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New technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations; however, there are currently few approaches to analyze the spatial context of the TIME. Thus, we have developed a framework for the spatial analysis of the TIME using Ripley’s K, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to ovarian cancer using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 158 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 259 tissue cores; 91 subjects with 254 ROIs). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes, cytotoxic T-cells, and regulatory T-cells, and overall survival. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and cytotoxic T-cells in their tumors had the best overall survival. In contrast, patients with low levels of regulatory T-cells but with a high level of spatial clustering (compare to those with a low level of spatial clustering) had better survival. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies.

Background Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM). Objective To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM. Design, setting, and participants We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred. Outcome measurements and statistical analysis The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls. Results and limitations Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only. Conclusions Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa. Patient summary In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction. © 2013 European Association of Urology.

28th European Photovoltaic Solar Energy Conference and Exhibition; 2467-2469, Innovation in laser processing methods and laser processing system architectures are required to help drive improvements in thin film photovoltaic (PV) device efficiencies and contribute to reductions of device manufacturing costs [1,2]. Laser scribes produced by conventional Gaussian beam laser processing using nanosecond lasers of thin film a-Si and CdTe devices often display sidewall non-uniformities, cracking, residual debris, and heat affected zones. These undesirable effects often adversely impact device efficiencies, device yield, and ultimately device manufacturing costs. Recent work has demonstrated that employment of picosecond lasers and shaped beam techniques can provide improved scribe quality [3, 4. 5]. In this work, we evaluate two shaped beam techniques for P1, P2 and P3 laser scribing of thin film a-Si and CdTe photovoltaic devices using 1064 nm and 532 nm flexible pulsewidth nanosecond and picosecond master oscillator fiber power amplifier (MOFPA) laser systems. Improvements in the spatial uniformity of the laser scribing process offer an attractive approach to meeting the industry’s demands for more robust, efficient, and cost effective thin film photovoltaic laser processing methods.

27th European Photovoltaic Solar Energy Conference and Exhibition; 2356-2358, Continuous improvement and innovation in laser processing methods and laser architectures are needed to further improve device efficiencies and reduce overall device manufacturing costs. In particular, P1 and P3 laser scribes of transparent conductive oxide layers, such as F:SnO2 or Al:ZnO (AZO) employed in thin film solar cell devices conventionally have been processed by Q-switched diode-pumped solid state lasers (DPSS) operating in the nanosecond regime. The principal wavelength employed for F:SnO2 scribing has been in the near infrared at or near 1064 nm while AZO has also been widely scribed at harmonic wavelengths, including in the near ultraviolet at or near 355 nm. Scribes produced with these laser systems often display undesirable sidewall non-uniformities, heat affected zones, film lift off, cracking, and excessive residual debris. Further, Q-switched DPSS laser architectures face scaling challenges as improvements in beam positioning technology demand laser performance at pulse repetition frequencies substantially higher than 200 KHz in order to keep pace with improvements in beam positioning speed and overall system throughput requirements. In addition, the lifetime and reliability of Q-switched ultraviolet DPSS lasers are well-known to be negatively impacted by the high photon energy in comparison to comparable pulse energy infrared laser systems. Recently, substantial work has been performed to investigate the effectiveness of sub-nanonsecond lasers on key laser scribing processes, including P1 molybdenum and P2 and P3 CdTe and a-Si scribes. In this work, we extend these investigations to evaluate the pulsewidth dependence of TCO laser scribe process performance and quality produced by 1064 nm master oscillator fiber power amplifier (MOFPA) laser systems in the picosecond regime.

26th European Photovoltaic Solar Energy Conference and Exhibition; 2471-2474, Improved P2 and P3 scribing of thin film a-Si and CdTe solar cells are demonstrated using a 532 nm picosecond fiber laser with a square flat-top shaped beam profile at the work surface. The shaped beam profile optimizes the application of the available pulse energy and results in significantly faster scribe rates than achievable with Gaussian profiles. The uniform application of the fluence also improves scribe quality. The sidewalls are extremely straight and sharp and the absorber material is completely and uniformly removed from the underlying TCO with no damage to the TCO itself. Defects like cracking of the substrate or absorber edges, or peeling of the metal contacts are eliminated by the sharp profile edges of the flat-top beam and single pulse material removal.

The study of architecture is by nature highly interdisciplinary. Design, structure, technology, ecology and economics must all be considered in the process of planning and building. Therefore it is important to encourage an integrated approach in terms of education and to create a interdisciplinary network of learning contents. Wissensraum Architektur is a contribution to this idea. Wissensraum Architektur is an internet-based system for teaching and learning at the Department of Architecture and Civil Engineering at Anhalt University of Applied Sciences in Dessau. The basis of Wissensraum is a pool of media elements and multimedia based components to which authors from different fields contribute. The authoring system allows instructors to create, by simple means, digital learning modules. Due to the modular structure, modular elements and sequences in varying relations and by different authors can be reused and restructured. A knowledge map visualizes relationships among the different learning content. In this way, a virtual campus in Dessau is created step by step. The didactical concept of Wissensraum supports Constructivist models of learning. Users can use the database for research and can create their own way of learning concerning particular themes. The availability via Internet makes it possible to work from any location at any time.

PURPOSE To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population. PATIENTS AND METHODS Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires. RESULTS Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service. CONCLUSION To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.

DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7–59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18–3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82–3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54–2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease.

Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and nonlethal disease. Experimental Design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes. Results: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P < 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion. Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies. Clin Cancer Res; 22(3); 765–72. ©2015 AACR.

To investigate the role of adiponectin receptor 2 (AdipoR2) in aggressive prostate cancer we used immunohistochemistry to characterize AdipoR2 protein expression in tumor tissue for 866 men with prostate cancer from the Physicians' Health Study and the Health Professionals Follow-up Study. AdipoR2 tumor expression was not associated with measures of obesity, pathological tumor stage or prostate-specific antigen (PSA) at diagnosis. However, AdipoR2 expression was positively associated with proliferation as measured by Ki-67 expression quartiles (P-trend < 0.0001), with expression of fatty acid synthase (P-trend = 0.001), and with two measures of angiogenesis (P-trend < 0.1). An inverse association was observed with apoptosis as assessed by the TUNEL assay (P-trend = 0.006). Using Cox proportional hazards regression and controlling for age at diagnosis, Gleason score, year of diagnosis category, cohort and baseline BMI, we identified a statistically significant trend for the association between quartile of AdipoR2 expression and lethal prostate cancer (P-trend = 0.02). The hazard ratio for lethal prostate cancer for the two highest quartiles, as compared to the two lowest quartiles, of AdipoR2 expression was 1.9 (95% confidence interval [CI]: 1.2-3.0). Results were similar when additionally controlling for categories of PSA at diagnosis and Ki-67 expression quartiles. These results strengthen the evidence for the role of AdipoR2 in prostate cancer progression.

Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), and androgen receptor (AR) status, as well as pathologic features and cancer-specific outcomes. In addition, the PI3K activation score was compared with mRNA expression profiling data for a large subset of men. Interestingly, those tumors with higher PI3K activation scores also had higher Gleason grade (P = 0.006), increased AR (r = 0.37; P < 0.001) and Ki67 (r = 0.24; P < 0.001), and decreased TUNEL (r = −0.12; P = 0.003). Although the PI3K activation score was not associated with an increased risk of lethal outcome, a significant interaction between lethal outcome, Gleason and high PI3K score (P = 0.03) was observed. Finally, enrichment of PI3K-specific pathways was found in the mRNA expression patterns differentiating the low and high PI3K activation scores; thus, the 4-marker IHC score of PI3K pathway activity correlates with features of PI3K activation. Implications: The relationship of this activation score to sensitivity to anti-PI3K agents remains to be tested but may provide more precision guidance when selecting patients for these therapies. Mol Cancer Res; 13(10); 1431–40. ©2015 AACR.