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Abstract Background Black men consistently have higher rates of prostate cancer (PCA)- related mortality. Advances in PCA treatment, screening, and hereditary cancer assessment center around germline testing (GT). Of concern is the significant under-engagement of Black males in PCA GT, limiting the benefit of precision therapy and tailored cancer screening despite longstanding awareness of these disparities. To address these critical disparities, the Socioecological Model (SEM) was employed to develop comprehensive recommendations to overcome barriers and implement equitable strategies to engage Black males in PCA GT. Methods Clinical/research experts, national organization leaders, and community stakeholders spanning multiple regions in US and Africa participated in developing a framework for equity in PCA GT grounded in the SEM. A novel mixed-methods approach was employed to generate key areas to be addressed and informed statements for consensus consideration utilizing the modified Delphi model. Statements achieving strong consensus (> =75% agreement) were included in final equity frameworks addressing clinical/community engagement and research engagement. Results All societal levels of the SEM (interpersonal, institutional, community, and policy/advocacy) must deliver information about PCA GT to Black males that address benefits/limitations, clinical impact, hereditary cancer implications, with acknowledgment of mistrust (mean scores [MS] 4.57-5.00). Interpersonal strategies for information delivery included engagement of family/friends/peers/Black role models to improve education/awareness and overcome mistrust (MS 4.65-5.00). Institutional strategies included diversifying clinical, research, and educational programs and integrating community liaisons into healthcare institutions (MS 4.57-5.00). Community strategies included partnerships with healthcare institutions and visibility of healthcare providers/researchers at community events (MS 4.65–4.91). Policy/advocacy included improving partnerships between advocacy and healthcare/community organizations while protecting patient benefits (MS 4.57-5.00). Media strategies were endorsed for the first time at every level (MS 4.56-5.00). Conclusion The SEM-based equity frameworks proposed provide the first multidisciplinary strategies dedicated to increase engagement of Black males in PCA GT, which are critical to reduce disparities in PCA-mortality through informing tailored screening, targeted therapy, and cascade testing in families.

Abstract Objectives The objective of this study is to validate a hypothesis that a non‐invasive optical imaging assay targeting genomic VPAC receptors on malignant cells shed in voided urine will represent either benign prostatic hyperplasia (BPH) or prostatic cancer (PCa). Risk for BPH in men 50–70 years old is 50–70% and PCa is 17%. BPH and PCa can coexist in 20% of men with BPH. Most commonly practiced methods to diagnose BPH do not distinguish BPH from PCa. Patients (or Materials) and Methods Males with BPH (N = 97, 60.8 ± 6.3 years, prostate‐specific antigen 0.7 ± 0.4 ng/mL) and without oncologic disease (N = 35, 63.4 ± 5.8 years, prostate‐specific antigen

Background and objective: Radiation therapy has increasingly been used in the management of pelvic malignancies. However, the use of radiation continues to pose a risk of a secondary malignancy to its recipients. This study investigates the risk of secondary malignancy development following radiation for primary pelvic malignancies. Methods: A retrospective cohort review of the Surveillance, Epidemiology, and End Results database from 1975 to 2016 was performed. Primary pelvic malignancies were subdivided based on the receipt of radiation, and secondary malignancies were stratified as pelvic or nonpelvic to investigate the local effect of radiation. Key findings and limitations: A total of 2 102 192 patients were analyzed (1 189 108 with prostate, 315 026 with bladder, 88 809 with cervical, 249 535 with uterine, and 259 714 with rectal/anal cancer). The incidence rate (defined as cases per 1000 person years) of any secondary malignancies (including but not limited to secondary pelvic malignancies) was higher in radiation patients than in nonradiation patients (incidence rate ratio [IRR] 1.04, confidence interval [CI] 1.03-1.05), with significantly greater rates noted in radiation patients with prostate (IRR 1.22, CI 1.21-1.24), uterine (IRR 1.34), and cervical (IRR 1.80, CI 1.72-1.88) cancer. While the overall incidence rate of any secondary pelvic malignancy was lower in radiation patients (IRR 0.79, CI 0.78-0.81), a greater incidence was still noted in the same cohorts including radiation patients with prostate (IRR 1.42, CI 1.39-1.45), uterine (IRR 1.15, CI 1.08-1.21), and cervical (IRR 1.72, CI 1.59-1.86) cancer. Conclusions and clinical implications: Except for localized cervical cancer, when put in the context of median overall survival, the impact of radiation likely does not carry enough weight to change practice patterns. Radiation for pelvic malignancies increases the risk for several secondary malignancies, and more specifically, secondary pelvic malignancies, but with a relatively low absolute risk of secondary malignancies, the benefits of radiation warrant continued use for most pelvic malignancies. Practice changes should be considered for radiation utilization in malignancies with excellent cancer-specific survival such as cervical cancer. Patient summary: The use of radiation for the management of pelvic malignancies induces a risk of secondary malignancies to its recipients. However, the absolute risk being low, the benefits of radiation warrant its continued use, and a change in practice patterns is unlikely.

The success of HER2-targeted cancer therapy is limited by treatment resistance. Here, the authors engineer an anti-HER2 biparatopic antibody with multiple mechanisms of action including induction of HER2 clustering to trigger complement dependent cytotoxicity, signal inhibition, antibody dependent cellular cytotoxicity and phagocytosis.

The ability of cancer cells to detach from the primary site and metastasize is the main cause of cancer- related death among all cancer types. Epithelial-to-mesenchymal transition (EMT) is the first event of the metastatic cascade, resulting in the loss of cell–cell adhesion and the acquisition of motile and stem-like phenotypes. A critical modulator of EMT in cancer cells is the stromal tumor microenvironment (TME), which can promote the acquisition of a mesenchymal phenotype through direct interaction with cancer cells or changes to the broader microenvironment. In this review, we will explore the role of stromal cells in modulating cancer cell EMT, with particular emphasis on the function of mesenchymal stromal/stem cells (MSCs) through the activation of EMT-inducing pathways, extra cellular matrix (ECM) remodeling, immune cell alteration, and metabolic rewiring.

pHLA complexes represent the largest class of cell surface markers on cancer cells, making them attractive for targeted cancer therapies. Adoptive cell therapies expressing TCRs that recognize tumor specific pHLAs take advantage of the unique selectivity and avidity of TCR: pHLA interactions. More recently, additional protein binding domains binding to pHLAs, known as TCR mimics (TCRm), were developed for tumor targeting of high potency therapeutic modalities, including bispecifics, ADCs, CAR T and -NK cells. TCRm compounds take advantage of the exquisite tumor specificity of certain pHLA targets, including cell lineage commitment markers and cancer testis antigens (CTAs). To achieve meaningful anti-tumor responses, it is critical that TCRm compounds integrate both, high target binding affinities and a high degree of target specificity. In this review, we describe the most advanced approaches to achieve both criteria, including affinity- and specificity engineering of TCRs, antibodies and alternative protein scaffolds. We also discuss the status of current TCRm based therapeutics developed in the clinic, key challenges, and emerging trends to improve treatment options for cancer patients treated with TCRm based therapeutics in Oncology.

BACKGROUND New therapeutic combinations to improve outcomes of patients with ovarian cancer are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer.METHODS This phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib, followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS).RESULTS Thirty-five patients were enrolled. Patients had a mean of 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab. The MTD was 400 mg. The most common adverse events included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). The overall RR was 79.3%, with a stable disease rate of 18%, resulting in a clinical benefit rate of 96.6%. Median PFS was 11.4 months. RR and PFS did not differ based on the number of lines of prior chemotherapy or prior maintenance therapy.CONCLUSION This work demonstrates that the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease.TRIAL REGISTRATION ClinicalTrials.gov NCT03056833.FUNDING This investigator-initiated trial was supported by Novartis, which provided drugs and funds for trial execution.

Abstract Analysis of the genomic landscape of prostate cancer has identified different molecular subgroups with relevance for novel or existing targeted therapies. The recent approvals of the poly(ADP‐ribose) polymerase (PARP) inhibitors olaparib and rucaparib in the metastatic castration‐resistant prostate cancer (mCRPC) setting signal the need to embed molecular diagnostics in the clinical pathway of patients with mCRPC to identify those who can benefit from targeted therapies. Best practice guidelines in overall biospecimen collection and processing for molecular analysis are widely available for several tumour types. However, there is no standard protocol for molecular diagnostic testing in prostate cancer. Here, we provide a series of recommendations on specimen handling, sample pre‐analytics, laboratory workflow, and testing pathways to maximise the success rates for clinical genomic analysis in prostate cancer. Early involvement of a multidisciplinary team of pathologists, urologists, oncologists, radiologists, nurses, molecular scientists, and laboratory staff is key to enable optimal workflow for specimen selection and preservation at the time of diagnosis so that samples are available for molecular analysis when required. Given the improved outcome of patients with mCRPC and homologous recombination repair gene alterations who have been treated with PARP inhibitors, there is an urgent need to incorporate high‐quality genomic testing in the routine clinical pathway of these patients.

Given limited funding, natural resources decision making is riddled with tradeoffs, including which species or landscapes to prioritize for management action. Florida’s Everglades wetland is home to numerous indicator species, some of which are endangered. But with a multitude of species comes differing hydrologic requirements to yield appropriate foraging and breeding conditions for each. The Everglades ecosystem is highly managed, with water being moved across the landscape to meet the habitat and reproductive needs of species of concern. Predictive modeling can help water managers understand potential consequences to targeted water conditions. EverForecast is a novel spatially explicit, hydrologic, and ecological operational forecast developed to inform conservation management decisions. Not only does EverForecast provide probable near-term water conditions, but also predicted species responses to those hydrologic conditions. Using examples from two focal regions of the Everglades, we show the magnitude of impacts to a suite of species and an almost 70% decline in suitable conditions for one species when prioritizing water management to meet the needs of another species. Although EverForecast is a relatively new decision support tool, its hydrologic outputs are already commonly used to make water management recommendations because it provides near-term hydrologic forecasts that scientists and managers need for water operations decision making. Because species management decisions have historically been made to target a single species at a time, it may take longer for full utility of EverForecast’s ability to quantify tradeoffs among species to become integrated into decision making.

Ines Daguet,1,2 Kayla Bergeron-Vezina,1,2 Marie-Philippe Harvey,1,2 Marylie Martel,1,2 Alexia Coulombe-Leveque,1– 3 Guillaume Leonard1– 3 1Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; 2Research Centre on Aging, CIUSSS de l’Estrie - CHUS, Sherbrooke, QC, Canada; 3School of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, CanadaCorrespondence: Guillaume LeonardResearch Centre on Aging, CIUSSS de l’Estrie – CHUS, 1036, rue Belvédère Sud, Sherbrooke, Québec J1H 4C4, CanadaTel +1 819-780-2220 Ext 45246Fax +1 819-820-6864Email guillaume.leonard2@usherbrooke.caBackground and Purpose: Aging is associated with an impairment of diverse physiological functions, including nociception. For example, older adults in comparison to young adults, show an overall increase in pain thresholds, reflecting a decline in pain sensitivity and changes in the nociceptive pathways. These results are, however, debated as they were not always replicated depending on the stimulus modality, duration, and location. The aim of the current study was to determine how the temporal evolution of pain intensity during a continuous tonic heat pain test is influenced by aging. More specifically, we wanted to 1) assess the effect of age on initial peak and late-phase pain and 2) determine whether potential age effects depend on the stimulation site.Participants and Methods: 13 young adults (average of 27.9 years old) and 13 older adults (average of 67.5 years old) participated in this study. Experimental heat pain was evoked on an appendicular (forearm) and axial (lower-back) body region, using a thermode (2-minute stimulation at a constant, individually-adjusted temperature). During the nociceptive stimulation, participants used a computerized visual analogue scale to continuously rate their pain.Results: We show that initial peak (0– 30 seconds) pain sensation was significantly lower in older adults compared to young adults, while late-phase (30– 120 seconds) pain sensation was similar across the two age groups. These results hold true for both stimulation sites, suggesting the existence of an age effect on both appendicular and axial body regions.Conclusion: The lower magnitude of initial peak pain observed in older adults, which affects both appendicular and axial body regions, could reflect generalized peripheral or central alterations of the nociceptive system in older adults. These alterations in older adults could have significant clinical impacts, such as an increased vulnerability to injury or an underestimation of the severity of their pain condition.Keywords: pain, experimental pain, age, aging, elderly, psychophysics

R Pelletier,1 L Purcell-Levesque,2 M-C Girard,2 P-M Roy,2 G Leonard2,3 1School of Rehabilitation, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; 2Research Center on Aging, Centre intégré universitaire de santé et de services sociaux de l’Estrie - Centre hospitalier universitaire de Sherbrooke (CIUSSS de l’Estrie - CHUS), Sherbrooke, Quebec, Canada; 3School of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, CanadaCorrespondence: G Leonard Email guillaume.leonard2@usherbrooke.caPurpose: Older adults are referred for outpatient physical therapy to improve their functional capacities. The goal of the present study was to determine if pain had an influence on functional outcomes in older adults who took part in an outpatient physical rehabilitation program.Patients and Methods: A retrospective study was performed on the medical records of patients aged 65 and over referred for outpatient physical therapy to improve physical functioning (n=178). Pain intensity (11-point numeric pain scale) and results from functional outcome measures (Timed Up and Go [TUG], Berg Balance Scale [BBS], 10-meter walk test, 6-minute walk test and Functional Autonomy Measuring System [SMAF]) were extracted at initial (T1) and final (T2) consultations. Paired t-tests were performed to determine if there were differences in functional outcome measures between T1 and T2 in all the patients. Patients were stratified to those with pain (PAIN, n=136) and those without pain (NO PAIN, n=42). Differences in functional outcome measures between T1 and T2 (delta scores) were compared between groups with independent t-tests with Welch corrections for unequal variances. Pearson correlation coefficients between initial pain intensity and changes in functional outcome measures (T2-T1) were also performed. Correcting for multiple comparisons, a p-value of p≤ 0.01 was considered as statistically significant.Results: The TUG, BBS, 10-meter walk test, 6-minute walk test all demonstrated improvement between T1 and T2 (all p< 0.01). There was no difference between groups for delta scores for TUG (p=0.14), BBS (p=0.03), 10-meter walk test (p=0.54), 6-minute walk test (p=0.94) and SMAF (p=0.23). Pearson correlation coefficients were weak between initial pain intensity and changes in functional outcome scores between T1 and T2 (r= − 0.16 to 0.15, all p-values > 0.10).Conclusion: These results suggest that pain is not an impediment to functional improvements in older individuals who participated in an outpatient physical rehabilitation program.Keywords: pain, function, physical therapy, older adults, disability

One of the most accurate and non-invasive prostate imaging methods is magnetic resonance imaging (MRI). Segmentation is needed to find the boundary of the prostate, either automatically or semi-automatically. Recently, fully convolutional neural networks (FCNN) are being used for this purpose. In this paper, to improve the FCNN performance for prostate MRI segmentation, we analyze various structures of shortcut connections together with the size of a deep network and suggest eight different FCNNs-based deep 2D network structures for automatic MRI prostate segmentation. Our evaluations on the PROMISE12 dataset with ten-fold cross-validation indicate improved and competitive results. We analyze the results in detail, considering MRI slices, MRI volumes, test folds, and also the impact on prostate segmentation of using an EndoRectal Coil to capture the prostate MRI. Our best 2D network outperforms the state-of-the-art 3D FCNN-based methods for prostate MRI segmentation on publicly available data, without any further post-processing.

Mark Duffy produced a complete set of grinding data on a pilot-scale tower mill. Here these data are analyzed in terms of grinding kinetics. The results show that the data can be fitted with a simple first-order breakage model, which is not normally observed in any grinding system, including other types of grinding machines such as tumbling ball mills and rod mills. The model has only two parameters, making it possible to determine the parameters using simple search methods. The results show that larger particles break faster than smaller particles, as is usually observed in all mills. Statistical analysis of the data showed that one of the parameters could be fixed for seven of the nine tests.

Breast and prostate cancer research to date has largely been predicated on the use of cell lines in vitro or in vivo. These limitations have led to the development of more clinically relevant models, such as organoids or murine xenografts that utilize patient‐derived material; however, issues related to low take rate, long duration of establishment, and the associated costs constrain use of these models. This study demonstrates that ex vivo culture of freshly resected breast and prostate tumor specimens obtained from surgery, termed patient‐derived explants (PDEs), provides a high‐throughput and cost‐effective model that retains the native tissue architecture, microenvironment, cell viability, and key oncogenic drivers. The PDE model provides a unique approach for direct evaluation of drug responses on an individual patient's tumor, which is amenable to analysis using contemporary genomic technologies. The ability to rapidly evaluate drug efficacy in patient‐derived material has high potential to facilitate implementation of personalized medicine approaches.

Abstract Periodicity of fire disturbance is a known driver of ecosystem function and is reported as important in both promoting and maintaining viable breeding habitat for the endangered Cape Sable Seaside Sparrow (Ammospiza maritima mirabilis; CSSS). In south Florida, the CSSS serves as a fine‐scale indicator of the marl and mixed‐marl prairie communities of the Florida Everglades. The CSSS distribution is affected by numerous well‐documented physical drivers, including water depth and fire regime. Here, we fit zero‐inflated negative binomial generalized linear mixed models and used model selection to determine the relationship between CSSS bird count observations from 1992 to 2014 and the spatially‐specific fire return interval on the landscape. CSSS bird count was highest at a 5–8‐year fire return interval and increased linearly with the percent of cell burned (400 × 400 m cells). The results of this study can inform management plans designed to maintain existing, and promote new, marl prairie habitat for conservation of the CSSS.

An important problem of cyber-security is malware analysis. Besides good precision and recognition rate, ideally, a malware detection scheme needs to be able to generalize well for novel malware families (a.k.a zero-day attacks). It is important that the system does not require excessive computation particularly for deployment on the mobile devices. In this paper, we propose a novel scheme to detect malware which we call Malytics. It is not dependent on any particular tool or operating system. It extracts static features of any given binary file to distinguish malware from benign. Malytics consists of three stages: feature extraction, similarity measurement, and classification. The three phases are implemented by a neural network with two hidden layers and an output layer. We show feature extraction, which is performed by tf-simhashing, is equivalent to the first layer of a particular neural network. We evaluate Malytics performance on both Android and Windows platforms. Malytics outperforms a wide range of learning-based techniques and also individual state-of-the-art models on both platforms. We also show Malytics is resilient and robust in addressing zero-day malware samples. The F1-score of Malytics is 97.21% and 99.45% on Android dex file and Windows PE files, respectively, in the applied datasets. The speed and efficiency of Malytics are also evaluated.

Management of men with prostate cancer is fraught with uncertainty as physicians and patients balance efficacy with potential toxicity and diminished quality of life. Utilization of genomics as a prognostic biomarker has improved the informed decision-making process by enabling more rationale treatment choices. Recently investigations have begun to determine whether genomic information from tumor transcriptome data can be used to impact clinical decision-making beyond prognosis. Here we discuss the potential of genomics to alter management of a patient who presented with high-risk prostate adenocarcinoma. We suggest that this information help selecting patients for advanced imaging, chemotherapies, or clinical trial.

Background: We examine the practical application of multiparametric MRI (mpMRI) prostate biopsy data using established pre-RP nomograms and its potential implications on RP intraoperative decision-making. We hypothesize that current nomograms are suboptimal in predicting outcomes with mpMRI targeted biopsy (TBx) data. Materials and methods: Patients who underwent mpMRI-based TBx prior to RP were assessed using the MSKCC and Briganti nomograms with the following iterations: (1) Targeted (T) (targeted only), (2) Targeted and Systematic (TS) and (3) Targeted Augmented (TA) (targeted core data; assumed negative systematic cores for 12 total cores). Nomogram outcomes, lymph node involvement (LNI), extracapsular extension (ECE), organ-confined disease (OCD), seminal vesicle invasion (SVI), were compared across iterations. Clinically significant impact on management was defined as a change in LNI risk above or below 2% (Δ2) or 5% (Δ5). Results: A total of 217 men met inclusion criteria. Overall, the TA iteration had more conservative nomogram outcomes than the T. Moreover, TA better predicted RP pathology for all four outcomes when compared with the T. In the entire cohort, Δ2 and Δ5 were 16.6–25.8% and 20.3–39.2%, respectively. In the subset of 190 patients with targeted and systematic cores, TA was a better approximation of TS outcomes than T in 71% (MSKCC) and 82% (Briganti) of patients. Conclusion: In established pre-RP nomograms, mpMRI-based TBx often yield variable and discordant results when compared with systematic biopsies. Future nomograms must better incorporate mpMRI TBx core data. In the interim, augmenting TBx data may serve to bridge the gap.

Abstract PARP‐1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP‐1 enzymatic activity. Further investigation of the PARP‐1‐regulated transcriptome and secondary strategies for assessing PARP‐1 activity in patient tissues revealed that PARP‐1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double‐strand breaks, suggesting that enhanced PARP‐1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP‐1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1‐mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP‐1 inhibition reduced HR factor availability and thus acted to induce or enhance “BRCA‐ness”. These observations bring new understanding of PARP‐1 function in cancer and have significant ramifications on predicting PARP‐1 inhibitor function in the clinical setting.

One-third of patients with heart disease develop heart failure, which is diagnosed through imaging and detection of circulating biomarkers. Imaging strategies reveal morphologic and functional changes but fall short of detecting molecular abnormalities that can lead to heart failure, and circulating biomarkers are not cardiac specific. Thus, there is critical need for biomarkers that are endogenous to myocardial tissues. The cardiac growth hormone secretagogue receptor 1a (GHSR1a), which binds the hormone ghrelin, is a potential biomarker for heart failure. We have synthesized and characterized a novel ghrelin peptidomimetic tracer, an 18 F-labeled analogue of G-7039, for positron emission tomography (PET) imaging of cardiac GHSR1a. In vitro analysis showed enhanced serum stability compared to natural ghrelin and significantly increased cellular uptake in GHSR1a-expressing OVCAR cells. Biodistribution studies in mice showed that tissue uptake of the tracer was independent of circulating ghrelin levels, and there was negligible cardiac uptake and high uptake in the liver, intestines, and kidneys. Specificity of tracer uptake was assessed using ghsr −/− mice; both static and dynamic PET imaging revealed no difference in cardiac uptake, and there was no significant correlation between cardiac standardized uptake values and GHSR1a expression. Our study lays the groundwork for further refinement of peptidomimetic PET tracers targeting cardiac GHSR1a.