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Identification of novel biomarkers differentially expressed between African-American and Caucasian-American prostate cancer patients

Ye, Fei; Han, Xiaoxia; Shao, Yonzhao; Lo, Jingzhi; Zhang, Fengxia; Wang, Jinhua; Melamed, Jonathan; Deng, Fang-Ming; Sfanos, Karen S; De Marzo, Angelo; Ren, Guoping; Wang, Dongwen; Zhang, David; Lee, Peng
Prostate cancer (PCa) incidence and mortality rate vary among racial and ethnic groups with the highest occurrence in African American (AA) men who have mortality rates twice that of Caucasians (CA). In this study, we focused on differential expression of proteins in AA prostate cancer compared to CA using Protein Pathway Array Analysis (PPAA), in order to identify protein biomarkers associated with PCa racial disparity. Fresh frozen prostate samples (n=90) obtained from radical prostatectomy specimens with PCa, including 25 AA tumor, 21 AA benign, 23 CA tumor, 21 CA benign samples were analyzed. A total of 286 proteins and phosphoproteins were assessed using PPAA. By PPAA analysis, 33 proteins were found to be significantly differentially expressed in tumor tissue (n=48, including both CA and AA) in comparison to benign tissue (n=42). We further compared protein expression levels between AA and CA tumor groups and found that 3 proteins were differentially expressed (P<0.05 and q<5%). Aurora was found to be significantly increased in AA tumors, while Cyclin D1 and HNF-3a proteins were downregulated in AA tumors. Predicted risk score was significantly different between AA and CA ethnic groups using logistic regression analysis. In conclusion, we identified Aurora, Cyclin D1 and HNF-3a proteins as being differentially expressed between AA and CA in PCa tissue. Our study suggests that these proteins might be involved in different pathways that lead to aggressive PCa behavior in AA patients, potentially serving as biomarkers for the PCa racial disparity.
PMID: 35530298
ISSN: 2156-6976
CID: 5214062

Effect of Serum Urate Lowering With Allopurinol on Blood Pressure in Young Adults: A Randomized, Controlled, Crossover Trial

Gaffo, Angelo L; Calhoun, David A; Rahn, Elizabeth J; Oparil, Suzanne; Li, Peng; Dudenbostel, Tanja; Feig, Daniel I; Redden, David T; Muntner, Paul; Foster, Phillip J; Biggers-Clark, Stephanie R; Mudano, Amy; Sattui, Sebastian E; Saddekni, Michael B; Bridges, S Louis; Saag, Kenneth G
OBJECTIVE:To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. METHODS:We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate-lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2-4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow-mediated dilation (FMD), and high-sensitivity C-reactive protein (hsCRP) levels. Adverse events were assessed. RESULTS:Ninety-nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent-to-treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM -1.39 ± 1.16 mm Hg) or placebo treatment phase (-1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus -0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events. CONCLUSION/CONCLUSIONS:Our findings indicate that urate-lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults.
PMID: 33779064
ISSN: 2326-5205
CID: 4910222

Metastasis and immune evasion from extracellular cGAMP hydrolysis

Li, Jun; Duran, Mercedes A; Dhanota, Ninjit; Chatila, Walid K; Bettigole, Sarah E; Kwon, John; Sriram, Roshan K; Humphries, Matthew Philip; Salto-Tellez, Manuel; James, Jacqueline A; Hanna, Matthew G; Melms, Johannes C; Vallabhaneni, Sreeram; Litchfield, Kevin; Usaite, Ieva; Biswas, Dhruva; Bareja, Rohan; Li, Hao Wei; Martin, Maria Laura; Dorsaint, Princesca; Cavallo, Julie-Ann; Li, Peng; Pauli, Chantal; Gottesdiener, Lee; DiPardo, Benjamin J; Hollmann, Travis J; Merghoub, Taha; Wen, Hannah Y; Reis-Filho, Jorge S; Riaz, Nadeem; Su, Shin-San Michael; Kalbasi, Anusha; Vasan, Neil; Powell, Simon N; Wolchok, Jedd D; Elemento, Olivier; Swanton, Charles; Shoushtari, Alexander N; Parkes, Eileen E; Izar, Benjamin; Bakhoum, Samuel F
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune stimulatory metabolite whose breakdown products include the immune suppressor, adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wildtype ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part, through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway.
PMID: 33372007
ISSN: 2159-8290
CID: 4731712

[Research progress on bone defect repair materials]

Cao, Guo-Ding; Pei, Yu-Qi; Liu, Jun; Li, Peng; Liu, Peng; Li, Xu-Sheng
In the process of repairing of bone defects, bone scaffold materials need to be implanted to restore the corresponding tissue structure at the injury. At present, the repair materials used for bone defects mainly include autogenous bone, allogeneic bone, metal materials, bioceramics, polymer materials and various composite materials. Different materials have demonstrated strong reconstruction ability in bone repair, but the ideal bone implants in the clinic are still yet to be established. Except for autogenous bone, other materials used in bone defect repair are unable to perfectly balance biocompatibility, bone formation, bone conduction and osteoinduction. Combining the latest advances in materials sciences and clinical application, we believe that composite materials supplementedwith Chinese medicine, tissue cells, cytokines, trace elements, etc. and manufactured using advanced technologies such as additive manufacturing technology may have ideal bone repair performance, and may have profound significance in clinical repair of bone defects of special type. This article reviewed to the domestic and foreign literature in recent years, and elaborates the current status of bone defect repair materials in clinical application and basic research in regard to the advantages, clinical options, shortcomings, and how to improve the autogenous bone, allogeneic bone and artificial bone materials, in order to provide a theoretical basis for clinical management of bone defects.
PMID: 33896142
ISSN: 1003-0034
CID: 4882422

Continuous care: Implementation of a virtual and in person transitional care management(TCM) clinicby internal medicine residents [Meeting Abstract]

Li, P; Kassapidis, V; Pandey, A; Bharadwaj, K; Moussa, M; Hayes, R; Sartori, D; Jervis, R
STATEMENT OF PROBLEM OR QUESTION (ONE SENTENCE): The transition between hospital and home is a vulnerable time for patients, who are at risk for readmission, medication reconciliation errors, and lack of follow up. LEARNING OBJECTIVES 1: Introduce a new type of visit to improve continuity of care for patients recently discharged from acute care LEARNING OBJECTIVES 2: Apply data from TCMvisits to identify areas for improvement in the hospital discharge process DESCRIPTION OF PROGRAM/INTERVENTION, INCLUDING ORGANIZATIONAL CONTEXT (E.G. INPATIENT VS. OUTPATIENT, PRACTICE OR COMMUNITY CHARACTERISTICS): The time between hospital discharge and primary care follow-up has historically been a vulnerable period for patients. The COVID-19 pandemic has exacerbated this transitional period, as patients have been forgoing their routine healthcare visits, losing touch with their primary care providers (PCPs), and not having a point of contact for their health needs after they leave the hospital. We launched a new resident-led virtual and in-person post-discharge clinic at an urban academic hospital connected in order to address the increasing need for follow-up care after hospital discharge. Patients admitted to the hospital who did not have a PCP or could not schedule a PCP visit within 10 days after being discharged were given the option of either an in-person or video TCM visit with an internal medicine resident. Each visit consisted of a templated set of questions, including whether medications were reconciled, and if follow-up appointments were scheduled. MEASURES OF SUCCESS (DISCUSS QUALITATIVE AND/OR QUANTITATIVEMETRICSWHICHWILL BE USEDTOEVALUATE PROGRAM/INTERVENTION): The primary endpoint for this pilot program was the total number of completed TCM visits. Secondary endpoints included the number of visits where there was a discrepancy in medications or follow-up appointments after hospital discharge. FINDINGS TO DATE (IT IS NOT SUFFICIENT TO STATE FINDINGS WILL BE DISCUSSED): Between October and December 2020, there were a total of 79 scheduled TCM visits (28 virtual visits and 51 in-person visits) and 51 (67%) completed visits. For the virtual visits, there was a 86% (24/28) completion rate. For in-person visits, there was a 53% (27/51) completion rate. In 31% (16/51) of the visits, subspecialty appointments were not scheduled at the time of discharge. In 12% (6/51) of the visits, there was a discrepancy with the medications patients were discharged with, with 50% (3/6) due to misprescribed antihyperglycemic agents. KEY LESSONS FOR DISSEMINATION (WHAT CAN OTHERS TAKE AWAY FOR IMPLEMENTATION TO THEIR PRACTICE OR COMMUNITY): The increased completion rate of virtual visits as compared to in-person visits (86%vs. 57%, respectively) suggests virtual visits may be a more convenient and preferable mode of follow-up for patients after hospital discharge. This pilot also shows how TCMvisit data can offer insights about the hospital discharge process that would otherwise go unnoticed. The data on discrepancies in medications reveals antihyperglycemic medication reconciliation may be a potential area of focus to improve the hospital discharge process. More data is needed to determine the effectiveness of this resident-led TCMinitiative, including its effects on hospital readmission rates. The preliminary data suggests that TCM visits, especially virtual visits, may effectively bridge gaps in care from the time patients leave the hospital until they establish more permanent care
ISSN: 1525-1497
CID: 4986522


Li, P.; Hayon, J.; Mahowald, C.
ISSN: 0012-3692
CID: 4573302

Sex specific associations in genome wide association analysis of renal cell carcinoma

Laskar, Ruhina S; Muller, David C; Li, Peng; Machiela, Mitchell J; Ye, Yuanqing; Gaborieau, Valerie; Foll, Matthieu; Hofmann, Jonathan N; Colli, Leandro; Sampson, Joshua N; Wang, Zhaoming; Bacq-Daian, Delphine; Boland, Anne; Abedi-Ardekani, Behnoush; Durand, Geoffroy; Le Calvez-Kelm, Florence; Robinot, Nivonirina; Blanche, Helene; Prokhortchouk, Egor; Skryabin, Konstantin G; Burdett, Laurie; Yeager, Meredith; Radojevic-Skodric, Sanja; Savic, Slavisa; Foretova, Lenka; Holcatova, Ivana; Janout, Vladimir; Mates, Dana; Rascu, Stefan; Mukeria, Anush; Zaridze, David; Bencko, Vladimir; Cybulski, Cezary; Fabianova, Eleonora; Jinga, Viorel; Lissowska, Jolanta; Lubinski, Jan; Navratilova, Marie; Rudnai, Peter; Świątkowska, Beata; Benhamou, Simone; Cancel-Tassin, Geraldine; Cussenot, Olivier; Trichopoulou, Antonia; Riboli, Elio; Overvad, Kim; Panico, Salvatore; Ljungberg, Borje; Sitaram, Raviprakash T; Giles, Graham G; Milne, Roger L; Severi, Gianluca; Bruinsma, Fiona; Fletcher, Tony; Koppova, Kvetoslava; Larsson, Susanna C; Wolk, Alicja; Banks, Rosamonde E; Selby, Peter J; Easton, Douglas F; Pharoah, Paul; Andreotti, Gabriella; Beane Freeman, Laura E; Koutros, Stella; Albanes, Demetrius; Männistö, Satu; Weinstein, Stephanie; Clark, Peter E; Edwards, Todd L; Lipworth, Loren; Carol, Hallie; Freedman, Matthew L; Pomerantz, Mark M; Cho, Eunyoung; Kraft, Peter; Preston, Mark A; Wilson, Kathryn M; Michael Gaziano, J; Sesso, Howard D; Black, Amanda; Freedman, Neal D; Huang, Wen-Yi; Anema, John G; Kahnoski, Richard J; Lane, Brian R; Noyes, Sabrina L; Petillo, David; Teh, Bin Tean; Peters, Ulrike; White, Emily; Anderson, Garnet L; Johnson, Lisa; Luo, Juhua; Chow, Wong-Ho; Moore, Lee E; Choueiri, Toni K; Wood, Christopher; Johansson, Mattias; McKay, James D; Brown, Kevin M; Rothman, Nathaniel; Lathrop, Mark G; Deleuze, Jean-Francois; Wu, Xifeng; Brennan, Paul; Chanock, Stephen J; Purdue, Mark P; Scelo, Ghislaine
Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
PMID: 31231134
ISSN: 1476-5438
CID: 3954992

Effect of Preanalytic Variables on an Automated PTEN Immunohistochemistry Assay for Prostate Cancer

Guedes, Liana B; Morais, Carlos L; Fedor, Helen; Hicks, Jessica; Gurel, Bora; Melamed, Jonathan; Lee, Peng; Gopalan, Anuradha; Knudsen, Beatrice S; True, Lawrence D; Scher, Howard I; Fine, Samson W; Trock, Bruce J; De Marzo, Angelo M; Lotan, Tamara L
CONTEXT.—/UNASSIGNED:Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predictive biomarker in prostate cancer. OBJECTIVE.—/UNASSIGNED:To assess the effects of preanalytic variables on an analytically validated and fully automated PTEN immunohistochemistry assay. DESIGN.—/UNASSIGNED:PTEN immunohistochemistry was performed on Ventana immunostaining systems. In benign prostate tissues, immunostaining intensity across variable conditions was assessed by digital image analysis. In prostate tumor tissues, immunostaining was scored visually. RESULTS.—/UNASSIGNED:Delay of fixation for 4 hours or longer at room temperature or 48 hours or longer at 4°C and duration of formalin fixation did not significantly alter immunostaining intensity. Intensity of staining was highest in 10% formalin compared with other fixatives. Tumor tissues with PTEN loss processed using protocols from 11 academic institutions were all evaluable and scored identically. PTEN immunostaining of needle biopsies where tissue blocks had been stored for less than 10 years was more frequently scored as nonevaluable compared with blocks that had been stored for 10 years or longer. This effect was less evident for radical prostatectomy specimens, where low rates of nonevaluable staining were seen for 23 years or more of storage. Storage of unstained slides for 5 years at room temperature prior to immunostaining resulted in equivalent scoring compared with freshly cut slides. Machine-to-machine variability assessed across 3 Ventana platforms and 2 institutions was negligible in 12 tumors, and platform-to-platform variability was also minor comparing Ventana and Leica instruments across 77 tumors (κ = 0.926). CONCLUSIONS.—/UNASSIGNED:Automated PTEN immunostaining is robust to most preanalytic variables in the prostate and may be performed on prostate tumor tissues subjected to a wide range of preanalytic conditions. These data may help guide assay development if PTEN becomes a key predictive biomarker.
PMID: 30295067
ISSN: 1543-2165
CID: 3334832

Prostate-specific loss of UXT promotes cancer progression

Wang, Yu; Schafler, Eric D; Thomas, Phillip A; Ha, Susan; David, Gregory; Adney, Emily; Garabedian, Michael J; Lee, Peng; Logan, Susan K
Ubiquitously-expressed, prefoldin-like chaperone (UXT) also called Androgen Receptor Trapped clone-27 (ART-27) is widely expressed in human tissues. Our previous studies showed that UXT regulates transcription repression including androgen receptor (AR) signaling in prostate cancer. Here we analyzed a tissue microarray consisting of normal prostate, benign prostatic hyperplasia, high grade prostatic intraepithelial neoplasia (HGPIN) and primary prostate cancer cases for UXT protein expression. We found that HGPIN and malignant tumors have significantly decreased UXT expression compared to the normal prostate. Loss of UXT expression in primary prostate cancer is positively associated with high Gleason grade and poor relapse-free survival. We engineered prostate-specific Uxt
PMID: 30774773
ISSN: 1949-2553
CID: 3658372

Prostate Cancers Detected by Magnetic Resonance Imaging-Targeted Biopsies Have a Higher Percentage of Gleason Pattern 4 Component and Are Less Likely to Be Upgraded in Radical Prostatectomies

Zhao, Yani; Deng, Fang-Ming; Huang, Hongying; Lee, Peng; Lepor, Hebert; Rosenkrantz, Andrew B; Taneja, Samir; Melamed, Jonathan; Zhou, Ming
CONTEXT/BACKGROUND:- In Gleason score GS (7) prostate cancers, the quantity of Gleason pattern 4 (GP 4) is an important prognostic factor and influences treatment decisions. Magnetic resonance imaging (MRI)-targeted biopsy has been increasingly used in clinical practice. OBJECTIVE:- To investigate whether MRI-targeted biopsy may detect GS 7 prostate cancer with greater GP 4 quantity, and whether it improves biopsy/radical prostatectomy GS concordance. DESIGN/METHODS:- A total of 243 paired standard and MRI-targeted biopsies with cancer in either standard or targeted or both were studied, 65 of which had subsequent radical prostatectomy. The biopsy findings, including GS and tumor volume, were correlated with the radical prostatectomy findings. RESULTS:- More prostate cancers detected by MRI-targeted biopsy were GS 7 or higher. Mean GP 4 percentage in GS 7 cancers was 31.0% ± 29.3% by MRI-targeted biopsy versus 25.1% ± 29.5% by standard biopsy. A total of 122 of 218 (56.0%) and 96 of 217 (44.2%) prostate cancers diagnosed on targeted biopsy and standard biopsy, respectively, had a GP 4 of 10% or greater ( P = .01). Gleason upgrading was seen in 12 of 59 cases (20.3%) from MRI-targeted biopsy and in 24 of 57 cases (42.1%) from standard biopsy ( P = .01). Gleason upgrading correlated with the biopsy cancer volume inversely and GP 4 of 30% or less in standard biopsy. Such correlation was not found in MRI-targeted biopsy. CONCLUSIONS:- Magnetic resonance imaging-targeted biopsy may detect more aggressive prostate cancers and reduce the risk of Gleason upgrading in radical prostatectomy. This study supports a potential role for MRI-targeted biopsy in the workup of prostate cancer and inclusion of percentage of GP 4 in the prostate biopsy reports.
PMID: 29965785
ISSN: 1543-2165
CID: 3186052