Publications by authors named "Jianfeng Xu"

667 Publications

Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.

Prostate 2021 Oct 21. Epub 2021 Oct 21.

Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois, USA.

Background: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis.

Methods: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models.

Results: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers.

Conclusions: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed.
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http://dx.doi.org/10.1002/pros.24252DOI Listing
October 2021

Design of a self-centring drill bit for orthopaedic surgery: A systematic comparison of the drilling performance.

J Mech Behav Biomed Mater 2021 11 25;123:104727. Epub 2021 Aug 25.

Department of Mechanical Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 1138656, Japan.

Bone drilling is an indispensable and demanding operation among many orthopaedic operations. A dedicated drill bit that can achieve low-trauma and self-centring drilling is in urgent need. In this study, a three-step orthopaedic low-traumatic drill bit design was proposed. In order to evaluate the drilling performance of the proposed drill, comprehensive comparison tests were carried out with various commercial medical drills in terms of skiving force, thrust force, temperature rise, and surface quality. The experimental results show that the proposed three-step drill design with the optimal point angle, a small chisel edge, transition arc and web thinning can obtain lower and more stable thrust force, slighter bending force, smaller temperature rise, and higher hole quality compared with the commercial drill bits. The proposed drill shows satisfactory drilling performance and has great application potential in clinical surgery.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104727DOI Listing
November 2021

The concurrence of DNA methylation and demethylation is associated with transcription regulation.

Nat Commun 2021 09 6;12(1):5285. Epub 2021 Sep 6.

Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.
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http://dx.doi.org/10.1038/s41467-021-25521-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421433PMC
September 2021

Prebiotic Photochemical Coproduction of Purine Ribo- and Deoxyribonucleosides.

J Am Chem Soc 2021 Sep 1;143(36):14482-14486. Epub 2021 Sep 1.

MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, U.K.

The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2'-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.
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http://dx.doi.org/10.1021/jacs.1c07403DOI Listing
September 2021

EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.

Clin Cancer Res 2021 Aug 31. Epub 2021 Aug 31.

Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.

Purpose: DNA methylation alterations have emerged as front-runners in cell-free DNA (cfDNA) biomarker development. However, much effort to date has focused on single cancers. In this context, gastrointestinal (GI) cancers constitute the second leading cause of cancer-related deaths worldwide; yet there is no blood-based assay for the early detection and population screening of GI cancers.

Experimental Design: Herein, we performed a genome-wide DNA methylation analysis of multiple GI cancers to develop a pan-GI diagnostic assay. By analyzing DNA methylation data from 1,781 tumor and adjacent normal tissues, we first identified differentially methylated regions (DMR) between individual GI cancers and adjacent normal, as well as across GI cancers. We next prioritized a list of 67,832 tissue DMRs by incorporating all significant DMRs across various GI cancers to design a custom, targeted bisulfite sequencing platform. We subsequently validated these tissue-specific DMRs in 300 cfDNA specimens and applied machine learning algorithms to develop three distinct categories of DMR panels RESULTS: We identified three distinct DMR panels: (i) cancer-specific biomarker panels with AUC values of 0.98 (colorectal cancer), 0.98 (hepatocellular carcinoma), 0.94 (esophageal squamous cell carcinoma), 0.90 (gastric cancer), 0.90 (esophageal adenocarcinoma), and 0.85 (pancreatic ductal adenocarcinoma); (ii) a pan-GI panel that detected all GI cancers with an AUC of 0.88; and (iii) a multi-cancer (tissue of origin) prediction panel, EpiPanGI Dx, with a prediction accuracy of 0.85-0.95 for most GI cancers.

Conclusions: Using a novel biomarker discovery approach, we provide the first evidence for a cfDNA methylation assay that offers robust diagnostic accuracy for GI cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1982DOI Listing
August 2021

Automatic Meningioma Segmentation and Grading Prediction: A Hybrid Deep-Learning Method.

J Pers Med 2021 Aug 12;11(8). Epub 2021 Aug 12.

Department of Neurosurgery, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu 610041, China.

The purpose of this study was to determine whether a deep-learning-based assessment system could facilitate preoperative grading of meningioma. This was a retrospective study conducted at two institutions covering 643 patients. The system, designed with a cascade network structure, was developed using deep-learning technology for automatic tumor detection, visual assessment, and grading prediction. Specifically, a modified U-Net convolutional neural network was first established to segment tumor images. Subsequently, the segmentations were introduced into rendering algorithms for spatial reconstruction and another DenseNet convolutional neural network for grading prediction. The trained models were integrated as a system, and the robustness was tested based on its performance on an external dataset from the second institution involving different magnetic resonance imaging platforms. The results showed that the segment model represented a noteworthy performance with dice coefficients of 0.920 ± 0.009 in the validation group. With accurate segmented tumor images, the rendering model delicately reconstructed the tumor body and clearly displayed the important intracranial vessels. The DenseNet model also achieved high accuracy with an area under the curve of 0.918 ± 0.006 and accuracy of 0.901 ± 0.039 when classifying tumors into low-grade and high-grade meningiomas. Moreover, the system exhibited good performance on the external validation dataset.
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http://dx.doi.org/10.3390/jpm11080786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401675PMC
August 2021

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

Br J Clin Pharmacol 2021 Aug 24. Epub 2021 Aug 24.

ViiV Healthcare, Research Triangle Park, NC, USA.

Aims: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women.

Methods: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC ), maximum observed concentration (C ) and plasma concentration at the end of the dosing interval (C ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored.

Results: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC , C and C were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal.

Conclusion: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.
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http://dx.doi.org/10.1111/bcp.15051DOI Listing
August 2021

Access to Chiral Polycyclic 1,4-Dihydropyridines via Organocatalytic Formal [3 + 3] Annulation of 2-(1-Alkynyl)-2-alken-1-ones with 3-Aminobenzofurans.

Org Lett 2021 08 9;23(16):6391-6395. Epub 2021 Aug 9.

Key Laboratory of Surface & Interface Science of Polymer Materials of Zhejiang Province, Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China.

A rational designed tandem reaction of 2-(1-alkynyl)-2-alken-1-ones with 3-aminobenzofurans enabled by a chiral bifunctional catalyst is described, affording biologically significant polycyclic 1,4-dihydropyridines in moderate to good yields (43-82%) with good to excellent enantioselectivities (83-99%). This formal [3 + 3] annulation reaction reveals good practicality when conducted on a gram scale, and the cycloadduct has the capability for further elaborations.
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http://dx.doi.org/10.1021/acs.orglett.1c02211DOI Listing
August 2021

Genetic Susceptibility for Low Testosterone in Men and Its Implications in Biology and Screening: Data from the UK Biobank.

Eur Urol Open Sci 2021 Jul 25;29:36-46. Epub 2021 May 25.

Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.

Background: Despite strong evidence of heritability, few studies have attempted to unveil the genetic underpinnings of testosterone levels.

Objective: To identify testosterone-associated loci in a large study and assess their biological and clinical implications.

Design Setting And Participants: The participants were men from the UK Biobank. A two-stage genome-wide association study (GWAS) was first used to identify/validate loci for low testosterone (LowT, <8 nmol/l) in 80% of men ( = 148 902). The cumulative effect of independent LowT risk loci was then evaluated in the remaining 20% of men.

Outcome Measurements And Statistical Analysis: Associations of single nucleotide polymorphisms (SNPs) with LowT were tested using an additive model. Analyses of the expression quantitative trait loci (eQTLs) were performed to assess the associations between significant SNPs and expression of nearby genes (within 1 Mbp). A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent SNPs on LowT risk.

Results And Limitations: The two-stage GWAS found SNPs in 141 loci of 41 cytobands that were significantly associated with LowT ( < 5 × 10), including 94 novel loci from 38 cytobands. An eQTL analysis of these 141 loci revealed significant associations with RNA expression of 155 genes, including previously implicated ( and ) and novel (, , and ) genes. Among the 141 loci, 42 were independently associated with LowT after a multivariable analysis. The GRS based on these 42 loci was significantly associated with LowT risk in independent individuals ( = 37 225,  = 3.16 × 10). The risk ratio for LowT between men in the top and those in the bottom GRS deciles was 4.98-fold. Results are limited in generalizability as only Caucasians were studied.

Conclusions: Identification of the genetic variants associated with LowT may improve our understanding of its etiology and identify high-risk men for LowT screening.

Patient Summary: We identified 141 new genetic loci that can be incorporated into a genetic risk score that can potentially identify men with low testosterone.
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http://dx.doi.org/10.1016/j.euros.2021.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317803PMC
July 2021

Optical Simulation and Experimental Assessment with Time-Walk Correction of TOF-PET Detectors with Multi-Ended Readouts.

Sensors (Basel) 2021 Jul 8;21(14). Epub 2021 Jul 8.

Institute of Biomedical Engineering, Shenzhen Bay Laboratory, Shenzhen 518107, China.

As a commonly used solution, the multi-ended readout can measure the depth-of-interaction (DOI) for positron emission tomography (PET) detectors. In the present study, the effects of the multi-ended readout design were investigated using the leading-edge discriminator (LED) triggers on the timing performance of time-of-flight (TOF) PET detectors. At the very first, the photon transmission model of the four detectors, namely, single-ended readout, dual-ended readout, side dual-ended readout, and triple-ended readout, was established in Tracepro. The optical simulation revealed that the light output of the multi-ended readout was higher. Meanwhile, the readout circuit could be triggered earlier. Especially, in the triple-ended readout, the light output at 0.5 ns was observed to be nearly twice that of the single-ended readout after the first scintillating photon was generated. Subsequently, a reference detector was applied to test the multi-ended readout detectors that were constructed from a 6 × 6 × 25 mm LYSO crystal. Each module is composed of a crystal coupled with multiple SiPMs. Accordingly, its timing performance was improved by approximately 10% after the compensation of fourth-order polynomial fitting. Finally, the compensated full-width-at-half-maximum (FWHM) coincidence timing resolutions (CTR) of the dual-ended readout, side dual-ended readout, and triple-ended readout were 216.9 ps, 231.0 ps, and 203.6 ps, respectively.
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http://dx.doi.org/10.3390/s21144681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309550PMC
July 2021

Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.

Prostate 2021 Sep 12;81(13):1002-1008. Epub 2021 Jul 12.

Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois, USA.

Background: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established.

Methods: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p < .005 was considered significant based on Bonferroni correction.

Results: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p < .005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62-6.69), 3.23 (2.23-4.56), 2.95 (2.01-4.22), 1.94 (1.43-2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%).

Conclusion: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.
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http://dx.doi.org/10.1002/pros.24195DOI Listing
September 2021

Baicalin Protects Vascular Tight Junctions in Piglets During Infection.

Front Vet Sci 2021 25;8:671936. Epub 2021 Jun 25.

Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, United States.

() can cause Glässer's disease and severely affect swine industry worldwide. This study is an attempt to address the issue of the capability of to damage the vascular barrier and the effects of baicalin on vascular tight junctions (TJ) in order to investigate the interactions between the pathogen and the porcine vascular endothelium. Piglets were challenged with and treated with or without baicalin. The expressions of vascular TJ genes were examined using RT-PCR. The distribution patterns of TJ proteins were detected by immunofluorescence. The involved signaling pathways were determined by Western blot assays on related proteins. can downregulate TJ expression and disrupt the distribution of TJ proteins. Baicalin can alleviate the downregulation of vascular TJ mRNA, maintain the distribution, and prevent the abnormalities of TJ. These results provide ample evidence that baicalin has the capacity to protect vascular TJ damaged by through inhibiting PKC and MLCK/MLC pathway activation. As a result, baicalin is a promising candidate for application as a natural agent for the prevention and control of infection.
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http://dx.doi.org/10.3389/fvets.2021.671936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267157PMC
June 2021

Germline Testing for Prostate Cancer Prognosis: Implications for Active Surveillance.

Urol Clin North Am 2021 Aug 10;48(3):401-409. Epub 2021 Jun 10.

Program for Personalized Cancer Care, Division of Urology, NorthShore University HealthSystem, 1001 University Place, Evanston, IL 60201, USA.

Available evidence supports routine implementation of germline genetic testing for many aspects of prostate cancer (PCa) decision making. The purpose of obtaining genetic testing for newly diagnosed men would be focused on identifying mutations that predispose to aggressive PCa. Based on an evidence-based review, the authors review germline rare pathogenic mutations in several genes that are significantly associated with aggressiveness, metastases, and mortality. Then recent studies of these germline mutations in predicting tumor grade reclassification among patients undergoing active surveillance are discussed. Single nucleotide polymorphisms-based polygenic risk scores in differentiating PCa aggressiveness and prognosis are reviewed.
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http://dx.doi.org/10.1016/j.ucl.2021.04.003DOI Listing
August 2021

Prostate Cancer Predisposition.

Urol Clin North Am 2021 Aug 12;48(3):283-296. Epub 2021 Jun 12.

Department of Medicine, Duke University School of Medicine and the Duke Cancer Institute, 2301 Erwin Road, DUH 1102, Durham, NC 27710-3703, USA.

The identification and characterization of alterations in prostate cancer (PCa)-predisposing genes can help to inform screening strategies in undiagnosed men and treatment options in men in both the clinically localized and in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PCa, the current role of genetics and PCa risk assessment, and how genetic risk factors affect aggressiveness and lethality of PCa.
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http://dx.doi.org/10.1016/j.ucl.2021.03.001DOI Listing
August 2021

Timescales for Prebiotic Photochemistry Under Realistic Surface Ultraviolet Conditions.

Astrobiology 2021 09 21;21(9):1099-1120. Epub 2021 Jun 21.

Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom.

Ultraviolet (UV) light has long been invoked as a source of energy for prebiotic chemical synthesis, but experimental support does not involve sources of UV light that look like the young Sun. Here we experimentally investigate whether the UV flux available on the surface of early Earth, given a favorable atmosphere, can facilitate a variety of prebiotic chemical syntheses. We construct a solar simulator for the UV light of the faint young Sun on the surface of early Earth, called StarLab. We then attempt a series of reactions testing different aspects of a prebiotic chemical scenario involving hydrogen cyanide (HCN), sulfites, and sulfides under the UV light of StarLab, including hypophosphite oxidation by UV light and hydrogen sulfide, photoreduction of HCN with bisulfite, the photoanomerization of α-thiocytidine, the production of a chemical precursor of a potentially prebiotic activating agent (nitroprusside), the photoreduction of thioanhydrouridine and thioanhydroadenosine, and the oxidation of ethanol (EtOH) by photochemically generated hydroxyl radicals. We compare the output of StarLab to the light of the faint young Sun to constrain the timescales over which these reactions would occur on the surface of early Earth. We predict that hypophosphite oxidation, HCN reduction, and photoproduction of nitroprusside would all operate on the surface of early Earth in a matter of days to weeks. The photoanomerization of α-thiocytidine would take months to complete, and the production of oxidation products from hydroxyl radicals would take years. The photoreduction of thioanhydrouridine with hydrogen sulfide did not succeed even after a long period of irradiation, providing a lower limit on the timescale of several years. The photoreduction of thioanhydroadenosine with bisulfite produced 2'-deoxyriboadenosine (dA) on the timescale of days. This suggests the plausibility of the photoproduction of purine deoxyribonucleotides, such as the photoproduction of simple sugars, proceeds more efficiently in the presence of bisulfite.
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http://dx.doi.org/10.1089/ast.2020.2335DOI Listing
September 2021

Design study of a PET detector with 0.5 mm crystal pitch for high-resolution preclinical imaging.

Phys Med Biol 2021 Jul 1;66(13). Epub 2021 Jul 1.

Institute of Biomedical Engineering Shenzhen Bay Laboratory, Shenzhen, 518132, People's Republic of China.

Preclinical positron emission tomography (PET) is a sensitive and quantitative molecule imaging modality widely used in characterizing the biological processes and diseases in small animals. The purpose of this study is to investigate the methods to optimize a PET detector for high-resolution preclinical imaging. The PET detector proposed in this study consists of a 28 × 28 array of LYSO crystals 0.5 × 0.5 × 6.25 mmin size, a wedged lightguide, and a 6 × 6 array of SiPMs 3 × 3 mmin size. The simulation results showed that the most uniform flood map was achieved when the thickness of the lightguide was 2.35 mm. The quality of the flood map was significantly improved by suppressing the electronics noises using the simple threshold method with a best threshold. The peak-to-valley ratio of flood map improved 25.4% when the algorithm of ICS rejection was applied. An energy resolution (12.96% ± 1.03%) was measured on the prototype scanner constructed with 12 proposed detectors. Lastly, a prototype preclinic PET imager was constructed with 12 optimized detectors. The point source experiment was performed and an excellent spatial resolution (axial: 0.56 mm, tangential: 0.46 mm, radial: 0.42 mm) was achieved with the proposed high-performance PET detectors.
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http://dx.doi.org/10.1088/1361-6560/ac0b82DOI Listing
July 2021

Association of Sickle Cell Trait with Risk and Mortality of COVID-19: Results from the United Kingdom Biobank.

Am J Trop Med Hyg 2021 Jun 15. Epub 2021 Jun 15.

Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.

Sickle cell trait (SCT) carriers inherit one copy of the Glu6Val mutation in the hemoglobin gene and is particularly common in Black individuals (5-10%). Considering the roles of hemoglobin in immune responses and the higher risk for coronavirus disease (COVID-19) among Black individuals, we tested whether Black SCT carriers were at increased risk for COVID-19 infection and mortality according to the United Kingdom Biobank. Among Black individuals who were tested for COVID-19, we found similar infection rates among SCT carriers (14/72; 19.7%) and noncarriers (167/791; 21.1%), but higher COVID-19 mortality rates among SCT carriers (4/14; 28.6%) than among noncarriers (21/167; 12.6%) (odds ratio [OR], 3.04; 95% confidence interval [CI], 0.69-11.82; P = 0.12). Notably, SCT carriers with preexisting diabetes had significantly higher COVID-19 mortality (4/4; 100%) than those without diabetes (0/10; 0%; (OR, 90.71; 95% CI, 5.66-infinite; P = 0.0005). These findings suggest that Black SCT carriers with preexisting diabetes are at disproportionally higher risk for COVID-19 mortality. Confirmation by larger studies is warranted.
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http://dx.doi.org/10.4269/ajtmh.20-1657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437181PMC
June 2021

A Novel Portable Gamma Radiation Sensor Based on a Monolithic Lutetium-Yttrium Oxyorthosilicate Ring.

Sensors (Basel) 2021 May 12;21(10). Epub 2021 May 12.

Shenzhen Bay Laboratory, The Institute of Biomedical Engineering, Shenzhen 518132, China.

Portable radiation detectors are widely used in environmental radiation detection and medical imaging due to their portability feature, high detection efficiency, and large field of view. Lutetium-yttrium oxyorthosilicate (LYSO) is a widely used scintillator in gamma radiation detection. However, the structure and the arrangement of scintillators limit the sensitivity and detection accuracy of these radiation detectors. In this study, a novel portable sensor based on a monolithic LYSO ring was developed for the detection of environmental radiation through simulation, followed by construction and assessments. Monte Carlo simulations were utilized to prove the detection of gamma rays at 511 keV by the developed sensor. The simulations data, including energy resolutions, decoding errors, and sensitivity, showed good potential for the detection of gamma rays by the as-obtained sensor. The experimental results using the VA method revealed decoding errors in the energy window width of 50 keV less than 2°. The average error was estimated at 0.67°, a sufficient value for the detection of gamma radiation. In sum, the proposed radiation sensor appears promising for the construction of high-performance radiation detectors and systems.
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http://dx.doi.org/10.3390/s21103376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150370PMC
May 2021

Synergistic effects of autophagy inhibitors combined with cisplatin against cisplatin-resistant nasopharyngeal cancer cells.

Biochem Cell Biol 2021 06 26;99(3):322-329. Epub 2021 May 26.

Hangzhou Cancer Hospital, No. 34 Yanguanxiang, Hangzhou Zhejiang 310002, China.

This study explored the synergistic effects of autophagy inhibitors combined with cisplatin against cisplatin-resistant nasopharyngeal cancer cells by treating HNE-1 and cisplatin (diamminedichloroplatinum; DDP)-resistant HNE1/DDP nasopharyngeal cancer cell lines with DDP, autophagy inhibitors, or a combination of autophagy inhibitors and DDP. Cell viability was determined via MTT (colorimetric) and colony-forming assays, and the rate of apoptosis was determined using propidium iodide (PI) and annexin V double-staining. The expressions of proteins were determined by Western blotting. For our in-vivo studies, a murine xenograft model was established to evaluate the anti-tumor effects of the combination of autophagy inhibitor and DDP. The results showed that treatment with DDP increased the expressions of ATP-binding cassette sub-family B member 1 (ABCB1), ATP Binding Cassette Subfamily C Member 1 (ABCC1), and P-glycoprotein 1 (P-gp) in the HNE1/DDP cell lines. Treatment with chloroquine decreased the expression levels of ABCB1, ABCC1, and P-gp, and increased the formation of LC3-II and the expression levels of p62 in the HNE1/DDP cells. Additionally, the combination of autophagy inhibitors and DDP produced a synergistic effect on DDP-induced cell death and apoptosis. Furthermore, the combination of the autophagy inhibitor and DDP showed significant anti-tumor effects in the xenograft mouse model. In summary, autophagy inhibitors show synergistic anti-tumor effects with DDP in vitro against DDP-resistant nasopharyngeal cancer cells and in vivo in our xenograft murine model.
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http://dx.doi.org/10.1139/bcb-2020-0283DOI Listing
June 2021

Diagnostic Performance of CMR, SPECT, and PET Imaging for the Identification of Coronary Artery Disease: A Meta-Analysis.

Front Cardiovasc Med 2021 7;8:621389. Epub 2021 May 7.

Department of Nuclear Sciences and Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China.

Myocardial perfusion imaging modalities, such as cardiac magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and positron emission tomography (PET), are well-established non-invasive diagnostic methods to detect hemodynamically significant coronary artery disease (CAD). The aim of this meta-analysis is to compare CMR, SPECT, and PET in the diagnosis of CAD and to provide evidence for further research and clinical decision-making. PubMed, Web of Science, EMBASE, and Cochrane Library were searched. Studies that used CMR, SPECT, and/or PET for the diagnosis of CAD were included. Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio with their respective 95% confidence interval, and the area under the summary receiver operating characteristic (SROC) curve were calculated. A total of 203 articles were identified for inclusion in this meta-analysis. The pooled sensitivity values of CMR, SPECT, and PET were 0.86, 0.83, and 0.85, respectively. Their respective overall specificity values were 0.83, 0.77, and 0.86. Results in subgroup analysis of the performance of SPECT with Tl showed the highest pooled sensitivity [0.85 (0.82, 0.88)] and specificity [0.80 (0.75, 0.83)]. Tc-tetrofosmin had the lowest sensitivity [0.76 (0.67, 0.82)]. In the subgroup analysis of PET tracers, results indicated that N had the lowest pooled sensitivity [0.83 (0.74, 0.89)], and the specificity was the highest [0.91 (0.81, 0.96)]. Our meta-analysis indicates that CMR and PET present better diagnostic performance for the detection of CAD as compared with SPECT.
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http://dx.doi.org/10.3389/fcvm.2021.621389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138058PMC
May 2021

Incorporation of Polygenic Risk Score into Guidelines for Inherited Risk Assessment for Prostate Cancer.

Eur Urol 2021 08 20;80(2):139-141. Epub 2021 May 20.

The Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2021.04.043DOI Listing
August 2021

Association of prostate cancer polygenic risk score with number and laterality of tumor cores in active surveillance patients.

Prostate 2021 Jul 6;81(10):703-709. Epub 2021 May 6.

The Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Background: Prostate cancer (PCa) is characterized by its tendency to be multifocal. However, few studies have investigated the endogenous factors that explain the multifocal disease. The primary objective of the current study is to test whether inherited PCa risk is associated with multifocal tumors in PCa patients.

Methods: Subjects in this study were PCa patients of European ancestry undergoing active surveillance at Johns Hopkins Hospital (N = 805) and NorthShore University HealthSystem (N = 432). The inherited risk was measured by genetic risk score (GRS), an odds ratio-weighted and population-standardized polygenic risk score based on known risk-associated single nucleotide polymorphisms. PCa multifocality was indirectly measured by the number and laterality of positive tumor cores from a 12-core systematic biopsy.

Results: In the combined cohort, 35.7% and 66.3% of patients had ≥2 tumor cores at the initial diagnostic biopsy and on at least one subsequent surveillance biopsy, respectively. For tumor laterality, 7.8% and 47.8% of patients had bilateral tumor cores at diagnostic and surveillance biopsies, respectively. We found, for the first time, that patients with higher numbers of positive cores at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values; p = .01 and p = 5.94E-04. Additionally, patients with bilateral tumors at diagnostic and surveillance biopsies, respectively, had significantly higher mean GRS values than those with unilateral tumors; p = .04 and p = .01. In contrast, no association was found between GRS and maximum core length of tumor or tumor grade at diagnostic/surveillance biopsies (all p > .05). Finally, we observed a modest trend that patients with higher GRS quartiles had a higher risk for tumor upgrading on surveillance biopsies. The trend, however, was not statistically significant (p > .05).

Conclusions: The associations of GRS with two measurements of PCa multifocality (core numbers and laterality) provide novel and consistent evidence for the link between inherited PCa risk and multifocal tumors.
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http://dx.doi.org/10.1002/pros.24140DOI Listing
July 2021

Molecular Dynamics Simulation on Cutting Mechanism in the Hybrid Machining Process of Single-Crystal Silicon.

Nanoscale Res Lett 2021 Apr 21;16(1):66. Epub 2021 Apr 21.

State Key Laboratory of Digital Manufacturing Equipment and Technology, School of Mechanical Science and Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China.

In this paper, molecular dynamics simulations are carried out to investigate the cutting mechanism during the hybrid machining process combined the thermal and vibration assistants. A modified cutting model is applied to study the material removal behavior and subsurface damage formation in one vibration cycle. The results indicate that during the hybrid machining process, the dominant material removal mechanism could transform from extrusion to shearing in a single vibration cycle. With an increase of the cutting temperature, the generation and propagation of cracks are effectively suppressed while the swelling appears when the dominant material removal mechanism becomes shearing. The formation mechanism of the subsurface damage in one vibration cycle can be distinct according to the stress distribution. Moreover, the generation of the vacancies in workpiece becomes apparent with increasing temperature, which is an important phenomenon in hybrid machining process.
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http://dx.doi.org/10.1186/s11671-021-03526-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060384PMC
April 2021

Illuminating Life's Origins: UV Photochemistry in Abiotic Synthesis of Biomolecules.

J Am Chem Soc 2021 05 21;143(19):7219-7236. Epub 2021 Apr 21.

MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, U.K.

Solar radiation is the principal source of energy available to Earth and has unmatched potential for the synthesis of organic material from primordial molecular building blocks. As well as providing the energy for photochemical synthesis of (proto)biomolecules of interest in origins of life-related research, light has also been found to often provide remarkable selectivity in these processes, for molecules that function in extant biology and against those that do not. As such, light is heavily implicated as an environmental input on the nascent Earth that was important for the emergence of complex yet selective chemical systems underpinning life. Reactivity and selectivity in photochemical prebiotic synthesis are discussed, as are their implications for origins of life scenarios and their plausibility, and the future directions of this research.
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http://dx.doi.org/10.1021/jacs.1c01839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240947PMC
May 2021

Cellular engineering of plant cells for improved therapeutic protein production.

Plant Cell Rep 2021 Jul 10;40(7):1087-1099. Epub 2021 Apr 10.

Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR, 72401, USA.

In vitro cultured plant cells, in particular the tobacco BY-2 cell, have demonstrated their potential to provide a promising bioproduction platform for therapeutic proteins by integrating the merits of whole-plant cultivation systems with those of microbial and mammalian cell cultures. Over the past three decades, substantial progress has been made in improving the plant cell culture system, resulting in a few commercial success cases, such as taliglucerase alfa (Elelyso), the first FDA-approved recombinant pharmaceutical protein derived from plant cells. However, compared to the major expression hosts (bacteria, yeast, and mammalian cells), plant cells are still largely underutilized, mainly due to low productivity and non-human glycosylation. Modern molecular biology tools, in particular RNAi and the latest genome editing technology CRISPR/Cas9, have been used to modulate the genome of plant cells to create new cell lines that exhibit desired "traits" for producing therapeutic proteins. This review highlights the recent advances in cellular engineering of plant cells towards improved recombinant protein production, including creating cell lines with deficient protease levels or humanized glycosylation, and considers potential development in the future.
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http://dx.doi.org/10.1007/s00299-021-02693-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035600PMC
July 2021

HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia.

Nat Commun 2021 03 29;12(1):1956. Epub 2021 Mar 29.

Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.

Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c). NPM1c maintains a unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC, a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c-associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c-driven leukemogenesis by rectifying the signature of NPM1c leukemic transcription programs. Furthermore, overexpression of HoxBlinc (HoxBlincTg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in (Npm1) mice. HoxBlincTg and Npm1 HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c signature genes to control their activation in HoxBlincTg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c leukemia. HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c AML.
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http://dx.doi.org/10.1038/s41467-021-22095-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007823PMC
March 2021

A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants.

Antimicrob Agents Chemother 2021 05 18;65(6). Epub 2021 May 18.

ViiV Healthcare, Research Triangle Park, North Carolina, USA.

GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes. This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on days 15 through 21. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored. Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time zero to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMRs (90% CI) of 0.886 (0.75 to 1.04) and 0.874 (0.68 to 1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed. GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV. (This study has been registered at ClinicalTrials.gov under identifier NCT03836729.).
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http://dx.doi.org/10.1128/AAC.02173-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316023PMC
May 2021

Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer.

JCI Insight 2021 Apr 22;6(8). Epub 2021 Apr 22.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University, Baltimore, Maryland, USA.

Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR- neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR+ CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR+/NE+ double-positive "amphicrine" mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53, and the loss of RB1 but occurred via emergence of an AR-/NE- double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.
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http://dx.doi.org/10.1172/jci.insight.146827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119192PMC
April 2021

Protective Effects of Baicalin on Peritoneal Tight Junctions in Piglets Challenged with .

Molecules 2021 Feb 26;26(5). Epub 2021 Feb 26.

Hubei Key Laboratory of Animal Nutrition and Feed Science, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan 430023, China.

() causes inflammation and damage to piglets. Whether polyserositis caused by is due to tight junctions damage and the protective effect of baicalin on it have not been examined. Therefore, this study aims to investigate the effects of baicalin on peritoneal tight junctions of piglets challenged with and its underlying molecular mechanisms. Piglets were challenged with and treated with or without baicalin. RT-PCR was performed to examine the expression of peritoneal tight junctions genes. Immunofluorescence was carried out to detect the distribution patterns of tight junctions proteins. Western blot assays were carried out to determine the involved signaling pathways. Our data showed that infection can down-regulate the tight junctions expression and disrupt the distribution of tight junctions proteins. Baicalin can alleviate the down-regulation of tight junctions mRNA in peritoneum, prevent the abnormalities and maintain the continuous organization of tight junctions. Our results provide novel evidence to support that baicalin has the capacity to protect peritoneal tight junctions from -induced inflammation. The protective mechanisms of baicalin could be associated with inhibition of the activation of PKC and MLCK/MLC signaling pathway. Taken together, these data demonstrated that baicalin is a promising natural agent for the prevention and treatment of infection.
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http://dx.doi.org/10.3390/molecules26051268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956672PMC
February 2021
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