Binder, Marley, McCoombe, Scott, Williams, ED, McCulloch, DR, Ward, Alister, Binder, Marley, McCoombe, Scott, Williams, ED, McCulloch, DR, and Ward, Alister
Yang, J, Antin, P, Berx, G, Blanpain, C, Brabletz, T, Bronner, M, Campbell, K, Cano, A, Casanova, J, Christofori, G, Dedhar, S, Derynck, R, Ford, HL, Fuxe, J, Garcia de Herreros, A, Goodall, GJ, Hadjantonakis, A-K, Huang, RJY, Kalcheim, C, Kalluri, R, Kang, Y, Khew-Goodall, Y, Levine, H, Liu, J, Longmore, GD, Mani, SA, Massague, J, Mayor, R, McClay, D, Mostov, KE, Newgreen, DF, Nieto, MA, Puisieux, A, Runyan, R, Savagner, P, Stanger, B, Stemmler, MP, Takahashi, Y, Takeichi, M, Theveneau, E, Thiery, JP, Thompson, EW, Weinberg, RA, Williams, ED, Xing, J, Zhou, BP, Sheng, G, Yang, J, Antin, P, Berx, G, Blanpain, C, Brabletz, T, Bronner, M, Campbell, K, Cano, A, Casanova, J, Christofori, G, Dedhar, S, Derynck, R, Ford, HL, Fuxe, J, Garcia de Herreros, A, Goodall, GJ, Hadjantonakis, A-K, Huang, RJY, Kalcheim, C, Kalluri, R, Kang, Y, Khew-Goodall, Y, Levine, H, Liu, J, Longmore, GD, Mani, SA, Massague, J, Mayor, R, McClay, D, Mostov, KE, Newgreen, DF, Nieto, MA, Puisieux, A, Runyan, R, Savagner, P, Stanger, B, Stemmler, MP, Takahashi, Y, Takeichi, M, Theveneau, E, Thiery, JP, Thompson, EW, Weinberg, RA, Williams, ED, Xing, J, Zhou, BP, and Sheng, G
Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.
Wafai, R, Williams, ED, de Souza, E, Simpson, PT, Reed, AEM, Kutasovic, JR, Waltham, M, Snell, CE, Blick, T, Thompson, EW, Hugo, HJ, Wafai, R, Williams, ED, de Souza, E, Simpson, PT, Reed, AEM, Kutasovic, JR, Waltham, M, Snell, CE, Blick, T, Thompson, EW, and Hugo, HJ
BACKGROUND: Breast cancers acquire aggressive capabilities via epithelial to mesenchymal transition (EMT), in which various integrins/integrin-linked kinase signalling are upregulated. METHODS: We investigated this in two patient-derived xenografts (PDXs) developed from breast-to-bone metastases, and its functional significance in a breast cancer cell line system. ED03 and EDW01 PDXs were grown subcutaneously in immunocompromised SCID mice through 11 passages and 7 passages, respectively. Tumour tissue was assessed using immunohistochemistry (IHC) for oestrogen receptor (ER)-alpha, E-cadherin, vimentin, Twist1, beta-catenin, P120-RasGAP, CD44, CD24 and Ki67, and RT-qPCR of EMT-related factors (CDH1, VIM, CD44, CD24), integrins beta 1 (ITGB1), alpha 2 (ITGA2) and ILK. Integrin and ILK expression in epidermal growth factor (EGF)-induced EMT of the PMC42-ET breast cancer cell line was assessed by RT-qPCR and Western blotting, as were the effects of their transient knockdown via small interfering RNA +/- EGF. Cell migration, changes in cell morphology and adhesion of siRNA-transfected PMC42-ET cells to various extracellular matrix (ECM) substrates was assessed. RESULTS: The ED03 (ER+/PR-/HER2-/lobular) and EDW01 (ER+/PR-/HER2-/ductal) PDXs were both classified as molecular subtype luminal A. ED03 xenografts exhibited mutated E-cadherin with minimal expression, but remained vimentin-negative across all passages. In EDW01, the hypoxic indicator gene CAIX and Twist1 were co-ordinately upregulated at passages 4-5, corresponding with a decrease in E-cadherin. At passages 6-7, VIM was upregulated along with ITGB1 and ITGA2, consistent with an increasing EMT. The ED03 PDX displayed minimal change over passages in mice, for all genes examined. ILK, ITGB1 and ITGA2 mRNAs were also increased in the EGF-induced EMT of PMC42-ET cells (in which CDH1 was downregulated) although siRNA against these targets revealed that this induction was not necessary for the observed EMT. However, t
Jaeschke, A, Jacobi, A, Lawrence, MG, Risbridger, GP, Frydenberg, M, Williams, ED, Vela, I, Hutmacher, DW, Bray, LJ, Taubenberger, A, Jaeschke, A, Jacobi, A, Lawrence, MG, Risbridger, GP, Frydenberg, M, Williams, ED, Vela, I, Hutmacher, DW, Bray, LJ, and Taubenberger, A
Reciprocal interactions between prostate epithelial cells and their adjacent stromal microenvironment not only are essential for tissue homeostasis but also play a key role in tumor development and progression. Malignant transformation is associated with the formation of a reactive stroma where cancer-associated fibroblasts (CAFs) induce matrix remodeling and thereby provide atypical biochemical and biomechanical signals to epithelial cells. Previous work has been focused on the cellular and molecular phenotype as well as on matrix stiffness and remodeling, providing potential targets for cancer therapeutics. So far, biomechanical changes in CAFs and adjacent epithelial cells of the prostate have not been explored. Here, we compared the mechanical properties of primary prostatic CAFs and patient-matched non-malignant prostate tissue fibroblasts (NPFs) using atomic force microscopy (AFM) and real-time deformability cytometry (RT-FDC). It was found that CAFs exhibit an increased apparent Young's modulus, coinciding with an altered architecture of the cytoskeleton compared with NPFs. In contrast, co-cultures of benign prostate epithelial (BPH-1) cells with CAFs resulted in a decreased stiffness of the epithelial cells, as well as an elongated morphological phenotype, when compared with co-cultures with NPFs. Moreover, the presence of CAFs increased proliferation and invasion of epithelial cells, features typically associated with tumor progression. Altogether, this study provides novel insights into the mechanical interactions between epithelial cells with the malignant prostate microenvironment, which could potentially be explored for new diagnostic approaches.
Watkins, Daphne C., primary, Goodwill, Janelle R., additional, Johnson, Natasha C., additional, Casanova, Allura, additional, Wei, Tao, additional, Allen, Julie Ober, additional, Williams, Ed-Dee G., additional, Anyiwo, Nkemka, additional, Jackson, Zachary A., additional, Talley, Lloyd M., additional, and Abelson, Jamie M., additional
aaskelainen J, Erik Schoenmakers, Ilona Zvetkova, Sharone Barone, Ömer Tarım, Christoffer Löf, Liao Xh, Jukka Kero, Nadia Schoenmakers, Hakan Cangul, Eva Goncalves Serra, Eamonn R. Maher, Konrad Patyra, Panudda Srichomkwun, Kristien Boelaert, Halil Saglam, Frankl Fek, Adeline K Nicholas, Samuel Refetoff, ren E, Manoocher Soleimani, Hideyuki Iwayama, Carl A. Anderson, Williams Ed, Timothy Barrett, V. K. K. Chatterjee, and Marja Ojaniemi
Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.
Williams, ED, Whitaker, KL, Piano, M, Marlow, LAV, Williams, ED, Whitaker, KL, Piano, M, and Marlow, LAV
OBJECTIVE: The majority of cancers are diagnosed following a decision to access medical help for symptoms. People from ethnic minority backgrounds have longer patient intervals following identification of cancer symptoms. This study quantified ethnic differences in barriers to symptomatic presentation including culturally specific barriers. Correlates of barriers (eg, migration status, health literacy, and fatalism) were also explored. METHODS: A cross-sectional survey of 720 White British, Caribbean, African, Indian, Pakistani, and Bangladeshi women aged 30 to 60 (n = 120/group) was carried out in England. Barrier items were taken from the widely used cancer awareness measure; additional culturally specific barriers to symptomatic presentation were included following qualitative work (11 barriers in total). Migration status, health literacy, and fatalism were included as correlates to help-seeking barriers. RESULTS: Ethnic minority women reported a higher number of barriers (P < .001, 2.6-3.8 more than White British women). Emotional barriers were particularly prominent. Women from ethnic minority groups were more likely to report "praying about a symptom" (P < .001, except Bangladeshi women) and "using traditional remedies" (P < .001, except Caribbean women). Among ethnic minority women, adult migration to the United Kingdom, low health literacy, and high fatalistic beliefs increased likelihood of reporting barriers to symptomatic presentation. For example, women who migrated as adults were more likely to be embarrassed (OR = 1.83; CI, 1.06-3.15), worry what the GP might find (OR = 1.91; CI, 1.12-3.26), and be low on body vigilance (OR = 4.44; CI, 2.72-7.23). CONCLUSIONS: Campaigns addressing barriers to symptomatic presentation among ethnic minority women should be designed to reach low health literacy populations and include messages challenging fatalistic views. These would be valuable for reducing ethnic inequalities in cancer outcomes.
Stylianou, N, Lehman, ML, Wang, C, Fard, AT, Rockstroh, A, Fazli, L, Jovanovic, L, Ward, M, Sadowski, MC, Kashyap, AS, Buttyan, R, Gleave, ME, Westbrook, TF, Williams, ED, Gunter, JH, Nelson, CC, Hollier, BG, Stylianou, N, Lehman, ML, Wang, C, Fard, AT, Rockstroh, A, Fazli, L, Jovanovic, L, Ward, M, Sadowski, MC, Kashyap, AS, Buttyan, R, Gleave, ME, Westbrook, TF, Williams, ED, Gunter, JH, Nelson, CC, and Hollier, BG
The propensity of cancer cells to transition between epithelial and mesenchymal phenotypic states via the epithelial-mesenchymal transition (EMT) program can regulate metastatic processes, cancer progression, and treatment resistance. Transcriptional investigations using reversible models of EMT, revealed the mesenchymal-to-epithelial reverting transition (MErT) to be enriched in clinical samples of metastatic castrate resistant prostate cancer (mCRPC). From this enrichment, a metastasis-derived gene signature was identified that predicted more rapid cancer relapse and reduced survival across multiple human carcinoma types. Additionally, the transcriptional profile of MErT is not a simple mirror image of EMT as tumour cells retain a transcriptional "memory" following a reversible EMT. This memory was also enriched in mCRPC samples. Cumulatively, our studies reveal the transcriptional profile of epithelial-mesenchymal plasticity and highlight the unique transcriptional properties of MErT. Furthermore, our findings provide evidence to support the association of epithelial plasticity with poor clinical outcomes in multiple human carcinoma types.
Parkins, Gregory A. and Williams, Ed
Change is a constant factor of the Special Forces Qualification Course, or SFQC, because the trainers at the JFK Special Warfare Center and School, or SWCS, are always striving to [...]
Williams, Ed
Williams, Ed
Our 1990 exchange of letters showed a senator's delight in tweaking the press. Jesse Helms went to the U.S. Senate in 1973, the same year I joined the Observer as [...]
Williams, ED, primary
Stylianou, N, primary, Lehman, ML, additional, Wang, C, additional, Fard, AT, additional, Rockstroh, A, additional, Fazli, L, additional, Jovanovic, L, additional, Ward, M, additional, Sadowski, MC, additional, Kashyap, AS, additional, Buttyan, R, additional, Gleave, ME, additional, Westbrook, TF, additional, Williams, ED, additional, Gunter, JH, additional, Nelson, CC, additional, and Hollier, BG, additional
Goodwill, Janelle R., primary, Anyiwo, Nkemka, additional, Williams, Ed-Dee G., additional, Johnson, Natasha C., additional, Mattis, Jacqueline S., additional, and Watkins, Daphne C., additional
Mitchell, Jamie, primary, Williams, Ed-Dee G., additional, Perry, Ramona, additional, and Lobo, Kavitha, additional
Mitchell, Jamie, primary, Hawkins, Jaclynn, additional, Williams, Ed-Dee G., additional, Eggly, Susan, additional, and Albrecht, Terrance L., additional
Geyer, Paul D. and Williams, Ed
The role of technical assistance centers in dealing with employer concerns about employing deaf or hearing-impaired workers is discussed. The Job Accommodations Network, the 10 regional Disability and Business Technical Assistance Centers and the state-level Assistive Technology Projects are among these centers.
Lindstrom, Patty Ann, Barrett, Frank J., Boyatzis, Richard E., Gorman, Margaret D., and Williams, Ed
The focus of this symposium is to introduce new empirical data and a model supporting how organizational purpose is transformed into the culture, strategic directives, practices and functional areas of organizations leading to value creation for employees, the organization, and society while advancing environments of change and innovation. The empirical data and accompanying model from recent research focus on shifting from "why" a company should have a purpose to "how" the purpose is implemented in environments of innovation and change. This focus is rare and only now seems to be getting the attention deserved. Building on recent empirical research, this symposium will explore the key themes which activate and accelerate the human impact of the implementation of organizational purpose on environments of change and innovation. The members of the panel have academic, as well as practitioner backgrounds, and represent supporting research initiatives. [ABSTRACT FROM AUTHOR]
Thankappan, KR, Sathish, T, Tapp, RJ, Shaw, JE, Lotfaliany, M, Wolfe, R, Absetz, P, Mathews, E, Aziz, Z, Williams, ED, Fisher, EB, Zimmet, PZ, Mahal, A, Balachandran, S, D'Esposito, F, Sajeev, P, Thomas, E, Oldenburg, B, Thankappan, KR, Sathish, T, Tapp, RJ, Shaw, JE, Lotfaliany, M, Wolfe, R, Absetz, P, Mathews, E, Aziz, Z, Williams, ED, Fisher, EB, Zimmet, PZ, Mahal, A, Balachandran, S, D'Esposito, F, Sajeev, P, Thomas, E, and Oldenburg, B
Background: The major efficacy trials on diabetes prevention have used resource-intensive approaches to identify high-risk individuals and deliver lifestyle interventions. Such strategies are not feasible for wider implementation in low- and middle-income countries (LMICs). We aimed to evaluate the effectiveness of a peer-support lifestyle intervention in preventing type 2 diabetes among high-risk individuals identified on the basis of a simple diabetes risk score. Methods and findings: The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial conducted in 60 polling areas (clusters) of Neyyattinkara taluk (subdistrict) in Trivandrum district, Kerala state, India. Participants (age 30–60 years) were those with an Indian Diabetes Risk Score (IDRS) ≥60 and were free of diabetes on an oral glucose tolerance test (OGTT). A total of 1,007 participants (47.2% female) were enrolled (507 in the control group and 500 in the intervention group). Participants from intervention clusters participated in a 12-month community-based peer-support program comprising 15 group sessions (12 of which were led by trained lay peer leaders) and a range of community activities to support lifestyle change. Participants from control clusters received an education booklet with lifestyle change advice. The primary outcome was the incidence of diabetes at 24 months, diagnosed by an annual OGTT. Secondary outcomes were behavioral, clinical, and biochemical characteristics and health-related quality of life (HRQoL). A total of 964 (95.7%) participants were followed up at 24 months. Baseline characteristics of clusters and participants were similar between the study groups. After a median follow-up of 24 months, diabetes developed in 17.1% (79/463) of control participants and 14.9% (68/456) of intervention participants (relative risk [RR] 0.88, 95% CI 0.66–1.16, p = 0.36). At 24 months, compared with the control group, intervention participants had a greater red
Navone, NM, van Weerden, WM, Vessella, RL, Williams, ED, Wang, Y, Isaacs, JT, Nguyen, HM, Culig, Z, van der Pluijm, G, Rentsch, CA, Marques, RB, de Ridder, CMA, Bubendorf, L, Thalmann, GN, Brennen, WN, Santer, FR, Moser, PL, Shepherd, P, Efstathiou, E, Xue, H, Lin, D, Buijs, J, Bosse, T, Collins, A, Maitland, N, Buzza, M, Kouspou, M, Achtman, A, Taylor, RA, Risbridger, G, Corey, E, Navone, NM, van Weerden, WM, Vessella, RL, Williams, ED, Wang, Y, Isaacs, JT, Nguyen, HM, Culig, Z, van der Pluijm, G, Rentsch, CA, Marques, RB, de Ridder, CMA, Bubendorf, L, Thalmann, GN, Brennen, WN, Santer, FR, Moser, PL, Shepherd, P, Efstathiou, E, Xue, H, Lin, D, Buijs, J, Bosse, T, Collins, A, Maitland, N, Buzza, M, Kouspou, M, Achtman, A, Taylor, RA, Risbridger, G, and Corey, E
BACKGROUND: While it has been challenging to establish prostate cancer patient-derived xenografts (PDXs), with a take rate of 10-40% and long latency time, multiple groups throughout the world have developed methods for the successful establishment of serially transplantable human prostate cancer PDXs using a variety of immune deficient mice. In 2014, the Movember Foundation launched a Global Action Plan 1 (GAP1) project to support an international collaborative prostate cancer PDX program involving eleven groups. Between these Movember consortium members, a total of 98 authenticated human prostate cancer PDXs were available for characterization. Eighty three of these were derived directly from patient material, and 15 were derived as variants of patient-derived material via serial passage in androgen deprived hosts. A major goal of the Movember GAP1 PDX project was to provide the prostate cancer research community with a summary of both the basic characteristics of the 98 available authenticated serially transplantable human prostate cancer PDX models and the appropriate contact information for collaborations. Herein, we report a summary of these PDX models. METHODS: PDX models were established in immunocompromised mice via subcutaneous or subrenal-capsule implantation. Dual-label species (ie, human vs mouse) specific centromere and telomere Fluorescence In Situ Hybridization (FISH) and immuno-histochemical (IHC) staining of tissue microarrays (TMAs) containing replicates of the PDX models were used for characterization of expression of a number of phenotypic markers important for prostate cancer including AR (assessed by IHC and FISH), Ki67, vimentin, RB1, P-Akt, chromogranin A (CgA), p53, ERG, PTEN, PSMA, and epithelial cytokeratins. RESULTS: Within this series of PDX models, the full spectrum of clinical disease stages is represented, including androgen-sensitive and castration-resistant primary and metastatic prostate adenocarcinomas as well as prostate carcino
Gregg, E, Thankappan, KR, Sathish, T, Tapp, RJ, Shaw, JE, Lotfaliany, M, Wolfe, R, Absetz, P, Mathews, E, Aziz, Z, Williams, ED, Fisher, EB, Zimmet, PZ, Mahal, A, Balachandran, S, D'Esposito, F, Sajeev, P, Thomas, E, Oldenburg, B, Gregg, E, Thankappan, KR, Sathish, T, Tapp, RJ, Shaw, JE, Lotfaliany, M, Wolfe, R, Absetz, P, Mathews, E, Aziz, Z, Williams, ED, Fisher, EB, Zimmet, PZ, Mahal, A, Balachandran, S, D'Esposito, F, Sajeev, P, Thomas, E, and Oldenburg, B
BACKGROUND: The major efficacy trials on diabetes prevention have used resource-intensive approaches to identify high-risk individuals and deliver lifestyle interventions. Such strategies are not feasible for wider implementation in low- and middle-income countries (LMICs). We aimed to evaluate the effectiveness of a peer-support lifestyle intervention in preventing type 2 diabetes among high-risk individuals identified on the basis of a simple diabetes risk score. METHODS AND FINDINGS: The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial conducted in 60 polling areas (clusters) of Neyyattinkara taluk (subdistrict) in Trivandrum district, Kerala state, India. Participants (age 30-60 years) were those with an Indian Diabetes Risk Score (IDRS) ≥60 and were free of diabetes on an oral glucose tolerance test (OGTT). A total of 1,007 participants (47.2% female) were enrolled (507 in the control group and 500 in the intervention group). Participants from intervention clusters participated in a 12-month community-based peer-support program comprising 15 group sessions (12 of which were led by trained lay peer leaders) and a range of community activities to support lifestyle change. Participants from control clusters received an education booklet with lifestyle change advice. The primary outcome was the incidence of diabetes at 24 months, diagnosed by an annual OGTT. Secondary outcomes were behavioral, clinical, and biochemical characteristics and health-related quality of life (HRQoL). A total of 964 (95.7%) participants were followed up at 24 months. Baseline characteristics of clusters and participants were similar between the study groups. After a median follow-up of 24 months, diabetes developed in 17.1% (79/463) of control participants and 14.9% (68/456) of intervention participants (relative risk [RR] 0.88, 95% CI 0.66-1.16, p = 0.36). At 24 months, compared with the control group, intervention participants had a greater reduction in IDRS
Mitchell, Jamie, Hawkins, Jaclynn, Williams, Ed-Dee G., Eggly, Susan, and Albrecht, Terrance L.
Grover, Harpreet Singh, primary, Dawson, Francis, additional, and Williams, Ed, additional
Mitchell, Jamie A., primary, Johnson-Lawrence, Vicki, additional, Williams, Ed-Dee G., additional, and Thorpe, Roland, additional
Tse, BWC, Volpert, M, Ratther, E, Stylianou, N, Nouri, M, McGowan, K, Lehman, ML, McPherson, SJ, Roshan-Moniri, M, Butler, MS, Caradec, J, Gregory-Evans, CY, McGovern, J, Das, R, Takhar, M, Erho, N, Alshalafa, M, Davicioni, E, Schaeffer, EM, Jenkins, RB, Ross, AE, Karnes, RJ, Den, RB, Fazli, L, Gregory, PA, Gleave, ME, Williams, ED, Rennie, PS, Buttyan, R, Gunter, JH, Selth, LA, Russell, PJ, Nelson, CC, Hollier, BG, Tse, BWC, Volpert, M, Ratther, E, Stylianou, N, Nouri, M, McGowan, K, Lehman, ML, McPherson, SJ, Roshan-Moniri, M, Butler, MS, Caradec, J, Gregory-Evans, CY, McGovern, J, Das, R, Takhar, M, Erho, N, Alshalafa, M, Davicioni, E, Schaeffer, EM, Jenkins, RB, Ross, AE, Karnes, RJ, Den, RB, Fazli, L, Gregory, PA, Gleave, ME, Williams, ED, Rennie, PS, Buttyan, R, Gunter, JH, Selth, LA, Russell, PJ, Nelson, CC, and Hollier, BG
Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.
Williams, Ed and Jacobs, Joel
Mitchell, Jamie A, primary, Cadet, Tamara, additional, Burke, Shanna, additional, Williams, Ed-Dee, additional, and Alvarez, Daniel, additional
Thomas, GA and Williams, ED
Paul, PJ, Raghu, D, Chan, A-L, Gulati, T, Lambeth, L, Takano, E, Herold, MJ, Hagekyriakou, J, Vessella, RL, Fedele, C, Shackleton, M, Williams, ED, Fox, S, Williams, S, Haupt, S, Gamell, C, Haupt, Y, Paul, PJ, Raghu, D, Chan, A-L, Gulati, T, Lambeth, L, Takano, E, Herold, MJ, Hagekyriakou, J, Vessella, RL, Fedele, C, Shackleton, M, Williams, ED, Fox, S, Williams, S, Haupt, S, Gamell, C, and Haupt, Y
Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.
Huo, CW, Waltham, M, Khoo, C, Fox, SB, Hill, P, Chen, S, Chew, GL, Price, JT, Nguyen, CH, Williams, ED, Henderson, M, Thompson, EW, Britt, KL, Huo, CW, Waltham, M, Khoo, C, Fox, SB, Hill, P, Chen, S, Chew, GL, Price, JT, Nguyen, CH, Williams, ED, Henderson, M, Thompson, EW, and Britt, KL
BACKGROUND: High mammographic density (HMD) not only confers a significantly increased risk of breast cancer (BC) but also is associated with BCs of more advanced stages. However, it is unclear whether BC progression and metastasis are stimulated by HMD. We investigated whether patient-derived HMD breast tissue could stimulate the progression of MCF10DCIS.com cells compared with patient-matched low mammographic density (LMD) tissue. METHODS: Sterile breast specimens were obtained immediately after prophylactic mastectomy from high-risk women (n = 10). HMD and LMD regions of each specimen were resected under radiological guidance. Human MCF10DCIS.com cells, a model of ductal carcinoma in situ (DCIS), were implanted into silicone biochambers in the groins of severe combined immunodeficiency mice, either alone or with matched LMD or HMD tissue (1:1), and maintained for 6 weeks. We assessed biochamber weight as a measure of primary tumour growth, histological grade of the biochamber material, circulating tumour cells and metastatic burden by luciferase and histology. All statistical tests were two-sided. RESULTS: HMD breast tissue led to increased primary tumour take, increased biochamber weight and increased proportions of high-grade DCIS and grade 3 invasive BCs compared with LMD. This correlated with an increased metastatic burden in the mice co-implanted with HMD tissue. CONCLUSIONS: Our study is the first to explore the direct effect of HMD and LMD human breast tissue on the progression and dissemination of BC cells in vivo. The results suggest that HMD status should be a consideration in decision-making for management of patients with DCIS lesions.
Skalamera, D, Dahmer-Heath, M, Stevenson, AJ, Pinto, C, Shah, ET, Daignault, SM, Said, NABM, Davis, M, Haass, NK, Williams, ED, Hollier, BG, Thompson, EW, Gabrielli, B, Gonda, TJ, Skalamera, D, Dahmer-Heath, M, Stevenson, AJ, Pinto, C, Shah, ET, Daignault, SM, Said, NABM, Davis, M, Haass, NK, Williams, ED, Hollier, BG, Thompson, EW, Gabrielli, B, and Gonda, TJ
Epithelial to mesenchymal transition (EMT) is a developmental program that has been implicated in progression, metastasis and therapeutic resistance of some carcinomas. To identify genes whose overexpression drives EMT, we screened a lentiviral expression library of 17000 human open reading frames (ORFs) using high-content imaging to quantitate cytoplasmic vimentin. Hits capable of increasing vimentin in the mammary carcinoma-derived cell line MDA-MB-468 were confirmed in the non-tumorigenic breast-epithelial cell line MCF10A. When overexpressed in this model, they increased the rate of cell invasion through Matrigel™, induced mesenchymal marker expression and reduced expression of the epithelial marker E-cadherin. In gene-expression datasets derived from breast cancer patients, the expression of several novel genes correlated with expression of known EMT marker genes, indicating their in vivo relevance. As EMT-associated properties are thought to contribute in several ways to cancer progression, genes identified in this study may represent novel targets for anti-cancer therapy.
Williams, Ed
The article presents an exhibition review "Liverpool Biennial: uMoya" from 10 June – 17 September 2023 showing Trans-Atlantic slave trade and the legacy of colonialism for today's culture and identity within the city.
Williams, Ed R.
The author examines methods of evaluating work place environments of handicapped employees. Information on the need for evaluations, techniques, and results of studies conducted on the topic are discussed., This study validated the Work Personality Profile (WPP) for use with individuals receiving supported employment services. Two hundred individuals from several supported employment programs participated in the study. Correlational methodologies and expert ratings (e.g., job coaches, case managers, and employers) examined the relationship of the WPP to indicators of content, concurrent, construct, and predictive validity. The WPP not only measures current work behavior within the supported employment work environment, but is useful as an indicator of job advancement and multiple future outcomes (e.g., promotability and salary). Further research should focus on procedures to implement the WPP into ongoing supported employment assessment. However, assessment information from the WPP would be useful in providing prompt and cost effective services., The Rehabilitation Act Amendments of 1992 mandated that ongoing support services be provided at least twice monthly, for individuals in supported employment placement, and that such support include comprehensive assessment. [...]
Williams, Ed
Byline: Ed Williams Many knew of this man named King, but did not understand him or his dream. The Rev. Martin Luther King Jr. believed that man was capable of [...]
Williams, Ed
Byline: Ed Williams Residents are being held with a gun barrel pointed at our heads. The tactic is fear. We are being told we will have to pay more taxes [...]
Mitchell, Jamie A., Cadet, Tamara, Burke, Shanna, Williams, Ed-Dee, and Alvarez, Daniel
Objectives: African Americans comprise 9% of the 46 million U.S. adults over age 65. Two thirds of older African American men (AAM) reside with companions. This study investigated the assumption that frequent contact with companions confers mainly health-related benefits for AAM. Methods: Utilizing secondary data from the National Alzheimer's Coordinating Center, the relationship between older AAM's mental health and related conditions (depression, anxiety, and sleep disturbances), companion living arrangements, and frequency of contact with the participants for 3,423 older AAM and their 1,161 companions, was examined. Results: The mean age of participants and companions was 74 years and 90% of AAM lived in a private residence. Logistic regression models indicated that an increased risk for anxiety was found when companions lived in (OR = 1.66), called daily (OR = 1.089), or visited daily (OR = 1.079). Finally, AAM had an increased likelihood of nonmedical sleep disturbances when companions lived in (OR = 1.67), called daily (1.105), or visited daily (1.078). Discussion: The frequency of contact with companions may be consequential for select mental health outcomes and associated physiological conditions for older AAM; the timing of contact requires further investigation. [ABSTRACT FROM AUTHOR]
Williams, ED, Rawal, L, Oldenburg, BF, Renwick, C, Shaw, JE, and Tapp, RJ
OBJECTIVE: There is an established link between health-related functioning (HRF) and cardiovascular disease (CVD) mortality, and it is known that those with diabetes predominantly die of CVD. However, few studies have determined the combined impact of diabetes and impaired HRF on CVD mortality. We investigated whether this combination carries a higher CVD risk than either component alone. RESEARCH DESIGN AND METHODS: The Australian Diabetes, Obesity and Lifestyle (AusDiab) study included 11,247 adults aged ≥ 25 years from 42 randomly selected areas of Australia. At baseline (1999-2000), diabetes status was defined using the World Health Organization criteria and HRF was assessed using the SF-36 questionnaire. RESULTS: Overall, after 7.4 years of follow-up, 57 persons with diabetes and 105 without diabetes had died from CVD. In individuals with and without diabetes, HRF measures were significant predictors of increased CVD mortality. The CVD mortality risks among those with diabetes or impaired physical health component summary (PCS) alone were similar (diabetes only: hazard ratio 1.4 [95% CI 0.7-2.7]; impaired PCS alone: 1.5 [1.0-2.4]), while those with both diabetes and impaired PCS had a much higher CVD mortality (2.8 [1.6-4.7]) compared with those without diabetes and normal PCS (after adjustment for multiple covariates). Similar results were found for the mental health component summary. CONCLUSIONS: This study demonstrates that the combination of diabetes and impaired HRF is associated with substantially higher CVD mortality. This suggests that, among those with diabetes, impaired HRF is likely to be important in the identification of individuals at increased risk of CVD mortality.
Laris, Alexis and Williams, Ed
The Internet is neither a doomsday for sales professionals nor a panacea for businesses. It will challenge companies of all sizes to adjust their sales processes to sell effectively using […]
WILLIAMS, ED
I'VE BEEN WORKING with very good editorial cartoonists, Doug Marlette and Kevin Siers, for 25 years. Here is the sum of the wisdom I've derived from the experience: It is [...]
Whiteside-Mansell, Leanne, primary, Weber, Judith L., additional, Moore, Page C., additional, Johnson, Danya, additional, Williams, Ed R., additional, Ward, Wendy L., additional, Robbins, James M., additional, and Phillips, B. Allyson, additional
Nouri, M, Ratther, E, Stylianou, N, Nelson, CC, Hollier, BG, Williams, ED, Nouri, M, Ratther, E, Stylianou, N, Nelson, CC, Hollier, BG, and Williams, ED
Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.
O'Neil, A, Williams, ED, Browne, JL, Horne, R, Pouwer, F, Speight, J, O'Neil, A, Williams, ED, Browne, JL, Horne, R, Pouwer, F, and Speight, J
OBJECTIVE: A socioeconomic gradient exists in Australia for type 2 diabetes mellitus (T2DM). It remains unclear whether economic hardship is associated with T2DM self-management behaviours. METHODS: Cross-sectional data from a subset of the Diabetes MILES - Australia study were used (n=915). The Economic Hardship Questionnaire was used to assess hardship. Outcomes included: healthy eating and physical activity (Diabetes Self-Care Inventory - Revised), medication-taking behaviour (Medication Adherence Rating Scales) and frequency of self-monitoring of blood glucose (SMBG). Regression modelling was used to explore the respective relationships. RESULTS: Greater economic hardship was significantly associated with sub-optimal medication-taking (Coefficient: -0.86, 95%CI -1.54, -0.18), and decreased likelihood of regular physical activity (Odds Ratio: 0.47, 0.29, 0.77). However, after adjustments for a range of variables, these relationships did not hold. Being employed and higher depression levels were significantly associated with less-frequent SMBG, sub-optimal medication-taking and less-regular healthy eating. Engaging in physical activity was strongly associated with healthy eating. CONCLUSIONS: Employment, older age and depressive symptoms, not economic hardship, were commonly associated with diabetes self-management. IMPLICATIONS: Work-based interventions that promote T2DM self-management in younger, working populations that focus on negative emotions may be beneficial.
Lokmic, Z, Mitchell, GM, Chong, NKW, Bastiaanse, J, Gerrand, Y-W, Zeng, Y, Williams, ED, Penington, AJ, Lokmic, Z, Mitchell, GM, Chong, NKW, Bastiaanse, J, Gerrand, Y-W, Zeng, Y, Williams, ED, and Penington, AJ
Human lymphatic vascular malformations (LMs), also known as cystic hygromas or lymphangioma, consist of multiple lymphatic endothelial cell-lined lymph-containing cysts. No animal model of this disease exists. To develop a mouse xenograft model of human LM, CD34(Neg)CD31(Pos) LM lymphatic endothelial cells (LM-LEC) were isolated from surgical specimens and compared to foreskin CD34(Neg)CD31(Pos) lymphatic endothelial cells (LECs). Cells were implanted into a mouse tissue engineering model for 1, 2 and 4 weeks. In vitro LM-LECs showed increased proliferation and survival under starvation conditions (P < 0.0005 at 48 h, two-way ANOVA), increased migration (P < 0.001, two-way ANOVA) and formed fewer (P = 0.029, independent samples t test), shorter tubes (P = 0.029, independent samples t test) than foreskin LECs. In vivo LM-LECs implanted into a Matrigel™-containing mouse chamber model assembled to develop vessels with dilated cystic lumens lined with flat endothelium, morphology similar to that of clinical LMs. Human foreskin LECs failed to survive implantation. In LM-LEC implanted chambers the percent volume of podoplanin(Pos) vessels was 1.18 ± 2.24 % at 1 week, 6.34 ± 2.68 % at 2 weeks and increasing to 7.67 ± 3.60 % at 4 weeks. In conclusion, the significantly increased proliferation, migration, resistance to apoptosis and decreased tubulogenesis of LM-LECs observed in vitro is likely to account for their survival and assembly into stable LM-like structures when implanted into a mouse vascularised chamber model. This in vivo xenograft model will provide the basis of future studies of LM biology and testing of potential pharmacological interventions for patients with lymphatic malformations.
Nicholas R. Lemoine, F. S. Wyllie, T Jones, Denise Sheer, J. A. Bond, Jorge S. Burns, David Wynford-Thomas, and Williams Ed
To overcome the difficulty of assessing oncogene action in human epithelial cell types, such as thyroid, which have limited proliferative potential in culture, we have explored the use of temperature-sensitive (ts) mutants of simian virus 40 (SV40) early region to create conditionally immortalized epithelial cell lines. Normal primary cultures of human thyroid follicular cells were transfected with a plasmid containing the SV40 early region from mutant tsA58. Expanding epithelial colonies were observed after 2 to 3 months, all of which grew to greater than 200 population doublings without crisis. All showed tight temperature dependence for growth. After switch-up to the restrictive temperature (40.5 degrees C), no further increase in cell number was seen after 1 to 2 days. However, DNA synthesis declined much more slowly; the dissociation from cell division led to marked polyploidy. Viability was maintained for up to 2 weeks. Introduction of an inducible mutant ras gene into ts thyroid cells led, as expected, to morphological transformation at the permissive temperature when ras was induced. Interestingly, this was associated with a marked reduction in net growth rate. At the restrictive temperature, induction of mutant ras caused rapid cell death. These results demonstrate the utility of a ts SV40 mutant to permit the study of oncogene action in an otherwise nonproliferative target cell and reveal important differences in the interaction between ras and SV40 T in these epithelial cells compared with previously studied cell types.
Freitas, Sara, primary, Gibson, David, additional, Du Plessis, Coert, additional, Halloran, Pat, additional, Williams, Ed, additional, Ambrose, Matt, additional, Dunwell, Ian, additional, and Arnab, Sylvester, additional
Whiteside-Mansell, Leanne, primary, Weber, Judith L., additional, Moore, Page C., additional, Johnson, Danya, additional, Williams, Ed R., additional, Ward, Wendy L., additional, Robbins, James M., additional, and Phillips, B. Allyson, additional
Chamberlain, C, McNamara, B, Williams, ED, Yore, D, Oldenburg, B, Oats, J, Eades, S, Chamberlain, C, McNamara, B, Williams, ED, Yore, D, Oldenburg, B, Oats, J, and Eades, S
Recently proposed international guidelines for screening for gestational diabetes mellitus (GDM) recommend additional screening in early pregnancy for sub-populations at a high risk of type 2 diabetes mellitus (T2DM), such as indigenous women. However, there are criteria that should be met to ensure the benefits outweigh the risks of population-based screening. This review examines the published evidence for early screening for indigenous women as related to these criteria. Any publications were included that referred to diabetes in pregnancy among indigenous women in Australia, Canada, New Zealand and the United States (n = 145). The risk of bias was appraised. There is sufficient evidence describing the epidemiology of diabetes in pregnancy, demonstrating that it imposes a significant disease burden on indigenous women and their infants at birth and across the lifecourse (n = 120 studies). Women with pre-existing T2DM have a higher risk than women who develop GDM during pregnancy. However, there was insufficient evidence to address the remaining five criteria, including the following: understanding current screening practice and rates (n = 7); acceptability of GDM screening (n = 0); efficacy and cost of screening for GDM (n = 3); availability of effective treatment after diagnosis (n = 6); and effective systems for follow-up after pregnancy (n = 5). Given the impact of diabetes in pregnancy, particularly undiagnosed T2DM, GDM screening in early pregnancy offers potential benefits for indigenous women. However, researchers, policy makers and clinicians must work together with communities to develop effective strategies for implementation and minimizing the potential risks. Evidence of effective strategies for primary prevention, GDM treatment and follow-up after pregnancy are urgently needed.
Williams, ED, Magliano, DJ, Tapp, RJ, Oldenburg, BF, Shaw, JE, Williams, ED, Magliano, DJ, Tapp, RJ, Oldenburg, BF, and Shaw, JE
BACKGROUND: The evidence supporting a relationship between stress and diabetes has been inconsistent. PURPOSE: This study examined the effects of stress on abnormal glucose metabolism, using a population-based sample of 3,759, with normoglycemia at baseline, from the Australian Diabetes, Obesity and Lifestyle study. METHODS: Perceived stress and stressful life events were measured at baseline, with health behavior and anthropometric information also collected. Oral glucose tolerance tests were undertaken at baseline and 5-year follow-up. The primary outcome was the development of abnormal glucose metabolism (impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes), according to WHO 1999 criteria. RESULTS: Perceived stress predicted incident abnormal glucose metabolism in women but not men, after multivariate adjustment. Life events showed an inconsistent relationship with abnormal glucose metabolism. CONCLUSIONS: Perceived stress predicted abnormal glucose metabolism in women. Healthcare professionals should consider psychosocial adversity when assessing risk factor profiles for the development of diabetes.
O'Neil, A, Stevenson, CE, Williams, ED, Mortimer, D, Oldenburg, B, Sanderson, K, O'Neil, A, Stevenson, CE, Williams, ED, Mortimer, D, Oldenburg, B, and Sanderson, K
PURPOSE: Health-related quality of life (HRQOL) can be significantly impaired by the presence of chronic conditions such as cardiovascular disease (CVD) and major depressive disorder (MDD). The aim of this paper was to (1) identify differences in HRQOL between individuals with CVD, MDD, or both, compared to a healthy reference group, (2) establish whether the influence of co-morbid MDD and CVD on HRQOL is additive or synergistic and (3) determine the way in which depression severity interacts with CVD to influence overall HRQOL. METHODS: Population-based data from the 2007 Australian National Survey of Mental Health and Well-being (NSMHWB) (n = 8841) were used to compare HRQOL of individuals with MDD and CVD, MDD but not CVD, CVD but not MDD, with a healthy reference group. HRQOL was measured using the Assessment of Quality of Life (AQOL). MDD was identified using the Composite International Diagnostic Interview (CIDI 3.0). RESULTS: Of all four groups, individuals with co-morbid CVD and depression reported the greatest deficits in AQOL utility scores (Coef: -0.32, 95% CI: -0.40, -0.23), after adjusting for covariates. Those with MDD only (Coef: -0.27, 95% CI: -0.30, -0.24) and CVD only (Coef: -0.08, 95% CI: -0.11, -0.05) also reported reduced AQOL utility scores. Second, the influence of MDD and CVD on HRQOL was shown to be additive, rather than synergistic. Third, a significant dose-response relationship was observed between depression severity and HRQOL. However, CVD and depression severity appeared to act independently of each other in impacting HRQOL. CONCLUSIONS: HRQOL is greatly impaired in individuals with co-morbid MDD and CVD; these conditions appear to influence HRQOL in an additive fashion. HRQOL alters with depression severity, therefore treating depression and improving HRQOL is of clinical importance.
Sathish, T, Williams, ED, Pasricha, N, Absetz, P, Lorgelly, P, Wolfe, R, Mathews, E, Aziz, Z, Thankappan, KR, Zimmet, P, Fisher, E, Tapp, R, Hollingsworth, B, Mahal, A, Shaw, J, Jolley, D, Daivadanam, M, Oldenburg, B, Sathish, T, Williams, ED, Pasricha, N, Absetz, P, Lorgelly, P, Wolfe, R, Mathews, E, Aziz, Z, Thankappan, KR, Zimmet, P, Fisher, E, Tapp, R, Hollingsworth, B, Mahal, A, Shaw, J, Jolley, D, Daivadanam, M, and Oldenburg, B
BACKGROUND: India currently has more than 60 million people with Type 2 Diabetes Mellitus (T2DM) and this is predicted to increase by nearly two-thirds by 2030. While management of those with T2DM is important, preventing or delaying the onset of the disease, especially in those individuals at 'high risk' of developing T2DM, is urgently needed, particularly in resource-constrained settings. This paper describes the protocol for a cluster randomised controlled trial of a peer-led lifestyle intervention program to prevent diabetes in Kerala, India. METHODS/DESIGN: A total of 60 polling booths are randomised to the intervention arm or control arm in rural Kerala, India. Data collection is conducted in two steps. Step 1 (Home screening): Participants aged 30-60 years are administered a screening questionnaire. Those having no history of T2DM and other chronic illnesses with an Indian Diabetes Risk Score value of ≥60 are invited to attend a mobile clinic (Step 2). At the mobile clinic, participants complete questionnaires, undergo physical measurements, and provide blood samples for biochemical analysis. Participants identified with T2DM at Step 2 are excluded from further study participation. Participants in the control arm are provided with a health education booklet containing information on symptoms, complications, and risk factors of T2DM with the recommended levels for primary prevention. Participants in the intervention arm receive: (1) eleven peer-led small group sessions to motivate, guide and support in planning, initiation and maintenance of lifestyle changes; (2) two diabetes prevention education sessions led by experts to raise awareness on T2DM risk factors, prevention and management; (3) a participant handbook containing information primarily on peer support and its role in assisting with lifestyle modification; (4) a participant workbook to guide self-monitoring of lifestyle behaviours, goal setting and goal review; (5) the health education booklet that i
For full access to our library's resources, please sign in.