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The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development., (©2019 American Association for Cancer Research.)

This study was conducted to quantify the human tolerance from inferior to superior impacts to whole lumbar spinal columns excised from 43 post mortem human subjects. The specimens were fixed at the ends, aligned in a consistent seated posture, load cells were attached to the proximal and distal ends of the fixation, and the impact was applied using a custom accelerator device. Pretest X-rays and computed tomography (CT) scans, prepositioned X-rays, and posttest X-rays, CT scans and dissection data were used to identify injuries. Right, left, and interval censoring processes were used for the survival analysis, 16 were right censored, 24 were interval censored, and three were left censored observations. Force-based injury risk curves were developed, and the optimal metric describing the underlying response to injury was identified using the Brier score metric. Material, geometry (disc and body areas), and demographic covariates were included in the analysis. The distal force was found to be optimal metric. The bone mineral density was a significant covariate for distal and proximal forces. Both material and geometrical factors affected the transmitted force in this mode of loading. These quantified data serve as the first set of human lumbar spinal column injury risk curves.

Community-academic partnerships are vital to address cancer disparities in geographic areas with diverse socioeconomic, language, and cultural barriers. Regarding breast health, immigrant and refugee women are a particularly vulnerable population, with considerably lower mammography rates than most communities, including racial and ethnic minorities. To promote health care equity in this high-risk population, we developed a community-academic partnership (CAP) model to promote breast health education at community faith-based centers in the city of Milwaukee, WI. In this paper, we describe the success of our partnerships, our lessons learned, and future directions.

Prostate cancer is the most common noncutaneous cancer in men in the United States. The current paradigm for screening and diagnosis is imperfect, with relatively low specificity, high cost, and high morbidity. This study aims to generate new image contrasts by learning a distribution of unique image signatures associated with prostate cancer. In total, 48 patients were prospectively recruited for this institutional review board-approved study. Patients underwent multiparametric magnetic resonance imaging 2 weeks before surgery. Postsurgical tissues were annotated by a pathologist and aligned to the in vivo imaging. Radiomic profiles were generated by linearly combining 4 image contrasts (T2, apparent diffusion coefficient [ADC] 0-1000, ADC 50-2000, and dynamic contrast-enhanced) segmented using global thresholds. The distribution of radiomic profiles in high-grade cancer, low-grade cancer, and normal tissues was recorded, and the generated probability values were applied to a naive test set. The resulting Gleason probability maps were stable regardless of training cohort, functioned independent of prostate zone, and outperformed conventional clinical imaging (area under the curve [AUC] = 0.79). Extensive overlap was seen in the most common image signatures associated with high- and low-grade cancer, indicating that low- and high-grade tumors present similarly on conventional imaging.

Cervical spine injuries can occur in military scenarios from events such as underbody blast events. Such scenarios impart inferior-to-superior loads to the spine. The objective of this study is to develop human injury risk curves (IRCs) under this loading mode using Post Mortem Human Surrogates (PMHS). Twenty-five PMHS head-neck complexes were obtained, screened for pre-existing trauma, bone densities were determined, pre-tests radiological images were taken, fixed in polymethylmethacrylate at the T2-T3 level, a load cell was attached to the distal end of the preparation, positioned end on custom vertical accelerator device based on the military-seating posture, donned with a combat helmet, and impacted at the base. Posttest images were obtained, and gross dissection was done to confirm injuries to all specimens. Axial and resultant forces at the cervico-thoracic joint was used to develop the IRCs using survival analysis. Data were censored into left, interval, and uncensored observations. The Brier score metric was used to rank the variables. The optimal metric describing the underlying response to injury was associated with the axial force, ranking slightly greater than the resultant force, both with BMD covariates. The results from the survival analysis indicated all IRCs are in the "fair" to "good" category, at all risk levels. The BMD was found to be a significant covariate that best describes the response of the helmeted head-neck specimens to injury. The present experimental protocol and IRCs can be used to conduct additional tests, matched-pair tests with the WIAMan and/or other devices to obtain injury assessment risk curves (IARCs) and injury assessment risk values (IARVs) to predict injury in crash environments, and these data can also be used for validating component-based head-neck and human body computational models.

Variable selection in the presence of grouped variables is troublesome for competing risks data: while some recent methods deal with group selection only, simultaneous selection of both groups and within-group variables remains largely unexplored. In this context, we propose an adaptive group bridge method, enabling simultaneous selection both within and between groups, for competing risks data. The adaptive group bridge is applicable to independent and clustered data. It also allows the number of variables to diverge as the sample size increases. We show that our new method possesses excellent asymptotic properties, including variable selection consistency at group and within-group levels. We also show superior performance in simulated and real data sets over several competing approaches, including group bridge, adaptive group lasso, and AIC / BIC-based methods.

The human cervical spine sustains compressive loading in automotive events and military operational activities, and the contact and noncontact loading are the two primary impact modes. Biomechanical and anatomical studies have shown differences between male and female cervical spines. Studies have been conducted to determine the human tolerance in terms of forces from postmortem human subject (PMHS) specimens from male and female spines; however, parametric risk curves specific to female spines are not available from contact loading to the head-neck complex under the axial mode. This study was conducted to develop female-spine based risk curves from PMHS tests. Data from experiments conducted by the authors using PMHS upright head-spines were combined with data from published studies using inverted head-spines. The ensemble consisted of 20 samples with ages ranging from 29 to 95 years. Except one, all specimens sustained neck injuries, consisting of fractures to cervical vertebrae, and disruptions to the intervertebral disc and facet joints, and ligaments. Parametric survival analysis was used to derive injury probability curves using the compressive force, uncensored for injury and right censored for noninjury data points. The specimen age was used as the covariate. Injury probability curves were derived using the best fit distribution, and the ± 95% confidence interval limits were obtained. Results indicated that age is a significant covariate for injury for the entire ensemble. Peak forces were extracted for 35, 45, and 63 (mean) years of age, the former two representing the young (military) and the latter, the automobile occupant populations. The forces of 1.2 kN and 2.9 kN were associated with 5% and 50% probability of injury at 35 years. These values at 45 years were 1.0 kN and 2.4 kN, and at 63 years, they were 0.7 kN and 1.7 kN. The normalized widths of the confidence intervals at these probability levels for the mean age were 0.74 and 0.48. The preliminary injury risk curves presented should be used with appropriate caution. This is the first study to develop risk curves for females of different ages using parametric survival analysis, and can be used to advance human safety, and design and develop manikins for military and other environments., (Published by Elsevier Ltd.)

Chromophobe renal cell carcinoma (CRCC) is not amenable to International Society for Urologic Pathology-endorsed nucleolar grading. Novel grading approaches were proposed, but the rarity of adverse pathology hampers their discriminatory value. We investigate simple linear micrometer measurements and a proposed immunostain in CRCCs. 32 patients' CRCCs were studied: 12 adverse cases (stage pT3, recurrence, or metastasis), 15 controls (stage ≤pT2, no recurrence or metastasis after >3 years), and 8 metastases (3 were paired with primary adverse cases). The ratio of greatest dimensions of largest and smallest nuclei, in each of 5 "worst" high-power fields, excluding those with degenerative features, was designated variation in nuclear size (VNS). Percent multinucleate cells (PMC) were also counted. Mouse anti PD-L2 monoclonal antibody immunostaining was performed. Mean VNS measured in adverse primary and control primary tumors were 3.7 ± 0.5 and 2.4 ± 0.4 respectively (P < .001), and 3.4 ± 0.4 for metastases (P < .001). Optimal VNS cut-off was 2.5, with sensitivity and specificity 0.85 and 0.81, respectively. PMCs were 6.0 ± 3.0 for adverse group, 5.7 ± 2.7 for controls, and 4.1 ± 1.6 for metastases (P = NS). PD-L2 could not discriminate adverse versus good primary tumors (χ 2 1.6, P = .2), but was higher in metastases (χ 2 6.9, P < .01), or metastases plus adverse primary tumors (χ 2 4.8, P = .03), compared to good-pathology primary tumors. In conclusion, VNS is an easily obtained measurement that can predict adverse behavior of chromophobe RCC, and may impart value for needle biopsy reporting and the choice of active surveillance. PD-L2 was elevated in metastases but was less useful for primary tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Milwaukee, a city characterized by high rates of racial segregation and a growing immigrant population, has large race-based breast cancer survival disparities. To address these disparities, breast health education workshops were offered through a community-academic partnership (CAP) to women from various ethnic backgrounds. This paper explores attendance, satisfaction, and rates of screening mammography among workshop attendees., Methods: Partnerships were formed with community-based organizations, a mobile mammography unit, and the Wisconsin Well Woman Program, a state-supported program providing free mammograms. Multilingual staff provided monthly breast health education workshops at community settings and coordinated transportation. Participants completed surveys that included demographics, prior screening history, barriers to screening, and program evaluation. Descriptive statistics were used to summarize and analyze data., Results: Over a 24-month period, 493 women-most of whom sought services at partnering organizations that serve primarily immigrants, refugees, and racial minorities-attended breast health workshops, with 374 participants completing surveys (mean age = 45 years). A total of 360 were ≥ 40 years old. Among these women, 188 (113 insured [60%], 75 uninsured [40%]) reported no prior mammogram in the past 2 to 5 years. After attending the workshop, mammogram uptake was 100% among the insured and 80% among the uninsured. Satisfaction with the workshops was high; 73% of attendees rated them highly informative., Conclusions: Our CAP offered culturally tailored breast health education and access to screening via a mobile unit that was well attended, highly rated, and increased screening mammography., (Copyright© Wisconsin Medical Society.)

Under body blast (UBB) loading to military transport vehicles is known to cause foot-ankle fractures to occupants due to energy transfer from the vehicle floor to the feet of the soldier. The soldier posture, the proximity of the event with respect to the soldier, the personal protective equipment (PPE) and age/sex of the soldier are some variables that can influence injury severity and injury patterns. Recently conducted experiments to simulate the loading environment to the human foot/ankle in UBB events (~5ms rise time) with variables such as posture, age and PPE were used for the current study. The objective of this study was to determine statistically if these variables affected the primary injury predictors, and develop injury risk curves. Fifty belowknee post mortem human surrogate (PMHS) legs were used for statistical analysis. Injuries to specimens involved isolated and multiple fractures of varying severity. The Sanders classification was used to grade calcaneus severity and the AO/OTA classification for distal tibia fracture. Injury risk curves were developed using survival regression analysis and covariates were included whenever statistically significant (p<0.05). With peak force as the injury predictor and age and boot as covariates, the model was statistically significant. However, boot use changed the pattern of injury from predominately calcaneus to predominantly tibia. Also, a severity based risk curve showed tolerance differences between calcaneus (minor/major) and tibia (severity-I/ severity- II) injuries. The tibia demonstrated higher tolerance as compared to either minor or major calcaneus injury. These findings can play a vital role in development of safety systems to mitigate injuries to the occupant.

Objective: Biomechanical data from post mortem human subject (PMHS) experiments are used to derive human injury probability curves and develop injury criteria. This process has been used in previous and current automotive crashworthiness studies, Federal safety standards, and dummy design and development. Human bone strength decreases as the individuals reach their elderly age. Injury risk curves using the primary predictor variable (e.g., force) should therefore account for such strength reduction when the test data are collected from PMHS specimens of different ages (age at the time of death). This demographic variable is meant to be a surrogate for fracture, often representing bone strength as other parameters have not been routinely gathered in previous experiments. However, bone mineral densities (BMD) can be gathered from tested specimens (presented in this manuscript). The objective of this study is to investigate different approaches of accounting for BMD in the development of human injury risk curves., Methods: Using simulated underbody blast (UBB) loading experiments conducted with the PMHS lower leg-foot-ankle complexes, a comparison is made between the two methods: treating BMD as a covariate and pre-scaling test data based on BMD. Twelve PMHS lower leg-foot-ankle specimens were subjected to UBB loads. Calcaneus BMD was obtained from quantitative computed tomography (QCT) images. Fracture forces were recorded using a load cell. They were treated as uncensored data in the survival analysis model which used the Weibull distribution in both methods. The width of the normalized confidence interval (NCIS) was obtained using the mean and ± 95% confidence limit curves., Principal Results: The mean peak forces of 3.9kN and 8.6kN were associated with the 5% and 50% probability of injury for the covariate method of deriving the risk curve for the reference age of 45 years. The mean forces of 5.4 kN and 9.2kN were associated with the 5% and 50% probability of injury for the pre-scaled method. The NCIS magnitudes were greater in the covariate-based risk curves (0.52-1.00) than in the risk curves based on the pre-scaled method (0.24-0.66). The pre-scaling method resulted in a generally greater injury force and a tighter injury risk curve confidence interval. Although not directly applicable to the foot-ankle fractures, when compared with the use of spine BMD from QCT scans to pre-scale the force, the calcaneus BMD scaled data produced greater force at the same risk level in general., Conclusions: Pre-scaling the force data using BMD is an alternate, and likely a more accurate, method instead of using covariate to account for the age-related bone strength change in deriving risk curves from biomechanical experiments using PMHS. Because of the proximity of the calcaneus bone to the impacting load, it is suggested to use and determine the BMD of the foot-ankle bone in future UBB and other loading conditions to derive human injury probability curves for the foot-ankle complex., (Copyright © 2017. Published by Elsevier Ltd.)

The presence and extent of cribriform pattern of prostate cancer portend recurrence and cancer death. The relative expressions within this morphology of the prognostically adverse loss of PTEN, and the downstream inactivation of cell cycle inhibitor p27/Kip1 had been uncertain. In this study, we examined 52 cases of cribriform cancer by immunohistochemistry for PTEN, p27, and CD44 variant (v)7/8, and a subset of 17 cases by chromogenic in situ hybridization (ISH) using probes for PTEN or CDKN1B (gene for p27). The fractions of epithelial pixels positive by immunohistochemistry and ISH were digitally assessed for benign acini, high-grade prostatic intraepithelial neoplasia, and 8 morphologic patterns of cancer. Immunostaining results demonstrated that (1) PTEN loss was significant for fused small acini, cribriform-central cells, small cribriform acini, and Gleason grade 5 cells in comparison with other acini; (2) p27 loss was significant only for cribriform-peripheral cells and borderline significant for fused small acini in comparison with benign acini; and (3) CD44v7/8 showed expression loss in cribriform-peripheral cells; other comparisons were not significant. ISH showed that cribriform cancer had significant PTEN loss normalized to benign acini (P<.02), whereas Gleason 3 cancer or fused small acini did not. With CDKN1B, the degree of signal loss among various cancer morphologies was insignificant. In conclusion, molecular disparities emerged between the fused small acini and cribriform patterns of Gleason 4 cancer. PTEN or p27 loss as prognostic factors demands distinct assessment in the varieties of Gleason 4 cancer, and in the biphenotypic peripheral versus central populations in cribriform structures., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Injury risk curves from biomechanical experimental data analysis are used in automotive studies to improve crashworthiness and advance occupant safety. Metrics such as acceleration and deflection coupled with outcomes such as fractures and anatomical disruptions from impact tests are used in simple binary regression models. As an improvement, the International Standards Organization suggested a different approach. It was based on survival analysis. While probability curves for side-impact-induced thorax and abdominal injuries and frontal impact-induced foot-ankle-leg injuries are developed using this approach, deficiencies are apparent. The objective of this study is to present an improved, robust and generalizable methodology in an attempt to resolve these issues. It includes: (a) statistical identification of the most appropriate independent variable (metric) from a pool of candidate metrics, measured and or derived during experimentation and analysis processes, based on the highest area under the receiver operator curve, (b) quantitative determination of the most optimal probability distribution based on the lowest Akaike information criterion, (c) supplementing the qualitative/visual inspection method for comparing the selected distribution with a non-parametric distribution with objective measures, (d) identification of overly influential observations using different methods, and (e) estimation of confidence intervals using techniques more appropriate to the underlying survival statistical model. These clear and quantified details can be easily implemented with commercial/open source packages. They can be used in retrospective analysis and prospective design of experiments, and in applications to different loading scenarios such as underbody blast events. The feasibility of the methodology is demonstrated using post mortem human subject experiments and 24 metrics associated with thoracic/abdominal injuries in side-impacts., (Published by Elsevier Ltd.)