Article Database

EJ Josey: Transformational Leader of the Modern Library Profession

Abstract:

This work provides a comprehensive examination of the life and professional career of EJ Josey within the broader historical and political landscape of the civil rights movement. In the era of Jim Crow, Josey rose to prominence in the library profession by challenging the American Library Association (ALA) to live up to its creed of equality for all. This was not easy during the 1950s and 1960s, during segregation. Using interviews with Josey and his contemporaries, as well as several archival sources, library educator Renate Chancellor analyzes Josey’s leadership, particularly within modern day racial currents. During his professional career, spanning over fifty years (1952-2002), Josey worked as a librarian (1953-1966), an administrator of library services (1966-1986), and as a professor of library science (1986-1995). He also served as President of the American Library Association and perhaps his most notable achievement, he successfully drafted a resolution that prevented state library associations from discriminating against African American librarians. This essentially ended segregation in the ALA. Josey’s transformative leadership provides a model to tackle today’s civil rights challenges both in and outside the library profession. This authoritative work copublished by the Association for Library and Information Science Education (ALISE) documents for the historical record a significant period of history that is underexplored in the scholarly literature. The target audience for this book are researchers, historians, LIS educators and students interested in understanding the complex struggle for civil and human rights in professional organizations.

The role of the retinoblastoma pathway (Rb) in high grade serous ovarian varcinoma (HGSC)

Abstract:

The Rb pathway functions as a cell cycle checkpoint and deregulation of its components, commonly found in malignancies, causes progression from G1 to S phase, promoting cellular proliferation. Because of Rb’s central role in checkpoint regulation, abrogation of the pathway can occur through multiple non-redundant mechanisms including Rb loss, hypermethylation or mutation, and CCND1 or CCNE amplification. Emerging evidence shows that tumour types can often be distinguished by particular alterations in one member of the pathway suggesting that different mechanisms of Rb abrogation may regulate tumour behaviour. We hypothesize that Rb pathway deregulation is frequent in HGSC, the most common and most aggressive histotype of ovarian cancer, and that the mechanism of Rb pathway deregulation identifies clinically distinct subgroups of HGSC.

Micro-dissected epithelium from HGSC and normal FTE samples were analyzed for differential gene expression using the Affymetrix U133 Plus 2.0 gene-chips, and expression values for p53, p21, p27, p16, CCND1, CCNE and Rb genes determined. Protein expression was assessed by immunohistochemistry (IHC) on tissue microarrays composed of ovarian/tubal carcinomas inclusive of the major histotypes. Digitized stained slides were quantified using automated image analysis and correlated with clinico-pathologic variables including outcome. Rb loss of heterozygosity (LOH) was tested by an Rb diagnostics protocol involving D13S153 and RB1.2 polymorphic marker analyses using PCR amplification, followed by comparisons of the tumour and its corresponding normal sample by MicroGene Clipper sequencers.

Gene expression analysis showed statistically significant over-expression of p53, CCNE E2F1/3 and p16 and down-regulation of p21 and CCND1 in HGSC compared to normal fallopian tube epithelium (p<0.001). Protein expression determined by IHC analysis of HGSC revealed a similar pattern of expression when compared to normal fallopian tube, the site of origin of this carcinoma. There were important differences in the expression of these proteins between HGSC subgroups, where up-regulation was observed for p16, CCNE, CCND1 and BIRC5 in 58.3%, 57%, 33.3%, and 58.3% respectively. Rb however, showed no statistically significant differences at the RNA level, but 40% of all HGSC profiled had a significant decrease in protein expression. Interestingly, LOH analysis revealed 76% of HGSC had Rb inactivation at the gene level. Furthermore, we observed statistically significant correlations (p=0.029) between p16 over-expression and Rb protein loss, using Fisher’s Exact test.

HGSC is characterized by both genetic and protein abrogation in the Rb pathway. Additionally, we observed differences in the mechanism of this G1/S checkpoint inactivation amongst HGSC patient samples which may represent important biological/clinical differences amongst sub-groups of serous cancer patients.

The Familial Ovarian Tumor Study: A Morphological and Immunohistochemical Review

Abstract:

Background: High grade serous carcinoma (HGSC) is associated with germline
mutations of BRCA1/2 in approximately 15% of cases. The aim was to determine
the accuracy of diagnostic classification of ovarian carcinoma and to determine if
morphological and immunohistochemical (IHC) features distinguish HGSC with
germline mutations from sporadic HGSC.
Design: Mutation screening and family pedigrees were obtained in 1414 women
diagnosed from 1995 to 1999 and from 2002 to 2004. Representative tumor blocks
were available for 645 cases. Tissue microarrays were stained for p53, WT-1, CK7,
CK20, CDX2, HNF-1, and PTEN. Reviewers were blinded to original diagnosis and
to germline mutation status. Included in this study are 65 patients with documented
BRCA mutations and a control group of HGSC patients (n=54) with both negative
family history and negative germline testing results.
Results: A significant number of cases received a revised diagnosis after a review
of morphology and IHC (n=128/645, 20%). The most frequently changed original
diagnoses were endometrioid carcinoma (n=46/128, 36%), and adenocarcinoma NOS
(n=19/128, 15%) – 89% were reclassified as HGSC. 15/128 (12%) cases originally
diagnosed as invasive adenocarcinoma were revised to borderline tumor. Metastatic
adenocarcinoma from the gastrointestinal tract was misclassified as a primary ovarian
endometrioid or mucinous adenocarcinoma (n=5/128, 4%). Cases from community
hospitals were more likely to have their diagnosis changed compared to those from
academic centres (p=0.002). All patients with BRCA germline mutations had High Grade
Serous Carcinoma. A morphological review showed that tumor infiltrating lymphocytes
(TILs) were more prominent in the tumours of patients with BRCA mutations (p=0.02)
compared to the Control group of sporadic HGSC. However, there was no significant
difference in tumor grade, architecture, atypia, mitotic count, frequency of giant bizarre
nuclei, presence of geographic necrosis, or IHC staining between HGSC patients with
and without BRCA germline mutations.
Conclusions: IHC studies and review by an experienced gynecological pathologist
are critical to correctly classify ovarian malignancies. Diagnoses are more likely
to be revised in cases from community hospitals. The quantity of TILs is the only
morphological feature that significantly differentiates BRCA germline mutation HGSC
from sporadic HGSC. Biomarkers currently commonly used do not differentiate BRCA
associated HGSC.

The challenging task of uncovering disparities in endometrial cancer

Abstract:

Over the last fifty years, the incidence of endometrial cancer has risen globally (1). While much of this rise may be attributed to increasing rates of obesity in many nations (2), endometrial cancer actually represents a diversity of histologies, with variable risk factors, genetic susceptibilities, and outcomes.

Somatic mutation detection by cervicovaginal swab as a potential screening test for endometrial cancer: A pilot study

Abstract:

Objective: There is no screening test for endometrial cancer, the most common gynecologic malignancy in the United States. Vaginal swabs accurately detect HPV and are useful for cervical cancer screening in underserved groups. Our objective was to evaluate somatic mutations within a cohort of endometrial cancer patients, and to assess concordant detection of these mutations by patient and physician-collected vaginal swabs as an exploratory platform for early detection and patient triage.

Soluble Flt‐1 regulates Flk‐1 activation to control hematopoietic and endothelial development in an oxygen‐responsive manner

Abstract:

Vascular endothelial growth factor (VEGF) and the vascular endothelial growth factor receptors (VEGFRs) regulate the development of hemogenic mesoderm. Oxygen concentration‐mediated activation of hypoxia‐inducible factor targets such as VEGF may serve as the molecular link between the microenvironment and mesoderm‐derived blood and endothelial cell specification. We used controlled‐oxygen microenvironments to manipulate the generation of hemogenic mesoderm and its derivatives from embryonic stem cells. Our studies revealed a novel role for soluble VEGFR1 (sFlt‐1) in modulating hemogenic mesoderm fate between hematopoietic and endothelial cells. Parallel measurements of VEGF and VEGFRs demonstrated that sFlt‐1 regulates VEGFR2 (Flk‐1) activation in both a developmental‐stage‐dependent and oxygen‐dependent manner. Early transient Flk‐1 signaling occurred in hypoxia because of low levels of sFlt‐1 and high levels of VEGF, yielding VEGF‐dependent generation of hemogenic mesoderm. Sustained (or delayed) Flk‐1 activation preferentially yielded hemogenic mesoderm‐derived endothelial cells. In contrast, delayed (sFlt‐1‐mediated) inhibition of Flk‐1 signaling resulted in hemogenic mesoderm‐derived blood progenitor cells. Ex vivo analyses of primary mouse embryo‐derived cells and analysis of transgenic mice secreting a Flt‐1‐Fc fusion protein (Fc, the region of an antibody which is constant and binds to receptors) support a hypothesis whereby microenvironmentally regulated blood and endothelial tissue specification is enabled by the temporally variant control of the levels of Flk‐1 activation.

Shifts in Practice Patterns: Addressing Disparities in Ovarian Cancer Care

Abstract:

Objectives: In recent years, neoadjuvant chemotherapy (NACT) and universal genetic testing has been added to our arsenal for managing epithelial ovarian cancer. Within our university health system, all of our attending physicians work at both a safety net hospital (SNH) as well as a comprehensive cancer center (CCC). As such our objective was to assess whether there were differences in current practice patterns between the two facilities especially regarding NACT and genetic testing despite having the same physicians practicing at both.

Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma

Abstract:

Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome

Abstract:

Racial and ethnic disparities among patients with low-grade serous ovarian carcinoma

Abstract:

Objective: Low-grade serous ovarian carcinoma (LGSC) is a rare subtype of ovarian cancer with a unique disease course. Our objective was to evaluate the effect of race and ethnicity on treatment outcomes in this disease.