BACKGROUND. Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival (OS) from endocrine therapies in castration resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. METHODS. Following generation and validation of a novel AR-V7 antibody for immunohistochemistry, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, full length AR (AR-FL) expression, response to therapy, and gene expression was determined. RESULTS. We demonstrated that AR-V7 protein is rarely expressed (<1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94% of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed suggesting mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical co-regulator of AR-V7 function. Finally, AR-V7 negative disease associated with better PSA responses (100% vs 54%; P = 0.03) and OS (74.3 vs 25.2mo, HR 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy). CONCLUSION. This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology, and to confirm its clinical significance.
Adam Sharp, Ilsa Coleman, Wei Yuan, Cynthia Sprenger, David Dolling, Daniel Nava Rodrigues, Joshua W. Russo, Ines Figueiredo, Claudia Bertan, George Seed, Ruth Riisnaes, Takuma Uo, Antje Neeb, Jonathan Welti, Colm Morrissey, Suzanne Carreira, Jun Luo, Peter S. Nelson, Steven P. Balk, Lawrence D. True, Johann De Bono, Stephen R. Plymate
BACKGROUND. Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling. Characterization of airway changes on computed tomography has been challenging due to the complexity of the recurring branching patterns, and this can be better measured using fractal dimensions. METHODS. We analyzed segmented airway trees of 8135 participants enrolled in the COPDGene cohort. The fractal complexity of the segmented airway tree was measured by the Airway Fractal Dimension (AFD) using the Minkowski-Bouligand box-counting dimension. We examined associations between AFD and lung function and respiratory morbidity using multivariable regression analyses. We further estimated the extent of peribronchial emphysema (%) within 5mm of the airway tree as this is likely to affect AFD. We classified participants into 4 groups based on median AFD and %peribronchial emphysema, and estimated survival. RESULTS. AFD was significantly associated with FEV1 (p<0.001) and FEV1/FVC (p<0.001) after adjusting for age, race, gender, smoking status, pack-years of smoking, body-mass-index, CT emphysema, air trapping, airway thickness, and CT scanner type. On multivariable analysis, AFD was also associated with respiratory-quality of life and six-minute walk distance, as well as exacerbations, lung function decline and mortality on longitudinal follow-up. We identified a subset of participants with AFDmedian who had worse survival compared with participants with high AFD and low peribronchial emphysema (adjusted HR = 2.72, 95%CI 2.20 to 3.35; p<0.001), a substantial number of whom were not identified by traditional spirometry severity grades. CONCLUSIONS. Airway fractal dimension as a measure of airway branching complexity and remodeling in smokers is associated with respiratory morbidity and lung function change, offers prognostic information additional to traditional CT measures of airway wall thickness, and can be used to estimate mortality risk.
Sandeep Bodduluri, Abhilash S. Kizhakke Puliyakote, Sarah E. Gerard, Joseph M. Reinhardt, Eric A. Hoffman, John D. Newell Jr., Hrudaya P. Nath, MeiLan K. Han, George R. Washko, Raúl San José Estépar, Mark T. Dransfield, Surya P. Bhatt
BACKGROUND. Injectable depot medroxyprogesterone acetate (DMPA) is one of the most popular contraception methods in areas of high HIV seroprevalence. Evidence is accumulating that use of DMPA might be associated with an increased risk of HIV-1 acquisition by women; however, mechanisms of this association are not completely understood. The goal of this study was to gain insight into mechanisms underlying the possible link between use of DMPA and risk of HIV-1 acquisition, exploring transcription profiling of ectocervical tissues. METHODS. Healthy women received either DMPA (n = 31) or combined oral contraceptive (COC), which has not been linked to an increased risk of HIV acquisition (n = 32). We conducted a comparative microarray-based whole-genome transcriptome profiling of human ectocervical tissues before and after 6 weeks of hormonal contraception use. RESULTS. The analysis identified that expression of 235 and 76 genes was significantly altered after DMPA and COC use, respectively. The most striking effect of DMPA, but not COC, was significantly altered expression (mostly downregulation) of many genes strategically involved in the maintenance of mucosal barrier function; the alterations, as indicated by Ingenuity Pathway Analysis (IPA), were most likely due to the DMPA-induced estrogen deficiency. Furthermore, IPA predicted that transcriptome alterations related to ectocervical immune responses were in general compatible with an immunosuppressive effect of DMPA, but, in some women, also with an inflammatory-like response. CONCLUSION. Our results suggest that impairment of cervicovaginal mucosal integrity in response to DMPA administration is an important mechanism contributing to the potential increased risk of HIV-1 acquisition in DMPA users. TRIAL REGISTRATION. ClinicalTrials.gov NCT01421368. FUNDING. This study was supported by the United States Agency for International Development (USAID) under Cooperative Agreement GPO-A-00-08-00005-00.
Irina A. Zalenskaya, Neelima Chandra, Nazita Yousefieh, Xi Fang, Oluwatosin E. Adedipe, Suzanne S. Jackson, Sharon M. Anderson, Christine K. Mauck, Jill L. Schwartz, Andrea R. Thurman, Gustavo F. Doncel
BACKGROUND. Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection. METHODS. Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed. RESULTS. Overall, 8.1% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMR mutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell–associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT. CONCLUSION. These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC. FUNDING. We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK.
Daniel Nava Rodrigues, Pasquale Rescigno, David Liu, Wei Yuan, Suzanne Carreira, Maryou B. Lambros, George Seed, Joaquin Mateo, Ruth Riisnaes, Stephanie Mullane, Claire Margolis, Diana Miao, Susana Miranda, David Dolling, Matthew Clarke, Claudia Bertan, Mateus Crespo, Gunther Boysen, Ana Ferreira, Adam Sharp, Ines Figueiredo, Daniel Keliher, Saud Aldubayan, Kelly P. Burke, Semini Sumanasuriya, Mariane Sousa Fontes, Diletta Bianchini, Zafeiris Zafeiriou, Larissa Sena Teixeira Mendes, Kent Mouw, Michael T. Schweizer, Colin C. Pritchard, Stephen Salipante, Mary-Ellen Taplin, Himisha Beltran, Mark A. Rubin, Marcin Cieslik, Dan Robinson, Elizabeth Heath, Nikolaus Schultz, Joshua Armenia, Wassim Abida, Howard Scher, Christopher Lord, Alan D’Andrea, Charles L. Sawyers, Arul M. Chinnaiyan, Andrea Alimonti, Peter S. Nelson, Charles G. Drake, Eliezer M. Van Allen, Johann S. de Bono
BACKGROUND. Evidence from rodent studies indicates that the sympathetic nervous system (SNS) regulates bone metabolism, principally via β2-adrenergic receptors (β2-ARs). Given conflicting human data, we used multiple approaches to evaluate the role of the SNS in regulating human bone metabolism. METHODS. (1) Bone biopsies were obtained from 19 young and 19 old women for assessment of ADRB1, ADRB2, and ADRB3 mRNA expression; (2) the relationship of β-blocker use to bone microarchitecture was assessed by high resolution-peripheral quantitative computed tomography in a population sample of 248 subjects; and (3) 155 postmenopausal women were randomized to one of five treatment groups for 20 weeks: placebo; propranolol, 20 mg twice a day (BID); propranolol, 40 mg BID; atenolol, 50 mg/d; and nebivolol, 5 mg/d. We took advantage of the β1-AR selectivity gradient of these drugs (propranolol [non-selective] << atenolol [relatively β1-AR selective] < nebivolol [highly β1-AR selective]) to define the β-AR selectivity for SNS effects on bone. RESULTS. (1) ADRB1and ADRB2, but not ADRB3, were expressed in human bone; (2) patients treated clinically with β1-AR selective blockers had better bone microarchitecture than non-users; and (3) relative to placebo, atenolol and nebivolol, but not propranolol, reduced the bone resorption marker serum C-telopeptide of type I collagen (by 19.5% and 20.6%, respectively; P < 0.01) and increased ultra-distal radius BMD (by 3.6% and 2.9%; P < 0.01 and P < 0.05, respectively). CONCLUSIONS. These three independent lines of evidence strongly support a role for adrenergic signaling in regulating bone metabolism in humans, principally via β1-ARs. TRIAL REGISTRATION. ClinicalTrials.gov NCT02467400. FUNDING. This research was supported by NIH grants AG004875, AR027065, and the Mayo Clinic CTSA (UL1 TR002377).
Sundeep Khosla, Matthew T. Drake, Tammie L. Volkman, Brianne S. Thicke, Sara J. Achenbach, Elizabeth J. Atkinson, Michael J. Joyner, Clifford J. Rosen, David G. Monroe, Joshua N. Farr
BACKGROUND. Intravenous immunoglobulin (IVIg), plasma exchange and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches to modulate IgG levels can however be associated with some severe adverse reactions and significant burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and convenient alternative for clearing pathogenic IgGs. METHODS. A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys. RESULTS. Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50% whilst multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or immunoglobulins other than IgG and no serious adverse events related to efgartigimod infusion were observed. CONCLUSION. Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases. TRIAL REGISTRATION. Clinicaltrials.gov NCT03457649. FUNDING. argenx bvba.
Peter Ulrichts, Antonio Guglietta, Torsten Dreier, Tonke van Bragt, Valérie Hanssens, Erik Hofman, Bernhardt Vankerckhoven, Peter Verheesen, Nicolas Ongenae, Valentina Lykhopiy, F. Javier Enriquez, JunHaeng Cho, Raimund J. Ober, E. Sally Ward, Hans de Haard, Nicolas Leupin
BACKGROUND. The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism and behaviour, and it is essential to health. Whereas time-of-day adapted therapy is increasingly reported to be highly successful, it needs to be personalized since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors including genetic predisposition, age, gender, environmental light levels and season. An easy and convenient diagnostic tool is currently missing. METHODS. To establish a validated test, we followed a three-stage biomarker development strategy: (i) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; (ii) these biomarkers were migrated to a clinically relevant gene expression-profiling platform (NanoString), and (iii) externally validated using an independent study with 28 early or late chronotypes. RESULTS. We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard dim light melatonin onset method at smaller monetary, time and sample number cost. CONCLUSION. The BodyTime assay provides a new diagnostic tool for personalization of healthcare according to the patient’s circadian clock. FUNDING. This study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.
Nicole Wittenbrink, Bharath Ananthasubramaniam, Mirjam Münch, Barbara Koller, Bert Maier, Charlotte Weschke, Frederik Bes, Jan de Zeeuw, Claudia Nowozin, Amely Wahnschaffe, Sophia Wisniewski, Mandy Zaleska, Osnat Bartok, Reut Ashwal-Fluss, Hedwig Lammert, Hanspeter Herzel, Michael Hummel, Sebastian Kadener, Dieter Kunz, Achim Kramer
BACKGROUND. A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3βHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients. METHODS. First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS. Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION. Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING. Prostate Cancer Foundation Challenge Award, National Cancer Institute.
Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Bo Hu, Tae Hyun Hwang, William Douglas Figg, Cody J. Peer, Caly Chien, Vadim S. Koshkin, Prateek Mendiratta, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi
BACKGROUND. The effect of a brief analytical treatment interruption (ATI) on the HIV-1 latent reservoir of individuals who initiate antiretroviral therapy (ART) during chronic infection is unknown. METHODS. We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI and at least 6 months of subsequent viral suppression in a clinical trial testing the effect of passive infusion of the broadly neutralizing Ab VRC01 during ATI. RESULTS. Measures of total HIV-1 DNA, cell-associated RNA, and infectious units per million cells (IUPM) (measured by quantitative viral outgrowth assay [QVOA]) were not statistically different before or after ATI. Phylogenetic analyses of HIV-1 env sequences from QVOA and proviral DNA demonstrated little change in the composition of the virus populations comprising the pre- and post-ATI reservoir. Expanded clones were common in both QVOA and proviral DNA sequences. The frequency of clonal populations differed significantly between QVOA viruses, proviral DNA sequences, and the viruses that reactivated in vivo. CONCLUSIONS. The results indicate that transient viremia from ATI does not substantially alter measures of the latent reservoir, that clonal expansion is prevalent within the latent reservoir, and that characterization of latent viruses that can reactivate in vivo remains challenging. TRIAL REGISTRATION. ClinicalTrials.gov NCT02463227 FUNDING. Funding was provided by the NIH.
D. Brenda Salantes, Yu Zheng, Felicity Mampe, Tuhina Srivastava, Subul Beg, Jun Lai, Jonathan Z. Li, Randall L. Tressler, Richard A. Koup, James Hoxie, Mohamed Abdel-Mohsen, Scott Sherrill-Mix, Kevin McCormick, E. Turner Overton, Frederic D. Bushman, Gerald H. Learn, Robert F. Siliciano, Janet M. Siliciano, Pablo Tebas, Katharine J. Bar
BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days with food intake held constant by controlled diet in an inpatient metabolic ward. In a non-randomized cross-over design, previously metreleptin-treated patients (n = 8) were continued on-metreleptin for five days, and off-metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naïve patients (n = 14), who were restudied after six months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcomes included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglycerides, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after starting metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11%, triglycerides by 41%, and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, lipolysis did not change independent of food intake, but decreased after six months on metreleptin on an ad libitum diet by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we showed that metreleptin improves insulin sensitivity, and decreases hepatic and circulating triglycerides, independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov, NCT01778556. FUNDING. This research was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases.
Rebecca J. Brown, Areli Valencia, Megan Startzell, Elaine Cochran, Peter J. Walter, H. Martin Garraffo, Hongyi Cai, Ahmed M. Gharib, Ronald Ouwerkerk, Amber B. Courville, Shanna Bernstein, Robert J. Brychta, Kong Y. Chen, Mary Walter, Sungyoung Auh, Phillip Gorden
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