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Prostate cancer is the most common solid tumor diagnosed in men in the United States and Western Europe. Primary treatment with radiation or surgery is largely successful at controlling localized disease. However, a significant number (up to one third of men) may develop biochemical recurrence (BR), defined as a rise in serum prostate-specific antigen (PSA) level. A general presumption is that BR will lead to overt progression in patients over subsequent years. There are a number of factors that a physician must consider when counseling and recommending treatment to a patient with a rising PSA. These include the following (1) various PSA-based definitions of BR; (2) source of PSA (ie, local or distant disease, residual benign prostate); (3) available modalities to treat the disease with the least morbidity; and (4) timing of therapy. In this article we review the current and future factors that clinicians should consider in the diagnosis and treatment of recurrent prostate cancer.

Prostate cancer is the most commonly diagnosed cancer and second most common cause of cancer death in American men. Although high-risk disease accounts for less than 15% of diagnoses, high-risk prostate cancer patients have a cancer-specific mortality rate of 15% at 10 years. There is currently no consensus on the optimal management of high-risk disease because (1) there are different primary modalities available (ie, surgery, radiation), for which there are no randomized trials comparing efficacy; and (2) unstandardized timing of different therapies (ie, neoadjuvant v concurrent v adjuvant), which makes comparisons of efficacy problematic. Increased understanding into the mechanisms leading to the formation of advanced metastatic disease has spurred the development of agents to target these pathways. However, new questions regarding optimal management of disease arise with regard to the role of these therapies in combination with "conventional" primary modalities for earlier stage, high-risk prostate cancer patients. In this article, we review the transforming world of multimodality therapy in high-risk prostate cancer.

In this study, modified converter slag (CS) was characterized in relation to its physicochemical structure, and used for the simultaneous removal of NH4(+) and PO4(3-) at low concentrations from aqueous solutions. The effects of contact time, pH, adsorbent dosage, and temperature on the adsorption process were studied in batch experiments. The results showed that the adsorption capacity of modified converter slag was found to sharply increase as a result of modification. The optimum pH is 5-8. The adsorption process was able to reach equilibrium in 90 minutes. Kinetic data were best described by the pseudo-second-order model. The sorption isotherms were a good fit with the Langmuir model. The maximum adsorption capacities of modified converter slag for NH4(+) and PO4(3-) were 2.59 mg/g and 1.185 mg/g, respectively. Thermodynamic studies indicated that the adsorption was a spontaneous and endothermic process. The calculated values of enthalpy change indicated that ligand exchange, chemical reactions, and precipitation are dominating mechanisms of PO4(3-) removal, while physisorption and ion-exchange are major mechanisms of NH4(+) removal.

Background Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient’s own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20–40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment. Because radiotherapy has immunomodulatory effects on the tumor microenvironment, it has the potential to synergize with immunotherapy and augment tumor response. NCT02318771 is a phase 1 clinical trial designed to investigate the immunomodulatory effects of radiation therapy in combination with pembrolizumab. Case presentation The patient is a 64-year-old male with metastatic clear cell renal cell carcinoma, Fuhrman grade 4, pathologically staged as T3 N0. Metastatic disease was well controlled for several years with sunitinib. Following disease progression, he was switched to axitinib. When disease progression continued, the patient was enrolled in NCT02318771, a phase 1 clinical trial combining radiotherapy and pembrolizumab. The patient experienced unusually rapid disease progression during treatment, which was confirmed by repeated CT scans to rule out pseudoprogression. Tissue biopsies and peripheral blood draws were obtained before, during, and after treatment. Samples were analyzed to provide plausible rationale for rapid treatment failure. Conclusions Biomarker analysis demonstrated an absence of TILs, which may be a cause of treatment failure as pembrolizumab works through T cell-dependent mechanisms. Furthermore, the presence of other non-redundant immune checkpoints in the periphery and tumor microenvironment presents a treatment challenge. Additionally, the radiation dose and fractionation schedule may have played a role in treatment failure as these factors play a role in the effect radiotherapy on the tumor microenvironment as well as the potential for synergy with immunotherapy. Trial registration An Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer, NCT02318771 .

Lessons Learned Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone. There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. Background. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. Methods. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1–7 every 21 days) per standard 3+3 design. Results. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. Conclusion. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.

We evaluated differences in treatment of black vs white patients with colon cancer and assessed their effects on survival, based on cancer stage.We collected data from the Surveillance, Epidemiology, and End Results-Medicare database and identified 6190 black and 61,951 white patients with colon cancer diagnosed from 1998 through 2009 and followed up through 2011. Three sets of 6190 white patients were matched sequentially, using a minimum distance strategy, to the same set of 6190 black patients based on demographic (age; sex; diagnosis year; and Surveillance, Epidemiology, and End Results registry), tumor presentation (demographic plus comorbidities, tumor stage, grade, and size), and treatment (presentation plus therapies) variables. We conducted sensitivity analyses to explore the effects of socioeconomic status in a subcohort that included 2000 randomly selected black patients. Racial differences in treatment were assessed using a logistic regression model; their effects on racial survival disparity were evaluated using the Kaplan-Meier method and the Cox proportional hazards model.After patients were matched for demographic variables, the absolute 5-year difference in survival between black and white patients was 8.3% (white, 59.2% 5-y survival; blacks, 50.9% 5-y survival) (P.0001); this value decreased significantly, to 5.0% (P .0001), after patients were matched for tumor presentation, and decreased to 4.9% (P.0001) when patients were matched for treatment. Differences in treatment therefore accounted for 0.1% of the 8.3% difference in survival between black and white patients. After patients were matched for tumor presentation, racial disparities were observed in almost all types of treatment; the disparities were most prominent for patients with advanced-stage cancer (stages III or IV, up to an 11.1% difference) vs early stage cancer (stages I or II, up to a 4.3% difference). After patients were matched for treatment, there was a greater reduction in disparity for black vs white patients with advanced-stage compared with early-stage cancer. In sensitivity analyses, the 5-year racial survival disparity was 7.7% after demographic match, which was less than the 8.3% observed in the complete cohort. This reduction likely was owing to the differences between the subcohort and the complete cohort in those variables that were not included in the demographic match. This value was reduced to 6.5% (P = .0001) after socioeconomic status was included in the demographic match. The difference decreased significantly to 2.8% (P = .090) after tumor presentation match, but was not reduced further after treatment match.We observed significant disparities in treatment and survival of black vs white patients with colon cancer. The disparity in survival appears to have been affected more strongly by tumor presentation at diagnosis than treatment. The effects of treatment differences on disparities in survival were greater for patients with advanced-stage vs early-stage cancer.

Antiangiogenic therapy has been successful for the treatment of solid tumors. Several strategies have been used to target angiogenesis in prostate cancer. These strategies include blocking proangiogenic factors via monoclonal antibodies or small molecule inhibitors targeting downstream signaling effector pathways, or using agents with immune-modulatory effects. This review examines the general concepts of tumor angiogenesis and the key clinical trials that have used these agents and other novel biologics in prostate cancer. Targeting angiogenesis is still a promising treatment strategy in prostate cancer with a rational trial design and combination approach.

Aflatoxins, mainly produced by Aspergillus flavus and A. parasiticus, are a group of potent mycotoxins with carcinogenic, hepatotoxic, and immunosuppressive properties. Many studies have been devoted to investigating their biosynthesis mechanism since they were discovered half a century ago. 5-Azacytidine (5-AC), a derivative of the nucleoside cytidine and an inactivator of DNA methyltransferase, is widely used for studies in epigenetics and cancer biology, and has also been used for studying secondary metabolism in fungi. In this study, 5-AC was applied to investigate its effect on the development and aflatoxin biosynthesis of A. flavus. The results indicate that 5-AC inhibits the ability to produce aflatoxin and also causes a fluffy aconidial phenotype. Further studies revealed that 5-AC affects gene expression of A. flavus to a limited degree, and the unique homolog of DNA methyltransferase gene (DmtA) expressed constitutively during different developmental stages of A. flavus irrespective of 5-AC. This work may provide some basic data to elucidate the role of 5-AC in aflatoxin biosynthesis and the development of A. flavus.

a t f t p p t At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers’ comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Dr.gjmorris@gmail.com. I look forward to a lively discussion.

Background This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of 153 Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC). Methods mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m 2 (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m 2 . 153 Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles). Results Thirteen patients received an average of 3.6 doses of docetaxel (range, 2–6 doses, median 4) and 1.5 doses of 153 Sm-lexidronam (range, 1–2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7–14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days–10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain. Conclusions Concurrent 6-month administration of 4 doses (75 mg/m 2 ) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg 153 Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.

BACKGROUND: Several phase II trials in men with noncastrate PSA-recurrent prostate cancer have assessed the impact of novel nonhormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS). METHODS: We performed a retrospective post hoc analysis of 146 men treated in 4 phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n = 39), imatinib (a tyrosine kinase inhibitor; n = 25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n = 22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n = 60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation. RESULTS: After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P = .05), baseline PSA slope (P = .01), on-study change in PSADT (P = .02), and on-study change in PSA slope (P = .03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% confidence interval [CI], 34.6-not reached) and 28.9 months (95% CI, 13.5-68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively. CONCLUSIONS: This hypothesis-generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate end point for screening new agents in these patients. Cancer 2011;. © 2011 American Cancer Society.

Remarkable clinical efficacy and durable responses to antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway have been observed in patients with multiple cancers, including classical Hodgkin lymphomas (cHL). However, the responses in the majority of Non-Hodgkin lymphoma patients, including mantle cell lymphoma (MCL), treated with anti- PD1/PDL1 antibodies have been modest to date. It has been postulated that the immune suppressive nature of the tumor microenvironment (TME) may play a role in limiting the efficacy of checkpoint blockade strategies. As such, identification of critical molecules in TME required for driving response and resistance is key to improve lymphoma immunotherapy. We have therefore generated in vivo and ex-vivo MCL lymphoma-stroma co-culture models and capitalize this model with primary human MCL cells as well. First, we found that co-injection of murine Fc-muMCL1 cells with stromal cells significantly promote lymphoma growthas compared to Fc-muMCL1 cells injected alone. This aggressive growth was associated with less tumor infiltrating cytotoxic T-cells in the TME. Second, to identify the tolerogenic mechanism(s) that drive immunosuppression in TME, we co-cultured MCL cells with stroma cells ex-vivo and found an increased translation and transcription of PD-L1 via upregulation of c-Myc. Furthermore, co-culture of patient primary lymphoma cells with stromal cell dramatically increases PD-L1 expression in both stromal cells and lymphoma cells. Tumor infiltrating T cells also induce PD-L1 expression in stromal cells. Of note, just by knocking down c-Myc in stromal cell we were able to block co-culture-induced PD-L1 expression, highlighting a critical role for c-Myc in driving this tolerogenic process in the TME. In lieu of the above findings, next we treated murine MCL in vitro with a bromodomain inhibitor (JQ1) and observed a significant decrease in c-Myc/PD-L1 expression which was associated with increased immunogenicity of malignant B-cells leading to a better T-cell activation. More importantly, treatment of MCL-bearing mice with a combination of a bromodomain inhibitor with anti-PD1 antibody resulted in enhanced inhibition of MCL growth, increased effector memory T cells and improved function of tumor infiltrating T cells in vivo. No such effects were observed in MCL-bearing mice treated with either agent alone. Taken together, we have identified the c-Myc/PD-L1 axis in stromal cells that by creating a tolerogenic/immunosuppressive TME imposes a significant barrier to the efficacy of checkpoint blockade therapy in lymphomas. This barrier seems not to be unsurmountable since the addition of a bromodomain inhibitor augmented the efficacy of checkpoint blockade by inducing a more immunogenic TME in MCL. Disclosures No relevant conflicts of interest to declare.

To report on the 15-year prostate cancer experience of our multidisciplinary genitourinary cancer clinic established in 1996 at the National Cancer Institute (NCI) -designated Jefferson Kimmel Cancer Center. Patients with genitourinary cancers were evaluated weekly by multiple specialists at a single site, and we focus on the 83% of patients with prostate cancer. To our knowledge, our multidisciplinary genitourinary cancer clinic is the longest continuously operating center of its kind at an NCI Cancer Center in the United States.Data from Jefferson's Oncology Data Services were compared to SEER prostate cancer outcomes. Data on treatment changes in localized disease, patient satisfaction, and related parameters were also assessed.Ten-year survival data approach 100% in stage I and II prostate cancer. Ten-year data for stage III (T3 N0M0) and stage IV (T4 N0M0) disease show that our institutional survival rate exceeds SEER. There is a shift toward robotically assisted laparoscopic radical prostatectomy and a slight decrease in brachytherapy relative to external beam radiation therapy in localized disease. Patient satisfaction is high as measured by survey instruments.Our long-term experience suggests a benefit of the multidisciplinary clinic approach to prostate cancer, most pronounced for high-risk, locally advanced disease. A high level of satisfaction with this patient-centered model is seen. The multidisciplinary clinic approach to prostate cancer may enhance outcomes and possibly reduce treatment regret through a coordinated presentation of all therapeutic options. This clinic model serves as an interdisciplinary educational tool for patients, their families, and our trainees and supports clinical trial participation.

Prostate cancer possesses its unique feature of low proliferation rate and slow growth. Ca(2+)-induced apoptosis is not dependent on cell cycle progression and targeting this pathway could circumvent the problems encountered using current cytotoxic chemotherapies for prostate cancer. Hypoxia-inducible factor 1alpha (HIF-1alpha) is another novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides, known inhibitors of the alpha-subunit of sarcolemmal Na(+)K(+)-ATPase, were recently found to block tumor growth via the inhibition of HIF-1alpha synthesis. Thus, cardiac glycosides disrupt two important cellular pathways and, therefore, may be useful as an anticancer therapy. This review will focus on HIF-1alpha and calcium signaling as novel cancer drug targets in prostate cancer. The possible application of digoxin and other cardiac glycosides in cancer therapeutics especially in prostate cancer is discussed.

Purpose: This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Experimental Design: Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. Results: The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression–related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. Conclusion: The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit. (Clin Cancer Res 2009;15(19):6241–9)

Meeting abstracts Pembrolizumab is an antibody designed against programmed cell-death protein-1 (PD-1), which is expressed on the surface of activated T cells. Tumor cells can upregulate PD-L1, which binds to PD-1 and mediates T cell anergy. By antagonizing the PD-1/PD-L1 binding, pembrolizumab can

The red sea bream (Pagrosomus major) 48-h embryo-larval bioassay was used to assess and compare the developmental toxicities of eight typical organic pollutants, including polycyclic aromatic hydrocarbons (PAHs), organophosphorus pesticides, polychlorinated biphenyls (PCBs) and alkylphenol. Toxicological endpoints such as survival rates of P. major embryos or larvae and the rates of hatching and of malformation (oedema, condensed blood, spinal curvatures or eye abnormalities) were noted and described within 48 h of exposure. The LC50, EC50, no-observed-effect concentration (NOEC) and lowest-observed-effect concentration (LOEC) were calculated, based on the dose-response relationship. The results showed that exposures to all of the selected organic pollutants except for methyl parathion produced acute toxic effects on P. major embryos and larvae, at different levels of exposure. The levels of acute toxicity of the eight typical organic pollutants for P. major embryos and larvae showed the following trend: benzo(a)pyrene > malathion > PCB 126 > pyrene > nonylphenol > phenanthrene > monocrotophos > methyl parathion. However, the larvae were more sensitive to these pollutants than embryos, according to the calculated LC50, EC50, NOEC and LOEC. This increased sensitivity of larvae could have resulted from losing the natural barrier function of the egg shell membrane. Benzo(a)pyrene, malathion, nonylphenol and monocrotophos delayed the development of P. major for both embryos and larvae, and decreased the hatching rate of the embryos. These results implied that the development of fish embryos and larvae could serve as potential biomarkers for evaluating organic contamination in the aquatic environment. The marine economic fish P. major was more sensitive to PAHs than the model fish, marine medaka (Oryzias melastigma). The estimated safe concentrations (SCs) for marine economic fish, as determined in our research, could provide a reference for the formulation of water quality criteria.

inTroDucTion Tumor lysis syndrome (TLS) is a metabolic disturbance caused by the destruction of rapidly dividing cancer cells following administration of cytotoxic chemotherapy. The subsequent release of intracellular material results in hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. The clinical presentation of TLS, including acute kidney injury, results from these electrolyte abnormalities and can be life-threatening. Here we present the second reported case of TLS in a woman with endometrial cancer.

This paper studied the induction kinetics of the enzyme 7-ethoxyresorufin O-deethylase in the liver of the marine fish, Acanthopagrus schlegeli following the exposure to benzo (a)pyrene for up to 14 days at concentrations of 0.5, 1.0, 2.0,5.0 μg l−1. The results demonstrated a dose-response relationship between hepatic enzyme activities induction and benzo(a)pyrene concentration. Hepatic enzyme activities were significantly induced by the second day with exposure to the lower concentrations of benzo(a)pyrene (0.5 μg l−1 and 1.0 μ g l−1), and at 12 hours of exposure for the higher concentrations (2.0 l−1 and 5.0 μ g l−1). After 7 days depuration, the activities of the enzyme of fish returned to the control level. This indicated that while benzo(a)pyrene has an effect on the hepatic enzyme activity, the fish can eliminate a major part of BaP metabolites.

This paper presents an integrated 26-MHz digitally controlled crystal oscillator (DCXO) for GSM standard that achieves a phase noise of -140 dBc/Hz at 1 kHz and -152 dBc/Hz at 10 kHz offset. The measured supply pushing at 26 MHz is 0.5 ppm/V. Frequency tuning is done by a predistorted 14-bit MOS capacitor digital-to-analog converter (DAC) where the top 10 bits are thermometer coded and the bottom 4 bits are /spl Sigma//spl Delta/ modulated. Monotonicity of /spl sim/0.004 ppm/step across the entire /spl sim/70 ppm tuning range is guaranteed by applying a sliding /spl Sigma//spl Delta/ modulation to the last exercised thermometer element. This DCXO consumes 3 mW at 1.4 V supply and occupies 0.18 mm/sup 2/ in the 90-nm CMOS process.

BACKGROUND Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized primarily in the stromal compartment of the human prostate and may regulate stromal as well as epithelial cell growth and survival. The primary cognate HB-EGF receptor, ErbB1, has been shown recently to be transactivated by G-protein coupled receptors (GPCRs) through regulated proteolytic cleavage of the membrane-bound, precursor form of HB-EGF. Previous studies have demonstrated that human prostate tissue, especially tissue from benign prostatic hyperplasia (BPH), has high angiotensin converting enzyme activity, and a high density of angiotensin (Ang) receptors in periurethral stromal cells. Because the pressor peptide Ang II signals through GPCRs, we tested the possibility that Ang II could transactivate ErbB1/ErbB2 in human prostate stromal (hPS) cells. METHODS Primary and early passage hPS cells were used as an in vitro model. Cells were stimulated by recombinant HB-EGF or Ang II and total cell lysates were harvested for immunoprecipitation and Western blot. Cell growth was measured by [3H]thymidine incorporation assay and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazoliumbromide (MTT) assay. RESULTS Ang II receptors AT1 and AT2 were expressed in hPS cells. ErbB1 and ErbB2 receptors were activated by HB-EGF. Furthermore, Ang II was able to transactivate both ErbB1 and ErbB2, and this transactivation activity could be abolished by pretreatment with [Glu-52]-diphtheria toxin/CRM197, a specific inhibitor of HB-EGF bioactivity. Consistent with its transactivation activity, Ang II modestly promoted hPS cell growth and this effect was abolished by pretreatment with the ErbB1 antagonist AG1478. CONCLUSION These experiments suggest a regulatory role for Ang II in the prostate stroma and implicate the endogenous stromal growth factor HB-EGF as a mediator of Ang II signaling in the prostate. Prostate 54: 1–7, 2003. © 2002 Wiley-Liss, Inc.

For high-data-rate wireless communication, low-voltage baseband converters integrated with DSP in deep submicrometer processes are area- and power-efficient. Through careful architecture selections and circuit techniques, this paper demonstrates a low-voltage (0.8 V), low-power (480 /spl mu/W), 6-b/22-MHz flash-interpolation ADC which occupies 0.3 mm/sup 2/ and achieves 33 dB SNDR and 47 dB SFDR. The power efficiency of this converter is 0.6 pJ/conv-step which compares favorably with all published results. We also introduce a nonlinear double interpolation technique that enables the use of a 0.13-/spl mu/m standard digital CMOS process without special resistors.

Peptide growth factors have been implicated in progression of prostate cancer (PCa) to the androgen-independent state; however, much of the evidence linking diffusible mitogens and survival factors to this process remains circumstantial. Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a prostate stroma-derived factor, promotes survival, proliferation, and neuroendocrine differentiation of androgen-dependent LNCaP PCa cells in vitro. To test whether sustained exposure to HB-EGF can confer an androgen-independent phenotype, we generated stable populations of LNCaP cells that express constitutively a secreted form of HB-EGF (LNCaP/sHB). LNCaP/sHB cells proliferated more rapidly under androgen-depleted conditions in vitro and formed larger tumors with higher frequency in intact and castrated severe combined immunodeficient mice, in comparison to control cells. LNCaP/sHB tumors also expressed higher levels of the neuroendocrine marker, neuron-specific enolase, compared with control tumors. In castrates, increased neuron-specific enolase expression in LNCaP/sHB tumors was associated with reduced androgen receptor (AR) levels. In vitro, AR protein levels were reduced in LNCaP/sHB cells, and in transient transfection assays using an androgen-responsive promoter (mouse mammary tumor virus-long terminal repeat), LNCaP/sHB cells showed reduced sensitivity to dihydrotestosterone compared with controls. This is the first demonstration that continuous exposure of AR-positive PCa cells to a single growth factor can promote an androgen-independent phenotype in vivo. These findings also emphasize the potential role of pathways other than the AR axis in acquisition of androgen independence.

The boundary integral equation approach has been shown to suffer a nonunique solution when the geometry is equal to a degenerate scale for a potential problem. In this paper, the degenerate scale problem in boundary element method for the two-dimensional Laplace equation is analytically studied in the continuous system by using degenerate kernels and Fourier series instead of using discrete system using circulants [Engng Anal. Bound. Elem. 25 (2001) 819]. For circular and multiply-connected domain problems, the rank-deficiency problem of the degenerate scale is solved by using the combined Helmholtz exterior integral equation formulation (CHEEF) concept. An additional constraint by collocating a point outside the domain is added to promote the rank of influence matrix. Two examples are shown to demonstrate the numerical instability using the singular integral equation for circular and annular domain problems. The CHEEF concept is successfully applied to overcome the degenerate scale and the error is suppressed in the numerical experiment.

For a plane elasticity problem, the boundary integral equation approach has been shown to yield a non-unique solution when geometry size is equal to a degenerate scale. In this paper, the degenerate scale problem in the boundary element method (BEM) is analytically studied using the method of stress function. For the elliptic domain problem, the numerical difficulty of the degenerate scale can be solved by using the hypersingular formulation instead of using the singular formulation in the dual BEM. A simple example is shown to demonstrate the failure using the singular integral equations of dual BEM. It is found that the degenerate scale also depends on the Poisson's ratio. By employing the hypersingular formulation in the dual BEM, no degenerate scale occurs since a zero eigenvalue is not imbedded in the influence matrix for any case.

e16058 Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b)pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: Twelve RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of January 13, 2017, 2 pts are still on active treatment. Two pts had partial response (18%) and were on study for at 54 and 63 weeks. One responder was treated with 8 Gy f/b pembro while 1 was treated with 1 dose pembro f/b RT f/b pembro. Five pts had stable disease of 18 to 45 weeks and 4 pts (36%, non-responders) had progression in 9 weeks. For adverse events, 1 pt developed grade 3 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include Fatigue, Nausea, Hyperglycemia, Lymphopenia, thrombocytopenia and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders comparing with responders. CD4+, CD8+ and NK cells and other markers are under analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T and NK cell kinetics are being examined. (ClinicalTrials.gov ID: NCT02318771) Clinical trial information: NCT02318771.

e593 Background: The use of radium-223 in patients with metastatic castration-resistant prostate cancer (mCRPC) improves overall survival (OS) and quality of life. Combination of radium-223 with second-generation anti-androgens has further improved OS; however, the optimal length of radium-223 treatment for maximal effect remains unknown. Methods: We reviewed 35 consecutive patients with mCRPC who received radium-223 from December 2012 to August 2015 at Thomas Jefferson University. Patients were divided into two groups: those who received full treatment of 6 injections (n = 18) versus those who received less than 6 injections (n = 17). Kaplan-Meier analysis of OS were tested for difference by treatment group using Log Rank test. Univariable association with survival outcomes was calculated with univariable Cox regression and Log Rank tests. Results: Mean age was 73 ± 10 years and Karnofsky performance status (KPS) ranged from 50-90 (median, 80). Median follow-up was 13.9 months. Eighteen patients were receiving concurrent second generation anti-androgens at the start of treatment. Median OS was 12 months for patients who received 6 injections and 6.48 months for patients who received less than 6 injections (p = 0.0045). The results of univariate Cox regression analysis revealed full treatment was associated with increased OS (p = 0.0013). On multivariate analysis accounting for KPS, full treatment was significantly associated with improved OS (p = 0.0028). Conclusions: In this retrospective, single-institution analysis, we demonstrated that full course completion of radium-223 was associated with improved OS in patients with mCRPC. These patients should be optimally supported during treatment to allow for therapy completion.

80 Background: Introducing amino acid sequence changes in highly expressed self-antigens for androgen sensitive prostate cancer pts might be sufficient to break tolerance, thus a DNA vaccine was developed using SynCon PSA and PSMA (INO-5150) that share 96.8 and 91.6% sequence identities to these native antigens, respectively. Administration of these antigens to prostate cancer pts along with plasmid encoded adjuvant IL-12 (INO-9012) via electroporation (EP) using the CELLECTRA5P device is postulated to break tolerance, resulting in an antigen-specific immune response which could lead to stabilization of disease progression. Methods: This Phase I, open-label, multicenter study included prostate cancer pts post-definitive therapy with a rising PSA ≥ 1.0 ng/ml after surgery, or ≥ 2.0 ng/ml above nadir after RT and PSA doubling time > 3 months, testosterone > 150 ng/dL and no evidence of metastasis within 12 months. INO-5150 with or without INO-9012 was administered IM followed by EP in 4 arms: low (2 mg) or high dose (8.5 mg) INO-5150 alone or with 1 mg INO-9012 on Day 0 and at week 3, 12, and 24 in 60 planned pts (15 pts/arm). DLT assessments were performed after dosing of the first 3 pts of each arm at Week 4. Results: Enrollment is complete in all 4 arms and at data cut-off (10Oct16), 62 enrolled pts received at least one, 60 pts received 3 and about half, 28 pts (10 in arm A, 8 in B, 7 in C, and 3 in D) received all 4 vaccinations. Safety: there were no DLTs noted. Four pts had five Grade 3 SAEs noted as pre-syncope, cardiac disorder, hospitalization for fall, ALT and AST elevation. No Grade 4-5 AEs were noted. Grade 1-3 treatment-emergent AEs occurred in 50 (81%) pts: 12 (75%) in arm A, 13 (87%) B, 13 (87%) C, and 12 (75%) in D. The most common AEs were injection site pain (24/39%), erythema (13/21%), swelling (12/19%), bruising (10/16%), hyperglycemia (8/13%) and fatigue (6/10%), all Grade 1-2. Assessments of immunological response, PSA kinetics and correlation with clinical outcome are ongoing and will be presented. Conclusions: INO-5150 (+) or (-) INO-9012 is generally safe and well-tolerable at all 4 dose levels in a biochemically relapsed prostate cancer patient population. Clinical trial information: NCT02514213.

Purpose Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls. Patients and Methods Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity. Results Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non–muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity. Conclusion AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.

For a Helmholtz eigenvalue problem with a multiply connected domain, the boundary integral equation approach as well as the boundary-element method is shown to yield spurious eigenvalues even if the complex-valued kernel is used. In such a case, it is found that spurious eigenvalues depend on the geometry of the inner boundary. Demonstrated as an analytical case, the spurious eigenvalue for a multiply connected problem with its inner boundary as a circle is studied analytically. By using the degenerate kernels and circulants, an annular case can be studied analytically in a discrete system and can be treated as a special case. The proof for the general boundary instead of the circular boundary is also derived. The Burton-Miller method is employed to eliminate spurious eigenvalues in the multiply connected case. Moreover, a modified method considering only the real-part formulation is provided. Five examples are shown to demonstrate that the spurious eigenvalues depend on the shape of the inner boundary. Good agreement between analytical prediction and numerical results are found.

Several cell functions related to growth and survival regulation have been attributed specifically to the membrane form of heparin-binding EGF-like growth factor (proHB-EGF), rather than to the diffusible, processed HB-EGF isoform. These findings suggest the existence of a functional binding partner specifically for the membrane form of the growth factor. In this study we have identified the prosurvival cochaperone, BAG-1, as a protein that interacts with the cytoplasmic tail domain of proHB-EGF. Interaction between BAG-1 and the 24-amino acid proHB-EGF cytoplasmic tail was initially identified in a yeast two-hybrid screen and was confirmed in mammalian cells. The proHB-EGF tail bound BAG-1 in an hsp70-independent manner and within a 97-amino acid segment that includes the ubiquitin homology domain in BAG-1 but does not include the hsp70 binding site. Effects of BAG-1 and proHB-EGF co-expression were demonstrated in cell adhesion and cell survival assays and in quantitative assays of regulated secretion of soluble HB-EGF. Because the BAG-1 binding site is not present on the mature, diffusible form of the growth factor, these findings suggest a new mechanism by which proHB-EGF, in isolation from the diffusible form, can mediate cell signaling events. In addition, because effects of BAG-1 on regulated secretion of soluble HB-EGF were also identified, this interaction has the potential to alter the signaling capabilities of both the membrane-anchored and the diffusible forms of the growth factor.

The physiological mechanisms by which soluble mediators of cell proliferation and survival alter expansion of the prostatic stroma in benign prostatic hyperplasia are poorly understood. We recently identified heparin-binding epidermal growth factor like growth factor (HB-EGF) as a product predominantly of the smooth muscle cell compartments of the adult human prostate. We assess the potential role of this growth factor as a stromal cell regulator.Primary cultures of desmin and alpha-actin positive human prostate stromal cells were shown to express several cell associated HB-EGF isoforms as well as the primary cognate HB-EGF receptor, ErbB1/HER1, suggesting the existence of an autocrine or juxtacrine regulatory loop. The related receptor tyrosine kinase, ErbB2/HER2, was also expressed as assessed by reverse transcriptase (RT) polymerase chain reaction (PCR). HB-EGF messenger RNA levels in human prostate stromal cells increased modestly (70%) in response to a repetitive mechanical stimulus, a lower response than has been reported for neonatal rat bladder smooth muscle cells, in which HB-EGF was originally identified as a mechanically responsive gene.HB-EGF, epidermal growth factor and basic fibroblast growth factor stimulated human prostate stromal cell growth, while a specific antagonist of HB-EGF, [Glu52]-diphtheria toxin/CRM197, inhibited human prostate stromal growth in serum-free medium by a mechanism that did not involve increased apoptosis. A function blocking antibody against CD9/DRAP27/MRP-1, a cell surface binding partner of the membrane form of HB-EGF, also stimulated human prostate stromal cell proliferation.HB-EGF is an endogenously produced human prostate stromal cell growth factor and, thus, may have a role as a physiologically relevant autocrine or juxtacrine mediator of stromal expansion in benign prostatic hyperplasia.

Background: Hypoxia inducible factor 1 (HIF-1α) is a potential valid cancer drug target in humans. Objectives: To search and identify novel inhibitors of HIF-1 from ‘old’ drugs that were already in clinical use or under clinical trial with known pharmacokinetics. Methods/results: Cell-based screen for inhibitors of HIF-1 transcriptional activity from the Hopkins Drug Library. Cardiac glycosides were the group of drugs showing significant inhibition of HIF-1 synthesis and expression of HIF-1 target genes in cancer cells. In vivo digoxin showed its antitumor activity in tumor xenografts model. Conclusions: HIF-1 is a critical target of digoxin and other cardiac glycosides for their anticancer activity.

In this study, modified converter slag (CS) was characterized in relation to its physicochemical structure, and used for the simultaneous removal of NH4(+) and PO4(3-) at low concentrations from aqueous solutions. The effects of contact time, pH, adsorbent dosage, and temperature on the adsorption process were studied in batch experiments. The results showed that the adsorption capacity of modified converter slag was found to sharply increase as a result of modification. The optimum pH is 5-8. The adsorption process was able to reach equilibrium in 90 minutes. Kinetic data were best described by the pseudo-second-order model. The sorption isotherms were a good fit with the Langmuir model. The maximum adsorption capacities of modified converter slag for NH4(+) and PO4(3-) were 2.59 mg/g and 1.185 mg/g, respectively. Thermodynamic studies indicated that the adsorption was a spontaneous and endothermic process. The calculated values of enthalpy change indicated that ligand exchange, chemical reactions, and precipitation are dominating mechanisms of PO4(3-) removal, while physisorption and ion-exchange are major mechanisms of NH4(+) removal.

311 Background: Aurora A kinase (AK) phosphorylates and interacts with androgen receptor (AR) and enhances AR DNA binding activity. We hypothesized that AK contributes to castration resistance in PCa, and targeting AK can inhibit AR function and re-sensitize PCa cells to AR signaling inhibitors such as abiraterone. Methods: Aphase I/II, open label, single institution trial to determine the safety and efficacy of AK inhibitor alisertib when given in combination with abiraterone plus prednisone (AP) was planned. Eligible subjects had mCRPC with disease progression on abiraterone. Androgen deprivation plus abiraterone and prednisone were maintained through the trial. Subjects were treated with dose escalation per standard 3+3 design. Planned 3 dose cohorts of alisertib were 30, 40, 50 mg PO BID D 1-7 every 21 D. Correlative studies included kinetics of neuroendocrine tumor markers, enumeration and AK gene amplification of CTCs. Results: Nine of 43 planned subjects were enrolled, 3 in cohort 1 without DLT. Two DLTs developed in cohort 2, thus 3 more patients were enrolled into cohort 1, and 2 developed DLT (total 2/6) in this cohort. The grade 3/4 toxicities (4/9) include neutropenic fever (1/9), neutropenia (1/9), fatigue with memory impairment (1/9), and mucositis (diarrhea and mouth sores, 1/9). Pharmacodynamically, adding alisertib did not affect circulating total testosterone and DHEA levels. Only one patient had decreased Chromogranin A level lasted for 4 months when compared to baseline. Four (4/9) patients had ≥ 5 CTCs at baseline but no conversion ( to < 5) was observed. No PSA decrease was observed during the study. Mean duration of study was 2.5 months. The toxicity / efficacy ratio did not warrant further dose expansion and the trial was terminated early after discussion with sponsor. Conclusions: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone. Clinical trial information: NCT01848067.

Aspergillus flavus is a common saprophyte and opportunistic pathogen producing aflatoxin (AF) and many other secondary metabolites. 5-Azacytidine (5-AC), a derivative of the nucleoside cytidine, is widely used for studies in epigenetics and cancer biology as an inactivator of DNA methyltransferase and is also used for studying secondary metabolism in fungi. Our previous studies showed that 5-AC affects development and inhibits AF production in A. flavus, and that A. flavus lacks DNA methylation. In this study, an RNA- Seq approach was applied to explore the mechanism of 5-AC's effect on A. flavus. We identified 240 signif- icantly differentially expressed (Q-value < 0.05) genes after 5-AC treatment, including two backbone genes respectively in secondary metabolite clusters #27 and #35. These two clusters are involved in development or survival of sclerotia. GO functional enrichment analysis showed that these significantly differentially expressed genes were mainly involved in catalytic activity and proteolytic functions. The expressed tran- scripts of most genes in the AF biosynthetic gene cluster in A. flavus showed no significant changes after treatment with 5-AC and were expressed at low levels, and the transcription regulator genes aflR and aflS in this cluster did not show differential expression relative to the sample without 5-AC treatment. We found that the veA gene, which encodes protein bridges VelB and LaeA, decreased profoundly the expressed tran- scripts, and brlA, which encodes an early regulator of development, increased its transcripts in A. flavus after 5-AC treatment. Our data support a model whereby 5-AC affects development through increasing the expression of brlA by depressing the expression of veA and AF production through suppressing veA expres- sion and dysregulating carboxypeptidase activity, which then prevents the aflatoxisomes (vesicles) from performing their normal function in AF formation. Furthermore, the suppressed veA expression weakens or even interrupts the connection between VelB and LaeA, leading to dysregulation of the expression pat- tern of genes involved in development and secondary metabolism in A. flavus. The RNA-seq data presented in this work were also served to improve the annotation of the A. flavus genome. This work provides a com- prehensive view of the transcriptome of A. flavus responsive to 5-AC and supports the conclusion that fungal development and secondary metabolism are co-regulated.

Purpose: The purpose of this study was to evaluate the efficacy and safety of administration of an intercostal nerve block (INB) with general anesthesia to elderly patients undergoing a distal gastrectomy. Methods: Elderly patients (>65 years) undergoing selective gastrectomy were randomly assigned to three groups (n = 80): general anesthesia (Group A); general + INB anesthesia (Group B); or, general + epidural anesthesia (Group C). General anesthesia was maintained with propofol, remifentanil and cisatracurium. The mean arterial blood pressure (MAP), heart rate (HR) and C-reactive protein (CRP) levels were determined before anesthesia (T0) and at 5 min after intubation (T1), skin incision (T2), exploration of the peritoneal cavity (T3), gastrointestinal anastomosis (T4), end of operation (T5) and 10 min after extubation (T6). Results: MAP decreased at T1 in all groups (P < 0.05) and at T2, T4 and T5 in Group C (P < 0.05) and was lower in Group C than Group B at T2 and T4 (P < 0.05). There were no differences in MAP between Groups A and B or between Groups B and C. HR increased at T2 - T6 in Group A (P < 0.05) and was higher at T2 - T6 in Group B and Group C (P < 0.05). CRP levels decreased at T2 - T5 in Groups B and C (P < 0.05) and were lower in Groups B and C compared with Group A (P < 0.05). Propofol and remifentanil doses were lower in Groups B and C (P < 0.05 and P < 0.01, respectively) and patients recovered faster than in Group A (P < 0.05). Conclusion: Administration of INB with general anesthesia enhanced analgesia, led to stable hemodynamics, and reduced anaesthetic consumption and postoperative stress response.

Internet users today have extremely high demands for bandwidth consuming content wherever they are and on multiple platforms, ranging from tiny screened phones to high-definition 3D home theaters. This has driven the rapid deployment of multiple broadband access solutions including legacy infrastructure driven DSL and cable, the almost limitless bandwidth provided by optical fiber to the home (FTTH), and the on-the-go appeal of wireless solutions including 3G/4G cellular or WiMAX. Over the past two decades, each of these technologies has successfully competed for the consumer's dollar, partly due to the differentiated ways data is accessed tel evisions were naturally connected to the CATV infrastructure and cell phones were linked to a wireless basestation. These traditional boundaries are blurring as cell phone calls are placed over WiFi networks and video content is delivered via an ISP. The common denominator is data access and the delivery method is irrelevant to the end user. As DSL continues to compete with cable and FTTH in the wireline space, more and more users are choosing wireless broadband solutions such as 3G, 4G, or WiMAX even for their home access. In this panel, we will review the good, the bad, and the ugly aspects of the recent history of broadband evolution and provide a vision of the future. What are the pros and cons of each technology? Do we need so many competing solutions? What will be the successful business models in the future will everyone (or anyone) make money? Which ones will be the winners ten years from now? Experts from academia, chip suppliers, and broadband systems vendors will share their visions on future broadband markets and technologies. Take your seat and enjoy the debate.

In this paper, the zygotes of Spraus macrocephalus were used to test the short-term toxicity effects of selected PAHs (naphthlene, phenanthene and pyrene) in in order to facilitate risk assessment of those compounds to the marine fishery environment. The results showed that the three PAHs could result in a series of toxicity effects on the incubation of zygotes, including cell division, the zygotes embryo development, and apparatus differentiation; and the stage of embryo forming was most sensitive. The relationship between the dose of the three PAHs and toxic effects is S-curve. The sensitive range of lethal concentrations of naphthlene, phenanthene and pyrene are 5-9, 0.05-0.5, 0.05-0.4 mg/L respectively. The sensitive range of teratogenic concentrations of naphthlene, phenanthene and pyrene are 0.01-4, 0.05-0.3, 0.05-0.3 mg/L respectively. The 48h LC50 of naphthlene, phenanthene and pyrene are 6.95, 0.178, 0.118mg/L respectively. The 48h EC50 of naphthlene, phenanthene and pyrene are 1.306, 0.115, 0.076mg/L respectively. In the three PAHs, Pyr is most toxic, then Phe and Nap to embryonic development, not only in mortality but also in abnormality. The ratio of LC50:EC50 of Nap, Phe and Pyr are 5.32, 1.55, 1.55 respectively. Nap has strong difference between mortality and abnormality toxicity, but Phe and Pyr has similar properties between mortality and abnormality.These data can fill in fish embryo toxicity data shortage of naphthlene, phenanthene and pyrene, and useful to improve aquatic environmental risk management.

BACKGROUND The clinical success of the nucleoside analogs 5-aza-cytidine (5-azaC) and 5-aza-2′deoxycytidine (5-aza-dC) as DNA methyltransferase (DNMT) inhibitors has spurred interest in the development of non-nucleoside inhibitors with improved pharmacologic and safety profiles. Because DNMT catalysis features attack of cytosine bases by an enzyme thiol group, we tested whether disulfiram (DSF), a thiol-reactive compound with known clinical safety, demonstrated DNMT inhibitory activity. METHODS Inhibition of DNMT1 activity by DSF was assessed using methyltransferase activity assays with recombinant DNMT1. Next, prostate cancer cell lines were exposed to DSF and assessed for: i) reduction of global 5-methyl cytosine (5meC) content using liquid chromatography/tandem mass spectrometry (LC-MS/MS); ii) gene-specific promoter demethylation by methylation-specific PCR (MSP); and iii) gene-reactivation by real-time RT-PCR. DSF was also tested for growth inhibition using prostate cancer cell lines propagated in vitro in cell culture and in vivo as xenografts in nude mice. RESULTS Disulfiram showed a dose-dependent inhibition of DNMT1 activity on a hemimethylated DNA substrate. In prostate cancer cells in culture, DSF exposure led to reduction of global genomic 5meC content, increase in unmethylated APC and RARB gene promoters, and associated re-expression of these genes, but did not significantly alter prostate-specific antigen (PSA) expression. DSF significantly inhibited growth and clonogenic survival of prostate cancer cell lines in culture and showed a trend for reduced growth of prostate cancer xenografts. CONCLUSIONS Disulfiram is a non-nucleoside DNMT1 inhibitor that can reduce global 5meC content, reactivate epigenetically silenced genes, and significantly inhibit growth in prostate cancer cell lines. Prostate 77:333–343, 2011. © 2010 Wiley-Liss, Inc.

This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of (153)Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC).mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m(2) (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m(2). (153)Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles).Thirteen patients received an average of 3.6 doses of docetaxel (range, 2-6 doses, median 4) and 1.5 doses of (153)Sm-lexidronam (range, 1-2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7-14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days-10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain.Concurrent 6-month administration of 4 doses (75 mg/m(2)) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg (153)Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.

We present a fully integrated analog path for a 3 G polar transmitter in 90 nm CMOS. It includes a quad band Digitally Controlled Oscillator providing modulation for the phase data and a single stage Digital Pre-Power Amplifier that combines the phase and amplitude signals while providing the dynamic range for WCDMA. The chip, with integrated LDOs, consumes 60 mA from a 1.4 V supply while providing 11 dBm CW power at 1950 MHz, 87 dB dynamic range without any calibration, and PN of -157 dBc/Hz at 40 MHz.

Purpose: The purpose of this study was to evaluate the ability of specific biomarkers to predict acute kidney injury (AKI) after partial nephrectomy. Methods: A prospective study of 89 patients undergoing partial nephrectomy was conducted in the First Affiliated Hospital of Fujian Medical University. The patients were divided into two groups according to AKI status: an AKI group and non-AKI group. Receiver operator characteristic (ROC) curves were generated and the areas under the curve (AUCs) were compared. Results: Twenty-eight subjects (31.5%) developed AKI while sixty-one subjects (68.5%) did not. Vascular clamping time in the AKI group was longer than that in the non-AKI group (29 ± 17 min vs. 24 ± 9 min, P = 0.042). Eight patients (28.6%) received blood infusion in the AKI group compared with five patients (8.2%) in the non-AKI group (P = 0.021). The area under ROC curve for AKI prediction was 0.792 [95% confidence interval (CI) 0.697 to 0.888, P < 0.000] for serum cystatin C 24 hours after surgery and 0.756 (95% CI 0.656 to 0.857, P < 0.000) for serum cystatin C 48 hours after surgery. Multivariate regression analysis showed transfusion [Hazard ratio (HR) 3.712, P = 0.044] and 24 hours serum cystatin C (HR 41.594, P = 0.001) correlated with AKI. Conclusions: Postoperative serum cystatin C may be an early predictor for AKI after partial nephrectomy. Transfusion may be an independent risk factor for AKI after partial nephrectomy.

26 Background: Cabazitaxel (C) improves overall survival and has been approved in second line chemotherapy for patients (pts) with metastatic castrate resistant PCa. We hypothesized that C is a radiosensitizer and performed a phase I trial of weekly C with standard IMRT and ADT for pts with high risk localized PCa. Methods: Conventional “3 + 3” design. Pts with newly diagnosed high risk PCa defined as either Gleason score (GS) 8 – 10, or T3/T4 with GS 7, or PSA > 20 with GS 7 are eligible. Dose escalation occurred only after all the cohort pts completed weekly C ( 4 cohorts at the dose of 4, 6, 8 and 10 mg/m2) and the total planned dose IMRT. ADT was started two months prior to C and IMRT then continued on for a total of 24 months. Daily bicalutamide started within 1 day to 2 weeks prior to LHRH agonist therapy and stopped on the last day of IMRT for approximately 4 month duration. IMRT is delivered to a total dose of 75.6 Gy at 1.8 Gy daily fraction for 8.5 – 9 wks. The primary objective of this study was to determine the safe dose of the combination of weekly C with IMRT and ADT . Results: At present, 14 pts of mean age 62 yrs (range 53 – 82), T2 - T4; mean PSA 89 (range 4 – 253); and median GS 9 (GS 7 – 10) were enrolled and 10 pts completed the chemo-radiation therapy. Grade 3 dose-limiting toxicites in the first two pts at the 8 mg/m2 C dose level were diarrhea and elevated transaminase, thus the maximum tolerable dose (MTD) of C with IMRT was determined to be 6 mg/m2. An expansion cohort is ongoing. In this dose level, there were ≤ grade 2 toxicities only (diarrhea, hypophosphatemia and leukopenia). No long term toxicities are observed. Standardized measurement of health status and quality of life will be presented. Conclusions: Concurrent weekly C with current standard IMRT is feasible with no unexpected toxicity. In combination with IMRT and ADT, the MTD of weekly C is 6 mg/m2 in pts with newly diagnosed high risk PCa. Clinical trial information: NCT01420250.

Proteins were obtained by ion-exchange chromatography and gel filtration from the dry sample of Pleurotus eryngii. In terms of detection on local lesion host, these components were confirmed to be anti-TMV and their inhibition rates reach more than 70%, or even 99%. The protein named xb68Ab of MW 23.7kD was purified by ion-exchange chromatography and gel filtration its inhibition rate against TMV are 99.43% and 98.9% on Nicotiana glutionosa and Chenopodium amaranticolor, respectively.

This paper presents the methodology of implementations and performance measurements of our mobile ad-hoc network (MANET) platforms. The work is prompted by the lack of published results concerning the issues associated with the implementation of MANET facilities on actual wireless networks, as opposed to results of simulation experiments. Our MANET is developed based on the settled IEEE 802.11b technology operating in the ad-hoc mode. The opportunity driven multiple access (ODMA), which is developed by IWICS Inc., is implemented on the platform and its performance has been examined through field tests along city streets. Based on the measurement results, ODMA-based MANET facilities are able to provide satisfactory wireless communication services in vehicular environments. The minimum data throughput of 20 kBytes/sec could be guaranteed in our testbed.

In order to achieve personalized cancer care, tools are needed to predict benefit from a specific therapy. Prostate cancer biomarker study is a key field to explore so that the natural course of a patient's disease can be predicted. A panel of inflammation/immune-related and prostate cancer-related genes was screened by Ross et al. to assess genes predictive of castration-resistant prostate cancer (CRPC) survival. They found that a six-gene model was superior to traditionally used clinic-pathological variables. Although the clinic utility of this model remains to be determined, the blood based technical achievement and potential may eventually improve personalized cancer care. CRPC is a late-stage prostate cancer typically evolved years after androgen deprivation therapy. Very recently, there has been a rapid increase in the number of effective systemic agents for men with metastatic CRPC (mCRPC),1 including abiraterone acetate and Enzalutamide (hormonal therapies), Sipuleucel-T (immunotherapy), Cabazitaxel (chemotherapy), Denosumab and Radium 223 (bone microenvironment targeting agents). However, the genetic heterogeneity of prostate cancer, the high cost of these therapies, and the uncertainty of the best use for these drugs in clinical decision-making, have highlighted the need for novel effective biomarkers to identify the right therapy and timing for the right patient and enable the monitoring of therapeutic response and disease progression. Ross et al.2 recently published their findings in Lancet Oncology about the possibility of whole blood transcriptional profiling as prognostic biomarker for men with CRPC. Peripheral blood was prospectively collected from 62 men with CRPC on various treatment regimens who were enrolled in a training set and from 140 patients with CRPC in a validation set from another institution. A panel of 168 inflammation/immune-related and prostate cancer-related genes was assessed with quantitative real-time PCR to assess genes predictive of survival. Latent class modeling was conducted to analyze the gene expression data, which generated a six-gene model (consisting of ABL2, SEMA4D, ITGAL, C1QA, TIMP1 and CDKN1A) that could separate CRPC patients into two risk groups: a low-risk group with a median survival of more than 34.9 months and a high-risk group with a median survival of 7.8 months (P

Regulated shedding of cell surface proteins is a mechanism for rapid activation of autocrine and paracrine signaling. Here we report that chelerythrine, a protein kinase C (PKC) inhibitor that possesses a variety of biological functions, is a potent inducer of heparin-binding epidermal growth factor-like growth factor (HB-EGF) shedding from the cell surface. Chelerythrine induced a time- and dose-dependent shedding of an HB-EGF–alkaline phosphatase (HB-EGF-AP) fusion protein expressed in MC2 rat prostate epithelial cells. The soluble form of HB-EGF-AP bound to heparin and exhibited potent biological activity as measured by DNA synthesis assay. Chelerythrine-induced HB-EGF shedding was metalloproteinase-(MMP-) mediated because specific MMP antagonists inhibited shedding by ≥60%. Chelerythrine stimulated production of reactive oxygen species, and antioxidants prevented chelerythrine-induced HB-EGF shedding, suggesting that the production of intracellular peroxides is necessary for this event. Consistent with this possibility, antioxidant- and MMP-inhibitable shedding was also demonstrated when hydrogen peroxide was used as an inducer. Although JNK/SAPK and p38 MAPK pathways were activated by chelerythine, these signaling mechanisms were not required to mediate the shedding event. However, JNK signaling was involved in chelerythrine-stimulated apoptosis. Our results suggest that HB-EGF shedding induced by chelerythrine is mediated predominantly via the production of reactive oxygen species. © 2004 Wiley-Liss, Inc.