Allosteric interactions prime androgen receptor dimerization and activation.

The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR hyperactivation and transcriptome expansion, in part, through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR domains and cofactors cooperate to bind DNA has remained elusive. Using single-particle cryo-electron microscopy, we isolated three conformations of AR bound to DNA, showing that AR forms a non-obligate dimer, with the buried dimer interface utilized by ancestral steroid receptors repurposed to facilitate cooperative DNA binding. We identify novel allosteric surfaces which are compromised in androgen insensitivity syndrome and reinforced by AR's oncoprotein cofactor, ERG, and by DNA-binding motifs. Finally, we present evidence that this plastic dimer interface may have been adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR's cooperative interactions translate to consequences in development and disease.

Author Correction: FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.

Structural Anomalies in Multifetal Gestations.

Multifetal gestations are at increased risk for structural anomalies relative to singletons. Determination of chorionicity is critical, as the risk is highest for monochorionic pregnancies. In a singleton gestation, counseling is structured around optimization of fetal outcomes and careful consideration of the patient's choices in management decisions. However, in multifetal gestations affected by a fetal anomaly, complex counseling with consideration for the pregnancy as a whole is necessary. We review the incidence of structural anomalies in twins and highlight unique considerations including selective termination for discordant anomalies. We emphasize the role of shared decision making between provider and patient.

Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG.

The androgen receptor (AR) is a type I nuclear hormone receptor and the primary drug target in prostate cancer due to its role as a lineage survival factor in prostate luminal epithelium. In prostate cancer, the AR cistrome is reprogrammed relative to normal prostate epithelium and particularly in cancers driven by oncogenic ETS fusion genes. The molecular basis for this change has remained elusive. Using purified proteins, we report a minimal cell-free system that demonstrates interdomain cooperativity between the ligand (LBD) and DNA binding domains (DBD) of AR, and its autoinhibition by the N terminus of AR. Furthermore, we identify ERG as a cofactor that activates AR's ability to bind DNA in both high and lower affinity contexts through direct interaction within a newly identified AR-interacting motif (AIM) in the ETS domain, independent of ERG's own DNA binding ability. Finally, we present evidence that this interaction is conserved among ETS factors whose expression is altered in prostate cancer. Our work highlights, at a biochemical level, how tumor-initiating ETS translocations result in reprogramming of the AR cistrome.

Applying the Rehabilitation Treatment Specification System to Functional Communication Treatment Approaches for Aphasia.

There are many different approaches to the rehabilitation of patients with aphasia, a communication disorder that affects a person's understanding and expression of spoken and written language. One approach called "functional communication interventions" aims to enhance communication success as opposed to solely improving linguistic abilities. This approach encompasses many skills (eg, gesturing) and factors (eg, access to communication supports) that support sending and receiving messages in "real-world" daily activities and environments. Functional communication treatments are highly diverse and not always well described. A framework that may provide structure to the description of functional communication interventions for aphasia is the Rehabilitation Treatment Specification System (RTSS). The RTSS was developed by an interdisciplinary research team to describe interventions across any rehabilitation discipline and in any setting or format. The RTSS uses a common language and a systematic approach to describing treatment and includes 3 connected elements-a single target, 1 or more ingredients, and a mechanism of action-that, taken together, attempt to explain how and why a treatment works. Although the RTTS has been described previously within the field of speech-language pathology, it has not yet been applied to the field of aphasiology. We applied the RTSS framework to a sample of peer-reviewed studies that represent functional communication treatments, including Promoting Aphasics' Communicative Effectiveness (PACE), modified Response Elaboration Training (M-RET), script training, conversation treatment, and communication partner training. We discuss both the advantages and disadvantages of using the RTSS framework to better understand the important elements of functional communication treatment approaches for aphasia.

Demystifying the Complexity of Aphasia Treatment: Application of the Rehabilitation Treatment Specification Systemx.

A considerable body of research supports the use of behavioral communication treatment as the standard of care for aphasia. In spite of robust progress in clinical aphasiology, many questions regarding optimal care remain unanswered. One of the major challenges to progress in the field is the lack of a common framework to adequately describe individual treatments, which, if available, would allow comparisons across studies as well as improved communication among researchers, clinicians, and other stakeholders. Here, we describe how aphasia treatment approaches can be systematically characterized using the Rehabilitation Treatment Specification System (RTSS). At the core of the RTSS is a tripartite structure that focuses on targets (the behavior that is expected to change as a result of treatment), ingredients (what a clinician does to affect change in the target), and mechanism(s) of action (why a given treatment works by linking the ingredients to the target). Three separate articles in the current issue specifically describe how the RTSS can be used to describe different kinds of aphasia treatment approaches: functional approaches, cognitive-linguistic approaches, and biological approaches. It is our hope that the application of the RTSS in clinical aphasiology will improve communication in published studies, grant proposals, and in the clinical care of persons with aphasia.

Prediction of Large-for-Gestational-Age Neonates by Different Growth Standards.

OBJECTIVE: Compare the accuracy of the Hadlock, the NICHD, and the Fetal Medicine Foundation (FMF) charts to detect large-for-gestational-age (LGA) and adverse neonatal outcomes (as a secondary outcome). METHODS: This is a secondary analysis from a prospective study that included singleton non-anomalous gestations with growth ultrasound at 26-36 weeks. LGA was suspected with estimated fetal weight > 90th percentile by the NICHD, FMF, and Hadlock charts. LGA was diagnosed with birth weight > 90th percentile. We tested the performance of these charts to detect LGA and adverse neonatal outcomes (neonatal intensive care unit admission, Ph < 7.1, Apgar <7 at 5 minutes, seizures, and neonatal death) by calculating the area under the curve, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: Of 1054 pregnancies, 123 neonates (12%) developed LGA. LGA was suspected in 58 (5.5%) by Hadlock, 229 (21.7%) by NICHD standard, and 231 (22%) by FMF chart. The NICHD standard (AUC: .79; 95% CI: .75-.83 vs. AUC .64; 95%CI: .6-.68; p = < .001) and FMF chart (AUC: .81 95% CI: .77-.85 vs. AUC .64; 95%CI: .6-.68; p = < .001) were more accurate than Hadlock. The FMF and NICHD had higher sensitivity (77.2 vs. 72.4 vs. 30.1%) but Hadlock had higher specificity for LGA (97.5 vs. 88.5 vs. 85.4%). All standards were poor predictors for adverse neonatal outcomes. CONCLUSIONS: The NICHD and the FMF standards may increase the detection rate of LGA in comparison to the Hadlock chart. However, this may increase obstetrical interventions.

Efficacy of Group Conversation Intervention in Individuals with Severe Profiles of Aphasia.

An estimated 390,000 to 520,000 individuals with severe aphasia (IWSA) currently live in the United States. IWSA experience profound social isolation, which is associated with a wide range of negative health outcomes, including mortality. Treatments for severe aphasia frequently focus on compensatory communication approaches or a discrete communication act rather than on participation-based treatment. The purpose of this study was to determine whether IWSA demonstrated improved performance on standardized language measures, patient-reported outcome measures, and connected speech samples as a result of client-centered conversation group treatment. Results of assessments conducted at pretreatment, posttreatment, and maintenance intervals were variable across participants. All participants demonstrated improvement in at least one of the outcome measures considered. Importantly, none of these measures fully captured how IWSA were able to convey their thoughts in supported conversation. The results lend support for the use of conversation treatment for, and for further study in, this subpopulation of individuals with aphasia.

Host-specific parvovirus evolution in nature is recapitulated by in vitro adaptation to different carnivore species.

Canine parvovirus (CPV) emerged as a new pandemic pathogen of dogs in the 1970s and is closely related to feline panleukopenia virus (FPV), a parvovirus of cats and related carnivores. Although both viruses have wide host ranges, analysis of viral sequences recovered from different wild carnivore species, as shown here, demonstrated that>95% were derived from CPV-like viruses, suggesting that CPV is dominant in sylvatic cycles. Many viral sequences showed host-specific mutations in their capsid proteins, which were often close to sites known to control binding to the transferrin receptor (TfR), the host receptor for these carnivore parvoviruses, and which exhibited frequent parallel evolution. To further examine the process of host adaptation, we passaged parvoviruses with alternative backgrounds in cells from different carnivore hosts. Specific mutations were selected in several viruses and these differed depending on both the background of the virus and the host cells in which they were passaged. Strikingly, these in vitro mutations recapitulated many specific changes seen in viruses from natural populations, strongly suggesting they are host adaptive, and which were shown to result in fitness advantages over their parental virus. Comparison of the sequences of the transferrin receptors of the different carnivore species demonstrated that many mutations occurred in and around the apical domain where the virus binds, indicating that viral variants were likely selected through their fit to receptor structures. Some of the viruses accumulated high levels of variation upon passage in alternative hosts, while others could infect multiple different hosts with no or only a few additional mutations. Overall, these studies demonstrate that the evolutionary history of a virus, including how long it has been circulating and in which hosts, as well as its phylogenetic background, has a profound effect on determining viral host range.

Integrating the iPad into an intensive, comprehensive aphasia program.

The proliferation of tablet technology and the development of apps to support aphasia rehabilitation offer increasing opportunities for speech-language pathologists in a clinical setting. This article describes the components of an Intensive Comprehensive Aphasia Program at Boston University and details how usage of the iPad (Apple Inc., Cupertino, CA) was incorporated. We describe how the iPad was customized for use in individual, dyadic, and group treatment formats and how its use was encouraged through home practice tasks. In addition to providing the participants with step-by-step instructions for the usage of each new app, participants had multiple opportunities for practice across various treatment formats. Examples of how the participants continued using their iPad beyond the program suggest how the usage of this device has generalized into their day-to-day life. An overall summary of performance on targeted linguistic measures as well as an analysis of functional and quality-of-life measures reveal statistically significant improvements pre- to posttreatment.

Efficacy of Aphasia Group Conversation Treatment via Telepractice on Language and Patient-Reported Outcome Measures.

PURPOSE: Conversation treatment for people with aphasia (PwA) can lead to significant changes in language impairment and quality of life. The COVID-19 pandemic has resulted in the greater use of telepractice treatment delivery. However, there is little evidence regarding the efficacy of telepractice conversation groups. This study investigated the effects of telepractice group conversation treatment on standardized measures of language function and socially oriented/patient-reported outcomes compared to in-person and no-treatment control data. METHOD: This study used a mixed within- and between-groups design (repeated measure/pre-post treatment), with a single-subject delayed treatment design (Shadish & Rindskopf, 2007) to establish baseline, pretreatment, and posttreatment periods for the telepractice group. Telepractice results pre- and posttreatment were compared with historical in-person and no-treatment control data obtained from a larger randomized control trial (RCT) from DeDe et al. (2019). The historical comparison data were a subset of RCT participants from the same location and included six in-person participants and seven no-treatment control group participants. RESULTS: Results of standardized testing conducted at baseline, pretreatment, and posttreatment intervals revealed significant improvement from pre- to posttreatment on repetition and picture description tasks for the telepractice group, and significant improvement from pre- to posttreatment on the Aphasia Communication Outcome Measure, total number of relevant utterances, and percentage of complete utterances for the in-person conversation group. No significant differences were observed in the no-treatment groups. CONCLUSIONS: In contrast to the no-treatment condition, both the in-person and telepractice conditions showed the benefits of conversation group treatment. The in-person treatment condition showed improvements in a wider number of outcome measures than the telepractice condition. Overall, the results prompt further research regarding telepractice group conversation treatment for PwA.

Using bibliotherapy to rebuild identity for people with aphasia: A book club experience.

BACKGROUND: Aphasia book clubs were developed to support connecting with literature and reading for pleasure within an aphasia-friendly environment. Bibliotherapy is an evidence-based therapeutic approach, in which a book is selected to address the challenges facing the reader. Its aim is to facilitate a deeper understanding of a lived experience in order to promote healing, strategy development, and adjustment. Aphasia book clubs provide an opportunity to discuss books about the challenges associated with aphasia. A recent book, Identity theft: Rediscovering ourselves after stroke recounts the stroke recovery story of Dr. Debra Meyerson and 22 other stroke survivors. Identity Theft focuses on the need to reconstruct positive identities despite remaining disabilities to facilitate rebuilding rewarding lives. The purpose of this study is to understand the impact of reading Identity Theft in an aphasia book club for people with aphasia (PwA). METHOD: 27 PwA read the book Identity Theft in one of four online aphasia book clubs offered by two universities. Weekly discussions were facilitated by graduate SLP students under the supervision of experienced clinicians. At the end of the 10 week program, semi-structured qualitative interviews were conducted with participants to understand the lived experience. Interviews were analyzed using reflexive thematic analysis. RESULTS: Analysis of the interview data generated four main themes and 13 subthemes. The main themes included: Mechanism for Reflection, Power of Community, Engaged Learning, and Therapeutic Environment. Interview extracts illustrate the way these themes support increasing self-efficacy and rebuilding a positive identity. CONCLUSION: The themes align positively with outcomes associated with the bibliotherapy process. Themes also integrate into a self-management model that promotes self-efficacy through education, support, awareness, problem solving and goal setting. Caveats included determining participant readiness to examine recovery issues and facilitator preparation. Aphasia book clubs surrounding psychosocial texts may help PwA reconstruct a positive post-stroke identity.

TAVR Beyond Fetal Viability: An Alternative to Preterm Delivery in Symptomatic Severe Aortic Stenosis.

A patient with structural valve degeneration of an aortic bioprosthesis with stenosis stage 3 underwent valve-in-valve transcatheter aortic valve replacement (TAVR) at 29 weeks with improvement. This is the first reported TAVR in the third trimester. TAVR may be an alternative to preterm delivery in cases of symptomatic aortic stenosis.

Neonatal outcomes and rationale for timing of birth in perinatal diabetes: a retrospective cohort study.

BACKGROUND: The American College of Obstetricians and Gynecologists recommends delivery in the 39th week of pregnancy for patients with pregestational and medication-controlled gestational diabetes with consideration for earlier delivery among those with poor glucose control. OBJECTIVE: We sought to evaluate the impact of birth before 39 weeks' gestation exclusively for diabetes-related indications on neonatal outcomes and clinician rationale for these recommendations. STUDY DESIGN: This was a retrospective cohort study of all singleton, nonanomalous pregnancies complicated by diabetes. Patients were identified through an obstetrical database containing information of 90,185 births from 2011 to 2021. Patients who delivered in a given week of gestation exclusively for diabetes-related indications were compared with ongoing pregnancies. Recommended births for other obstetrical indications were excluded from the diabetes-related indications cohorts. The primary outcome was neonatal intensive care unit admission. Secondary outcomes included neonatal intensive care unit length of stay, stillbirth, neonatal death, hypoglycemia, respiratory distress syndrome, and shoulder dystocia. For all births before 39 weeks' gestation, the electronic medical records were reviewed to confirm the rationale for the intervention for a diabetes-indicated condition. RESULTS: From the 90,185 recorded births that occurred in 2011 to 2021, 4750 patients with diabetes were identified. Of those, 30.5% (n=1449) had a recommended birth for a diabetes-related indications with 2.2% of those (n=32) occurring at 36 weeks' gestation, 7.9% (n=114) at 37 weeks' gestation, 9.7% (n=141) at 38 weeks' gestation, and 63.0% (n=913) at 39 weeks' gestation. Births that occurred at 36 and 37 weeks' gestation exclusively for diabetes-related indications had higher rates of neonatal intensive care unit admission than the respective ongoing pregnancies (62.5% vs 8.7%; P<.001 and 25.4% vs 7.2%; P<.001). There was no difference in neonatal intensive care unit admission for births at 38 or 39 weeks' gestation when compared with ongoing pregnancy. For neonates born at 36 and 37 weeks' gestation in comparison with ongoing pregnancies, the median neonatal intensive care unit length of stay was 11.0 vs 2.8 days, (P<.001) and 4.4 vs 2.6 days (P=.026), respectively. There were significantly increased rates of neonatal hypoglycemia and respiratory distress syndrome among births that occurred at 36, 37, and 38 weeks' gestation when compared with ongoing pregnancies. There were no differences in the rate of stillbirth in this cohort. Primary factors cited for early birth were poor glycemic control (71.4%), recommendation by a maternal-fetal medicine specialist (38.7%), and suspected fetal macrosomia (27.9%). Overall, 46.7%, 32.8%, and 20.6% of patients had 1, 2, or ≥3 indications, respectively, listed as rationale for early birth. Overall, few objective measures were used to recommend birth before 39 weeks' gestation owing to diabetes. CONCLUSION: In pregnancies complicated by diabetes, early birth exclusively for diabetes-related indications was associated with increased neonatal intensive care unit admission and length of stay and with neonatal morbidity. Little objective data are documented by clinicians to support their recommendations for early birth associated with diabetes. Additional clinical guidelines are needed to define suboptimal glucose control necessitating birth before 39 weeks' gestation.

Evaluation and Treatment of Urinary Incontinence in Women.

This review focuses on the diagnosis, evaluation, and treatment of urinary incontinence (UI). UI is a common diagnosis that is encountered among women in their lifetime. Stress, urge (overactive bladder), and overflow are the most commonly encountered types of incontinence, but anatomic and neurologic causes are important to rule out. There are many treatment options available for the management of UI, and most patients will benefit from conservative strategies including weight loss, timed voiding, fluid intake reduction, pelvic floor strengthening exercises, and medications. For those who do not achieve adequate improvement with conservative measures, surgical intervention can provide good symptom relief.

Birthweight and Apgar at 5 minutes of life for the prediction of severe neonatal outcomes in preterm prelabor rupture of membranes.

OBJECTIVE: The aim of our study was to investigate the predictive accuracy of clinical variables available after delivery for severe neonatal outcomes (SNO) in pregnancies complicated by PPROM. MATERIALS AND METHODS: This was a secondary analysis of a prospective cohort of pregnancies complicated by PPROM. We included expectant mothers from 13-46 years of age who were between 23 and 36 6/7 weeks of gestation. We excluded multiple gestations, complex fetal anomalies, those with fetal demise and outborn infants. Our primary outcome was a composite of SNO (respiratory distress syndrome, necrotizing enterocolitis, Intra-ventricular hemorrhage, sepsis, and death). The variables assessed where gestational age at delivery, birthweight, Apgar score at 5 min of life, Apgar <7 at 5 min of life, small for gestational age, sex, umbilical artery pH, and mode of delivery. Logistic regression was performed to evaluate the predictive accuracy of each of these variables. Stepwise multivariable logistic regression was utilized to assess the effect of variables with univariate analysis p value <.10 and those baseline characteristics with a statistically significant association with our composite score. RESULTS: We included 108 infants. SNO was diagnosed in 44 (41%) neonates. The Apgar score at 5 min (AUC = 0.89; p= <.001), the birthweight (AUC = 0.88; p= <.001), gestational age at delivery (AUC = 0.87; p= <.001), and the Apgar score < 7 at 5 min (AUC = 0.73; p= <0.001) were statistical significant predictors of SNO. Sex (p=.15), mode of delivery (p=.15), umbilical artery Ph (p=.28), SGA (p=.85) were not statistically significant predictors of SNO. After stepwise multivariable logistic regression only the Apgar at 5 min and birth weight remained statistically significant predictors for SNO (AUC = 0.94). CONCLUSIONS: In pregnancies complicated by PPROM the birthweight and the Apgar at 5 min of life are accurate predictors of a composite score of SNO. We acknowledge the need for larger and more diverse studies to corroborate our findings. BRIEF RATIONALE: We assessed the predictive accuracy of clinical variables available after delivery for severe neonatal outcomes in pregnancies complicated by PPROM. We found that the birthweight and the Apgar score at 5 min were accurate predictors of such outcomes in this population. Our results may aid providers in the counseling of premature infants born after PPROM.

A Randomized Controlled Trial of the Effects of Group Conversation Treatment on Monologic Discourse in Aphasia.

PURPOSE: Evidence has shown that group conversation treatment may improve communication and reduce social isolation for people with aphasia. However, little is known about the impact of conversation group treatment on measures of discourse. This project explored the impact of conversation treatment on measures of monologic discourse. METHOD: In this randomized controlled trial, 48 participants with chronic aphasia were randomly assigned to dyadic, large group, or control conditions. Conversation group treatment was provided for 1 hr, twice per week, for 10 weeks. Discourse samples were collected and coded at pretreatment, posttreatment, and 6-week maintenance. There were three narrative tasks: (a) Comprehensive Aphasia Test (CAT) picture description, (b) Cat Rescue Picture, and (c) Cinderella retell. All narratives were coded using the percent correct information units (percent CIUs), the CAT standardized narrative analysis method, and the complete utterance (CU) method. RESULTS: No significant changes were observed on percent CIU, which was the primary outcome measure. The treated groups demonstrated improvement on aspects of the CU method following treatment, whereas the control group did not. Significant changes were observed for other CIU measures and the CAT standardized narrative analysis in both the treated and control groups. CONCLUSIONS: The results suggest that the CU measures were more sensitive to the effects of conversation treatment in monologic discourse compared to CIU and CAT measures. Changes were more common in absolute rather than relative values, suggesting that conversation treatment impacts the overall amount of language produced rather than efficiency of production.

Disease- and Therapy-Specific Impact on Humoral Immune Responses to COVID-19 Vaccination in Hematologic Malignancies.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti-SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20-directed therapies, and anti-CD38/B-cell maturation antigen-directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not. Significance: Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577. This article is highlighted in the In This Issue feature, p. 549.

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.

Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.