The interaction between the PI3K/Akt cascade and the androgen receptor in the development and progression of castrate resistant prostate cancer

Prostate cancer has high cancer incidence in males and is the second highest cause of male cancer related mortality. Currently the main stay therapy for localised and metastatic disease is maximum androgen blockade (MAB). This aims to inhibit androgen production or action, thereby reducing stimulation of the androgen receptor (AR). This in turn prevents the activation of androgen-regulated genes, which normally result in on-going growth and survival. Inhibition of testicular androgen production may be achieved surgically (bilateral orchidectomy) or chemically, using gonadotropin-releasing hormone (GnRH) agonists. The latter induces castrate levels of testosterone by down-regulating pituitary GnRH receptors (and therefore gonadotropin hormone production) through constant stimulation. The action of androgen may be blocked at a peripheral level using anti androgens, which inhibit ligand binding to AR and subsequent activation. Although this approach has initial response rates of over 80% the majority of men relapse with castrate resistant prostate cancer (CRPC) and this is the cause of significant morbidity and mortality. To overcome this and to improve patients treatment options the mechanisms of castrate resistance need to be addressed. The PI3K/Akt cascade regulates several cellular processes such as proliferation and apoptosis. Akt activation results in phosphorylation of multiple substrates and has been implicated in prostate carcinogenesis and castration resistance. Research has suggested that Akt interacts with signallingcascades implemented in carcinogenesis, in particular the NFkB cascade and AR signalling. The current study investigated the hypothesis that the expression and activation of PI3K/Akt cascade influences the progression to castrate resistant disease using clinical prostate cancer tumours. Fluorescent insitu hybridisation and Immunohistochemistry revealed that PTEN deletion was a common event in castrate resistant prostate cancer and low PTEN protein expression was significantly associated with a poor outcome. PTEN negatively regulates PI3K signalling. Consequently increased levels of PI3K and activated Akt (pAkt ser 308 and pAkt ser 473) were significantly associated with a shorter time to biochemical relapse and shorter disease specific survival. Inhibition of PI3K resulted in a significant reduction in cellular proliferation and Akt phosphorylation. The downstream affects of Akt activation were also investigated. Akt has been reported to directly activate the NFkB signallingcascade both directly and indirectly but no correlations between Akt and NFkB were observed in the current study. Using an immunohistochemical approach NFkB, IкBα and MMP-9 expression were observed to be significantly associated with shorter time to death from relapse and disease specific death. MMP-9 and IкBα expression were also significantly associated with metastases at relapse. Using paired hormone naive and castrate resistant LNCaP cells lines allowed the functional consequences of NFkB inhibition to be investigated. Reduced NFkB activation significantly inhibited cellular proliferation and induced apoptosis in both cell lines. Having shown a significant link between expression and activation of the PI3K cascade and progression to castrate resistant disease, the interaction between Akt and the AR was investigated in both clinical prostate tumours and cell lines. The phosphorylation of AR at the Akt consensus site serine 213 (pARser213) was significantly associated with disease progression. Patients with high expression pARser213 had a significantly shorter time to death from relapse and disease specific survival. Additionally 42% of patients displayed an increase in pARser213 expression, these patients also had a significantly shorter time to death from relapse and disease specific survival. Inhibition of PI3K resulted in a reduction of pARser213 expression in both cell lines and using siRNA knockdown to target PI3K p85 regulatory subunit reduced pARser213 expression. This research highlights the impact of both the PI3K/Akt and NFkB signallingcascades on prostate cancer progression and development of castrate resistant disease. In particular this study highlights the impact of Akt phosphorylation in castrate resistant prostate cancer patients. Therefore phosphorylation of AR at serine 213 may serve as a diagnostic tool to predict patient outcome in response to maximum androgen blockade and inhibition of AR 213 phosphorylation via the Akt cascade may be an effective therapeutic avenue to investigate for treatment of prostate cancer

Assuring the Influenza Vaccine Supply

Influenza disease epidemics occur seasonally in the United States and cause significant morbidity and mortality among certain high-risk groups. Influenza vaccines have been shown to decrease mortality and morbidity from influenza infection and are a safe and effective means of influenza prevention. Despite the availability of vaccine many high-risk groups are not vaccinated annually as is recommended by public health and medical experts. Lack of predictable, widespread vaccine uptake contributes to production and market issues affecting a consistently adequate and timely influenza vaccine supply. Problems with vaccine production in general are exacerbated by unique qualities of influenza vaccine production. Added to these problems is the urgent need to prepare for an impending influenza pandemic. Addressing these issues will involve public education and promotion of influenza vaccine, research and development of new vaccine technology and government intervention to assure a safe and adequate influenza vaccine supply.Master of Public Healt

Phosphorylation of androgen receptors at serine 515 is a potential prognostic marker for triple negative breast cancer

1.7 million cases of breast cancer are diagnosed every year with 522,000 deaths. Molecular classifications of breast cancer have resulted in improved treatments. However, treatments for triple negative breast cancer (TNBC) are lacking. Analysis of molecular targets for TNBC is a priority. One potential candidate is androgen receptor (AR) phosphorylation. This study assessed the role of AR phosphorylation at ser81/ser515 and their two upstream effectors, cyclin-dependent kinase 1 (pCDK1) and extracellular-regulated kinase 1/2 (pERK1/2) in 332 ductal breast cancer patients by immunohistochemistry. pERK1/2 combined with AR-515 associated with improved cancer-specific survival (CSS, p = 0.038), decreased size (p = 0.001), invasive grade (p < 0.001), necrosis (p = 0.003), b-lymphocytes (p = 0.020), molecular subtype (p < 0.001) and estrogen receptor (ER)/progesterone receptor (PR)-status (p < 0.001). The cohort was therefore stratified into ER+ve and ER-ve patients. In ER+ve tumours, pERK1/2 combined with AR-515 associated with improved CSS (p = 0.038), smaller size (p = 0.004), invasive grade (p = 0.001), decreased b-lymphocytes (p = 0.013) and increased plasma cells (p = 0.048). In contrast, in TNBC patients, phosphorylation of AR-515 associated with poorer CSS (p = 0.007). pERK1/2 combined with AR-515 associated with decreased inflammation (p = 0.003), increased tumour stroma (p = 0.003) and tumour budding (p = 0.011), with trends towards decrease CSS (p = 0.065) and macrophage levels (p = 0.093). In Conclusions, AR-515 may be an important regulator of inflammation in breast cancer potential via ERK1/2 phosphorylation. AR-515 is a potential prognostic marker and therapeutic target for TNBC

Loss of signal transducer and activator of transcription 1 is associated with prostate cancer recurrence

STAT1 loss has previously been implicated in cell line studies to modify prostate cancer cell growth and survival, however the clinical significance of this has not previously been established. This study investigated if STAT1 loss was associated with patient outcome measures and the phenotypic consequence of STAT1 silencing. STAT1 expression was assessed in two patient cohorts with localised (n = 78) and advanced prostate cancer at initial diagnosis (n = 39) by immunohistochemistry (IHC). Impact of STAT1 silencing on prostate cancer cells lines was assessed using Cell Death detection ELISA, TLDA gene signature apoptosis arrays, WST-1 assay, xCELLigence system, clonogenic assay, and wound healing assay. In the localised patient cohort, low expression of STAT1 was associated with shorter time to disease recurrence (3.8 vs 7.3 years, P = 0.02) and disease specific survival (6.6 vs 9.3 years, P = 0.05). In the advanced patient cohort, low expression was associated with shorter time to disease recurrence (2.0 vs 3.9 years, P = 0.001). When STAT1 was silenced in PC3 cells (AR negative) and LNCaP cells (AR positive) silencing did not influence levels of apoptosis in either cell line and had little effect on cell viability in the LNCaP cells. In contrast, STAT1 silencing in the PC3 cells resulted in a pronounced increase in cell viability (WST-1 assay: mock silenced vs STAT1 silenced, P < 0.001), clonagenicity (clonogenic assay: mock silenced vs STAT1 silenced, P < 0.001), and migration (wound healing: mock silenced vs STAT1 silenced, P < 0.001). In conclusion, loss of STAT1 may promote prostate cancer recurrence in AR negative patients via increasing cell viability

The relationship between androgen receptor, components of tumour microenvironment and survival in breast cancer molecular subtypes

Background: The androgen receptor (AR) pathway has emerged as a potential therapeutic target in breast cancer with increased attention to provide biological insight into triple negative breast cancer (TNBC). The present study assessed the role of AR within the tumour microenvironment in patients with invasive ductal breast cancer. Methods: Immunohistochemical analysis of AR was performed on a breast cancer tissue microarray of 850 patients. These results were correlated with clinicopathological data and cancer specific survival (CSS). Results: Positive AR expression was seen in 75% of luminal A, 70% of B, 47% of Her2 like and 31% of TNBC. AR was associated with invasive grade (p<0.001), estrogen receptor /progesterone receptor (p<0.001), molecular subtypes (p<0.001), necrosis (p<0.001), reduced inflammation (p<0.001), and increased tumour budding (p=0.001). AR was consistently associated with tumour budding in molecular subtypes; luminal A (p=0.022), Her2 like (p=0.035) and TNBC (p=0.034). In TNBC, AR was associated with poor CSS (P=0.013). Conclusion: AR may be an important regulator of tumour budding in breast cancer. AR is a potential prognostic marker and therapeutic target for patients with TNBC

The relationship between androgen receptor, components of tumour microenvironment and survival in breast cancer molecular subtypes

Background: The androgen receptor (AR) pathway has emerged as a potential therapeutic target in breast cancer with increased attention to provide biological insight into triple negative breast cancer (TNBC). The present study assessed the role of AR within the tumour microenvironment in patients with invasive ductal breast cancer. Methods: Immunohistochemical analysis of AR was performed on a breast cancer tissue microarray of 850 patients. These results were correlated with clinicopathological data and cancer specific survival (CSS). Results: Positive AR expression was seen in 75% of luminal A, 70% of B, 47% of Her2 like and 31% of TNBC. AR was associated with invasive grade (p<0.001), estrogen receptor /progesterone receptor (p<0.001), molecular subtypes (p<0.001), necrosis (p<0.001), reduced inflammation (p<0.001), and increased tumour budding (p=0.001). AR was consistently associated with tumour budding in molecular subtypes; luminal A (p=0.022), Her2 like (p=0.035) and TNBC (p=0.034). In TNBC, AR was associated with poor CSS (P=0.013). Conclusion: AR may be an important regulator of tumour budding in breast cancer. AR is a potential prognostic marker and therapeutic target for patients with TNBC

Androgen receptor phosphorylation at serine 308 and serine 791 predicts enhanced survival in castrate resistant prostate cancer patients

We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR<sub>94</sub>), 308 (pAR<sub>308</sub>), 650(pAR<sub>650</sub>) and 791(pAR<sub>791</sub>). No correlations with clinical parameters were observed for pAR<sub>94</sub> or pAR<sub>650</sub> in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR<sub>308</sub> is significantly associated with a longer time to disease specific death (p= 0.011) and high pAR<sub>791</sub> expression significantly associated with a longer time to disease recurrence (p= 0.018) in HNPC tumours and longer time to death from disease recurrence (p= 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p= 0.022) and low proliferating tumours (p= 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer

Nurses Alumni Association Bulletin, Fall 1994

1994-1995 Meeting Dates Calendar 1995 Annual Luncheon - Meeting Notice Officers and Committee Chairs Bulletin Publication Committee 1994-1995 Meeting Dates Calendar The President\u27s Message Treasurer\u27s Report News About Our Graduates Fiftieth Anniversary Resume of Minutes of Alumni Association Meetings Department of Nursing 1993-1994 Alumni Office News Jefferson 2000 Fund The Women\u27s Center for Health Promotion Discount Parking for Alumni Cadet Nurse Corps Medical Anecdotes of Faith Ukranian-American Teacher Exchange Happy Birthday Committee Reports In Memoriam, Names of Deceased Graduates Luncheon Photos Class News Jefferson Alumni Identification Card Relief Fund Application Scholarship Application Membership Application Pins, Transcripts, Class Address Lists, Change of address Forms Campus Ma

High IKKα expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)-positive breast cancer

The aim of our study was to examine the relationship between tumour IKKα expression and breast cancer recurrence and survival. Immunohistochemistry was employed in a discovery and a validation tissue microarray to assess the association of tumour IKKα expression and clinico-pathological characteristics. After siRNA-mediated silencing of IKKα, cell viability and apoptosis were assessed in MCF7 and MDA-MB-231 breast cancer cells. In both the discovery and validation cohorts, associations observed between IKKα and clinical outcome measures were potentiated in oestrogen receptor (ER) positive Luminal A tumours. In the discovery cohort, cytoplasmic IKKα was associated with disease-free survival (p = 0.029) and recurrence-free survival on tamoxifen (p < 0.001) in Luminal A tumours. Nuclear IKKα and a combination of cytoplasmic and nuclear IKKα (total tumour cell IKKα) were associated with cancer-specific survival (p = 0.012 and p = 0.007, respectively) and recurrence-free survival on tamoxifen (p = 0.013 and p < 0.001, respectively) in Luminal A tumours. In the validation cohort, cytoplasmic IKKα was associated with cancer-specific survival (p = 0.023), disease-free survival (p = 0.002) and recurrence-free survival on tamoxifen (p = 0.009) in Luminal A tumours. Parallel experiment with breast cancer cells in vitro demonstrated the non-canonical NF-κB pathway was inducible by exposure to lymphotoxin in ER-positive MCF7 cells and not in ER-negative MDA-MB-231 cells. Reduction in IKKα expression by siRNA transfection increased levels of apoptosis and reduced cell viability in MCF7 but not in MDA-MB-231 cells. IKKα is an important determinant of poor outcome in patients with ER-positive invasive ductal breast cancer and thus may represent a potential therapeutic target

Nurses Alumni Association Bulletin, Fall 1995

1995-1996 Meeting Dates Calendar 1996 Annual Luncheon-Meeting Notice Officers and Committee Chairs Bulletin Publication Committee 1995-1996 Meeting Dates Calendar The President\u27s Message Financial Report What\u27s New Fiftieth Anniversary Resume of Minutes of Alumni Association Meetings Scholarship Funds at Work CAHS Alumni Board/Diploma School Alumni Office News Jefferson Health System Oldest Veteran Dies 1OOth Anniversary Pearl Harbor Remembered Memories Janet Hindson Retires Happy Birthday Scholarship Fund donors for 1994 Committee Reports By-Laws Development Bulletin Relief Fund Satellite Social Scholarship In Memoriam, Names of Deceased Graduates Class News Luncheon Photos Jefferson Alumni Identification Card The Diploma School of Nursing Alumni Association-Mabel C. Prevost Letter of Appreciation Tribute To a Mother An End Must Come Stuff For Senior Citizens to Chuckle Over Membership Application Relief Fund Application To Order: A Chronological History and Alumni Directory From TJU Bookstore Scholarship Fund Application Pins, Transcripts, Class Address List, Change of Address Forms, Alumni Identification Card Campus Map Picture - Class of 1893-189