Publications by authors named "Adrie Van Bokhoven"

47 Publications

"The Urinary Proteomic Profile Implicates Key Regulators for Urologic Chronic Pelvic Pain Syndrome (UCPPS): A MAPP Research Network Study".

Mol Cell Proteomics 2021 Nov 10:100176. Epub 2021 Nov 10.

Department of Urology, Boston Children's Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA.

Urologic chronic pelvic pain syndrome (UCPPS) is a condition of unknown etiology characterized by pelvic pain, and urinary frequency and/or urgency. As the proximal fluid of this syndrome, urine is an ideal candidate sample matrix for an unbiased study of UCPPS. In this study, a large, discovery-phase, TMT-based quantitative urinary proteomics analysis of 244 subjects was performed. The subjects included patients with UCPPS (n=82), healthy controls (HC) (n=94) and disparate chronic pain diseases, termed positive controls (PC) (n=68). Utilizing training and testing cohorts, we identified and validated a small and distinct set of proteins that distinguished UCPPS from HC (n=9) and UCPPS from PC (n=3). Validated UCPPS: HC proteins were predominantly ECM/ECM modifying or immunomodulatory/host defense in nature. Significantly varying proteins in the UCPPS: HC comparison were overrepresented by members of several dysregulated biological processes including decreased immune cell migration, decreased development of epithelial tissue and increased bleeding. Comparison with the PC cohort enabled evaluation of UCPPS-specific upstream regulators, contrasting UCPPS with other conditions that cause chronic pain. Specific to UCPPS were alterations in the predicted signaling of several upstream regulators, including alpha-catenin, IL6, EGF, and TGFB1, among others. These findings advance our knowledge of the etiology of UCPPS and inform potential future clinical translation into a diagnostic panel for UCPPS.
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http://dx.doi.org/10.1016/j.mcpro.2021.100176DOI Listing
November 2021

Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer.

Life (Basel) 2021 Aug 27;11(9). Epub 2021 Aug 27.

Division of Medical Oncology, Department of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits.
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http://dx.doi.org/10.3390/life11090884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465783PMC
August 2021

Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors.

J Natl Compr Canc Netw 2021 Aug 4. Epub 2021 Aug 4.

3Center for Rare Melanomas.

Background: Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands.

Patients And Methods: We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti-PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis.

Results: Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells.

Conclusions: In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland-directed therapies or surgical resection.
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http://dx.doi.org/10.6004/jnccn.2020.7800DOI Listing
August 2021

Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer.

Cancer Res 2021 06 1;81(12):3255-3269. Epub 2021 Feb 1.

Department of Pharmacology, University of Colorado Comprehensive Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.

Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT). RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with ephrinB2 FC protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy. SIGNIFICANCE: Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3255/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260469PMC
June 2021

Prospective Observational Study Revealing Early Pulmonary Function Changes Associated With Brigatinib Initiation.

J Thorac Oncol 2021 03 9;16(3):486-491. Epub 2020 Dec 9.

Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Introduction: Symptomatic early onset pulmonary events (EOPEs) were observed in 3% to 6% of patients within 1 week of starting brigatinib at 90 mg daily for 7 days followed by 180 mg daily. We conducted a prospective observational cohort study to measure pulmonary function changes on initiating brigatinib.

Methods: Patients initiating brigatinib were eligible. Pulmonary function test (PFT) with diffusing capacity for carbon monoxide (DLCO), Borg dyspnea scale, six-minute walk test, and blood draw for cytometry by time-of-flight were performed at baseline, day 2, and day 8 plus or minus day 15 of brigatinib. The primary end point was the incidence of PFT-defined EOPEs, prespecified as greater than or equal to 20% DLCO reduction from baseline. An interim analysis was performed owing to a higher than expected incidence of DLCO reduction.

Results: A total of 90% (nine of 10) experienced DLCO reduction with the nadir occurring on day 2 or day 8. Median DLCO nadir was -13.33% from baseline (range: -34.44 to -5.00). Three participants met the PFT-defined EOPE criteria. All patients, including these three, were asymptomatic, none required brigatinib interruption or dose reduction, and all patients escalated to 180 mg without further issues. Despite continued dosing, by day 15, all assessed patients experienced DLCO recovery. Dyspnea and six-minute walk test results did not correlate with DLCO changes. Patients with a PFT-defined EOPE had significantly higher levels of activated neutrophils at baseline and day 8.

Conclusions: DLCO reduction occurred in 90% during the first 8 days of brigatinib dosing without any related symptoms. DLCO improved in all six patients assessed at day 15 despite continued dosing and dose escalation. Pretreatment levels of neutrophil activation should be explored as a biomarker for developing EOPEs.
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http://dx.doi.org/10.1016/j.jtho.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920919PMC
March 2021

Association of Longitudinal Changes in Symptoms and Urinary Biomarkers in Patients with Urological Chronic Pelvic Pain Syndrome: A MAPP Research Network Study.

J Urol 2021 02 7;205(2):514-523. Epub 2020 Oct 7.

Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts.

Purpose: We analyzed a series of novel noninvasive urinary biomarkers for their ability to objectively monitor the longitudinal clinical status of patients with urological chronic pelvic pain syndrome.

Materials And Methods: Baseline, 6 and 12-month urine samples were collected (216) and used to quantify vascular endothelial growth factor, vascular endothelial growth factor (VEGF) receptor 1 (R1), neutrophil gelatinase associated lipocalin (NGAL), matrix metalloproteinase-2, matrix metalloproteinase (MMP)-9, and MMP-9/NGAL complex by enzyme-linked immunosorbent assays. Patient symptom changes were classified as improved, stable or worse using a functional clustering algorithm. Proportional odds models were used to evaluate the association between symptom change and urinary biomarkers.

Results: Across all sampled participants, longitudinal decreases in normalized VEGF concentration (pg/μg) were associated with pain severity improvement, and decreases in MMP-9, NGAL and VEGF-R1 concentration (pg/ml) as well as NGAL normalized concentration were associated with improved urinary symptoms. Longitudinal decreases in normalized VEGF-R1 were associated with pain improvement in patients with moderate widespreadness, no bladder symptoms and no painful filling. Lower baseline normalized VEGF-R1 concentration was associated with pain improvement in patients with pelvic pain only. Higher baseline MMP-9/NGAL levels were associated with pain and urinary improvement across all participants. Moreover, longitudinal increases in MMP-2 concentration was associated with improved pain in men and patients with painful filling.

Conclusions: Our results suggest these urinary biomarkers may be useful in monitoring urological chronic pelvic pain syndrome symptom changes with respect to both urinary severity and pain severity. With further testing, they may represent objective biological measures of urological chronic pelvic pain syndrome progression and/or resolution while also providing insight into the pathophysiology of urological chronic pelvic pain syndrome.
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http://dx.doi.org/10.1097/JU.0000000000001391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139408PMC
February 2021

Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).

J Thorac Oncol 2020 11 24;15(11):1748-1757. Epub 2020 Jul 24.

Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado; Tisch Cancer Institute, Mount Sinai Health System, New York, New York.

Introduction: Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use.

Methods: The two-stage validation used independent core laboratories, objective quality control standards, locked test parameters, and large multi-institutional specimen and data sets. The first stage validation confirmed a signature's ability to stratify patient survival. The second-stage validation determined which signature(s) optimally improved risk discrimination when added to baseline clinical predictors. Participants were prospectively enrolled in institutional (cohort I) or cooperative group (cohort II) biospecimen and data collection protocols. All cases underwent a central review of clinical, pathologic, and biospecimen parameters using objective criteria to determine final inclusion (cohort I: n = 249; cohort II: n = 234). Primary selection required that a signature significantly predict a 3-year survival after surgical resection in cohort I. Signatures meeting this criterion were further tested in cohort II, comparing risk prediction using baseline risk factors alone versus in combination with the signature.

Results: Male sex, advanced age, and higher stage were associated with shorter survival in cohort I and established a baseline clinical model. Of the three signatures validated in cohort I, one signature was validated in cohort II and statistically significantly enhanced the prognosis relative to the baseline model (C-index difference 0.122; p < 0.05).

Conclusions: These results represent the first rigorous validation of a test appropriate to direct adjuvant treatment or clinical trials for patients with lung squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.jtho.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278226PMC
November 2020

The Multidisciplinary Approach to The Study of Chronic Pelvic Pain (MAPP) Research Network*: Design and implementation of the Symptom Patterns Study (SPS).

Neurourol Urodyn 2020 08 23;39(6):1803-1814. Epub 2020 Jun 23.

Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Aims: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments.

Methods: This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol.

Results: Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing.

Conclusions: This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions.
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http://dx.doi.org/10.1002/nau.24423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025696PMC
August 2020

Analysis of viruses present in urine from patients with interstitial cystitis.

Virus Genes 2020 Aug 23;56(4):430-438. Epub 2020 May 23.

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA.

The question of whether some cases of interstitial cystitis may have an infectious etiology has been debated for some time. Previous studies have looked for the presence of certain specific viruses, but generally did not use the types of sensitive and unbiased approaches that are currently available. As part of the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network, we examined urine specimens from interstitial cystitis patients who provided specimens over time and also reported various symptoms at the time of urine collection. We first performed next-generation sequencing to look for the presence of viruses in urines, and detected two human polyomaviruses that are known to be excreted into urine, BKPyV and JCPyV. We were especially interested in BKPyV because it is a known cause of another bladder disease, hemorrhagic cystitis, in bone marrow transplant recipients. Further analysis of individual samples indicates a trend toward higher excretion of polyomaviruses in patients experiencing increased symptoms.
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http://dx.doi.org/10.1007/s11262-020-01767-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339973PMC
August 2020

Vitamin D Pathway and Other Related Polymorphisms and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial.

Cancer Prev Res (Phila) 2020 06 26;13(6):521-530. Epub 2020 Feb 26.

Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Vitamin D may influence prostate cancer risk, but evidence is inconsistent. We conducted a nested case-control study in the Prostate Cancer Prevention Trial (PCPT). Cases ( = 1,128) and controls ( = 1,205) were frequency matched on age, first-degree relative with prostate cancer, and PCPT treatment arm (finasteride/placebo); African-Americans were oversampled and case/control status was biopsy confirmed. We selected 21 SNPs in vitamin D-related genes , and ) to test genotype and genotype-treatment interactions in relation to prostate cancer. We also tested mean serum 25(OH)D differences by minor allele distributions and tested for serum 25(OH)D-genotype interactions in relation to prostate cancer risk. Log-additive genetic models (Bonferroni-corrected within genes) adjusted for age, body mass index, PSA, and family history of prostate cancer revealed a significant interaction between treatment arm and /rs222016 (finasteride OR = 1.37, placebo OR = 0.85; < 0.05), /rs222014 (finasteride OR = 1.36, placebo OR = 0.85; < 0.05), and /rs703842 (finasteride OR = 0.76, placebo OR = 1.10; < 0.05) among Caucasians, and /rs6599638 (finasteride OR = 4.68, placebo OR = 1.39; < 0.05) among African-Americans. rs1544410 and /rs703842 had significant treatment interactions for high-grade disease among Caucasians (finasteride OR = 0.81, placebo OR = 1.40; < 0.05 and finasteride OR = 0.70, placebo OR = 1.28; < 0.05, respectively). Vitamin D-related SNPs influenced serum 25(OH)D, but gene-serum 25(OH)D effect modification for prostate cancer was marginally observed only for /rs2248359. In conclusion, evidence that vitamin D-related genes or gene-serum 25(OH)D associations influence prostate cancer risk is modest. We found some evidence for gene-finasteride interaction effects for prostate cancer in Caucasians and African-Americans. Results suggest only minimal associations of vitamin D with total or high-grade prostate cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272271PMC
June 2020

Assessment of high-grade prostate cancer risk using prostate cancer biomarkers.

Can J Urol 2020 02;27(1):10080-10085

Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Introduction: To identify patients at risk of high-grade prostate cancer using prostate cancer biomarkers.

Materials And Methods: A total of 601 men were screened for prostate cancer in 2012, 2015, and 2016 using prostate cancer biomarkers: prostate health index (phi), 4KScore, and SelectMDx. The first two are blood tests that incorporate several PSA isoforms; SelectMDx measures mRNA levels of homeobox C6 and distal-less homeobox 1 in post-digital rectal examination urine samples. The performance of each biomarker was evaluated using cut off values based on published literature. Gleason Grade Group (GG) ≥ 2 is considered as high-grade prostate cancer.

Results: For patients with PSA < 1.5 ng/mL, none were at risk for GG ≥ 2 cancer based on SelectMDx > 0%, whereas 17.1% were at intermediate to high risk of finding GG ≥ 2 cancer with 4KScore ≥ 7.5%, and 3.5% were at risk of finding any prostate cancer with phi ≥ 36 at biopsy. For cut offs revised for finding men at high risk for GG ≥ 2 cancer at biopsy, only one patient with PSA < 1.5 ng/mL would be at risk with 4KScore ≥ 20% and none with phi ≥ 52.7. For patients with PSA 1.5 to 3.99 ng/mL, 2%, 8%, and 1% were at high risk for finding GG ≥ 2 cancer at biopsy based on phi, 4KScore, and SelectMDx, respectively.

Conclusions: Men with PSA < 1.5 ng/mL are at very low risk of finding high-grade prostate cancer at biopsy. However, some men with PSA between 1.5 to 3.99 ng/mL may be at intermediate to high risk for high-grade prostate cancer. Thus, primary care physicians could run biomarkers test and refer those with positive biomarker results to a specialist for further evaluation.
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February 2020

Distinct tumor microenvironments of lytic and blastic bone metastases in prostate cancer patients.

J Immunother Cancer 2019 11 8;7(1):293. Epub 2019 Nov 8.

Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.

The most common metastatic lesions of prostate cancer are in bone and can be classified into three distinct pathology subtypes: lytic, blastic, and an indeterminate mixture of both. We investigated a cohort of decalcified formalin-fixed and paraffin-embedded (FFPE) patient specimens from the bone that contained metastatic prostate cancer with lytic or blastic features. These tissue sections were utilized for immunohistochemistry (IHC) staining, isolation of RNA for gene expression, and Digital Spatial Profiling (DSP) of changes in both the tumor and microenvironment. A diverse set of unique immune cell populations and signaling pathways to both lytic and blastic types of prostate cancer metastases were present. In blastic lesions immune cells were enriched for pSTAT3 and components of the JAK-STAT pathway. In lytic-type lesions, immune cells were enriched for pAKT activity and components of the PI3K-AKT pathway. Enrichment for immune checkpoints including PD-L1, B7-H4, OX40L, and IDO-1 were identified in blastic prostate cancer, providing new therapeutic targets for patients with bone metastases. Biopsies could guide selection of patients into appropriate therapeutic interventions based on protein levels and RNA expression of desired targets in metastatic disease. Molecular pathology has been an excellent complement to the diagnosis, treatment, and management of primary tumors and could be successfully extended to patients with metastatic lesions.
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http://dx.doi.org/10.1186/s40425-019-0753-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839115PMC
November 2019

Urinary fungi associated with urinary symptom severity among women with interstitial cystitis/bladder pain syndrome (IC/BPS).

World J Urol 2020 Feb 26;38(2):433-446. Epub 2019 Apr 26.

Department of Microbiology and Immunology, Drexel College of Medicine, Philadelphia, PA, USA.

Purpose: To correlate the presence of fungi with symptom flares, pain and urinary severity in a prospective, longitudinal study of women with IC/BPS enrolled in the MAPP Research Network.

Methods: Flare status, pelvic pain, urinary severity, and midstream urine were collected at baseline, 6 and 12 months from female IC/BPS participants with at least one flare and age-matched participants with no reported flares. Multilocus PCR coupled with electrospray ionization/mass spectrometry was used for identification of fungal species and genus. Associations between "mycobiome" (species/genus presence, relative abundance, Shannon's/Chao1 diversity indices) and current flare status, pain, urinary severity were evaluated using generalized linear mixed models, permutational multivariate analysis of variance, Wilcoxon's rank-sum test.

Results: The most specific analysis detected 13 fungal species from 8 genera in 504 urine samples from 202 females. A more sensitive analysis detected 43 genera. No overall differences were observed in fungal species/genus composition or diversity by flare status or pain severity. Longitudinal analyses suggested greater fungal diversity (Chao1 Mean Ratio 3.8, 95% CI 1.3-11.2, p = 0.02) and a significantly greater likelihood of detecting any fungal species (OR = 5.26, 95% CI 1.1-25.8, p = 0.04) in high vs low urinary severity participants. Individual taxa analysis showed a trend toward increased presence and relative abundance of Candida (OR = 6.63, 95% CI 0.8-58.5, p = 0.088) and Malassezia (only identified in 'high' urinary severity phenotype) for high vs low urinary symptoms.

Conclusion: This analysis suggests the possibility that greater urinary symptom severity is associated with the urinary mycobiome urine in some females with IC/BPS.
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http://dx.doi.org/10.1007/s00345-019-02764-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815247PMC
February 2020

A Culture-Independent Analysis of the Microbiota of Female Interstitial Cystitis/Bladder Pain Syndrome Participants in the MAPP Research Network.

J Clin Med 2019 Mar 26;8(3). Epub 2019 Mar 26.

c/o Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

We surveyed urine microbiota of females diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) and matched control participants enrolled in the National Institutes of Health (NIH) Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network using the culture-independent methodology. Midstream urine specimens were analyzed with the Plex-ID molecular diagnostic platform that utilizes polymerase chain reaction⁻electrospray ionization⁻time-of-flight⁻mass spectrometry (PCR-ESI-TOF MS) to provide a comprehensive identification of bacterial and select fungal species. IC/BPS and control participants were evaluated for differences (presence, diversity, and abundance) in species and genus. Urine specimens obtained from 181 female IC/BPS and 182 female control participants detected a total of 92 species (41 genera). Mean (SD) species count was 2.49 (1.48) and 2.30 (1.28) among IC/BPS and control participants, respectively. Overall species composition did not significantly differ between IC/BPS and control participants at any level ( = 0.726 species level, = 0.222 genus level). IC/BPS participants urine trended to an overabundance of ( = 0.09) detected but had a lower prevalence of compared with control participants ( = 0.002). The relative abundance data analysis mirrored the prevalence data differences with no significant differences in most species or genus abundance other than and ( = 0.08 and = 0.001, respectively). No cause and/or effect conclusion can be drawn from this observation, but it suggests that a more comprehensive evaluation (vaginal, bowel, catheterized bladder and/or tissue-based specimens) of the lower urinary tract microbiota in IC/BPS patients is warranted.
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http://dx.doi.org/10.3390/jcm8030415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462969PMC
March 2019

Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients.

Cancer Med 2019 03 8;8(3):1110-1123. Epub 2019 Jan 8.

Cancer Biology Department, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.

African American men face a stark prostate cancer (PCa)-related health disparity, with the highest incidence and mortality rates compared to other races. Additional and innovative measures are warranted to reduce this health disparity. Here, we focused on the identification of a novel serum exosome-based "protein signature" for potential use in the early detection and better prognosis of PCa in African American men. Nanoparticle tracking analyses showed that compared to healthy individuals, exosome concentration (number/ml) was increased by ~3.2-fold (P ˂ 0.05) in the sera of African American men with PCa. Mass spectrometry-based proteomic analysis of serum exosomes identified seven unique and fifty-five overlapping proteins (up- or downregulated) in African Americans with PCa compared to healthy African Americans. Furthermore, ingenuity pathway analyses identified the inflammatory acute-phase response signaling as the top pathway associated with proteins loaded in exosomes from African American PCa patients. Interestingly, African American PCa E006AA-hT cells secreted exosomes strongly induced a proinflammatory M2-phenotype in macrophages and showed calcium response on sensory neurons, suggesting a neuroinflammatory response. Additionally, proteomic analyses showed that the protein Isoform 2 of Filamin A has higher loading (2.6-fold) in exosomes from African Americans with PCa, but a lesser loading (0.6-fold) was observed in exosomes from Caucasian men with PCa compared to race-matched healthy individuals. Interestingly, TCGA and Taylor's dataset as well as IHC analyses of PCa tissue showed a lower Filamin A expression in tissues of PCa patients compared with normal subjects. Overall, these results support the usefulness of serum exosomes to noninvasively detect inflammatory phenotype and to discover novel biomarkers associated with PCa in African American men.
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http://dx.doi.org/10.1002/cam4.1885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434210PMC
March 2019

Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network.

Nat Rev Urol 2019 03;16(3):187-200

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.

Urologic chronic pelvic pain syndrome (UCPPS), which encompasses interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, is characterized by chronic pain in the pelvic region or genitalia that is often accompanied by urinary frequency and urgency. Despite considerable research, no definite aetiological risk factors or effective treatments have been identified. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network uses a novel integrated strategy to characterize UCPPS as a systemic disorder that potentially involves multiple aetiologies. The first phase, MAPP I, included >1,000 participants who completed an intensive baseline assessment followed by a 12-month observational follow-up period. MAPP I studies showed that UCPPS pain and urinary symptoms co-vary, with only moderate correlation, and should be evaluated separately and that symptom flares are common and can differ considerably in intensity, duration and influence on quality of life. Longitudinal clinical changes in UCPPS correlated with structural and functional brain changes, and many patients experienced global multisensory hypersensitivity. Additionally, UCPPS symptom profiles were distinguishable by biological correlates, such as immune factors. These findings indicate that patients with UCPPS have objective phenotypic abnormalities and distinct biological characteristics, providing a new foundation for the study and clinical management of UCPPS.
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http://dx.doi.org/10.1038/s41585-018-0135-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800057PMC
March 2019

Preselection of Lung Cancer Cases Using FGFR1 mRNA and Gene Copy Number for Treatment With Ponatinib.

Clin Lung Cancer 2019 01 7;20(1):e39-e51. Epub 2018 Sep 7.

Division of Medical Oncology, University of Colorado, Aurora, CO.

Introduction: Preclinically, high epidermal growth factor receptor 1 (FGFR1) messenger RNA (FGFR1-MRNA) and FGFR1 amplification (FGFR1-AMP) predicted sensitivity to fibroblast growth factor receptor inhibitors in non-small-cell lung cancer and small-cell lung cancer cell lines. KRAS mutations did not preclude sensitivity.

Patients And Methods: Metastatic EGFR- and ALK-negative lung cancers were screened for FGFR1-MRNA by in-situ hybridization (ISH) and FGFR1-AMP by silver in-situ hybridization (SISH). Patients with positive findings were offered ponatinib, a multi-kinase inhibitor of FGFR1-4. Differences in overall survival (OS) between cohorts were assessed by the log-rank test. Association of FGFR1 positivity with clinicopathologic features were assessed by Fisher exact test and Kruskal-Wallis rank sum test.

Results: A total of 171 cases were prescreened: 9 (7.3%) of 123 SISH; 53 (42.1%) of 126 ISH; and 6 cases concordantly positive for SISH and ISH. SISH cases had fewer coincident KRAS mutations (P = .03) than SISH cases, and ISH cases had worse OS (P = .020) than ISH cases. Data distributions suggested a distinct higher positivity cut point for FGFR1 ISH (≥ 20%), occurring in 29 (23%) of 126 cases, was associated with small-cell lung cancer histology (P = .022), soft tissue metastases (P = .050) and shorter OS (P = .031). Four patients received ponatinib on study: All ISH by the initial cut point, 2 of 4 by higher cut point, 1 of 4 SISH. Tolerability was poor. The best response for the 2 higher ISH cases was stable disease and progressive disease for the 2 lower ISH cases.

Conclusion: Elevated FGFR1-MRNA is more common than FGFR1-AMP and associated with worse OS. Higher FGFR1 mRNA expression may be associated with a specific phenotype and is worthy of further exploration. Ponatinib's poor tolerance suggests further fibroblast growth factor receptor exploration in ISH cases should utilize more selective FGFR1 inhibitors.
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http://dx.doi.org/10.1016/j.cllc.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339510PMC
January 2019

Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma.

J Thorac Oncol 2019 01 22;14(1):25-36. Epub 2018 Sep 22.

Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado. Electronic address:

Objectives: Anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti-PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti-PD-1/PD-L1 immunotherapy-related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti-PD-1/PD-L1 treatment in early-stage SqCLC.

Methods: A total of 255 specimens from patients with early-stage SqCLC were identified within participating centers of the Strategic Partnering to Evaluate Cancer Signatures program. PD-L1 protein expression by immunohistochemistry was evaluated by using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer (Dako, Carpinteria, CA). Tumor mutation burden (TMB) was calculated on the basis of data from targeted genome sequencing. The T-effector and interferon gamma (IFN-γ) gene signature was determined from Affymetrix gene chip data (Affymetrix, Santa Clara, CA) from frozen specimens.

Results: The prevalence of PD-L1 expression was 9.8% at a tumor proportion score cutoff of at least 50%. PD-L1 mRNA and programmed cell death 1 ligand 2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells. PD-L1 protein expression on tumor-infiltrating immune cells was correlated with the T-effector and IFN-γ gene signature (p < 0.001), but not with TMB. For TCs, all of these biomarkers were independent of each other and neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes.

Conclusions: Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the cohort with early-stage SqCLC found them to be independent of each other, and none was associated with overall survival. Our results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on TCs and an adaptive mechanism on immune cells.
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http://dx.doi.org/10.1016/j.jtho.2018.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309634PMC
January 2019

Requirement for MUC5AC in KRAS-dependent lung carcinogenesis.

JCI Insight 2018 08 9;3(15). Epub 2018 Aug 9.

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

With more than 150,000 deaths per year in the US alone, lung cancer has the highest number of deaths for any cancer. These poor outcomes reflect a lack of treatment for the most common form of lung cancer, non-small cell lung carcinoma (NSCLC). Lung adenocarcinoma (ADC) is the most prevalent subtype of NSCLC, with the main oncogenic drivers being KRAS and epidermal growth factor receptor (EGFR). Whereas EGFR blockade has led to some success in lung ADC, effective KRAS inhibition is lacking. KRAS-mutant ADCs are characterized by high levels of gel-forming mucin expression, with the highest mucin levels corresponding to worse prognoses. Despite these well-recognized associations, little is known about roles for individual gel-forming mucins in ADC development causatively. We hypothesized that MUC5AC/Muc5ac, a mucin gene known to be commonly expressed in NSCLC, is crucial in KRAS/Kras-driven lung ADC. We found that MUC5AC was a significant determinant of poor prognosis, especially in patients with KRAS-mutant tumors. In addition, by using mice with lung ADC induced chemically with urethane or transgenically by mutant-Kras expression, we observed significantly reduced tumor development in animals lacking Muc5ac compared with controls. Collectively, these results provide strong support for MUC5AC as a potential therapeutic target for lung ADC, a disease with few effective treatments.
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http://dx.doi.org/10.1172/jci.insight.120941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129115PMC
August 2018

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer.

Breast Cancer Res 2018 08 2;20(1):82. Epub 2018 Aug 2.

Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.

Background: Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC.

Methods: This dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients.

Results: Forty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6-32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14-45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations.

Conclusions: Single-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies.

Trial Registration: ClinicalTrials.gov, NCT01639248 . Registered on July 12, 2012.
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http://dx.doi.org/10.1186/s13058-018-1014-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090978PMC
August 2018

Altered Cell-Cycle Control, Inflammation, and Adhesion in High-Risk Persistent Bronchial Dysplasia.

Cancer Res 2018 09 11;78(17):4971-4983. Epub 2018 Jul 11.

Department of Medicine/Division of Pulmonary Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Persistent bronchial dysplasia is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. In this study, we hypothesized that differences in gene expression profiles between persistent and regressive bronchial dysplasia would identify cellular processes that underlie progression to SCC. RNA expression arrays comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes [ANOVA, FDR ≤ 0.05). Thirty-one pathways showed significantly altered activity between the two groups, many of which were associated with cell-cycle control and proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Cultured persistent bronchial dysplasia cells exhibited increased expression of Polo-like kinase 1 (PLK1), which was associated with multiple cell-cycle pathways. Treatment with PLK1 inhibitor induced apoptosis and G-M arrest and decreased proliferation compared with untreated cells; these effects were not seen in normal or regressive bronchial dysplasia cultures. Inflammatory pathway activity was decreased in persistent bronchial dysplasia, and the presence of an inflammatory infiltrate was more common in regressive bronchial dysplasia. Regressive bronchial dysplasia was also associated with trends toward overall increases in macrophages and T lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of bronchial dysplasia. These results identify alterations in the persistent subset of bronchial dysplasia that are associated with high risk for progression to invasive SCC. These alterations may serve as strong markers of risk and as effective targets for lung cancer prevention. Gene expression profiling of high-risk persistent bronchial dysplasia reveals changes in cell-cycle control, inflammatory activity, and epithelial differentiation/cell-cell adhesion that may underlie progression to invasive SCC. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147150PMC
September 2018

The effect of digital rectal exam on the 4Kscore for aggressive prostate cancer.

Prostate 2018 05 19;78(7):506-511. Epub 2018 Feb 19.

University of Colorado, Anschutz Medical Campus, Aurora, Colorado.

Background: The 4Kscore is a new commercially available blood-based diagnostic test which predicts risk for aggressive, clinically significant prostate cancer on prostate biopsy. The 4Kscore is currently restricted to patients who have not had a digital rectal exam (DRE) in the previous 96 h, owing to prior mixed data suggesting that prostate specific antigen (PSA) isoforms may increase by a statistically significant-if not necessarily clinically significant-amount shortly after DRE. Our primary objective was to determine if 4Kscore test results are affected by a preceding DRE.

Methods: Participants at a Prostate Cancer Awareness Week screening event sponsored by the Prostate Conditions Education Council filled out clinical history questionnaires and had blood samples for 4Kscore testing drawn prior to DRE, then 15-45 min following DRE. Patients with prior cancer diagnosis, 5-alpha reductase inhibitor medication use, or lower urinary tract procedures in the prior 6 months were excluded, resulting in a population of 162 participants for analysis. Values were then compared to determine if there was a significant difference in 4Kscore following DRE.

Results: A statistically significant increase was seen in levels of 3 kallikreins measured (total PSA, free PSA, and intact PSA; median <0.03 ng/mL for all). This resulted in a small but statistically significant decrease in post-DRE 4Kscore (median absolute score decrease 0.43%). Using a 4Kscore cutoff of 7.5% resulted in reclassification of 10 patients (6.2%), nine of whom were "downgraded" from above the cutoff to below.

Conclusions: If the blood draw for the 4 K score is performed after a screening DRE, there is a statistically significant difference in the 4 K score results, but in the vast majority of cases it would not affect clinical decision making.
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http://dx.doi.org/10.1002/pros.23495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237549PMC
May 2018

A Case-Crossover Study of Urological Chronic Pelvic Pain Syndrome Flare Triggers in the MAPP Research Network.

J Urol 2018 05 27;199(5):1245-1251. Epub 2017 Dec 27.

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.

Purpose: Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers.

Materials And Methods: We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression.

Results: In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress).

Conclusions: Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies.
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http://dx.doi.org/10.1016/j.juro.2017.12.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911194PMC
May 2018

Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade.

Oncotarget 2017 Aug 21;8(34):56051-56065. Epub 2017 Apr 21.

Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.

Prostate cancer (PCa) is the most common malignancy among Western men and the second leading-cause of cancer related deaths. For men who develop metastatic castration resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. Using immunohistochemistry we have found that the CPT1A isoform is abundant in PCa compared to benign tissue (n=39, p<0.001) especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased androgen receptor (AR) action and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of these findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust growth inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting.
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http://dx.doi.org/10.18632/oncotarget.17359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593544PMC
August 2017

Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

BJU Int 2017 07 11;120(1):130-142. Epub 2017 Apr 11.

Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.

Objective: To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies.

Methods: Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF-R1) and NGAL were assayed and quantitated using mono-specific enzyme-linked immunosorbent assays for each protein. Log-transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t-test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver-operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression.

Results: Significantly higher normalized concentrations (pg/μg) of VEGF, VEGF-R1 and MMP-9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP-9 and MMP-9/NGAL complex, and urinary severity was significantly positively associated with MMP-9, MMP-9/NGAL complex and VEGF-R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP-9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP-2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF-R1.

Conclusion: Altered levels of MMP-9, MMP-9/NGAL complex and VEGF-R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP-9 and VEGF-R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.
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http://dx.doi.org/10.1111/bju.13832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951631PMC
July 2017

Urinary Metabolomics Identifies a Molecular Correlate of Interstitial Cystitis/Bladder Pain Syndrome in a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Cohort.

EBioMedicine 2016 May 31;7:167-74. Epub 2016 Mar 31.

Center for Women's Infectious Diseases Research, Washington University in St. Louis School of Medicine, St. Louis, MO, United States; Division of Infectious Diseases, Washington University in St. Louis School of Medicine, St. Louis, MO, United States; Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, United States. Electronic address:

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood syndrome affecting up to 6.5% of adult women in the U.S. The lack of broadly accepted objective laboratory markers for this condition hampers efforts to diagnose and treat this condition. To identify biochemical markers for IC/BPS, we applied mass spectrometry-based global metabolite profiling to urine specimens from a cohort of female IC/BPS subjects from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. These analyses identified multiple metabolites capable of discriminating IC/BPS and control subjects. Of these candidate markers, etiocholan-3α-ol-17-one sulfate (Etio-S), a sulfoconjugated 5-β reduced isomer of testosterone, distinguished female IC/BPS and control subjects with a sensitivity and specificity >90%. Among IC/BPS subjects, urinary Etio-S levels are correlated with elevated symptom scores (symptoms, pelvic pain, and number of painful body sites) and could resolve high- from low-symptom IC/BPS subgroups. Etio-S-associated biochemical changes persisted through 3-6months of longitudinal follow up. These results raise the possibility that an underlying biochemical abnormality contributes to symptoms in patients with severe IC/BPS.
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http://dx.doi.org/10.1016/j.ebiom.2016.03.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909380PMC
May 2016

Diffuse reflectance spectroscopy can differentiate high grade and low grade prostatic carcinoma.

Annu Int Conf IEEE Eng Med Biol Soc 2016 Aug;2016:5148-5151

Prostate tumors are graded by the revised Gleason Score (GS) which is the sum of the two predominant Gleason grades present ranging from 6-10. GS 6 cancer exclusively with Gleason grade 3 is designated as low grade (LG) and correlates with better clinical prognosis for patients. GS >7 cancer with at least one of the Gleason grades 4 and 5 is designated as HG indicate worse prognosis for patients. Current transrectal ultrasound guided prostate biopsies often fail to correctly diagnose HG prostate cancer due to sampling errors. Diffuse reflectance spectra (DRS) of biological tissue depend on tissue morphology and architecture. Thus, DRS could potentially differentiate between HG and LG prostatic carcinoma. A 15-gauge optical biopsy needle was prototyped to take prostate biopsies after measuring DRS with a laboratory fluorometer. This needle has an optical sensor that utilizes 8×100 μm optical fibers for tissue excitation and a single 200 μm central optical fiber to measure DRS. Tissue biopsy cores were obtained from 20 surgically excised prostates using this needle after measuring DRS at 5 nm intervals between 500-700 nm wavelengths. Tissue within a measurement window was histopathologically classified as either benign, LG, or HG and correlated with DRS. Partial least square analysis of DRS identified principal components (PC) as potential classifiers. Statistically significant PCs (p<;0.05) were tested for their ability to classify biopsy tissue using support vector machine and leave-one-out cross validation method. There were 29 HG and 49 LG cancers among 187 biopsy cores included in the study. Study results show 76% sensitivity, 80% specificity, 93% negative predictive value, and 50% positive predictive value for HG versus benign, and 76%, 73%, 84%, and 63%, for HG versus LG prostate tissue classification. DRS failed to diagnose 7/29 (24%) HG cancers. This study demonstrated that an optical biopsy needle guided by DRS has sufficient accuracy to differentiate HG from LG carcinoma and benign tissue. It may allow precise targeting of HG prostate cancer providing more accurate assessment of the disease and improvement in patient care.
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http://dx.doi.org/10.1109/EMBC.2016.7591886DOI Listing
August 2016

Assessment of the Lower Urinary Tract Microbiota during Symptom Flare in Women with Urologic Chronic Pelvic Pain Syndrome: A MAPP Network Study.

J Urol 2016 Feb 26;195(2):356-62. Epub 2015 Sep 26.

Departments of Microbiology & Immunology and Otolaryngology-Head and Neck Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania.

Purpose: We compared culture independent assessment of microbiota of the lower urinary tract in standard culture negative female patients with urological chronic pelvic pain syndrome who reported symptom flare vs those who did not report a flare.

Materials And Methods: Initial stream (VB1) and midstream (VB2) urine specimens (233 patients with urological chronic pelvic pain syndrome) were analyzed with Ibis T-5000 Universal Biosensor system technology for comprehensive identification of microorganism species. Differences between flare and nonflare groups for presence or number of different species within a higher level group (richness) were examined by permutational multivariate analysis of variance and logistic regression.

Results: Overall 81 species (35 genera) were detected in VB1 and 73 (33) in VB2. Mean (SD) VB1 and VB2 species count per person was 2.6 (1.5) and 2.4 (1.5) for 86 flare cases and 2.8 (1.3) and 2.5 (1.5) for 127 nonflare cases, respectively. Overall the species composition did not significantly differ between flare and nonflare cases at any level (p=0.14 species, p=0.95 genus in VB1 and VB2, respectively) in multivariate analysis for richness. Univariate analysis, unadjusted as well as adjusted, confirmed a significantly greater prevalence of fungi (Candida and Saccharomyces) in the flare group (15.7%) compared to the nonflare group in VB2 (3.9%) (p=0.01). When adjusted for antibiotic use and menstrual phase, women who reported a flare remained more likely to have fungi present in VB2 specimens (OR 8.3, CI 1.7-39.4).

Conclusions: Among women with urological chronic pelvic pain syndrome the prevalence of fungi (Candida and Saccharomyces sp.) was significantly greater in those who reported a flare compared to those who did not.
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http://dx.doi.org/10.1016/j.juro.2015.09.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770794PMC
February 2016

Prostate Biopsy Markers of Inflammation are Associated with Risk of Clinical Progression of Benign Prostatic Hyperplasia: Findings from the MTOPS Study.

J Urol 2015 Aug 28;194(2):454-61. Epub 2015 Mar 28.

Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Purpose: Factors associated with worsening of benign prostatic hyperplasia are not well understood. We measured inflammatory markers from prostate biopsies to study if inflammation is related to clinical progression of benign prostatic hyperplasia.

Materials And Methods: We measured inflammatory cell markers CD45, CD4, CD8 and CD68 in transition zone biopsies from 859 men in the MTOPS biopsy substudy. Using novel imaging techniques we quantified amounts of moderate/severe inflammation. Benign prostatic hyperplasia clinical progression was defined as a confirmed 4-point or greater increase in the AUA symptom score from baseline, or the occurrence of urinary incontinence or acute urinary retention. Baseline clinical parameters including concomitant medication use were determined. Kaplan-Meier curves and multivariate Cox proportional hazard models were used to determine the risk of progression.

Results: Inflammation as measured by CD45, CD4 and CD68 increased the risk of clinical progression of benign prostatic hyperplasia. CD4 showed the highest risk where men in the highest tertile of moderate/severe inflammation were at twice the risk of progression compared to men in the lower 2 tertiles combined (HR 2.03, p=0.001). Inflammation was more strongly associated with progression defined by acute urinary retention or incontinence (HR ranging from 2.39 [CD8, p=0.03] to 3.08 [CD4, p=0.01]) than an AUA symptom score increase (CD4, HR 1.86, p=0.01). Men who reported use of nonsteroidal anti-inflammatory drugs or steroids at baseline tended to be at higher risk for progression.

Conclusions: Although our data show that inflammation increases the risk of progression, our findings suggest that inflammation has a greater role in men who have conditions requiring anti-inflammatory medications.
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http://dx.doi.org/10.1016/j.juro.2015.03.103DOI Listing
August 2015

Search for Microorganisms in Men with Urologic Chronic Pelvic Pain Syndrome: A Culture-Independent Analysis in the MAPP Research Network.

J Urol 2015 Jul 14;194(1):127-35. Epub 2015 Jan 14.

Departments of Microbiology & Immunology and Otolaryngology-Head and Neck Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania.

Purpose: We used next-generation, state-of-the-art, culture independent methodology to survey urine microbiota of males with urologic chronic pelvic pain syndrome and control participants enrolled in the MAPP Network to investigate a possible microbial etiology.

Materials And Methods: Male patients with urologic chronic pelvic pain syndrome and matched controls were asked to provide initial, midstream and post-prostatic massage urine specimens. Specimens were analyzed with Ibis T-5000 Universal Biosensor technology to provide comprehensive identification of bacterial and select fungal species. Differences between urologic chronic pelvic pain syndrome and control study participants for the presence of species or species variation in a higher taxonomic grouping (genus) were evaluated using permutational multivariate analysis of variance and logistic regression.

Results: Initial and midstream urine specimens were obtained from 110 (post-prostatic massage urine in 67) participants with urologic chronic pelvic pain syndrome and 115 (post-prostatic massage urine in 62) controls. Overall 78, 73 and 54 species (42, 39 and 27 genera) were detected in initial, midstream and post-prostatic massage urine specimens, respectively. Mean (SD) initial, midstream and post-prostatic massage urine species count per person was 1.62 (1.28), 1.38 (1.36) and 1.33 (1.24) for cases, and 1.75 (1.32), 1.23 (1.15) and 1.56 (0.97) for controls, respectively. Overall species and genus composition differed significantly between participants with urologic chronic pelvic pain syndrome and controls in initial stream urine (p=0.002 species level, p=0.004 genus level), with Burkholderia cenocepacia overrepresented in urologic chronic pelvic pain syndrome. No significant differences were observed at any level in midstream or post-prostatic massage urine samples.

Conclusions: Assessment of baseline culture-independent microbiological data from male subjects enrolled in the MAPP Network has identified overrepresentation of B. cenocepacia in urologic chronic pelvic pain syndrome. Future studies are planned to further evaluate microbiota associations with variable and changing urologic chronic pelvic pain syndrome symptom patterns.
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http://dx.doi.org/10.1016/j.juro.2015.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475477PMC
July 2015
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