A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer.

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers.

Allele-specific epigenetic activity in prostate cancer and normal prostate tissue implicates prostate cancer risk mechanisms.

Genome-wide association studies (GWASs) of prostate cancer have identified >250 significant risk loci, but the causal variants and mechanisms for these loci remain largely unknown. Here, we sought to identify and characterize risk-harboring regulatory elements by integrating epigenomes from primary prostate tumor and normal tissues of 27 individuals across the H3K27ac, H3K4me3, and H3K4me2 histone marks and FOXA1 and HOXB13 transcription factors. We identified 7,371 peaks with significant allele specificity (allele-specific quantitative trait locus [asQTL] peaks). Showcasing their relevance to prostate cancer risk, H3K27ac T-asQTL peaks were the single annotation most enriched for prostate cancer GWAS heritability (40×), significantly higher than corresponding non-asQTL H3K27ac peaks (14×) or coding regions (14×). Surprisingly, fine-mapped GWAS risk variants were most significantly enriched for asQTL peaks observed in tumors, including asQTL peaks that were differentially imbalanced with respect to tumor-normal states. These data pinpointed putative causal regulatory elements at 20 GWAS loci, of which 11 were detected only in the tumor samples. More broadly, tumor-specific asQTLs were enriched for expression QTLs in benign tissues as well as accessible regions found in stem cells, supporting a hypothesis where some germline variants become reactivated during or after transformation and can be captured by epigenomic profiling of the tumor. Our study demonstrates the power of allele specificity in chromatin signals to uncover GWAS mechanisms, highlights the relevance of tumor-specific regulation in the context of cancer risk, and prioritizes multiple loci for experimental follow-up.

Allele-Specific QTL Fine Mapping with PLASMA.

Although quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulation that are concordant with traditional QTLs but typically less susceptible to technical/environmental noise. However, existing methods for estimating causal variant probabilities (i.e., fine mapping) cannot produce valid estimates from asQTL signals due to complexities in linkage disequilibrium (LD). We introduce PLASMA (Population Allele-Specific Mapping), a fine-mapping method that integrates QTL and asQTL information to improve accuracy. In simulations, PLASMA accurately prioritizes causal variants over a wide range of genetic architectures. Applied to RNA-seq data from 524 kidney tumor samples, PLASMA achieves a greater power at 50 samples than conventional QTL-based fine mapping at 500 samples, with more than 17% of loci fine mapped to within five causal variants, compared to 2% by QTL-based fine mapping, and a 6.9-fold overall reduction in median credible set size compared to QTL-based fine mapping when applied to H3K27AC ChIP-seq from just 28 prostate tumor/normal samples. Variants in the PLASMA credible sets for RNA-seq and ChIP-seq were enriched for open chromatin and chromatin looping, respectively, at a comparable or greater degree than credible variants from existing methods while containing far fewer markers. Our results demonstrate how integrating AS activity can substantially improve the detection of causal variants from existing molecular data.

Effectiveness of physical activity interventions for improving depression, anxiety and distress: an overview of systematic reviews.

OBJECTIVE: To synthesise the evidence on the effects of physical activity on symptoms of depression, anxiety and psychological distress in adult populations. DESIGN: Umbrella review. DATA SOURCES: Twelve electronic databases were searched for eligible studies published from inception to 1 January 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews with meta-analyses of randomised controlled trials designed to increase physical activity in an adult population and that assessed depression, anxiety or psychological distress were eligible. Study selection was undertaken in duplicate by two independent reviewers. RESULTS: Ninety-seven reviews (1039 trials and 128 119 participants) were included. Populations included healthy adults, people with mental health disorders and people with various chronic diseases. Most reviews (n=77) had a critically low A MeaSurement Tool to Assess systematic Reviews score. Physical activity had medium effects on depression (median effect size=-0.43, IQR=-0.66 to -0.27), anxiety (median effect size=-0.42, IQR=-0.66 to -0.26) and psychological distress (effect size=-0.60, 95% CI -0.78 to -0.42), compared with usual care across all populations. The largest benefits were seen in people with depression, HIV and kidney disease, in pregnant and postpartum women, and in healthy individuals. Higher intensity physical activity was associated with greater improvements in symptoms. Effectiveness of physical activity interventions diminished with longer duration interventions. CONCLUSION AND RELEVANCE: Physical activity is highly beneficial for improving symptoms of depression, anxiety and distress across a wide range of adult populations, including the general population, people with diagnosed mental health disorders and people with chronic disease. Physical activity should be a mainstay approach in the management of depression, anxiety and psychological distress. PROSPERO REGISTRATION NUMBER: CRD42021292710.

Morbidity and mortality of fragility proximal humerus fractures: a retrospective cohort study of patients presenting to a level one trauma center.

PURPOSE: Fragility fractures are a significant source of morbidity and have high associated mortality. Identifying risk factors for poor outcomes is essential for guiding treatment and for setting expectations for patients and their families. Although fragility hip fractures have been abundantly explored, there is a paucity of information regarding proximal humerus fractures (PHFs). METHODS: We retrospectively review the electronic medical records of 379 patients who presented to a level 1 trauma center with a PHF secondary to a fall. Patient demographics, handedness, comorbidities, treatment, imaging data, follow-up data, and death date (if applicable) were recorded. RESULTS: Our cohort consisted of 279 females and 100 males with an average age of 71.4 years. Distribution of injuries was 178 left, 141 right, and 7 bilateral. Compared with handedness, 179 were ipsilateral, 141 were contralateral, and 59 were unknown. A total of 81.3% of injuries were treated nonoperatively, whereas 18.7% were managed surgically. One-year mortality was 17.4%, and 2-year mortality was 24.0%.Males demonstrated a 2.28 increased risk of 1-year mortality (P = .004). Patients who died within 1 year of fracture had significantly higher Charlson comorbidity index scores (P < .0001) and age (P = .0003). Risk of death was significantly lower in patients who underwent surgery compared with those who were treated nonoperatively (P = .01). Patients who used an assist device before fracture had 4.2 increased risk of 1-year mortality (P < .0001). Patients who presented from nursing homes or assisted living had a 2.1 increased risk of 1-year mortality (P = .02). Patients with severe liver disease had a 5.5 increased risk of 1-year mortality (P < .0001), and those with metastatic cancer had a 13.7 increased risk of 1-year mortality (P < .0001). Bilateral fractures, side of injury in relation to handedness, rehospitalization, Neer classification, and PCP follow-up within 30 days were not associated with increased mortality. CONCLUSIONS: Increased understanding risk factors for mortality after PHF will allow for more informed patient discussions regarding treatment outcomes and risk of death. Our data suggest that mortality at 1 year for fragility PHF is universally high regardless of risk factors. This risk is increased in patients who are older, functionally limited, or who have medical comorbidities. Our data demonstrate the importance of medical optimization of patients with a fragility PHF and underscore the importance of fall prevention in high-risk patients.

The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer.

BACKGROUND: Breast cancer 2 (BRCA2)-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. METHODS: A retrospective analysis of a single-institution cohort of men with castration-resistant, metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001 through 2015, 8081 adult men with prostate cancer who had a consultation and/or underwent treatment at Dana-Farber Cancer Institute provided blood samples and consented to analyses of biologic material and clinical records. A subgroup of 141 men received at least 2 doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These patients were categorized according to the absence or presence of pathogenic germline mutations in BRCA2 based on DNA sequencing from whole blood. The primary outcome was the response rate to carboplatin/docetaxel chemotherapy, defined according to a decline in prostate-specific antigen that exceeded 50% within 12 weeks of initiating this regimen. Associations between BRCA2 mutation status and response to carboplatin-based chemotherapy were tested using the Fisher exact test, with a 2-sided P value < .05 as the threshold for significance. RESULTS: Pathogenic germline BRCA2 variants were observed in 8 of 141 men (5.7%; 95% confidence interval, 2.5%-10.9%). Six of 8 BRCA2 carriers (75%) experienced prostate-specific antigen declines >50% within 12 weeks, compared with 23 of 133 noncarriers (17%; absolute difference, 58%; 95% confidence interval, 27%-88%; P < .001). Prostate cancer cell lines functionally corroborated these clinical findings. CONCLUSIONS: BRCA2-associated, castration-resistant prostate cancer is associated with a higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2-associated prostate cancer. Cancer 2017;123:3532-9. © 2017 American Cancer Society.

Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Postexposure Prophylaxis in Animal Models of Inhalational Anthrax.

The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative to Bacillus anthracis aerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery.

Efficacy Projection of Obiltoxaximab for Treatment of Inhalational Anthrax across a Range of Disease Severity.

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolized Bacillus anthracis spores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% compared to 0% and 0% for placebo (P = 0.0010 and P = 0.0013, respectively). Across four macaque studies, survival was 6.3% to 78.6% following 4 to 32 mg/kg obiltoxaximab. In two macaque studies, 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P = 0.0085, P = 0.0053, P = 0.0068). Pretreatment bacteremia and toxemia levels inversely correlated with survival. Overall, obiltoxaximab monotherapy neutralized PA and increased survival across the range of disease severity, indicating clinical benefit of toxin neutralization with obiltoxaximab in both early and late stages of inhalational anthrax.

The essential role of peripheral respiratory chemoreceptor inputs in maintaining breathing revealed when CO2 stimulation of central chemoreceptors is diminished.

Central sleep apnoea is a condition characterized by oscillations between apnoea and hyperpnoea during sleep. Studies in sleeping dogs suggest that withdrawal of peripheral chemoreceptor (carotid body) activation following transient ventilatory overshoots plays an essential role in causing apnoea, raising the possibility that sustaining carotid body activity during ventilatory overshoots may prevent apnoea. To test whether sustained peripheral chemoreceptor activation is sufficient to drive breathing, even in the absence of central chemoreceptor stimulation and vagal feedback, we used a vagotomized, decerebrate dual-perfused in situ rat preparation in which the central and peripheral chemoreceptors are independently and artificially perfused with gas-equilibrated medium. At varying levels of carotid body stimulation (CB PO2/PCO2: 40/60, 100/40, 200/15, 500/15 Torr), we decreased the brainstem perfusate PCO2 in 5 Torr steps while recording phrenic nerve activity to determine the central apnoeic thresholds. The central apnoeic thresholds decreased with increased carotid body stimulation. When the carotid bodies were strongly stimulated (CB 40/60), the apnoeic threshold was 3.6 ± 1.4 Torr PCO2 (mean ± SEM, n = 7). Stimulating carotid body afferent activity with either hypercapnia (60 Torr PCO2) or the neuropeptide pituitary adenylate cyclase-activating peptide restored phrenic activity during central apnoea. We conclude that peripheral stimulation shifts the central apnoeic threshold to very hypocapnic levels that would likely increase the CO2 reserve and have a protective effect on breathing. These data demonstrate that peripheral respiratory chemoreceptors are sufficient to stave off central apnoeas when the brainstem is perfused with low to no CO2.

Epigenomic charting and functional annotation of risk loci in renal cell carcinoma.

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.

Pro-inflammatory cytokines do not affect basal or hypoxia-stimulated discharge of rat vagal paraganglia.

Vagal paraganglia are structurally similar to the carotid body and are chemosensitive to reduction in the P(O(2)). We hypothesized that they may also mediate communication between the immune system and the central nervous system via pro-inflammatory cytokines or endotoxin. In vitro experiments with isolated superior laryngeal nerve (SLN) paraganglia were performed to test this hypothesis. We exposed the cells to increasing concentrations of interleukin-1ß, tumour necrosis factor-α or interleukin-6 (0.1, 0.3 and 1 ng ml(-1)) or bacterial lipopolysaccharide (LPS, 10 and 100 ng ml(-1)) during both normoxia ( P(O(2)) ≈ 100 mmHg) and hypoxia (P(O(2)) < 40 mmHg) whilst single-fibre recordings were made from the main SLN trunk using a glass suction electrode. The results of these experiments confirmed previous findings that these cells respond strongly to changes in P(O(2)), significantly increasing their discharge rate in response to hypoxia (from 0.71 ± 0.23 to 10.95 ± 1.74 Hz, P < 0.0001). However, neither the cytokines nor LPS had any significant effect on the baseline discharge rate of the SLN units at any concentration. When compared with time-matched controls, the cytokines and LPS also had no effect on the peak hypoxic discharge rate of the SLN (P = 0.59 and 0.65, respectively). In conclusion, neither the basal nor the hypoxic discharge rate of the SLN paraganglia is modulated by the inflammatory mediators tested above, suggesting that these structures are not the afferent limb of an 'immune reflex'.

Dispositional Mindfulness May Have Protected Athletes from Psychological Distress During COVID-19 in Australia.

Promoting athlete wellbeing has become a priority in elite sport, and the COVID-19 pandemic has accentuated the need for a comprehensive understanding of risk and protective factors. Existing sport research has not yet considered whether specific cognitive factors such as dispositional mindfulness and executive function may protect athletes against psychological distress. In a sample of high-performance Australian football athletes (n = 27), we administered measures of dispositional mindfulness (MAAS), executive function (AOSPAN; eStroop), and psychological distress (APSQ) at pre-season, coinciding with the initial (2020) COVID-19-related sport shutdown in Australia. Measures of executive function and psychological distress were re-administered at the end of the COVID-19 affected competitive season in 2020. Athletes reported significantly elevated psychological distress relative to previous estimates of distress among high-performance athletes established in prior studies. Executive functions, including working memory and inhibitory control were not significantly associated with psychological distress or dispositional mindfulness at either timepoint. However, baseline mindfulness was associated with reduced distress at both pre-season (r = -0.48, p = .03) and end of season (r = -0.56, p = .004), suggesting that dispositional mindfulness may have afforded protective buffering against symptoms of distress. Correlation data alone does not establish a directional connection from mindfulness to reduced distress, and future research is required to elucidate this association and/or establish the mechanism/s by which dispositional mindfulness may protect against psychological distress in this population.

Microfluidic-mediated self-assembly of phospholipids for the delivery of biologic molecules.

The encapsulation of biologic molecules using a microfluidic platform is a procedure that has been understudied but shows great promise from initial reported studies. The study focusses upon the encapsulation of bovine serum albumin (BSA) under various parameters and using multiple phospholipids to identify optimal conditions for the manufacturing of protein loaded lipid nanoparticles. Additionally, encapsulation of the enzyme trypsin (TRP) has been investigated to show the eligibility of the system to other biological medications. All liposomes were subject to rigorous physicochemical characterisation, including differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR), to document the successful synthesis of the liposomes. Drug-loaded liposome stability was investigated over a 28-day period at 5 °C and 37 °C, which showed encouraging results for 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) at all concentrations of BSA used. The sample containing 1 mg/ml BSA grew by only 10% over the study, which considering liposomes should be affected highly by biologic adsorption, shows great promise for the formulations. Encapsulation and in vitro release studies showed improved loading capacity for BSA compared to conventional methods, whilst maintaining a concise controlled release of the active pharmaceutical ingredient (API).

Instantaneous effects of mindfulness meditation on tennis return performance in elite junior athletes completing an implicitly sequenced serve return task.

Single-session meditation augmentation of sport-specific skill performance was tested with elite junior tennis athletes. Athletes completed one of two styles of mindfulness meditation (focused-attention or open-monitoring) or a control listening condition prior to performing an implicitly sequenced tennis serve return task involving the goal of hitting a target area placed on the service court. Unbeknownst to athletes, six distinct serves followed a repeating second-order conditional sequence for two task blocks before the sequence was altered in a third transfer block. Task performance was operationalized as serve return outcome and analyzed using beta regression modeling. Models analyzed group by block differences in the proportion of returned serves (i.e., non-aces), returns placed in the service court, and target hits. Contrary to previous laboratory findings, results did not support meditation-related augmentation of performance and/or sequence learning. In fact, compared to control, meditation may have impaired performance improvements and acquisition of serve sequence information. It is possible that the effects of single-session meditation seen in laboratory research may not extend to more complex motor tasks, at least in highly-trained adolescents completing a well-learned skill. Further research is required to elucidate the participant, task, and meditation-related characteristics that might promote single-session meditation performance enhancement.

Sport Participation and Subjective Outcomes of Health in Middle-Aged Men: A Scoping Review.

Although sport participation is intrinsically motivating and improves the physical health of middle-aged men, its influence on subjective health measures, such as health-related quality of life, self-rated health, or well-being is unclear. The purpose of this scoping review was to describe the existing literature that has assessed male sport participants and their subjective health. MEDLINE, Embase, Emcare, PsycInfo, SPORTDiscus, Cochrane Library, and Web of Science were searched, and reference lists of included studies were pearled. Included were original peer-reviewed studies reporting a marker of subjective health in males, 35 to 54 years (average), who participated in sport. The search identified 21 eligible articles, 18 quantitative, 2 mixed-methods, and 1 qualitative, from 13 different countries. Eighteen studies were cross-sectional. A broad range of outcomes were assessed, with the most common being quality of life/health-related quality of life (n = 6) and self-rated health (n = 6). Most studies assessing quality of life, health-related quality of life, or self-rated health demonstrated a positive association with sport participation, while sport participation was not related to measures of life satisfaction, flourishing, happiness or global well-being; however, limited studies examined these latter outcomes. Sport participation appears to be related to better select subjective health outcomes in middle-aged men. However, most available data are cross-sectional and thus causation cannot be determined. Randomized intervention trials are required to determine whether sport participation improves the subjective health of middle-aged men.Open Science Framework registration: https://osf.io/zypds.

Effectiveness of wearable activity trackers to increase physical activity and improve health: a systematic review of systematic reviews and meta-analyses.

Wearable activity trackers offer an appealing, low-cost tool to address physical inactivity. This systematic review of systematic reviews and meta-analyses (umbrella review) aimed to examine the effectiveness of activity trackers for improving physical activity and related physiological and psychosocial outcomes in clinical and non-clinical populations. Seven databases (Embase, MEDLINE, Ovid Emcare, Scopus, SPORTDiscus, the Cochrane Library, and Web of Science) were searched from database inception to April 8, 2021. Systematic reviews of primary studies using activity trackers as interventions and reporting physical activity, physiological, or psychosocial outcomes were eligible for inclusion. In total, 39 systematic reviews and meta-analyses were identified, reporting results from 163 992 participants spanning all age groups, from both healthy and clinical populations. Taken together, the meta-analyses suggested activity trackers improved physical activity (standardised mean difference [SMD] 0·3-0·6), body composition (SMD 0·7-2·0), and fitness (SMD 0·3), equating to approximately 1800 extra steps per day, 40 min per day more walking, and reductions of approximately 1 kg in bodyweight. Effects for other physiological (blood pressure, cholesterol, and glycosylated haemoglobin) and psychosocial (quality of life and pain) outcomes were typically small and often non-significant. Activity trackers appear to be effective at increasing physical activity in a variety of age groups and clinical and non-clinical populations. The benefit is clinically important and is sustained over time. Based on the studies evaluated, there is sufficient evidence to recommend the use of activity trackers.

Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets.

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer.

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana-Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.