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Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies., (© 2024 Wiley Periodicals LLC.)

Background: Abuse of fentanyl and its analogs is a major contributor to the opioid overdose epidemic in the United States, but detecting and quantifying trace amounts of such drugs remains a challenge without resorting to sophisticated mass spectrometry-based methods., Methods: A sensitive immunoassay with a sub-picogram limit of detection for fentanyl and a wide range of fentanyl analogs has been developed, using a novel high-affinity antibody fused with NanoLuc, a small-size luciferase that can emit strong and stable luminescence. When used with human urine samples, the assay has a sub-picogram limit of detection for fentanyl, with results fully concordant with LC-MS., Results: When applied to clinical samples, the novel chemiluminescence immunoassay can detect low positive fentanyl missed by routine screening immunoassays, with a limit of detection of 0.8 pg/mL in human urine. When applied to environmental samples, the assay can detect levels as low as 0.25 pg fentanyl per inch2 of environment surface. Assay turnaround time is less than 1 h, with inexpensive equipment and the potential for high-throughput automation or in-field screening., Conclusions: We have established a novel assay that may have broad applications in clinical, environmental, occupational, and forensic scenarios for detection of trace amounts of fentanyl and its analogs., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Several dermatologic concerns are known to disproportionally affect transgender and gender-diverse (TGD) adults, but little is known about dermatologic conditions in TGD youth. This study assesses the prevalence of acne, androgenic alopecia, scarring from gender-affirming procedures, and eczema in pediatric TGD patients seen at Boston Children's Hospital between April 2021 and April 2022. The results demonstrate that, for TGD youth, the studied dermatologic concerns are common, referral rates to dermatology are low, and acne is significantly associated with testosterone use. Future studies should examine additional dermatologic concerns and barriers to accessing dermatologic care for this historically underserved population., (© 2024 Wiley Periodicals LLC.)

Universal depression screening in adolescent primary care often encompasses questions about suicide risk. We conducted a retrospective chart review of well-child visits where adolescents (ages 13-17.9) had endorsed self-injurious thoughts and behaviors or suicidal ideation. The goal was to investigate primary care providers' follow-up actions, including documentation, further assessment, and referrals. Over 3-quarters of the progress notes showed evidence of further assessment, and two-thirds documented same-day actions, including mental health referrals, emergency department referrals, safety plans, medication changes, primary-care follow-up, and talking to parents. Actions varied by depression severity. Cases without interventions often had justifications. Owing to the variety of possible meanings and severity underlying positive screens, providers implemented an array of interventions, using clinical judgment to tailor actions to patients' individual needs and preferences. From these observations, we propose that standardized guidelines for suicide risk screening and follow-up should involve a clinical assessment and individualized treatment planning., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

There are limited therapeutic options for patients with advanced prostate cancer (PCa). We previously found that heat shock factor 1 (HSF1) expression is increased in PCa and is an actionable target. In this manuscript, we identify that HSF1 regulates the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystathionine-β-synthase (CBS). We find that HSF1 directly binds the CBS gene and upregulates CBS mRNA levels. Targeting CBS decreases PCa growth and induces tumor cell death while benign prostate cells are largely unaffected. Combined inhibition of HSF1 and CBS results in more pronounced inhibition of PCa cell proliferation and reduction of transsulfuration pathway metabolites. Combination of HSF1 and CBS knockout decreases tumor size for a small cell PCa xenograft mouse model. Our study thus provides new insights into the molecular mechanism of HSF1 function and an effective therapeutic strategy against advanced PCa., (© 2024. The Author(s).)

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.

Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10 -5 ), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families., (© 2023. The Author(s).)

Introduction: Early enteral feeding in critically ill/injured patients promotes gut integrity and immunocompetence and reduces infections and intensive care unit/hospital stays. Aeromedical evacuation (AE) often takes place concurrently. As a result, AE and early enteral feeding should be inseparable., Materials and Methods: This retrospective descriptive study employed AE enteral nutrition (EN) data (2007-2019) collected from patients who were U.S. citizens and mechanically ventilated. The dataset was created from the En Route Critical Care, Transportation Command Regulating and Command and Control Evacuation System, and Theater Medical Data Store databases. Comparisons were performed between patients extracted and patients not extracted, patients treated with EN and patients treated without EN, and within the EN group, between AE Fed and AE Withheld. The impact of the nutrition support in the Joint Trauma System Clinical Practice Guidelines (CPG) was assessed using the 'before' and 'after' methodology., Results: An uptick in feeding rates was found after the 2010 CPG, 15% → 17%. With the next two CPG iterations, rates rose significantly, 17% → 48%. Concurrently, AE feeding holds rose significantly, 10% → 24%, later dropping to 17%. In addition, little difference was found between those patients not enterally fed preflight and those enterally fed across collected demographic, mission, and clinical parameters. Likewise, no difference was found between those enterally fed during AE and those withheld. Yet, 83% of the study's patients were not fed, and 18% of those that were fed had feeding withheld for AE., Conclusions: It appeared that the Clinical Practice Guidelines (CPGs) reinforced the value of feeding, but may well have sensitized to the threat of aspiration. It also appeared that early enteral feeding was underprescribed and AE feeding withholds were overprescribed. Consequently, an algorithm was devised for the Theater Validating Flight Surgeon, bearing in mind relevant preflight/inflight/clinical issues, with prescriptions designed to boost feeding, diminish AE withholding, and minimize complications., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With increased prevalence and duration of pediatric mental health boarding that disparately impacts transgender and gender diverse (TGD) youth, it is critical to consider disparities that TGD youth experience in accessing mental health care. Although mental health care for TGD youth has long been considered specialty care, frontline, primary medical, and mental health clinicians must be equipped to serve TGD patients' psychiatric needs. Inequities that TGD youth face require examination and intervention at multiple levels, including societal discrimination, lack of culturally responsive primary mental health care, and barriers to gender-affirming care in emergency departments and psychiatric inpatient units.

Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression. © 2023 The Pathological Society of Great Britain and Ireland., (© 2023 The Pathological Society of Great Britain and Ireland.)

Pediatric hydrocephalus, the leading reason for brain surgery in children, is characterized by enlargement of the cerebral ventricles classically attributed to cerebrospinal fluid (CSF) overaccumulation. Neurosurgical shunting to reduce CSF volume is the default treatment that intends to reinstate normal CSF homeostasis, yet neurodevelopmental disability often persists in hydrocephalic children despite optimal surgical management. Here, we discuss recent human genetic and animal model studies that are shifting the view of pediatric hydrocephalus from an impaired fluid plumbing model to a new paradigm of dysregulated neural stem cell (NSC) fate. NSCs are neuroprogenitor cells that comprise the germinal neuroepithelium lining the prenatal brain ventricles. We propose that heterogenous defects in the development of these cells converge to disrupt cerebrocortical morphogenesis, leading to abnormal brain-CSF biomechanical interactions that facilitate passive pooling of CSF and secondary ventricular distention. A significant subset of pediatric hydrocephalus may thus in fact be due to a developmental brain malformation leading to secondary enlargement of the ventricles rather than a primary defect of CSF circulation. If hydrocephalus is indeed a neuroradiographic presentation of an inborn brain defect, it suggests the need to focus on optimizing neurodevelopment, rather than CSF diversion, as the primary treatment strategy for these children., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An understanding of the molecular features associated with prostate cancer progression (PCa) and resistance to hormonal therapy is crucial for the identification of new targets that can be utilized to treat advanced disease and prolong patient survival. The glycome, which encompasses all sugar polymers (glycans) synthesized by cells, has remained relatively unexplored in the context of advanced PCa despite the fact that glycans have great potential value as biomarkers and therapeutic targets due to their high density on the cell surface. Using imaging mass spectrometry (IMS), we profiled the N-linked glycans in tumor tissue derived from 131 patients representing the major disease states of PCa to identify glycosylation changes associated with loss of tumor cell differentiation, disease remission, therapy resistance and disease recurrence, as well as neuroendocrine (NE) differentiation which is a major mechanism for therapy failure. Our results indicate significant changes to the glycosylation patterns in various stages of PCa, notably a decrease in tri- and tetraantennary glycans correlating with disease remission, a subsequent increase in these structures with the transition to therapy-resistant PCa, and downregulation of complex N-glycans correlating with NE differentiation. Furthermore, both nonglucosylated and monoglucosylated mannose 9 demonstrate aberrant upregulation in therapy-resistant PCa which may be useful therapeutic targets as these structures are not normally presented in healthy tissue. Our findings characterize changes to the tumor glycome that occur with hormonal therapy and the development of castration-resistant PCa (CRPC), identifying several glycan markers and signatures which may be useful for diagnostic or therapeutic purposes., (© 2023. The Author(s).)

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity., Methods: A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses., Results: Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05)., Conclusions: Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dysfunction of motile cilia in ependymal cells has been proposed to be a pathogenic cause of cerebrospinal fluid (CSF) overaccumulation leading to ventricular expansion in hydrocephalus, primarily based on observations of enlarged ventricles in mouse models of primary ciliary dyskinesia. Here, we review human and animal evidence that warrants a rethinking of the cilia hypothesis in hydrocephalus. First, we discuss neuroembryology and physiology data that do not support a role for ependymal cilia as the primary propeller of CSF movement across the ventricles in the human brain, particularly during in utero development prior to the functional maturation of ependymal cilia. Second, we highlight that in contrast to mouse models, motile ciliopathies infrequently cause hydrocephalus in humans. Instead, gene mutations affecting motile cilia function impact not only ependymal cilia but also motile cilia found in other organ systems outside of the brain, causing a clinical syndrome of recurrent respiratory infections and situs inversus, symptoms that do not typically accompany most cases of human hydrocephalus. Finally, we postulate that certain cases of hydrocephalus associated with ciliary gene mutations may arise not necessarily just from loss of cilia-generated CSF flow but also from altered neurodevelopment, given the potential functions of ciliary genes in signaling and neural stem cell fate beyond generating fluid flow. Further investigations are needed to clarify the link between motile cilia, CSF physiology, and brain development, the understanding of which has implications for the care of patients with hydrocephalus and other related neurodevelopmental disorders., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although immunocompromised patients have a higher risk of developing cutaneous squamous cell carcinomas, it is unknown whether immune status is an independent risk factor for poor outcomes., Objective: To compare cutaneous squamous cell carcinoma outcomes in immunocompromised and immunocompetent patients when controlling for T-stage., Methods: We performed a retrospective cohort study at 2 tertiary care centers, examining 989 primary tumors from 814 immunocompromised patients (solid organ transplant: 259 [31.7%], chronic lymphocytic leukemia: 113 [13.9%]) and 6608 tumors from 4198 immunocompetent patients. Our primary outcome was the composite of disease-specific death or tumor metastasis ("poor outcomes")., Results: Immunocompromised patients had 50% more high T-stage tumors (ie, Brigham and Women's Hospital stage T2b and T3), than immunocompetent patients (3.3% vs 4.9%, respectively; P < .001). Significant predictors of poor outcomes included tumor stage (sub hazards ratio [SHR], 14.8 for high T-stage tumors; 95% confidence interval [CI], 8.0-27.6; P < .001) and male sex (SHR, 2.3; 95% CI, 1.4-3.8; P = .002). Immune status was not a significant predictor (SHR, 1.04; 95% CI, 0.69-1.6; P = .85)., Limitations: This study is retrospective., Conclusion: Although immunocompromised patients had 50% more high T-stage tumors than immunocompetent patients, immunocompromised patients had a similar chance of metastasis and disease-specific death when adjusting for T-stage in our cohort of primary tumors., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Abstract: The associate membership of the American Association for the Surgery of Trauma (AAST) was established in 2019 to create a defined but incorporated entity within the larger AAST for the next generation of acute care surgeons. The Associate Member Council (AMC) was subsequently established in 2020 to provide the new AM with an elected group of leaders who would represent them within the AAST. In its inaugural year, this cohort of junior faculty and surgical trainees had developed for the AM a set of bylaws, a mission statement, a strategic vision, and a succession plan. The experience of the AAST AMC is exemplary of what can be accomplished with collaboration, mentorship, innovation, and tenacity. It has the potential to serve as a template for the creation and vitalization of future professional groups. In this piece, the AMC proposes a blueprint for the successful conception of a new organization., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

A stroke volume of arterial blood that arrives to the brain housed in the rigid cranium must be matched over the cardiac cycle by an equivalent volume of ejected venous blood. We hypothesize that the brain maintains this equilibrium by organizing coherent arterial and venous pulse waves. To test this hypothesis, we applied wavelet computational methods to diagnostic cerebral angiograms in four human patients, permitting the capture and analysis of cardiac frequency phenomena from fluoroscopic images acquired at faster than cardiac rate. We found that the cardiac frequency reciprocal phase of a small region of interest (ROI) in a named artery predicts venous anatomy pixel-wise and that the predicted pixels reconstitute venous bolus passage timing. Likewise, a small ROI in a named vein predicts arterial anatomy and arterial bolus passage timing. The predicted arterial and venous pixel groups maintain phase complementarity across the bolus travel. We thus establish a novel computational method to analyze vascular pulse waves from minimally invasive cerebral angiograms and provide the first direct evidence of arteriovenous coupling in the intact human brain. This phenomenon of arteriovenous coupling may be a physiologic mechanism for how the brain precisely maintains mechanical equilibrium against volume displacement and kinetic energy transfer resulting from cyclical deformations with each heartbeat. The study also paves the way to study deranged arteriovenous coupling as an underappreciated pathophysiologic disturbance in a myriad of neurological pathologies linked by mechanical disequilibrium., Competing Interests: The wavelet angiography methods are described in United States patents 10,123,761, 10,653,379, and 11,123,035. Massachusetts General Hospital and W.E.B. Have assigned rights to these to Angiowave Imaging, Inc., in return for shares. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Koch, Duy, Grannan, Patel, Raymond, Agarwalla, Kahle and Butler.)

Background: Hormonal therapy targeting the androgen receptor inhibits prostate cancer (PCa), but the tumor eventually recurs as castration-resistant prostate cancer (CRPC)., Objective: To understand the mechanisms by which subclones within early PCa develop into CRPC., Design, Setting, and Participants: We isolated epithelial cells from fresh human PCa cases, including primary adenocarcinoma, locally recurrent CRPC, and metastatic CRPC, and utilized single-cell RNA sequencing to identify subpopulations destined to become either CRPC-adeno or small cell neuroendocrine carcinoma (SCNC)., Outcome Measurements and Statistical Analysis: We revealed dynamic transcriptional reprogramming that promotes disease progression among 23226 epithelial cells using single-cell RNA sequencing, and validated subset-specific progression using immunohistochemistry and large cohorts of publically available genomic data., Results and Limitations: We identified a small fraction of highly plastic CRPC-like cells in hormone-naïve early PCa and demonstrated its correlation with biochemical recurrence and distant metastasis, independent of clinical characteristics. We show that progression toward castration resistance was initiated from subtype-specific lineage plasticity and clonal expansion of pre-existing neuroendocrine and CRPC-like cells in early PCa., Conclusions: CRPC-like cells are present early in the development of PCa and are not exclusively the result of acquired evolutionary selection during androgen deprivation therapy. The lethal CRPC and SCNC phenotypes should be targeted earlier in the disease course of patients with PCa., Patient Summary: Here, we report the presence of pre-existing castration-resistant prostate cancer (CRPC)-like cells in primary prostate cancer, which represents a novel castration-resistant mechanism different from the adaptation mechanism after androgen deprivation therapy (ADT). Patients whose tumors harbor increased pre-existing neuroendocrine and CRPC-like cells may become rapidly resistant to ADT and may require aggressive early intervention., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Advanced and aggressive prostate cancer (PCa) depends on glutamine for survival and proliferation. We have previously shown that inhibition of glutaminase 1, which catalyzes the rate-limiting step of glutamine catabolism, achieves significant therapeutic effect; however, therapy resistance is inevitable. Here we report that while the glutamine carbon is critical to PCa survival, a parallel pathway of glutamine nitrogen catabolism that actively contributes to pyrimidine assembly is equally important for PCa cells. Importantly, we demonstrate a reciprocal feedback mechanism between glutamine carbon and nitrogen pathways which leads to therapy resistance when one of the two pathways is inhibited. Combination treatment to inhibit both pathways simultaneously yields better clinical outcome for advanced PCa patients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Dilation of the fluid-filled cerebral ventricles (ventriculomegaly) characterizes hydrocephalus and is frequently seen in autism and schizophrenia. Recent work suggests that the genomic study of congenital hydrocephalus may be unexpectedly fertile ground for revealing insights into neural stem cell regulation, human cerebrocortical development, and pathogenesis of neuropsychiatric disease., Competing Interests: Declaration of interests D.H.G. and C.A.W. are members of the Neuron advisory board. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Prostate Cancer (PCa) is the most commonly diagnosed malignancy and second leading cause of cancer-related mortality in men. With the use of next generation sequencing and proteomic platforms, new biomarkers are constantly being developed to both improve diagnostic sensitivity and specificity and help stratify patients into different risk groups for optimal management. In recent years, it has become well accepted that altered glycosylation is a hallmark of cancer progression and that the glycan structures resulting from these mechanisms show tremendous promise as both diagnostic and prognostic biomarkers. In PCa, a wide range of structural alterations to glycans have been reported such as variations in sialylation and fucosylation, changes in branching, altered levels of Lewis and sialyl Lewis antigens, as well as the emergence of high mannose "cryptic" structures, which may be immunogenic and therapeutically relevant. Furthermore, aberrant expression of galectins, glycolipids, and proteoglycans have also been reported and associated with PCa cell survival and metastasis. In this review, we discuss the findings from various studies that have explored altered N- and O- linked glycosylation in PCa tissue and body fluids. We further discuss changes in O -GlcNAcylation as well as altered expression of galectins and glycoconjugates and their effects on PCa progression. Finally, we emphasize the clinical utility and potential impact of exploiting glycans as both biomarkers and therapeutic targets to improve our ability to diagnose clinically relevant tumors as well as expand treatment options for patients with advanced disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors JH., (Copyright © 2021 Butler and Huang.)

Objective: To evaluate the role of discordant Day-3 follicle stimulating hormone (FSH) & anti-Müllerian hormone (AMH) levels in predicting pregnancy outcome after controlled ovarian stimulation (COS) followed by intrauterine insemination or timed intercourse., Methods: Retrospective study of 745 couples with regular menstrual cycles, at least one patent fallopian tube, and normal semen analysis that underwent infertility treatment between June 2013 and March 2017. Women with documented serum AMH and FSH levels (<10 (mIU/ml were considered normal), and undergo COS were studied. Clinical pregnancy rate is the cumulative pregnancy obtained after maximum of three cycles of COS with or without IUI., Results: As expected, patients with normal concordant AMH/FSH achieved a significantly ( p  < .01) higher pregnancy than all other groups. 22.4% of those with discordant normal AMH/abnormal FSH became pregnant while only 10.8% of those with discordant abnormal AMH/normal FSH levels did. 11.7% of patients with abnormal concordant values achieved pregnancy. Patients with discordant abnormal AMH/normal FSH were not statistically different ( p  = .084) from abnormal concordance AMH/FSH but significantly ( p  < .01) lower than normal concordant AMH/FSH. However, patients with discordant normal AMH/abnormal FSH were statistically different from both concordant normal and concordant abnormal AMH/FSH values ( p  < .04)., Conclusions: This study showed that both discordant abnormal Day-3 FSH and/or abnormal AMH serum levels, as well as concordant abnormal FSH and AMH values, were predictive of lower clinical pregnancy rates after COS. However, abnormal FSH with a normal AMH does not have as poor a prognosis as the presence of an abnormal AMH.

Background: Stereotactic needle biopsy remains the cornerstone for tissue diagnosis for tumors located in regions of the brain that are difficult to access through open surgery., Objective: We perform a meta-analysis of the literature to examine the relation between number of samples taken during biopsy and diagnostic yield, morbidity and mortality., Methods: We identified 2416 patients from 28 cohorts in studies published in PubMed database that studied stereotactic needle biopsies for tumor indications. Meta-analysis by proportions and meta-regression analyses were performed., Results: On meta-analysis, the morbidity profile of the published needle biopsy studies clustered into three groups: studies that performed < 3 samples (n = 8), 3-6 samples (n = 13), and > 6 samples during biopsy (n = 7). Pooled estimates for biopsy related morbidity were 4.3%, 16.3%, and 17% for studies reporting < 3, 3-6, and > 6 biopsy samples, respectively. While these morbidity estimates significantly differed (p < 0.001), the diagnostic yields reported for studies performing < 3 biopsies, 3-6 samples, and > 6 samples were comparable. Pooled estimates of diagnostic yield for these three groups were 90.4%, 93.8%, and 88.1%, respectively. Mortality did not significantly differ between studies reporting differing number of samples taken during biopsy., Conclusions: Our meta-analysis suggests that morbidity risk in needle biopsy is non-linearly associated with the number of samples taken. There was no association between the number of biopsies taken, and diagnostic yield or mortality., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Radiation therapy (RT) is used for pediatric craniopharyngioma in the definitive, adjuvant, or salvage settings. Proton RT may be useful owing to tumor proximity to eloquent anatomy. We report clinical outcomes for a large cohort treated with proton therapy., Methods: We conducted a retrospective review of pediatric patients (≤21 years) treated with surgery and proton therapy for craniopharyngioma between August 2002 and October 2018. Clinical characteristics, treatment course, and outcomes were recorded. Acute toxicity was graded using Common Terminology Criteria for Adverse Events, version 5.0. Late toxicity was assessed using neuroendocrine, neuro-ophthalmologic, and neuropsychological testing., Results: Among 77 patients, median age at diagnosis was 8.6 years (range, 1.3-20); median age at radiation was 9.6 years (range, 2.3-20.5). Most common presenting symptoms were headache (58%), visual impairment (55%), and endocrinopathy (40%). Patients underwent a median of 2 surgical interventions (range, 1-7) before protons. At initial surgery, 18% had gross total resection, 60% had subtotal resection, and 22% had biopsy/cyst decompression. Median RT dose was 52.2 Gy (relative biologic effectiveness). Common acute toxicities were headache (29%), fatigue (35%), and nausea/vomiting (12%). Only 4% developed any acute grade 3 toxicity. Nine patients experienced cyst growth requiring replanning or surgical decompression. At a median of 4.8 years from RT (range, 0.8-15.6), there were 6 local failures and 3 deaths, 2 related to disease progression. Effect of tumor and treatment contributed to late toxicity including Moyamoya syndrome (13%), visual impairment (40%), and endocrine deficiency requiring hormone replacement (94%). Subclinical decline in functional independence and adaptive skills in everyday life was detected at follow-up., Conclusions: Surgery and proton therapy results in excellent disease control for pediatric craniopharyngioma. Severe acute toxicity is rare. Late toxicities from tumor, surgery, and radiation remain prevalent. Endocrine and ophthalmology follow-up is necessary, and neuropsychological testing may identify patients at risk for treatment-related cognitive and adaptive functioning changes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The dysregulation of androgen receptor ( AR ) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 ( NDRG1 ) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro . Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 ( DNMT1 ) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

INTRODUCTION: Decompression sickness (DCS) can occur during unpressurized flight to altitudes >18,000 ft (FL180; 5486 m). To our knowledge, this has not been studied in general aviation (GA). This knowledge gap may have public health and safety implications because the most popular models of GA aircraft by sales volume are capable of flying >FL180. METHODS: Data from a 1-yr period in a commercial flight tracking database were analyzed to identify flights >FL180 in unpressurized, piston aircraft in the United States. Peak altitude and duration at that altitude were used to calculate DCS risk employing the U.S. Air Force (USAF) Altitude Decompression Sickness Risk Assessment Computer (ADRAC). Registration numbers were cross referenced in publicly available federal databases to identify any events that might be attributable to impairment due to DCS. A web-based survey of practices and associated symptoms was also made available to GA pilots through an online discussion forum. RESULTS: During the data collection period, 1696 flights occurred. The DCS risk was calculated to be 1.9 4.2%. There were 42 responses to the survey. Of these, 25 (59.5%) pilots reported having flown at altitudes >FL180 and 21 (84%) of them reported symptoms possibly attributable to DCS. None sought medical attention. No safety events were identified for any of the aircraft during the study period. CONCLUSION: The risk of DCS in the GA community is not zero. As GA aircraft performance profiles advance and sales increase, this may have significant implications from a public health and safety perspective. Further study is warranted. Harrison MF, Butler WP, Murad MH, Toups GN. Decompression sickness risk assessment and awareness in general aviation . Aerosp Med Hum Perform. 2021; 92(3):138145.

Prostate cancer (PCa) is a common cause of cancer-related mortality in men worldwide. Although most men are diagnosed with low grade, indolent tumors that are potentially curable, a significant subset develops advanced disease where hormone therapy is required to target the androgen receptor (AR). Despite its initial effect, hormone therapy eventually fails and the tumor progresses to lethal stages even through continued inhibition of AR. This review article focuses on the role of PCa cellular heterogeneity in therapy resistance and disease progression. Although AR-positive luminal-type cells represent the vast majority of PCa cells, there exists a minor component of AR-negative neuroendocrine (NE) cells that are resistant to hormonal therapy and are enriched by the treatment. In addition, it is now well accepted that a significant subset of hormonally treated tumors recur as small cell neuroendocrine carcinoma (SCNC), further highlighting the importance of targeting NE cells in addition to the more abundant luminal-type cancer cells. Although it has been long recognized that NE cells are present in PCa, their underlying function in benign prostate and molecular mechanisms contributing to PCa progression remains poorly understood. In this article, we review the morphology and function of NE cells in benign prostate and PCa as well as underlying molecular mechanisms. In addition, we review the major reported mechanisms for transformation from common adenocarcinoma histology to the highly lethal SCNC, a significant clinical challenge in the management of advanced PCa., (© The Author(s) 2021. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.)

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

Background: Complicated gallstone disease (CGD) is a common condition requiring intervention during pregnancy to avert adverse birth outcomes (ABO)., Methods: Cohort study using the California OSHPD 2007-2014 database. Records of pregnant patients were analyzed for gallbladder calculus within four months of delivery. Biliary system interventions were evaluated as the primary exposure., Results: Of 7,597 patients, those with CGD had a greater likelihood of biliary system procedures than those with uncomplicated gallstone disease (36.6% vs. 2.5%, p < 0.001). Patients with CGD also had increased odds of ABO (OR 2.02, 95% CI, 1.48-2.76). Compared to patients without biliary system procedures, those with interventions for gallstones had an OR of 3.46 (95% CI, 2.48-4.82) for ABO. After adjustment, biliary system intervention for CGD had an even greater risk of ABO (OR 4.26, 95% CI, 2.86-6.35)., Conclusions: The risk of ABO is significantly increased in women with CGD and intervention for gallstones., Competing Interests: Declaration of competing interest The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (Copyright © 2020. Published by Elsevier Inc.)

The development of prostate cancer (PCa) from androgen-deprivation therapy (ADT) sensitive to castration resistant (CRPC) seriously impacts life quality and survival of PCa patients. Emerging evidence shows that long noncoding RNAs (lncRNAs) play vital roles in cancer initiation and progression. However, the inherited mechanisms of how lncRNAs participate in PCa progression and treatment resistance remain unclear. Here, we found that a long noncoding RNA LINC00675 was upregulated in androgen-insensitive PCa cell lines and CRPC patients, which promoted PCa progression both in vitro and in vivo. Knockdown of LINC00675 markedly suppressed tumor formation and attenuated enzalutamide resistance of PCa cells. Mechanistically, LINC00675 could directly modulate androgen receptor's (AR) interaction with mouse double minute-2 (MDM2) and block AR's ubiquitination by binding to it. Meanwhile, LINC00675 could bind to GATA2 mRNA and stabilize its expression level, in which GATA2 could act as a co-activator in the AR signaling pathway. Notably, we treated subcutaneous xenografts models with enzalutamide and antisense oligonucleotides (ASO) targeting LINC00675 in vivo and found that targeting LINC00675 would benefit androgen-deprivation-insensitive models. Our findings disclose that the LINC00675/MDM2/GATA2/AR signaling axis is a potential therapeutic target for CRPC patients.

Dietary polyphenols are protective for chronic diseases. Their blood transport has not been well investigated. This work examines multiple classes of polyphenols and their interactions with albumin, lipoproteins, and red blood cell (RBC) compartments using four models and determines the % polyphenol in each compartment studied. The RBC alone model showed a dose-response polyphenol association with RBCs. A blood model with flavanones determined the % polyphenol that was inside RBCs and bound to the surface using a new albumin washing procedure. It was shown that RBCs can methylate flavanones. The whole blood model separated the polyphenol into four compartments with the aid of affinity chromatography. More polyphenols were found with albumin and lipoproteins (high-density lipoproteins and low-density lipoproteins) than with RBCs. In the plasma model, the polyphenols associated almost equally between lipoproteins and albumin. RBCs and lipoproteins are shown to be important reservoirs and transporters of polyphenols in blood.

Background: The aim of this study was to evaluate quetiapine-associated pulmonary complications (PC) in critically injured trauma patients., Methods: Injured adults admitted during 2016 to the ICU at a Level I trauma center were analyzed. Outcomes were evaluated by competing risks survival analysis., Results: Of 254 admissions, 40 (15.7%) had PC and 214 (84.3%) were non-events. PC patients were more severely injured, had longer hospital stays and were more likely to die. Patients administered quetiapine were more likely to develop PC and acquire PC earlier than those without quetiapine. Quetiapine was a positive risk factor for PC (sHR 2.24, p = 0.013). Stratification by ventilator use revealed non-ventilated patients administered quetiapine had the highest risk for PC (sHR 4.66, p = 0.099)., Conclusions: Quetiapine exposure in critically injured trauma patients was associated with increased risk of PC. Guidelines for treatment of delirium with quetiapine in critically injured trauma patients should account for this risk., Competing Interests: Declaration of competing interest The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Open repair of ruptured abdominal aortic aneurysm (rAAA) has shown improved outcomes at trauma centers. Whether the benefit of trauma center designation extends to endovascular repair of rAAA is unknown., Methods: Retrospective cohort study using the California Office of Statewide Health Planning and Development 2007 to 2014 discharge database to identify patients with rAAA. Data included demographic and admission factors, discharge disposition, International Classification of Diseases, Ninth Revision, Clinical Modification codes, and hospital characteristics. Hospitals were categorized by trauma center designation and teaching hospital status. The effect of repair type and trauma center designation (level I, level II, or other-other trauma centers and nondesignated hospitals) was evaluated to determine rates and risks of 9 postoperative complications, in-hospital mortality, and 30-day postdischarge mortality., Results: Of 1941 rAAA repair patients, 61.2% had open and 37.8% had endovascular; 1.0% had both. Endovascular repair increased over the study interval. Hospitals were 12.0% level I, 25.0% level II, and 63.0% other. A total of 48.7% of hospitals were teaching hospitals (level I, 100%; level II, 42.2%; and other, 41.8%). Endovascular repair was significantly more common at teaching hospitals (41.5% vs 34.3%, P < .001) and was the primary repair method at level I trauma centers ( P < .001). Compared with open repair, endovascular repair was protective for most complications and in-hospital mortality. The risk for in-hospital mortality was highest among endovascular patients at level II trauma centers (hazard ratio 1.67, 95% confidence interval [CI]: 0.95-2.92) and other hospitals (hazard ratio 1.66, 95% CI: 1.01-2.72)., Conclusions: Endovascular repair overall was associated with a lower risk of adverse outcomes. Endovascular repair at level I trauma centers had a lower risk of in-hospital mortality which may be a result of their teaching hospital status, organizational structure, and other factors. The weight of the contributions of such factors warrants further study.

Object: Spinal cord surgeries carry a high risk for significant neurological impairments. The initial techniques for spinal cord mapping emerged as an aid to identify the dorsal columns and helped select a safe myelotomy site in intramedullary tumor resection. Advancements in motor mapping of the cord have also been made recently, but exclusively with tumor surgery. We hereby present our experiences with dynamic mapping of the corticospinal tract (CST) in other types of spinal cord procedures that carry an increased risk of postoperative motor deficit, and thus could directly benefit from this technique., Case Reports: Two patients with intractable unilateral lower extremity pain due to metastatic disease of the sacrum and a thoraco-lumbar chordoma, respectively underwent thoracic cordotomy to interrupt the nociceptive pathways. A third patient with progressive leg weakness underwent cord untethering and surgical repair of a large thoracic myelomeningocele. In all three cases, multimodality intraoperative neurophysiologic testing included somatosensory and motor evoked potentials monitoring as well as dynamic mapping of the CST., Conclusion: CST mapping allowed safe advancement of the cordotomy probe and exploration of the meningocele sac with untethering of the anterior-lateral aspect of the cord respectively, resulting in postoperative preservation or improvement of motor strength from the pre-operative baseline. Stimulus thresholds varied likely with the distance between the stimulating probe and the CST as well as with the baseline motor strength in the mapped myotomes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Backgrounds: p53 is a tumor suppressor that prevents cancer onset and progression, and mutations in the p53 gene cause loss of the tumor suppressor function of the protein. The mutant p53 protein in tumor cells can form aggregates which contribute to the dominant-negative effect over the wild-type p53 protein, causing loss of p53 tumor suppression or gain of novel oncogenic functions. Mutations in p53 have been implicated in the pathogenesis of primary prostate cancer (PCa), and are often detected in recurrent and metastatic disease. Thus, targeting mutant p53 may constitute an alternative therapeutic strategy for advanced PCa for which there are no other viable options., Methods: In this study, we used immunoprecipitation, immunofluorescence, clonogenic survival, and cell proliferation assays, flow cytometric analysis and in vivo xenograft to investigate the biological effects of ReACp53, a cell-permeable peptide inhibitor of p53 aggregation, on mutant p53-carrying PCa cells., Results: Our results show that ReACp53 targets amyloid aggregates of mutant p53 protein and restores the p53 nuclear function as transcriptional factor, induces mitochondrial cell death and reduces DNA synthesis of mutant p53-carrying PCa cells; ReACp53 also inhibits xenograft tumor growth in vivo., Conclusions: The data presented here suggest a therapeutic potential of targeting mutant p53 protein in advanced PCa setting, which has a clinical impact for aggressive PCa with transforming how such tumors are managed.

Head direction (HD) cells, which fire action potentials whenever an animal points its head in a particular direction, are thought to subserve the animal's sense of spatial orientation. HD cells are found prominently in several thalamo-cortical regions including anterior thalamic nuclei, postsubiculum, medial entorhinal cortex, parasubiculum, and the parietal cortex. While a number of methods in neural decoding have been developed to assess the dynamics of spatial signals within thalamo-cortical regions, studies conducting a quantitative comparison of machine learning and statistical model-based decoding methods on HD cell activity are currently lacking. Here, we compare statistical model-based and machine learning approaches by assessing decoding accuracy and evaluate variables that contribute to population coding across thalamo-cortical HD cells., (Copyright © 2019 Xu, Wu, Winter, Mehlman, Butler, Simmons, Harvey, Berkowitz, Chen, Taube, Wilber and Clark.)

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR + luminal tumor cells and AR - neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR + luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)