.
Citation Format: Raj-Kumar P-K, Liu J, Kovatich AJ, Kvecher L, Shriver CD, Hu H. Use of principal component analyses to select ER-balanced subset for gene centering in PAM50 subtyping [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-06-04.</jats:p
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