Publications by authors named "I Richard Thompson"

1,359 Publications

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High Throughput Field Phenotyping for Plant Height Using UAV-Based RGB Imagery in Wheat Breeding Lines: Feasibility and Validation.

Front Plant Sci 2021 16;12:591587. Epub 2021 Feb 16.

International Maize and Wheat Improvement Center (CIMMYT), Texcoco, Mexico.

Plant height (PH) is an essential trait in the screening of most crops. While in crops such as wheat, medium stature helps reduce lodging, tall plants are preferred to increase total above-ground biomass. PH is an easy trait to measure manually, although it can be labor-intense depending on the number of plots. There is an increasing demand for alternative approaches to estimate PH in a higher throughput mode. Crop surface models (CSMs) derived from dense point clouds generated via aerial imagery could be used to estimate PH. This study evaluates PH estimation at different phenological stages using plot-level information from aerial imaging-derived 3D CSM in wheat inbred lines during two consecutive years. Multi-temporal and high spatial resolution images were collected by fixed-wing ( ) and multi-rotor ( ) unmanned aerial vehicle (UAV) platforms over two wheat populations (50 and 150 lines). The PH was measured and compared at four growth stages (GS) using ground-truth measurements (PHground) and UAV-based estimates (PHaerial). The CSMs generated from the aerial imagery were validated using ground control points (GCPs) as fixed reference targets at different heights. The results show that PH estimations using were consistent with those obtained from , showing some slight differences due to image processing settings. The GCPs heights derived from CSM showed a high correlation and low error compared to their actual heights ( ≥ 0.90, ≤ 4 cm). The coefficient of determination () between PHground and PHaerial at different GS ranged from 0.35 to 0.88, and the root mean square error () from 0.39 to 4.02 cm for both platforms. In general, similar and higher heritability was obtained using PHaerial across different GS and years and ranged according to the variability, and environmental error of the PHground observed (0.06-0.97). Finally, we also observed high Spearman rank correlations (0.47-0.91) and (0.63-0.95) of PHaerial adjusted and predicted values against PHground values. This study provides an example of the use of UAV-based high-resolution RGB imagery to obtain time-series estimates of PH, scalable to tens-of-thousands of plots, and thus suitable to be applied in plant wheat breeding trials.
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http://dx.doi.org/10.3389/fpls.2021.591587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921806PMC
February 2021

A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.

Lancet 2021 Feb 13;397(10275):695-703. Epub 2021 Feb 13.

University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Background: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.

Methods: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.

Findings: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.

Interpretation: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.

Funding: National Institutes of Health and National Cancer Institute.
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http://dx.doi.org/10.1016/S0140-6736(21)00152-5DOI Listing
February 2021

Smoking modifies pancreatic cancer risk loci on 2q21.3.

Cancer Res 2021 Feb 11. Epub 2021 Feb 11.

Division of Cancer Epidemiology and Genetics, National Cancer Institute

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% CI 0.82-0.93; former smokers 1.00, 95 CI 0.91-1.07; current smokers 1.25, 95%CI 1.12-1.40, interaction P-value=3.08x10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high LD with rs1818613 (r2=0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
February 2021

A randomized phase II study of coexpression extrapolation (COXEN) with neoadjuvant chemotherapy for bladder cancer (SWOG S1314; NCT02177695).

Clin Cancer Res 2021 Feb 10. Epub 2021 Feb 10.

Administration, CHRISTUS Santa Rosa Hospital - Medical Center.

Purpose: Dose-dense Methotrexate-Vinblastine-Adriamycin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). The aim of this study was to validate the score from a Coexpression extrapolation (COXEN) algorithm-generated gene expression model (GEM) as a biomarker in patients undergoing radical cystectomy.

Experimental Design: Eligibility included cT2-T4a N0 M0, urothelial BC, {greater than or equal to} 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy; 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. The primary objective assessed pre-specified dichotomous treatment specific COXEN score as predictive of pT0 rate or {less than or equal to} pT1 (downstaging) at surgery.

Results: Among 167 evaluable patients, the odds ratio for pT0 with the GC GEM score in GC-treated patients was 2.63 (p=0.10; 95% CI [0.82,8.36]); for the ddMVAC COXEN GEM score with ddMVAC treatment, the OR was 1.12 (p=0.82, 95% CI [0.42, 2.95]). The GC GEM score was applied to pooled arms (GC and ddMVAC) for downstaging with an OR of 2.33 (p=0.02; 95% CI [1.11, 4.89]). In an intention to treat analysis of eligible patients (n=227), pT0 rates for ddMVAC and GC were 28% and 30% (p = 0.75); downstaging was 47% and 40% (p = 0.27), respectively.

Conclusions: Treatment-specific COXEN scores were not significantly predictive for response to individual chemotherapy treatment. The COXEN GEM GC score was significantly associated with downstaging in the pooled arms. Additional biomarker development is planned.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2409DOI Listing
February 2021

Phase I Trial of Encapsulated Rapamycin in Prostate Cancer Patients Under Active Surveillance to Prevent Progression.

Cancer Prev Res (Phila) 2021 Jan 29. Epub 2021 Jan 29.

Urology, The University of Texas Health Science Center at San Antonio.

No approved medical therapies prevent progression of low-grade prostate cancer (PCa). Rapamycin inhibits cell proliferation and augments immune responses, producing an antitumor effect. Encapsulated rapamycin (eRapa) incorporates rapamycin into a pH-sensitive polymer, ensuring consistent dosing. Here, we present results from a phase I trial evaluating the safety and tolerability of eRapa in patients with PCa. Patients with Gleason <=7 (3+4) disease (low- and intermediate-risk) under active surveillance were enrolled in a 3+3 study with three eRapa dosing cohorts (cohort 1: 0.5mg/week; cohort 2: 1.0 mg/week; and cohort 3: 0.5mg/day). Patients were treated for three months and followed for an additional three months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1: n=3; cohort 2: n=3; cohort 3: n=8) were enrolled. In cohort 3, one dose-limiting toxicity (DLT; neutropenia) and two non-DLT grade 1-2 adverse events (AEs) occurred that resulted in patient withdrawal. All AEs in cohorts 1-2 were grade 1. Peak serum rapamycin concentration was 7.1ng/mL after a 1mg dose. Stable trough levels (~2.0ng/mL) developed after 48-72 hours. Daily dosing mildly worsened QoL, though QoL recovered after treatment cessation in all categories except fatigue. Weekly dosing increased naïve T-cell populations. Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower-grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0383DOI Listing
January 2021

Association of Serum Carotenoids and Retinoids with Intraprostatic Inflammation in Men without Prostate Cancer or Clinical Indication for Biopsy in the Placebo Arm of the Prostate Cancer Prevention Trial.

Nutr Cancer 2021 Jan 29:1-8. Epub 2021 Jan 29.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, β-carotene, β-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except β-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), -trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.
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http://dx.doi.org/10.1080/01635581.2021.1879879DOI Listing
January 2021

Baseline Circulating Tumor Cell Count as a Prognostic Marker of PSA Response and Disease Progression in Metastatic Castrate-Sensitive Prostate Cancer (SWOG S1216).

Clin Cancer Res 2021 Jan 26. Epub 2021 Jan 26.

University of Utah Huntsman Cancer Institute, Salt Lake City, Utah.

Purpose: In metastatic castrate-sensitive prostate cancer (mCSPC), combined androgen axis inhibition is a standard of care. Noninvasive biomarkers that guide initial therapy decisions are needed. We hypothesized that CellSearch circulating tumor cell (CTC) count, an FDA-cleared assay in metastatic castrate-resistant prostate cancer (mCRPC), is a relevant biomarker in mCSPC.

Experimental Design: SWOG S1216 is a phase III prospective randomized trial of androgen deprivation therapy (ADT) combined with orteronel or bicalutamide for mCSPC. CellSearch CTC count was measured at registration (baseline). Prespecified CTC cut-off points of 0, 1-4, and ≥5 were correlated with baseline patient characteristics and, in a stratified subsample, were also correlated with two prespecified trial secondary endpoints: 7-month PSA ≤0.2 ng/mL versus 0.2-4.0 versus >4.0 (intermediate endpoint for overall survival); and progression-free survival (PFS) ≤ versus >2 years.

Results: A total of 523 patients submitted baseline samples, and CTCs were detected (median 3) in 33%. Adjusting for two trial stratification factors (disease burden and timing of ADT initiation), men with undetectable CTCs had nearly nine times the odds of attaining 7-month PSA ≤ 0.2 versus > 4.0 [OR 8.8, 95% confidence interval (CI), 2.7-28.6, < 0.001, = 264] and four times the odds of achieving > 2 years PFS (OR 4.0, 95% CI, 1.9-8.5, < 0.001, = 336) compared with men with baseline CTCs ≥5.

Conclusions: Baseline CTC count in mCSPC is highly prognostic of 7-month PSA and 2-year PFS after adjusting for disease burden and discriminates men who are likely to experience poor survival outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3587DOI Listing
January 2021

Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Authors:
David V Conti Burcu F Darst Lilit C Moss Edward J Saunders Xin Sheng Alisha Chou Fredrick R Schumacher Ali Amin Al Olama Sara Benlloch Tokhir Dadaev Mark N Brook Ali Sahimi Thomas J Hoffmann Atushi Takahashi Koichi Matsuda Yukihide Momozawa Masashi Fujita Kenneth Muir Artitaya Lophatananon Peggy Wan Loic Le Marchand Lynne R Wilkens Victoria L Stevens Susan M Gapstur Brian D Carter Johanna Schleutker Teuvo L J Tammela Csilla Sipeky Anssi Auvinen Graham G Giles Melissa C Southey Robert J MacInnis Cezary Cybulski Dominika Wokołorczyk Jan Lubiński David E Neal Jenny L Donovan Freddie C Hamdy Richard M Martin Børge G Nordestgaard Sune F Nielsen Maren Weischer Stig E Bojesen Martin Andreas Røder Peter Iversen Jyotsna Batra Suzanne Chambers Leire Moya Lisa Horvath Judith A Clements Wayne Tilley Gail P Risbridger Henrik Gronberg Markus Aly Robert Szulkin Martin Eklund Tobias Nordström Nora Pashayan Alison M Dunning Maya Ghoussaini Ruth C Travis Tim J Key Elio Riboli Jong Y Park Thomas A Sellers Hui-Yi Lin Demetrius Albanes Stephanie J Weinstein Lorelei A Mucci Edward Giovannucci Sara Lindstrom Peter Kraft David J Hunter Kathryn L Penney Constance Turman Catherine M Tangen Phyllis J Goodman Ian M Thompson Robert J Hamilton Neil E Fleshner Antonio Finelli Marie-Élise Parent Janet L Stanford Elaine A Ostrander Milan S Geybels Stella Koutros Laura E Beane Freeman Meir Stampfer Alicja Wolk Niclas Håkansson Gerald L Andriole Robert N Hoover Mitchell J Machiela Karina Dalsgaard Sørensen Michael Borre William J Blot Wei Zheng Edward D Yeboah James E Mensah Yong-Jie Lu Hong-Wei Zhang Ninghan Feng Xueying Mao Yudong Wu Shan-Chao Zhao Zan Sun Stephen N Thibodeau Shannon K McDonnell Daniel J Schaid Catharine M L West Neil Burnet Gill Barnett Christiane Maier Thomas Schnoeller Manuel Luedeke Adam S Kibel Bettina F Drake Olivier Cussenot Géraldine Cancel-Tassin Florence Menegaux Thérèse Truong Yves Akoli Koudou Esther M John Eli Marie Grindedal Lovise Maehle Kay-Tee Khaw Sue A Ingles Mariana C Stern Ana Vega Antonio Gómez-Caamaño Laura Fachal Barry S Rosenstein Sarah L Kerns Harry Ostrer Manuel R Teixeira Paula Paulo Andreia Brandão Stephen Watya Alexander Lubwama Jeannette T Bensen Elizabeth T H Fontham James Mohler Jack A Taylor Manolis Kogevinas Javier Llorca Gemma Castaño-Vinyals Lisa Cannon-Albright Craig C Teerlink Chad D Huff Sara S Strom Luc Multigner Pascal Blanchet Laurent Brureau Radka Kaneva Chavdar Slavov Vanio Mitev Robin J Leach Brandi Weaver Hermann Brenner Katarina Cuk Bernd Holleczek Kai-Uwe Saum Eric A Klein Ann W Hsing Rick A Kittles Adam B Murphy Christopher J Logothetis Jeri Kim Susan L Neuhausen Linda Steele Yuan Chun Ding William B Isaacs Barbara Nemesure Anselm J M Hennis John Carpten Hardev Pandha Agnieszka Michael Kim De Ruyck Gert De Meerleer Piet Ost Jianfeng Xu Azad Razack Jasmine Lim Soo-Hwang Teo Lisa F Newcomb Daniel W Lin Jay H Fowke Christine Neslund-Dudas Benjamin A Rybicki Marija Gamulin Davor Lessel Tomislav Kulis Nawaid Usmani Sandeep Singhal Matthew Parliament Frank Claessens Steven Joniau Thomas Van den Broeck Manuela Gago-Dominguez Jose Esteban Castelao Maria Elena Martinez Samantha Larkin Paul A Townsend Claire Aukim-Hastie William S Bush Melinda C Aldrich Dana C Crawford Shiv Srivastava Jennifer C Cullen Gyorgy Petrovics Graham Casey Monique J Roobol Guido Jenster Ron H N van Schaik Jennifer J Hu Maureen Sanderson Rohit Varma Roberta McKean-Cowdin Mina Torres Nicholas Mancuso Sonja I Berndt Stephen K Van Den Eeden Douglas F Easton Stephen J Chanock Michael B Cook Fredrik Wiklund Hidewaki Nakagawa John S Witte Rosalind A Eeles Zsofia Kote-Jarai Christopher A Haiman

Nat Genet 2021 Jan 20. Epub 2021 Jan 20.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1038/s41588-021-00786-2DOI Listing
January 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Authors:
David V Conti Burcu F Darst Lilit C Moss Edward J Saunders Xin Sheng Alisha Chou Fredrick R Schumacher Ali Amin Al Olama Sara Benlloch Tokhir Dadaev Mark N Brook Ali Sahimi Thomas J Hoffmann Atushi Takahashi Koichi Matsuda Yukihide Momozawa Masashi Fujita Kenneth Muir Artitaya Lophatananon Peggy Wan Loic Le Marchand Lynne R Wilkens Victoria L Stevens Susan M Gapstur Brian D Carter Johanna Schleutker Teuvo L J Tammela Csilla Sipeky Anssi Auvinen Graham G Giles Melissa C Southey Robert J MacInnis Cezary Cybulski Dominika Wokołorczyk Jan Lubiński David E Neal Jenny L Donovan Freddie C Hamdy Richard M Martin Børge G Nordestgaard Sune F Nielsen Maren Weischer Stig E Bojesen Martin Andreas Røder Peter Iversen Jyotsna Batra Suzanne Chambers Leire Moya Lisa Horvath Judith A Clements Wayne Tilley Gail P Risbridger Henrik Gronberg Markus Aly Robert Szulkin Martin Eklund Tobias Nordström Nora Pashayan Alison M Dunning Maya Ghoussaini Ruth C Travis Tim J Key Elio Riboli Jong Y Park Thomas A Sellers Hui-Yi Lin Demetrius Albanes Stephanie J Weinstein Lorelei A Mucci Edward Giovannucci Sara Lindstrom Peter Kraft David J Hunter Kathryn L Penney Constance Turman Catherine M Tangen Phyllis J Goodman Ian M Thompson Robert J Hamilton Neil E Fleshner Antonio Finelli Marie-Élise Parent Janet L Stanford Elaine A Ostrander Milan S Geybels Stella Koutros Laura E Beane Freeman Meir Stampfer Alicja Wolk Niclas Håkansson Gerald L Andriole Robert N Hoover Mitchell J Machiela Karina Dalsgaard Sørensen Michael Borre William J Blot Wei Zheng Edward D Yeboah James E Mensah Yong-Jie Lu Hong-Wei Zhang Ninghan Feng Xueying Mao Yudong Wu Shan-Chao Zhao Zan Sun Stephen N Thibodeau Shannon K McDonnell Daniel J Schaid Catharine M L West Neil Burnet Gill Barnett Christiane Maier Thomas Schnoeller Manuel Luedeke Adam S Kibel Bettina F Drake Olivier Cussenot Géraldine Cancel-Tassin Florence Menegaux Thérèse Truong Yves Akoli Koudou Esther M John Eli Marie Grindedal Lovise Maehle Kay-Tee Khaw Sue A Ingles Mariana C Stern Ana Vega Antonio Gómez-Caamaño Laura Fachal Barry S Rosenstein Sarah L Kerns Harry Ostrer Manuel R Teixeira Paula Paulo Andreia Brandão Stephen Watya Alexander Lubwama Jeannette T Bensen Elizabeth T H Fontham James Mohler Jack A Taylor Manolis Kogevinas Javier Llorca Gemma Castaño-Vinyals Lisa Cannon-Albright Craig C Teerlink Chad D Huff Sara S Strom Luc Multigner Pascal Blanchet Laurent Brureau Radka Kaneva Chavdar Slavov Vanio Mitev Robin J Leach Brandi Weaver Hermann Brenner Katarina Cuk Bernd Holleczek Kai-Uwe Saum Eric A Klein Ann W Hsing Rick A Kittles Adam B Murphy Christopher J Logothetis Jeri Kim Susan L Neuhausen Linda Steele Yuan Chun Ding William B Isaacs Barbara Nemesure Anselm J M Hennis John Carpten Hardev Pandha Agnieszka Michael Kim De Ruyck Gert De Meerleer Piet Ost Jianfeng Xu Azad Razack Jasmine Lim Soo-Hwang Teo Lisa F Newcomb Daniel W Lin Jay H Fowke Christine Neslund-Dudas Benjamin A Rybicki Marija Gamulin Davor Lessel Tomislav Kulis Nawaid Usmani Sandeep Singhal Matthew Parliament Frank Claessens Steven Joniau Thomas Van den Broeck Manuela Gago-Dominguez Jose Esteban Castelao Maria Elena Martinez Samantha Larkin Paul A Townsend Claire Aukim-Hastie William S Bush Melinda C Aldrich Dana C Crawford Shiv Srivastava Jennifer C Cullen Gyorgy Petrovics Graham Casey Monique J Roobol Guido Jenster Ron H N van Schaik Jennifer J Hu Maureen Sanderson Rohit Varma Roberta McKean-Cowdin Mina Torres Nicholas Mancuso Sonja I Berndt Stephen K Van Den Eeden Douglas F Easton Stephen J Chanock Michael B Cook Fredrik Wiklund Hidewaki Nakagawa John S Witte Rosalind A Eeles Zsofia Kote-Jarai Christopher A Haiman

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
January 2021

Diffraction by a rigid strip in a plate modelled by Mindlin theory.

Authors:
Ian Thompson

Proc Math Phys Eng Sci 2020 Nov 25;476(2243):20200648. Epub 2020 Nov 25.

Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, UK.

We consider a plane flexural wave incident on a semi-infinite rigid strip in a Mindlin plate. The boundary conditions on the strip lead to three Wiener-Hopf equations, one of which decouples, leaving a scalar problem and a 2 × 2 matrix problem. The latter is solved using a simple method based on quadrature. The far-field diffraction coefficient is calculated and some numerical results are presented. We also show how the results reduce to the simpler Kirchhoff model in the low-frequency limit.
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http://dx.doi.org/10.1098/rspa.2020.0648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735304PMC
November 2020

Bacterial wax synthesis.

Biotechnol Adv 2021 Jan-Feb;46:107680. Epub 2020 Dec 15.

Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, United Kingdom. Electronic address:

Biological wax esters offer a sustainable, renewable and biodegradable alternative to many fossil fuel derived chemicals including plastics and paraffins. Many species of bacteria accumulate waxes with similar structure and properties to highly desirable animal and plant waxes such as Spermaceti and Jojoba oils, the use of which is limited by resource requirements, high cost and ethical concerns. While bacterial fermentations overcome these issues, a commercially viable bacterial wax production process would require high yields and renewable, affordable feedstock to make it economically competitive and environmentally beneficial. This review describes recent progress in wax ester generation in both wild type and genetically engineered bacteria, with a focus on comparing substrates and quantifying obtained waxes. The full breadth of wax accumulating species is discussed, with emphasis on species generating high yields and utilising renewable substrates. Key areas of the field that have, thus far, received limited attention are highlighted, such as waste stream valorisation, mixed microbial cultures and efficient wax extraction, as, until effectively addressed, these will slow progress in creating commercially viable wax production methods.
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http://dx.doi.org/10.1016/j.biotechadv.2020.107680DOI Listing
December 2020

Vertical Distribution of Insect Pests Using Insect Towers Placed Near Potato Fields in the Lower Columbia Basin.

J Econ Entomol 2021 Feb;114(1):180-186

Department of Crop and Soil Science, Hermiston Agricultural Research and Extension Center, Oregon State University, Hermiston, OR.

This study was conducted at the Oregon State University Hermiston Agricultural Research and Extension Center, Hermiston, Umatilla County, OR, during the 2016 and 2017 potato, Solanum tuberosum L. (Solanales: Solanaceae), growing seasons. The objective was to determine the vertical distribution of hemipteran (Bactericera cockerelli Šulc, Circulifer tenellus Baker, Myzus persicae Sulzer, Macrosiphum euphorbiae Thomas, and Lygus spp.) and thysanopteran (Frankliniella occidentalis Pergande and Thrips tabaci Lindeman) potato pests using insect towers placed near potato fields. Towers were 8 m tall and secured to the ground with metal cables. In each tower, yellow sticky cards were mounted at 1.5 m intervals up to 7.6 m aboveground. Data were collected at 7-d intervals from mid-April until mid or end of August. This study showed that B. cockerelli, C. tenellus, M. persicae, Lygus spp., and both species of thrips were captured on sticky cards placed closest to the ground; in both years, as sticky card height increased, abundances decreased. In contrast, trapped M. euphorbiae numbers were not affected by sticky card height. To our knowledge, this is the first study in the lower Columbia Basin of Oregon that evaluated the vertical distribution of major potato pests.
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http://dx.doi.org/10.1093/jee/toaa263DOI Listing
February 2021

Dysregulation of endocytic machinery and ACE2 in small airways of smokers and COPD patients can augment their susceptibility to SARS-CoV-2 (COVID-19) infections.

Am J Physiol Lung Cell Mol Physiol 2021 01 11;320(1):L158-L163. Epub 2020 Nov 11.

Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia.

Lungs of smokers and chronic obstructive pulmonary disease (COPD) are severely compromised and are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attack. The dangerous combination of enhanced SARS-CoV-2 attachment receptor protein ACE2 along with an increase in endocytic vacuoles will enable viral attachment, entry, and replication. The objective of the study was to identify the presence of SARS-CoV-2 host attachment receptor angiotensin-converting enzyme-2 (ACE2) along with endocytic vacuoles, early endosome antigen-1 (EEA1), late endosome marker RAB7, cathepsin-L, and lysosomal associated membrane protein-1 (LAMP-1) as lysosome markers in the airways of smokers and COPD patients. The study design was cross-sectional and involved lung resections from 39 patients in total, which included 19 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I or GOLD stage II COPD, of which 9 were current smokers with COPD (COPD-CS) and 10 were ex-smokers with COPD (COPD-ES), 10 were normal lung function smokers, and 10 were never-smoking normal controls. Immunostaining for ACE2, EEA1, RAB7, and cathepsin-L was done. A comparative description for ACE2, EEA1, RAB7, and cathepsin-L expression pattern is provided for the patient groups. Furthermore, staining intensity for LAMP-1 lysosomes was measured as the ratio of the LAMP-1-stained areas per total area of epithelium or subepithelium, using Image ProPlus v7.0 software. LAMP-1 expression showed a positive correlation to patient smoking history while in COPD LAMP-1 negatively correlated to lung function. The active presence of ACE2 protein along with endocytic vacuoles such as early/late endosomes and lysosomes in the small airways of smokers and COPD patients provides evidence that these patient groups could be more susceptible to COVID-19.
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http://dx.doi.org/10.1152/ajplung.00437.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869956PMC
January 2021

Single-cell analyses identify dysfunctional CD16 CD8 T cells in smokers.

Cell Rep Med 2020 Jul;1(4)

Environmental Epigenomics and Disease Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, 27709.

Tobacco smoke exposure contributes to the global burden of communicable and chronic diseases. To identify immune cells affected by smoking, we use single-cell RNA sequencing on peripheral blood from smokers and nonsmokers. Transcriptomes reveal a subpopulation of (CD16)-expressing Natural Killer (NK)-like CD8 T lymphocytes that increase in smokers. Mass cytometry confirms elevated CD16 CD8 T cells in smokers. Inferred as highly differentiated by pseudotime analysis, NK-like CD8 T cells express markers characteristic of effector memory re-expressing CD45RA T (T) cells. Indicative of immune aging, smokers' CD8 T cells are biased toward differentiated cells and smokers have fewer naïve cells than nonsmokers. DNA methylation-based models show that smoking dose is associated with accelerated aging and decreased telomere length, a biomarker of T cell senescence. Immune aging accompanies T cell senescence, which can ultimately lead to impaired immune function. This suggests a role for smoking-induced, senescence-associated immune dysregulation in smoking-mediated pathologies.
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http://dx.doi.org/10.1016/j.xcrm.2020.100054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644053PMC
July 2020

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 Dec 23;29(12):2735-2739. Epub 2020 Sep 23.

Division of Cancer Epidemiology, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii.

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710600PMC
December 2020

African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

Int J Cancer 2021 Jan 24;148(1):99-105. Epub 2020 Sep 24.

Institute of Cancer Research, Sutton, UK.

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.
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http://dx.doi.org/10.1002/ijc.33282DOI Listing
January 2021

Tailoring Intensity of Active Surveillance for Low-Risk Prostate Cancer Based on Individualized Prediction of Risk Stability.

JAMA Oncol 2020 10 8;6(10):e203187. Epub 2020 Oct 8.

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

Importance: Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost.

Objective: To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments.

Design, Setting, And Participants: The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data.

Exposures: Active surveillance for prostate cancer.

Main Outcomes And Measures: Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy.

Results: A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P = .004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P < .001 and ≥2 vs 0: HR, 0.18 [95% CI, 0.08-0.4]; P < .001), time since diagnosis (HR, 1.62 [95% CI, 1.28-2.05]; P < .001), body mass index (HR, 1.08 [95% CI, 1.05-1.12]; P < .001), prostate size (HR, 0.40 [95% CI, 0.25-0.62]; P < .001), prostate-specific antigen at diagnosis (HR, 1.51 [95% CI, 1.15-1.98]; P = .003), and prostate-specific antigen kinetics (HR, 1.46 [95% CI, 1.23-1.73]; P < .001). For prediction of nonreclassification at 4 years, the area under the receiver operating curve was 0.70 for the PASS cohort and 0.70 for the UCSF validation cohort. This model achieved a negative predictive value of 0.88 (95% CI, 0.83-0.94) for those in the bottom 25th percentile of risk and of 0.95 (95% CI, 0.89-1.00) for those in the bottom 10th percentile.

Conclusions And Relevance: In this study, among men with low-risk prostate cancer, heterogeneity prevailed in risk of subsequent disease reclassification. These findings suggest that active surveillance intensity can be modulated based on an individual's risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen.
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http://dx.doi.org/10.1001/jamaoncol.2020.3187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453344PMC
October 2020

A comparison of general, genitourinary, bowel, and sexual quality of life among long term survivors of prostate, bladder, colorectal, and lung cancer.

J Geriatr Oncol 2021 Mar 29;12(2):305-311. Epub 2020 Jul 29.

Department of Urology and Department of Preventive Medicine, University of Southern California/Norris Cancer Center, 1441 Eastlake Ave, Los Angeles, CA 90033, USA; Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, TN 37232, USA. Electronic address:

Objectives: Studies of local stage prostate cancer survivors suggest that treatments carry risk of persistent impotence, incontinence, and bowel dysfunction. To examine impacts of cancer type and side effects on health-related quality of life (HRQoL) in long-term cancer survivorship, we evaluated 5-year follow-up of patients with prostate cancer and compared results with a matched group of male long-term survivors of other local-stage cancers.

Materials And Methods: We examined genitourinary, bowel and sexual symptoms, and general quality of life. Matched survivors of colorectal, lung, and bladder cancers were recruited via registries in 3 different regions in the United States. Patients were surveyed 3-5 years after diagnosis with the SF-12 and EPIC to evaluate general mental and physical health-related quality of life (HRQoL) and patient function and bother.

Results: We analyzed responses from long-term prostate (n = 77) and bladder, colorectal, and lung cancer (n = 124) patients. In multivariate analysis, long-term local stage prostate cancer survivors had significantly higher SF-12 physical component scores but did not differ from long-term survivors of other cancers in terms of their SF-12 mental summary scores. Prostate survivors had similar mental, urinary, bowel, and sexual HRQoL compared to long-term survivors of other local stage cancers.

Conclusion: Long-term general and prostate-specific HRQoL was similar between local stage prostate and bladder, colorectal, and lung patients with cancer. Future research focusing on factors other than initial treatment and the cancer type per se may provide more meaningful information regarding factors that predict disparities on HRQoL among longer-term survivors of early stage male cancers.
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http://dx.doi.org/10.1016/j.jgo.2020.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855401PMC
March 2021

Elevated intracellular cyclic-di-GMP level in Shewanella oneidensis increases expression of c-type cytochromes.

Microb Biotechnol 2020 11 30;13(6):1904-1916. Epub 2020 Jul 30.

Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore City, Singapore.

Electrochemically active biofilms are capable of exchanging electrons with solid electron acceptors and have many energy and environmental applications such as bioelectricity generation and environmental remediation. The performance of electrochemically active biofilms is usually dependent on c-type cytochromes, while biofilm development is controlled by a signal cascade mediated by the intracellular secondary messenger bis-(3'-5') cyclic dimeric guanosine monophosphate (c-di-GMP). However, it is unclear whether there are any links between the c-di-GMP regulatory system and the expression of c-type cytochromes. In this study, we constructed a S. oneidensis MR-1 strain with a higher cytoplasmic c-di-GMP level by constitutively expressing a c-di-GMP synthase and it exhibited expected c-di-GMP-influenced traits, such as lowered motility and increased biofilm formation. Compared to MR-1 wild-type strain, the high c-di-GMP strain had a higher Fe(III) reduction rate (21.58 vs 11.88 pM of Fe(III)/h cell) and greater expression of genes that code for the proteins involved in the Mtr pathway, including CymA, MtrA, MtrB, MtrC and OmcA. Furthermore, single-cell Raman microspectroscopy (SCRM) revealed a great increase of c-type cytochromes in the high c-di-GMP strain as compared to MR-1 wild-type strain. Our results reveal for the first time that the c-di-GMP regulation system indirectly or directly positively regulates the expression of cytochromes involved in the extracellular electron transport (EET) in S. oneidensis, which would help to understand the regulatory mechanism of c-di-GMP on electricity production in bacteria.
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http://dx.doi.org/10.1111/1751-7915.13636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533324PMC
November 2020

Age-related macular degeneration in a randomized trial of selenium and vitamin E in men: the Select Eye Endpoints (SEE) study (SWOG S0000B).

Acta Ophthalmol 2020 Jul 23. Epub 2020 Jul 23.

Department of Urology, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA.

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http://dx.doi.org/10.1111/aos.14538DOI Listing
July 2020

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Cancer Res 2020 09 8;80(18):4004-4013. Epub 2020 Jul 8.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC ( = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( = 0.22) and primary sclerosing cholangitis ( = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861352PMC
September 2020

Use of Aspirin and Statins in Relation to Inflammation in Benign Prostate Tissue in the Placebo Arm of the Prostate Cancer Prevention Trial.

Cancer Prev Res (Phila) 2020 10 24;13(10):853-862. Epub 2020 Jun 24.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Aspirin and statin use may lower the risk of advanced/fatal prostate cancer, possibly by reducing intraprostatic inflammation. To test this hypothesis, we investigated the association of aspirin and statin use with the presence and extent of intraprostatic inflammation, and the abundance of specific immune cell types, in benign prostate tissue from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial. Men were classified as aspirin or statin users if they reported use at baseline or during the 7-year trial. Presence and extent of inflammation were assessed, and markers of specific immune cell types (CD4, CD8, FoxP3, CD68, and c-KIT) were scored, in slides from end-of-study prostate biopsies taken irrespective of clinical indication, per trial protocol. Logistic regression was used to estimate associations between medication use and inflammation measures, adjusted for potential confounders. Of 357 men included, 61% reported aspirin use and 32% reported statin use. Prevalence and extent of inflammation were not associated with medication use. However, aspirin users were more likely to have low FoxP3, a T regulatory cell marker [OR, 5.60; 95% confidence interval (CI), 1.16-27.07], and statin users were more likely to have low CD68, a macrophage marker (OR, 1.63; 95% CI, 0.81-3.27). If confirmed, these results suggest that these medications may alter the immune milieu of the prostate, which could potentially mediate effects of these medications on advanced/fatal prostate cancer risk.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541466PMC
October 2020

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Cancer Epidemiol Biomarkers Prev 2020 Sep 16;29(9):1784-1791. Epub 2020 Jun 16.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.

Methods: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.

Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the (family with sequence similarity 63 member A) gene (significance threshold < 1.25 × 10) was observed in the meta-analysis ( = 1.2 ×10, = 4.2 ×10).

Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.

Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483330PMC
September 2020

Rational design of aptamer switches with programmable pH response.

Nat Commun 2020 06 10;11(1):2946. Epub 2020 Jun 10.

Department of Electrical Engineering, Stanford University, Stanford, CA, 94305, USA.

Aptamer switches that respond sensitively to pH could enhance control over molecular devices, improving their diagnostic and therapeutic efficacy. Previous designs have inserted pH-sensitive DNA motifs into aptamer sequences. Unfortunately, their performance was limited by the motifs' intrinsic pH-responses and could not be tuned to operate across arbitrary pH ranges. Here, we present a methodology for converting virtually any aptamer into a molecular switch with pH-selective binding properties - in acidic, neutral, or alkaline conditions. Our design inserts two orthogonal motifs that can be manipulated in parallel to tune pH-sensitivity without altering the aptamer sequence itself. From a single ATP aptamer, we engineer pH-controlled target binding under diverse conditions, achieving pH-induced selectivity in affinity of up to 1,000-fold. Importantly, we demonstrate the design of tightly regulated aptamers with strong target affinity over only a narrow pH range. Our approach offers a highly generalizable strategy for integrating pH-responsiveness into molecular devices.
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http://dx.doi.org/10.1038/s41467-020-16808-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286914PMC
June 2020

The association between serum sex steroid hormone concentrations and intraprostatic inflammation in men without prostate cancer and irrespective of clinical indication for biopsy in the placebo arm of the Prostate Cancer Prevention Trial.

Prostate 2020 08 7;80(11):895-905. Epub 2020 Jun 7.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer.

Methods: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI).

Results: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05).

Conclusions: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.
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http://dx.doi.org/10.1002/pros.24023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384586PMC
August 2020

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. Electronic address:

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
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http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

Comparative Survival of Asian and White Metastatic Castration-Resistant Prostate Cancer Men Treated With Docetaxel.

JNCI Cancer Spectr 2020 Apr 29;4(2):pkaa003. Epub 2020 Jan 29.

Medical Oncology and Urology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, USA.

There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined. Men enrolled in these trials had a diagnosis of prostate adenocarcinoma. The median overall survival was 18.8 months (95% confidence interval [CI] = 17.4 to 22.1 months) and 21.2 months (95% CI = 20.8 to 21.7 months) for Asian and white men, respectively. The pooled hazard ratio for death for Asian men compared with white men, adjusted for baseline prognostic factors, was 0.95 (95% CI = 0.84 to 1.09), indicating that Asian men were not at increased risk of death. This large analysis showed that Asian men did not have shorter OS duration than white men treated with docetaxel.
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http://dx.doi.org/10.1093/jncics/pkaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190204PMC
April 2020

Magnetic Resonance Imaging for the Detection of High Grade Cancer in the Canary Prostate Active Surveillance Study.

J Urol 2020 10 28;204(4):701-706. Epub 2020 Apr 28.

Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.

Purpose: We investigated the ability of prostate magnetic resonance imaging to detect Gleason Grade Group 2 or greater cancer in a standardized, multi-institutional active surveillance cohort.

Materials And Methods: We evaluated men enrolled in Canary Prostate Active Surveillance Study with Gleason Grade Group less than 2 and who underwent biopsy within 12 months of multiparametric magnetic resonance imaging. Our primary outcome was biopsy reclassification to Gleason Grade Group 2 or greater. We evaluated the performance of magnetic resonance imaging PI-RADS® score and clinical factors. Multivariable logistic regression models were fit with magnetic resonance imaging and clinical factors and used to perform receiver operating curve analyses.

Results: There were 361 participants with 395 prostate magnetic resonance imaging studies with a median followup of 4.1 (IQR 2.0-7.6) years. Overall 108 (27%) biopsies showed reclassification. Defining positive magnetic resonance imaging as PI-RADS 3-5, the negative predictive value and positive predictive value for detecting Gleason Grade Group 2 or greater cancer was 83% (95% CI 76-90) and 31% (95% CI 26-37), respectively. PI-RADS was significantly associated with reclassification (PI-RADS 5 vs 1 and 2 OR 2.71, 95% CI 1.21-6.17, p=0.016) in a multivariable model but did not improve upon a model with only clinical factors (AUC 0.768 vs 0.762). In 194 fusion biopsies higher grade cancer was found in targeted cores in 21 (11%) instances, while 25 (13%) had higher grade cancer in the systematic cores.

Conclusions: This study adds the largest cohort data to the body of literature for magnetic resonance imaging in active surveillance, recommending systematic biopsy in patients with negative magnetic resonance imaging and the inclusion of systematic biopsy in patients with positive magnetic resonance imaging.
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http://dx.doi.org/10.1097/JU.0000000000001088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483329PMC
October 2020

Clinical outcomes in men of diverse ethnic backgrounds with metastatic castration-resistant prostate cancer.

Ann Oncol 2020 07 11;31(7):930-941. Epub 2020 Apr 11.

Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, USA.

Background: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen.

Patients And Methods: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors.

Results: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively.

Conclusions: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.
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http://dx.doi.org/10.1016/j.annonc.2020.03.309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580036PMC
July 2020