bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust SiZer Approach for Varying Coefficient Models
Authors: Zhang Hui-Guo , Mei Chang-Lin , Wang He-Ling
Published: May 2013

Varying coefficient models have widely been applied to many practical fields for exploring dynamic patterns of the regression relationships. In this study, we propose a robust scenario of SiZer (significant zero crossing of derivatives) inference approach based on the local least absolute deviation fitting procedure and the bootstrap confidence interval to uncover the statistically significant features of the coefficient functions in a varying coefficient model under different smoothing scales. The simulation study shows that the proposed SiZer approach is quite robust to outliers and performs well in finding the significant features of the coefficient functions. Furthermore, a real environmental data set is analyzed to demonstrate the application of the proposed approach.
Full-Thickness Eyelid Lesions in Sarcoidosis
Authors: Collins Megan E. , Petronic-Rosic Vesna , Sweiss Nadera J. , Marcet Marcus M.
Published: May 2013

Eyelid involvement in sarcoidosis is very rare. A search of the medical literature indicates one previous report of sarcoidosis with destructive eyelid lesions. We describe the case of a 50-year-old woman with severe systemic sarcoidosis, which included her eyelids. To our knowledge, the case presented herein represents the first to show the full-thickness histopathology of destructive eyelid lesions in sarcoidosis.
Life Style Factors Associated with Premenstrual Syndrome among El-Minia University Students, Egypt
Authors: Seedhom Amany Edward , Mohammed Eman Sameh , Mahfouz Eman Mohammed
Published: May 2013

Aim. To determine the score and frequency of premenstrual syndrome (PMS) among female college students and to detect the possible risk factors of PMS. A trial of life style modification regarding prevention and control of PMS symptoms was carried out using counseling. Materials and Methods. A cross-sectional study was conducted on 253 El-Minia University unmarried female students. A self-administered questionnaire inquiring about symptoms of PMS in the previous three months and risk factors possibly related to it was used. PMS score was calculated. Multiple regression analysis was performed to determine which of several biopsychosocial and dietary factors influenced PMS. Life style modification counseling was done to prevent and control PMS.
Results. The study revealed that 80.2% of the participants experienced various degrees of PMS symptoms which were significantly associated with a family history of PMS, physical inactivity, habitual excess consumption of coffee, BMI, frequent consumption of fast food, and smoking, but these factors explained only 52% of the variability in the logistic regression model. Conclusion. We recommend the introduction of a reproductive health component into school and college health education programs and encourage female adolescents and young adults to adopt a healthy behavior.
Association between Thrombophilia and the Post-Thrombotic Syndrome
Authors: Rabinovich Anat , Kahn Susan R.
Published: May 2013

The post thrombotic syndrome (PTS) is a chronic condition that develops in 20%–40% of deep vein thrombosis (DVT) patients. While risk factors that predispose to the development of venous thromboembolism (VTE) are widely known, factors that influence the development of PTS after DVT have not been well elucidated. Over 10% of the general population is affected by one or more identifiable inherited thrombophilias which have been shown to underlie at least 1/3 of cases of VTE. The various thrombophilias are important risk factors for VTE, but it is unknown whether they also increase the risk for development of PTS. We performed a review of studies that have reported on the association between thrombophilia and the development of PTS in populations of patients with DVT and with chronic venous ulcers. Studies vary with regards to the definition of PTS, study design, follow-up period, and present conflicting results. Based on these results, the question of whether thrombophilia predisposes to the development of PTS remains unanswered.
Modeling the Spread of Tuberculosis in Semiclosed Communities
Authors: Herrera Mauricio , Bosch Paul , Nájera Manuel , Aguilera Ximena
Published: May 2013

We address the problem of long-term dynamics of tuberculosis (TB) and latent tuberculosis (LTB) in semiclosed communities. These communities are congregate settings with the potential for sustained daily contact for weeks, months, and even years between their members. Basic examples of these communities are prisons, but certain urban/rural communities, some schools, among others could possibly fit well into this definition. These communities present a sort of ideal conditions for TB spread. In order to describe key relevant dynamics of the disease in these communities, we consider a five compartments SEIR model with five possible routes toward TB infection: primary infection after a contact with infected and infectious individuals (fast TB), endogenous reactivation after a period of latency (slow TB), relapse by natural causes after a cure, exogenous reinfection of latently infected, and exogenous reinfection of recovered individuals. We discuss the possible existence of multiple endemic equilibrium states and the role that the two types of exogenous reinfections in the long-term dynamics of the disease could play.
Outcomes of Chronic Hemodialysis Patients in the Intensive Care Unit
Authors: Chan Melanie , Ostermann Marlies
Published: May 2013

Patients with end-stage renal disease (ESRD) experience higher rates of hospitalisation, cardiovascular events, and all-cause mortality and are more likely to require admission to the intensive care unit (ICU) than patients with normal renal function. Sepsis and cardiovascular diseases are the most common reasons for ICU admission. ICU mortality rates in patients requiring chronic hemodialysis are significantly higher than for patients without ESRD; however, dialysis patients have a better ICU outcome than those with acute kidney injury (AKI) requiring renal replacement therapy suggesting that factors other than loss of renal function contribute to their prognosis. Current evidence suggests, the longer-term outcomes after discharge from ICU may be favourable and that long-term dependence on dialysis should not prejudice against prompt referral or admission to ICU.
Role of the Nrf2-ARE Pathway in Liver Diseases
Authors: Shin Sang Mi , Yang Ji Hye , Ki Sung Hwan
Published: May 2013

The liver is a central organ that performs a wide range of functions such as detoxification and metabolic homeostasis. Since it is a metabolically active organ, liver is particularly susceptible to oxidative stress. It is well documented that liver diseases including hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are highly associated with antioxidant capacity. NF-E2-related factor-2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense genes expression in the liver. It is activated in response to electrophiles and induces its target genes by binding to the antioxidant response element (ARE). Therefore, the roles of the Nrf2-ARE pathway in liver diseases have been extensively investigated. Studies from several animal models suggest that the Nrf2-ARE pathway collectively exhibits diverse biological functions against viral hepatitis, alcoholic and nonalcoholic liver disease, fibrosis, and cancer via target gene expression. In this review, we will discuss the role of the Nrf2-ARE pathway in liver pathophysiology and the potential application of Nrf2 as a therapeutic target to prevent and treat liver diseases.
Effects of Spirulina on Cyclophosphamide-Induced Ovarian Toxicity in Rats: Biochemical and Histomorphometric Evaluation of the Ovary
Authors: Yener Nese Arzu , Sinanoglu Orhun , Ilter Erdin , Celik Aygen , Sezgin Gulbuz , Midi Ahmet , Deveci Ugur , Aksungar Fehime
Published: May 2013

Cyclophosphamide (Cyc) is known to cause ovotoxicity and infertility in women. Our aim is to investigate the possible ovotoxic effects of Cyc and possible antioxidant and protective effects of blue-green algae, Spirulina (Sp), in rat ovaries. Eighteen rats were given: group I (n=6, control); group II (n=6, CP), a single dose Cyc; group III (n=6, Sp+Cyc), 7 days Sp+single dose Cyc. Tissue malondialdehyde (MDA) levels, superoxide dismutase (SOD), and catalase (CAT) activities are assessed biochemically. Normal and atretic primordial and primary follicle counts for all sections obtained for each ovary are calculated. Mean number of follicle counts for each group are compared. In Sp+Cyc group, tissue MDA levels were significantly lower than those in the CP and higher than those in the C group (CP>Sp+Cyc>C). Tissue SOD activity was significantly higher in Sp+Cyc group than that in the CP group and lower than that in the C group (C>Sp+Cyc>C). No statistically significant difference was found between the ovarian CAT activities in any group. Histomorphometrically, there was also no significant difference between the mean numbers of normal and atretic small follicle counts. Our results suggest that single dose Cyc has adverse effects on oxidant status of the ovaries and Sp has protective effects in Cyc-induced ovotoxicity.
Pigmented Viral-Associated Conjunctival Carcinoma
Authors: Charles Norman C. , Marr Brian P. , Stenson Susan M. , Mittal Khushbakhat R.
Published: May 2013

A 54-year-old African-American woman developed a pigmented papillary squamous cell carcinoma in the palpebral and bulbar conjunctiva of the right eye in areas that received no sun exposure. In situ hybridization performed on the tumor showed human papilloma virus 16. The left eye showed a pedunculated nonpigmented conjunctival dysplasia. The tumors were extirpated by cryosurgery and topical interferon alfa 2b in the right eye and simple surgical excision in the left eye.
A Multiagent Dynamic Assessment Approach for Water Quality Based on Improved Q-Learning Algorithm
Authors: Ni Jianjun , Ren Li , Liu Minghua , Zhu Daqi
Published: May 2013

The dynamic water quality assessment is a challenging and critical issue in water resource management systems. To deal with this complex problem, a dynamic water assessment model based on multiagent technology is proposed, and an improved Q-learning algorithm is used in this paper. In the proposed Q-learning algorithm, a fuzzy membership function and a punishment mechanism are introduced to improve the learning speed of Q-learning algorithm. The dynamic water quality assessment for different regions and the prewarning of water pollution are achieved by using an interaction factor in the proposed approach. The proposed approach can deal with various situations, such as static and dynamic water quality assessment. The experimental results show that the water quality assessment based on the proposed approach is more accurate and efficient than the general methods.
The Effect of Pioglitazone on Antioxidant Levels and Renal Histopathology in Streptozotocin-Induced Diabetic Rats
Authors: Kuru Karabas Munire , Ayhan Mediha , Guney Engin , Serter Mukadder , Meteoglu Ibrahim
Published: May 2013

Objective. Diabetic nephropathy is the most commonly seen cause of chronic renal failure, and oxidative stress is important in etiology. In the present study, favorable effects (if any) of the treatment with a thiazolidinedione group drug, pioglitazone, on antioxidant enzyme levels in the renal tissue, renal histopathology, and inflammatory cytokine levels have been investigated.Method. Forty male Wistar rats were divided into 4 groups as the control, diabetic control, and 10 and 30 mg pioglitazone-administered diabetic groups. After 4 weeks, antioxidant enzyme levels in renal tissues and inflammatory markers were investigated.Results. Blood glucose levels did not differ between the diabetic control and drug-administered groups. In pioglitazone-administered rats, histopathological findings such as tubular dilation, necrotic tubular epithelium, glomerular focal necrosis, and vascular consolidation were observed at a lesser extent than the diabetic control group. Any difference was not detected between the diabetic groups with respect to the levels of malondialdehyde, superoxide dismutase, catalase, glutathione, nitric oxide, interleukin-6, and tumor necrosis factor-alpha.Conclusion. Pioglitazone regressed development of histopathological lesions such as glomerular focal necrosis, tubular epithelial necrosis, tubular dilation, and vascular wall consolidation. However, any favorable effect on antioxidant enzyme levels in renal tissues and inflammation markers was not detected.
Development of Optimal Water-Resources Management Strategies for Kaidu-Kongque Watershed under Multiple Uncertainties
Authors: Zhou Y. , Li Y. P. , Huang G. H. , Huang Y.
Published: May 2013

In this study, an interval-stochastic fractile optimization (ISFO) model is advanced for developing optimal water-resources management strategies under multiple uncertainties. The ISFO model can not only handle uncertainties presented in terms of probability distributions and intervals with possibility distribution boundary, but also quantify subjective information (i.e., expected system benefit preference and risk-averse attitude) from different decision makers. The ISFO model is then applied to a real case of water-resources systems planning in Kaidu-kongque watershed, China, and a number of scenarios with different ecological water-allocation policies under variedp-necessity fractiles are analyzed. Results indicate that different policies for ecological water allocation can lead to varied water supplies, economic penalties, and system benefits. The solutions obtained can help decision makers identify optimized water-allocation alternatives, alleviate the water supply-demand conflict, and achieve socioeconomic and ecological sustainability, particularly when limited water resources are available for multiple competing users.
LDPC Decoder with an Adaptive Wordwidth Datapath for Energy and BER Co-Optimization
Authors: Mohsenin Tinoosh , Shirani-mehr Houshmand , Baas Bevan M.
Published: May 2013

An energy efficient low-density parity-check
(LDPC) decoder using an adaptive wordwidth datapath is presented.
The decoder switches between a Normal Mode and a reduced wordwidth Low Power Mode. Signal toggling is reduced as variable node processing inputs change in fewer bits. The duration of time that the decoder stays in a given mode is optimized for power and BER requirements and the received SNR. The paper explores different Low Power Mode algorithms to reduce the wordwidth and their implementations. Analysis of the BER performance and power consumption from fixed-point numerical and post-layout power simulations, respectively, is presented for a full parallel 10GBASE-T LDPC decoder in 65 nm CMOS. A 5.10 mm2 low power decoder implementation achieves 85.7 Gbps while operating at 185 MHz and dissipates 16.4 pJ/bit at 1.3 V with early termination. At 0.6 V the decoder throughput is 9.3 Gbps (greater than 6.4 Gbps required for 10GBASE-T) while dissipating an average power of 31 mW. This is 4.6 lower than the state of the art reported power with an SNR loss of 0.35 dB at .
On Attractivity and Positivity of Solutions for Functional Integral Equations of Fractional Order
Authors: Huang Xianyong , Cao Junfei
Published: May 2013

We investigate a class of functional integral equations of fractional order given byx(t)=q(t)+f1(t,x(α1(t)),x(α2(t)))+(f2(t,x(β1(t)),x(β2(t)))/Γ(α))×∫0t(t−s)α−1f3(t,s,x(γ1(s)),x(γ2(s)))ds: sufficient conditions for the existence, global attractivity, and ultimate positivity of solutions of the equations are derived. The main tools include the techniques of measures of noncompactness and a recent measure theoretic fixed point theorem of Dhage. Our investigations are placed in the Banach space of continuous and bounded real-valued functions defined on unbounded intervals. Moreover, two examples are given to illustrate our results.
Determinants of Attrition to Follow-Up in a Multicentre Cohort Study in Children-Results from the IDEFICS Study
Authors: Hense Sabrina , Pohlabeln Hermann , Michels Nathalie , Mårild Staffan , Lissner Lauren , Kovacs Eva , Moreno Luis A. , Hadjigeorgiou Charalampos , Veidebaum Toomas , Iacovello Licia , Pitsiladis Yannis , Reisch Lucia , Siani Alfonso , Ahrens Wolfgang
Published: May 2013

Cohort participant retention is a crucial element and may depend on several factors. Based on data from a multicentre cohort of European children, the effect of baseline participation on attrition and the association with and the impact of single determinants in relation to the extent of attrition were investigated. Data was available for 16,225 children from the IDEFICS baseline survey (2007/2008). Attrition was defined as nonparticipation in the first follow-up examination (2009/2010). Determinants of attrition were analysed by logistic regression. The statistical significance level was set at α=0.01 to account for the large sample size. The strongest associations were seen for baseline item non-response, especially when information on migration background (odds ratio (OR) = 1.55; 99% confidence interval (CI): 1.04, 2.31), single parenthood (OR = 1.37; 99% CI: 1.12, 1.67), or well-being (OR = 1.46; 99% CI: 1.19, 1.79) was lacking. Drop-out proportion rose with the number of missing items. Overweight, low education, single parenthood and low well-being scores were independent determinants of attrition. Baseline participation, and the individual determinant effects seemed unrelated to the variation of the extent of attrition between study centres. A high level of item nonresponse as well as overweight and disadvantageous sociodemographic conditions were identified as main attrition determinants, suggesting the consideration of these aspects in conduct and analysis of cohort studies in childhood obesity research.
A Review on the Structural Studies of Batteries and Host Materials by X-Ray Absorption Spectroscopy
Authors: Giorgetti Marco
Published: May 2013

This review highlights the use of the X-ray absorption spectroscopy (XAS) as a local structural tool for selected atoms in several host materials. The main characteristics of XAS to be element-sensitive and its applicability to all states of matter, including crystalline solids and amorphous and liquid states, permit an in-depth study of the structural properties of a large variety of materials. This includes intercalation materials where a host structure can accommodate guest species. Host guest equilibria are at the basis of a large variety of technological applications; in particular they have been used for energy storage, ion-exchange membranes, electrochromism, and analytical sensing. A selection of XAS experiments conducted in the field of batteries, mainly on cathodes, and applications in the field of metal hexacyanoferrates and double layered hydroxides are outlined.
An Interval-Parameter Fuzzy Linear Programming with Stochastic Vertices Model for Water Resources Management under Uncertainty
Authors: Han Yan , Huang Yuefei , Jia Shaofeng , Liu Jiahong
Published: May 2013

An interval-parameter fuzzy linear programming with stochastic vertices (IFLPSV) method is developed for water resources management under uncertainty by coupling interval-parameter fuzzy linear programming (IFLP) with stochastic programming (SP). As an extension of existing interval parameter fuzzy linear programming, the developed IFLPSV approach has advantages in dealing with dual uncertainty optimization problems, which uncertainty presents as interval parameter with stochastic vertices in both of the objective functions and constraints. The developed IFLPSV method improves upon the IFLP method by allowing dual uncertainty parameters to be incorporated into the optimization processes. A hybrid intelligent algorithm based on genetic algorithm and artificial neural network is used to solve the developed model. The developed method is then applied to water resources allocation in Beijing city of China in 2020, where water resources shortage is a challenging issue. The results indicate that reasonable solutions have been obtained, which are helpful and useful for decision makers. Although the amount of water supply from Guanting and Miyun reservoirs is declining with rainfall reduction, water supply from the South-to-North Water Transfer project will have important impact on water supply structure of Beijing city, particularly in dry year and extraordinary dry year.
Four New Species Records of Umbelopsis (Mucoromycotina) from China
Authors: Wang Ya-ning , Liu Xiao-yong , Zheng Ru-yong
Published: May 2013

Four species of Umbelopsis newly found in China, that is, U. angularis, U. dimorpha, U. nana, and U. versiformis, are reported in this paper. Descriptions and illustrations are provided for each of them.
A Case of QT Prolongation Associated with Panhypopituitarism
Authors: Arpaci Dilek , Demir Mustafa Volkan , Garip Tayfun , Tamer Ali
Published: May 2013

We describe a 37-year-old patient with panhypopituitarism who experienced symptoms and signs of hormonal insufficiency and QT prolongation on electrocardiogram without electrolyte disturbances. After hormonal (steroidal and thyroid) replacement therapy electrocardiographic findings were normalized. Hormonal disorders should be considered as a cause of long QT intervals which may lead to torsade de pointes, even if plasma electrolyte levels are normal, because life-threatening arrhythmia is treatable by supplementation of the hormone that is lacking.
Association between 8-oxo-7,8-dihydro-2′-deoxyguanosine Excretion and Risk of Postmenopausal Breast Cancer: Nested Case–Control Study
Authors: Loft Steffen , Olsen Anja , Møller Peter , Poulsen Henrik E. , Tjønneland Anne
Published: May 2013

Background: Oxidative stress may be important in carcinogenesis and a possible risk factor for breast cancer. The urinary excretion of oxidatively generated biomolecules, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), represents biomarkers of oxidative stress, reflecting the rate of global damage to DNA in steady state.

Methods: In a nested case–control design, we examined associations between urinary excretion of 8-oxodG and risk of breast cancer in a population-based cohort of 24,697 postmenopausal women aged 50 to 64 years with 3 to 7 years follow-up. The accruing cases of breast cancer were matched to controls by age at diagnosis, baseline age, and hormone replacement therapy (HRT). Spot urine samples collected at entry was analyzed for 8-oxodG by high-performance liquid chromatography with electrochemical detection. Incidence rate ratio (IRR; 95% confidence intervals) based on 336 matched pairs with all information was estimated per unit increase in 8-oxodG divided by creatinine for all and estrogen receptor (ER) positive and negative breast cancers.

Results: There was a borderline significant positive association between 8-oxodG and risk of all breast cancer (IRR: 1.08; 1.00–1.17 per unit increase in nmol/mmol creatinine). This association was significant with respect to the risk of ER-positive cancer (IRR: 1.11; 1.01–1.23) and among women not using HRT (IRR: 1.11; 0.97–1.26) or with low dietary iron intake (IRR: 1.10; 1.06–1.37 per unit increase) for all breast cancer.

Conclusions: We observed positive association between 8-oxodG excretion and risk of especially ER-positive breast cancer.

Impact: Our results suggest that oxidative stress with damage to DNA is important for the development of breast cancer. Cancer Epidemiol Biomarkers Prev; 22(7); 1289–96. ©2013 AACR.
High Prevalence of BRCA1 and BRCA2 Germline Mutations with Loss of Heterozygosity in a Series of Resected Pancreatic Adenocarcinoma and Other Neoplastic Lesions
Authors: Lucas Aimee L. , Shakya Reena , Lipsyc Marla D. , Mitchel Elana B. , Kumar Sheila , Hwang Caroline , Deng Liyong , Devoe Catherine , Chabot John A. , Szabolcs Matthias , Ludwig Thomas , Chung Wendy K. , Frucht Harold
Published: May 2013

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal.

Experimental Design: This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted.

Results: Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P = .01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs.

Conclusions: We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals. Clin Cancer Res; 19(13); 3396–403. ©2013 AACR.
Drug Repurposing for Gastrointestinal Stromal Tumor
Authors: Pessetto Ziyan Y. , Weir Scott J. , Sethi Geetika , Broward Melinda A. , Godwin Andrew K.
Published: May 2013

Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, “drug repurposing” or “repositioning,” has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds, auranofin (Ridaura) and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including imatinib-resistant cells. One of the most notable drug hits, auranofin, an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis, was found to inhibit thioredoxin reductase activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with auranofin was independent of imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for patients with GIST, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. Mol Cancer Ther; 12(7); 1299–309. ©2013 AACR.
NF-κB Inhibition by Bortezomib Permits IFN-γ–Activated RIP1 Kinase–Dependent Necrosis in Renal Cell Carcinoma
Authors: Thapa Roshan J. , Chen Peirong , Cheung Mitchell , Nogusa Shoko , Pei Jianming , Peri Suraj , Testa Joseph R. , Balachandran Siddharth
Published: May 2013

Advanced renal cell carcinoma (RCC) is an invariably fatal cancer. Currently, small-molecule inhibitors that target cell growth, angiogenesis, or nutrient-sensing pathways represent the primary pharmacologic interventions for this disease, but these inhibitors only delay tumor progression and are not curative. The cytokine IFN-γ showed the potential to provide lasting remission in several phase I/II trials for advanced RCCs, but subsequent trials, including a multicenter phase III study using IFN-γ as a monotherapy for RCCs, were less promising. Notably, these trials were designed to exploit the indirect immunomodulatory effects of IFN-γ, whereas its direct antitumor properties—including its ability to trigger programmed cell death in tumors—remain mostly untapped. Here, we show that the proteasome inhibitor bortezomib (PS-341, Velcade) sensitizes otherwise resistant RCC cells to direct necrotic death by IFN-γ. Mechanistically, we show that bortezomib functions, at least in part, by inhibiting prosurvival NF-κB signaling. In the absence of this signal, IFN-γ triggers programmed necrosis (or “necroptosis”) dependent on the kinase RIP1. When taken together with the observation that NF-κB signaling is elevated in RCCs, these results provide rationale for the combined use of IFN-γ and bortezomib in the treatment of metastatic RCCs. Mol Cancer Ther; 12(8); 1568–78. ©2013 AACR.
Abstract A17: Antagonizing HOX function triggers apoptosis in prostate cancer cells
Authors: Morgan Richard , Simpson Guy , Boxall Angela , Michael Agnieszka , Pandha Hardev
Published: May 2013

The HOX genes are a family of transcription factors that determine the identity of cells and tissues during embryonic development and in adult stem cell maturation, and are known to have an oncogenic function in a number of hematological and solid malignancies. HOX genes are also highly expressed in prostate tumors relative to normal prostate tissue, but the redundant nature of HOX function has made the significance of these observations hard to assess by conventional gene knock out studies. Here we use the previously characterized antagonist HXR9 to target the post translational association of HOX proteins with the PBX co-factor and show that this is sufficient to trigger apoptosis in the prostate derived cell lines LNCaP, PC3 and DU145, in vitro. Furthermore HXR9 causes tumor shrinkage in murine and CAM models of prostate cancer. These results suggest that the interaction between HOX proteins and their PBX cofactor might be a therapeutic target in prostate cancer.

Note: This abstract was not presented at the conference because the presenter was unable to attend.

Citation Format: Richard Morgan, Guy Simpson, Angela Boxall, Agnieszka Michael, Hardev Pandha. Antagonizing HOX function triggers apoptosis in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A17.
Abstract A2: A Study of the effects of MDV3100 in the tumor microenvironment of bone metastatic castrate resistant prostate cancer (bmCRPC)
Authors: Efstathiou Eleni , Troncoso Patricia , Mohler James , Logothetis Christopher J. , Titus Mark , Tsavachidou Dimitra , Wen Sijin , Hoang Anh , Ashe Robynne , Karlou Maria , Berman Craig
Published: May 2013

Background: Androgen signaling remains a central driver in castrate-resistant prostate cancer. We performed a study to determine the effect of the antiandrogen MDV 3100 on bone marrow infiltrating CRPC.

Methods: From February 2010 to June 2011, we performed an open-label, observational study of 60 bmCRPC patients (pts), who underwent transilial bone marrow biopsy (BMB) at baseline, 8 weeks and end of study. Pts received MDV3100 160mg orally once daily. The primary objective was to evaluate androgen signaling in bone marrow infiltrating cancer and testosterone in blood (BT) and bone marrow (BMT) and correlate findings with clinical observations. Androgen receptor (AR) c-terminus n-terminus, AR Variant 7 (ARV7), ERG, CYP17, phospho Src (pSrc), expression and mitotic index (Ki67 ) were assessed by immunohistochemistry, AR copy number by qPCR and BT and BMT by liquid chromatography mass spectrometry.

Initial Findings: Maximal PSA decline of ≥50% occurred in 29 (48%) of 60 pts, and ≥90% in 13 (22%). Tumor involvement in BMB was detected in 28 (47%) pretreatment BMBs. Paired tumor infiltrated BMBs were found in 23 (38%) pts. Increased androgen receptor expression (n-terminal antibody used for IHC) was observed at pretreatment with heterogeneous CYP17 and pSrc extent of expression.

Pretreatment intense nuclear AR expression combined with ≥10% CYP17 tumor expression or increased BMT correlate with ≥50% PSA decline (p value 0.02). AR subcellular localization shift from dominant nuclear to cytoplasmic and regression of bone marrow tumor infiltration correlate with ≥50% PSA decline (p value 0.05). Increased pretreatment p-Src expression is associated with lack of PSA decline (p value 0.002). Increase in BMT and BT is observed after 8 weeks of MDV3100 (mean pretreatment BMT 0.026 ng/ml, Wk8 BMT 0.04 in 33pts, p value 0.0001) (pretreatment BT 0.041, wk8 BT 0.066 in 37 pts, p value <0.0001).

Interpretation: Pretreatment expression profile is consistent with persistent androgen signaling in bmCRPC. MDV3100 induces pharmacodynamic changes in androgen signaling. AR changes likely account for the reported therapeutic effect of MDV3100. These data prompt exploratory combinations of MDV3100 with androgen biosynthesis inhibitors and src inhibitors.

Citation Format: Eleni Efstathiou, Patricia Troncoso, James Mohler, Christopher J. Logothetis, Mark Titus, Dimitra Tsavachidou, Sijin Wen, Anh Hoang, Robynne Ashe, Maria Karlou, Craig Berman. A study of the effects of MDV3100 in the tumor microenvironment of bone metastatic castrate-resistant prostate cancer (bmCRPC) [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A2.
Abstract A32: A urinary mRNA profile to increase the specificity of PSA and reduce the number of unnecessary biopsies
Authors: Rigau Marina , Altadill Tatiana , Doll Andreas , Sequeiros Tamara , Olivan Mireia , Garcia Marta , Sanchez Alex , Montes Melania , Ortega Israel , Morote Juan , Reventos Jaume
Published: May 2013

Background: Several studies have demonstrated the usefulness of monitoring an RNA transcript, such as PCA3, in post-prostate massage (PM) urine for increasing the specificity of prostate-specific antigen (PSA) in the detection of prostate cancer (PCa). However, a single marker may not necessarily reflect the multifactorial nature of PCa.

Methods: We analyzed post-PM urine samples from 154 consecutive patients, who presented for prostate biopsies because of elevated serum PSA (>4 ng/ml) and/or abnormal digital rectal exam. We tested whether the putative PCa biomarkers PSMA, PSGR, and PCA3 could be detected by quantitative real-time PCR in post-PM urine sediment. We combined these findings with PSAD to test if a combination of these biomarkers could improve the specificity of actual diagnosis. Afterwards, we specifically tested our model for clinical usefulness in the PSA diagnostic “gray zone” (4–10 ng/ml) on a target subset of 82 men with no prior biopsy.

Results: By univariate analysis, we found that the PSMA, PSGR, PCA3 and PSAD scores were significant predictors of PCa. Using a multiplex model, the area under the multireceiver operating characteristic curve was 0.80 versus 0.89 in the diagnostic gray zone. Fixing the sensitivity at 96%, we obtained a specificity of 40% and 62% in the gray zone. By this approach it would be possible to save approximately 35% of unnecessary biopsies with a sensitivity of 95%.

Conclusions: Taken together, these results provide a strategy for the development of a more accurate model for PCa diagnosis. In the future, a multiplexed, urine-based diagnostic test for PCa with a higher specificity, but the same sensitivity as the serum-PSA test, could be used to determine better which patients should undergo biopsy.

Citation Format: Marina Rigau, Tatiana Altadill, Andreas Doll, Tamara Sequeiros, Mireia Olivan, Marta Garcia, Alex Sanchez, Melania Montes, Israel Ortega, Juan Morote, Jaume Reventos. A urinary mRNA profile to increase the specificity of PSA and reduce the number of unnecessary biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A32.
Abstract A42: In vitro proliferation, apoptosis, cell cycle progression, and gene analysis for 25- hydroxyvitamin D-1α-hydroxylase (1α-OHase) transfected LNCaP cells.
Authors: Banks Mara , Holick Michael F.
Published: May 2013

Vitamin D is converted to 25(OH)D, which is the major vitamin D metabolite in circulating blood. However, 25(OH)D must be converted to 1α,25(OH)2D for most of its biological actions. 25- hydroxyvitamin D-1α-hydroxylase (1α-OHase) is the enzyme that hydroxylates the1-alpha position of 25(OH)D and creates the biologically active form of vitamin D, 1α,25(OH)2D. 1α,25(OH)2D has been shown to induce cell cycle regulation, apoptosis and inhibit proliferation in prostate cancer cells. Previous studies have demonstrated that prostate and some prostate cancer cells have the ability to convert 25(OH) D to 1α,25(OH)2D. This ability along with epidemiological evidence correlating an inverse relationship between serum 25(OH)D levels and prostate cancer risk suggests that vitamin D and its metabolizing enzymes may be important for prostate cancer prevention. Since LNCaP cells are androgen sensitive, possess a functional vitamin D receptor, have 24-OHase activity but lack 1α-OHase activity, this cell line was the model used to transfect 1α-OHase and determine what the effects local conversion to 1α,25(OH)2D had on prostate cancer cells. LNCaP cells transfected with the sense strand of 1α-OHase have been designated 1α-S. We hypothesize that local intracellular conversion of 25(OH) D to 1α,25(OH)2D is important to the anti-carcinogenic autocrine/paracrine functions of vitamin D. Cellular proliferation, apoptosis and cell cycle progression were assessed using 3[H]-thymidine incorporation, DNA fragmentation and fluorescence activated cell sorting, respectively. Gene analysis was done using Real Time PCR to elucidate the molecular mechanism(s) involved in vitamin D's anti-carcinogenic effects. A dose dependent decrease in 3[H]-thymidine incorporation in 1α-S cells was observed with 25(OH)D at 10−6M concentration having the greatest decrease (54.1± 9.0%). In 1α-S cells treated with 25(OH)D at 10−6M, there was 2.1 times more DNA fragmentation than untreated LNCaP cells or LNCaP treated with 25(OH) D at 10−6M. Cell cycle progression was also analyzed with 10−6M 25(OH)D treatment in 1α-S resulted in 94.9% of cells being in the G1 phase. Gene expression analysis showed an increase in cell cycle regulatory genes; p21 (14.1±0.5 fold), p27 (5.2±0.4 fold) and p53 (3.8±0.4 fold). Apoptotic gene expression, bax and bcl-2, were induced (3.8±0.4 fold) and suppressed (0.04±0.3 fold) in 1α-S cells, respectively. This study supports the idea that the local intracellular conversion to 1α,25(OH)2D is important to prostate cancer prevention.

Citation Format: Mara Banks, Michael F. Holick. In vitro proliferation, apoptosis, cell cycle progression, and gene analysis for 25- hydroxyvitamin D-1α-hydroxylase (1α-OHase) transfected LNCaP cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A42.
Abstract A46: A new transgenic mouse model of prostate cancer that displays rapid progression from prostate intraepithelial neoplasia to invasive carcinoma.
Authors: Bjerke Glen , Yang Chun-Song , Frierson Henry , Paschal Bryce , Wotton David
Published: May 2013

Understanding the molecular, biochemical, and cellular mechanisms that underpin prostate cancer progression will reveal new opportunities for targeted therapies. Our NCI-supported Program Project on “Signaling and Progression in Prostate Cancer” is a team of basic and clinician scientists that share the overall goal of defining how prostate cancer cells subvert signal transduction pathways during progression to androgen independence. Projects and cores within our program are developing new model systems intended to recapitulate human disease progression. Core B in the program (Transgenic Models and Animal Imaging) has developed a new transgenic mouse model by combining mutant alleles of genes known to have important roles in human prostate cancer. The model is based on the phosphatase and tensin homolog (Pten) tumor suppressor, which is mutated in approximately 30% of primary prostate cancers. Prostate-specific deletion of Pten in mice has been shown by multiple groups to cause prostatic intraepithelial neoplasia (PIN), which slowly progresses to invasive cancer. This suggests that Pten loss allows the initiation of cancer, but that progression is subject to restraint mechanisms. We hypothesized that a restraint mechanism might depend on signaling via the TGFβ pathway, owing to the prominent role that TGFβ plays in growth control. We show that conditional deletion of Pten and Tgfbr2, the type II receptor for TGFβ, in prostate epithelium results in large, poorly differentiated prostate tumors with 100% penetrance by 12 weeks of age. Mice with Pten and Tgfbr2 deletions acquire invasive adenocarcinoma and bladder obstruction and most die by 15 weeks of age. Androgen depletion by castration does not provide a survival benefit for these mice. Pten loss causes an increase in expression of the cyclin-dependent kinase inhibitor p27, which likely restrains progression in this setting. However, when both Pten and Tgfbr2 are deleted, p27 levels are reduced and cyclin D levels increase. Our results suggest that Tgfbr2 is an important tumor suppressor in prostate cancer and that its loss allows rapid progression when combined with loss of the Pten tumor suppressor. Disruption of the TGFβ-mediated restraint provides a rapid, penetrant, and physiologically relevant preclinical model that will be helpful for analyzing restraint- and progression-related gene expression and signal transduction changes in Pten-dependent tumorigenesis.

Citation Format: Glen Bjerke, Chun-Song Yang, Henry Frierson, Bryce Paschal, David Wotton. A new transgenic mouse model of prostate cancer that displays rapid progression from prostate intraepithelial neoplasia to invasive carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A46.
Abstract B51: Ligand-independent EphA2 signaling through Akt is preferentially activated in prostate cancer bone metastases and is important for tumor growth
Authors: Petty Aaron , Miao Hui , Guo Hong , Morrissey Colm , Chinnaiyan Arul , Wu Hong , Wang Bingcheng
Published: May 2013

Prostate cancer progression to castration-resistance (CRPC) and metastasis represent the major challenges to effective prostate cancer therapy. PI3 kinase/Akt pathway activation has been linked to CRPC progression and metastasis, but the precise mechanisms have only been partially determined. Recently, we discovered that ligand-independent activation of the EphA2 receptor tyrosine kinase by Akt on a serine 897 site (S897) promotes cell migration and invasion, while stimulation with its ligand, ephrin-A1, downregulates EphA2 and inhibits migration and invasion. In the current study, we sought to determine whether ligand-independent EphA2 activation by Akt is linked to prostate cancer metastasis and progression to CRPC through biochemical and immunohistochemical analyses. Analysis of a panel of human prostate cancer tissues revealed EphA2 overexpression and increased S897 phosphorylation primarily in bone metastases, the primary metastatic site. Similarly, EphA2 was overexpressed in human cell lines from bone and brain metastases, but not in those from lymph node metastasis or primary tumor. Further analysis in a PTEN-deletion mouse model of aggressive prostate cancer revealed increased S897 phosphorylation in prostate glands from PTEN-null mice, compared to wild type prostate glands. To determine the potential link of EphA2 phosphorylation to CRPC progression, we compared S897 phosphorylation in xenograft tumors from both LAPC9 androgen-dependent and castration-resistant prostate cancer cell lines and found increased S897 phosphorylation in tumors from castration-resistant cells. Finally, abolishing S897 phosphorylation through the S897A point mutation inhibited growth of PC3 prostate cancer cells in a xenograft mouse model. Our study supports a link between ligand-independent EphA2 activation and prostate cancer progression and metastasis to bone, as well as primary tumor growth, highlighting a potential new mechanism involved in malignant prostate cancer progression.

Citation Format: Aaron Petty, Hui Miao, Hong Guo, Colm Morrissey, Arul Chinnaiyan, Hong Wu, Bingcheng Wang. Ligand-independent EphA2 signaling through Akt is preferentially activated in prostate cancer bone metastases and is important for tumor growth [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B51.
Abstract B7: ETS1 overexpression in prostate cancer cells
Authors: Bentel Jacqueline M. , Harvey Jennet , Thomas Marc A. , Rodgers Jamie J. , Rouse Ebony J. , Preece Darren M. , Chai Siaw M. , Epis Michael R. , Cohen Ronald J. , Leedman Peter J. , Roehrig Kimberley
Published: May 2013

The ETS1 transcription factor is overexpressed in human prostate cancers in comparison to nonmalignant prostate and exhibits nuclear, in addition to aberrant cytoplasmic localisation. A previous report has identified direct interaction between ETS1 and the androgen receptor (AR) in the prostate cancer cell line, LNCaP and we have demonstrated that this ligand-dependent interaction is mediated via the ETS (DNA binding) domain of ETS1 and the ligand-binding domain of the AR. In a cohort of 44 prostate cancer cases, mRNA for the full-length ETS1 isoform, p54ETS1 was detected in all prostate tumour and adjacent nonmalignant prostate tissues, while expression of the internally truncated p42ETS1 isoform was very low or undetectable. In protein lysates extracted from the same cases, p54ETS1 was detected in all samples, with expression of a lower molecular weight ETS1 corresponding in size to the dominant negative p27ETS1 isoform also observed. Increased expression of one or both of the ETS1 isoforms was identified in 38 (86%) cases, supporting the elevated expression of ETS1 in human prostate tumours. Both ETS1 and the AR upregulate expression of the prostatic tumour suppressor, NKX3.1 via sequences located in the 5′ promoter and 3′ untranslated region (3′UTR), respectively. Although unresponsive to androgens, the proximal ∼2kb of the NKX3.1 promoter, and in particular a 76bp sequence surrounding the ETS binding site (EBS) become androgen responsive following ETS1 overexpression. In addition, in LNCaP cells that stably overexpress p54ETS1, the biphasic proliferative responses to androgens, where low (≤10−10M) DHT concentrations stimulate proliferation and higher (>10−10M) DHT levels inhibit proliferation, were altered and DHT concentrations as low as 10−12M inhibited proliferation. The findings indicate that the increased expression of ETS1 commonly observed in human prostate tumours may modify the androgen responsiveness of the cancer cells, augmenting AR-mediated regulation of androgen target genes and potentially sensitising prostate cancer cells to the very low androgen levels in men treated with androgen ablation therapies.

Citation Format: Jacqueline M. Bentel, Jennet Harvey, Marc A. Thomas, Jamie J. Rodgers, Ebony J. Rouse, Darren M. Preece, Siaw M. Chai, Michael R. Epis, Ronald J. Cohen, Peter J. Leedman, Kimberley Roehrig. ETS1 overexpression in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B7.