Nomogram Using Prostate Health Index for Predicting Prostate Cancer in the Gray Zone: Prospective, Multicenter Study.

PURPOSE: To create a nomogram that can predict the probability of prostate cancer using prostate health index (PHI) and clinical parameters of patients. And the optimal cut-off value of PHI for prostate cancer was also assessed. MATERIALS AND METHODS: A prospective, multi-center study was conducted. PHI was evaluated prior to biopsy in patients requiring prostate biopsy due to high prostate-specific antigen (PSA). Among screened 1,010 patients, 626 patients with clinically suspected prostate cancer with aged 40 to 85 years, and with PSA levels ranging from 2.5 to 10 ng/mL were analyzed. RESULTS: Among 626 patients, 38.82% (243/626) and 22.52% (141/626) were diagnosed with prostate cancer and clinically significant prostate cancer, respectively. In the PSA 2.5 to 4 ng/mL group, the areas under the curve (AUCs) of the nomograms for overall prostate cancer and clinically significant prostate cancer were 0.796 (0.727-0.866; p<0.001), and 0.697 (0.598-0.795; p=0.001), respectively. In the PSA 4 to 10 ng/mL group, the AUCs of nomograms for overall prostate cancer and clinically significant prostate cancer were 0.812 (0.783-0.842; p<0.001), and 0.839 (0.810-0.869; p<0.001), respectively. CONCLUSIONS: Even though external validations are necessary, a nomogram using PHI might improve the prediction of prostate cancer, reducing the need for prostate biopsies.

Low-Dose Ionizing Radiation-Crosslinking Immunoprecipitation (LDIR-CLIP) Identified Irradiation-Sensitive RNAs for RNA-Binding Protein HuR-Mediated Decay.

Although ionizing radiation (IR) is widely used for therapeutic and research purposes, studies on low-dose ionizing radiation (LDIR) are limited compared with those on other IR approaches, such as high-dose gamma irradiation and ultraviolet irradiation. High-dose IR affects DNA damage response and nucleotide-protein crosslinking, among other processes; however, the molecular consequences of LDIR have been poorly investigated. Here, we developed a method to profile RNA species crosslinked to an RNA-binding protein, namely, human antigen R (HuR), using LDIR and high-throughput RNA sequencing. The RNA fragments isolated via LDIR-crosslinking and immunoprecipitation sequencing were crosslinked to HuR and protected from RNase-mediated digestion. Upon crosslinking HuR to target mRNAs such as PAX6, ZFP91, NR2F6, and CAND2, the transcripts degraded rapidly in human cell lines. Additionally, PAX6 and NR2F6 downregulation mediated the beneficial effects of LDIR on cell viability. Thus, our approach provides a method for investigating post-transcriptional gene regulation using LDIR.

Corrigendum: Correction of the Figure. Trends of stratified prostate cancer risk in a single Korean province from 2003 to 2021: A multicenter study conducted using regional training hospital data.

This corrects the article on p. 140 in vol. 64, PMID: 36882172.

Trends of stratified prostate cancer risk in a single Korean province from 2003 to 2021: A multicenter study conducted using regional training hospital data.

PURPOSE: To identify changes in prostate cancer (PCa) risk-stratification during the last two decades in Korea, where the social perception of PCa was limited due to a relatively low incidence but has recently been triggered by the rapidly increasing incidence of benign prostate hyperplasia. MATERIALS AND METHODS: Retrospective data of patients who had received a diagnosis of PCa in a single Korean province (Daegu-Gyeongsangbuk) at all seven training hospitals in the years 2003, 2007, 2011, 2015, 2019, and 2021 were subjected to analysis. Changes in PCa risk-stratification were investigated with respect to serum prostate-specific antigen (PSA), Gleason score (GS), and clinical stage. RESULTS: Of the 3,393 study subjects that received a diagnosis of PCa, 64.1% had high-risk disease, 23.0% intermediate, and 12.9% low-risk disease. The proportion diagnosed with high-risk disease was 54.8% in 2003, 30.6% in 2019, but then increased to 35.1% in 2021. The proportion of patients with high PSA (>20 ng/mL) steadily decreased from 59.4% in 2003 to 29.6% in 2021, whereas the proportion with a high GS (>8) increased from 32.8% in 2011 to 34.0% in 2021, and the proportion with advanced stage disease (over cT2c) increased from 26.5% in 2011 to 37.1% in 2021. CONCLUSIONS: In this retrospective study, conducted in a single Korean province, high-risk PCa accounted for the largest proportion of newly registered Korean PCa patients during the last two decades and increased in the early 2020s. This outcome supports the adoption of nationwide PSA screening, regardless of current Western guidelines.

Synergistic Interactions of Neighboring Platinum and Iron Atoms Enhance Reverse Water-Gas Shift Reaction Performance.

The limitations of conventional strategies in finely controlling the composition and structure demand new promotional effects for upgrading the reverse water-gas shift (RWGS) catalysts for enhanced fuel production. We report the design and synthesis of a hetero-dual-site catalyst for boosting RWGS performance by controllably loading Fe atoms at the neighboring Pt atom on the surface of commercial CeO2. The Fe-Pt/CeO2 exhibits a remarkably high catalytic performance (TOFPt: 43,519 h-1) for CO2 to CO conversion with ∼100% CO selectivity at a relatively low temperature of 350 °C. Furthermore, the catalyst retains over 80% activity after 200 h of continuous operation. The experimental and computational investigations reveal a "two-way synergistic effect", where Fe atoms can not only serve as promotors to alter the charge density of Pt atoms but also be activated by the excess active hydrogen species generated by Pt atoms, enhancing catalytic activity and stability.

Two independent variants of epidermal growth factor receptor associated with risk of glioma in a Korean population.

Gliomas are the most common primary tumors in the brain and spinal cord. In previous GWASs, SNPs in epidermal growth factor receptor (EGFR) have been reported as risk loci for gliomas. However, EGFR variants associated with gliomas in the Korean population remain unstudied. This study explored the association of EGFR SNPs with the risk of glioma. We genotyped 13 EGFR exon SNPs in a case-control study that included 324 Korean patients diagnosed with glioma and 480 population-based controls. Statistical analyses of the association between EGFR SNPs and glioma risk were conducted using logistic regression. Both stepwise analysis and conditional logistic analysis were performed to identify independent associations among genotyped variants. We confirmed that two SNPs (rs2227983, rs1050171) were significantly associated with glioma (rs2227983: odds ratio = 1.42, Pcorr = 0.009; rs1050171: odds ratio = 1.68, Pcorr = 0.005). Additionally, the stepwise analysis and conditional logistic analysis indicated that both SNPs created variants with independent genetic effects. This study is the first to show evidence that functional variants of EGFR, namely, rs2227983 (K521R) and rs1050171 (Q787Q), are associated with an increased risk of glioma in the Korean population. Future work should confirm the functional association between EGFR variants and glioma.

Asian-specific 3'UTR variant in CDKN2B associated with risk of pituitary adenoma.

BACKGROUND: Previous genomewide association studies (GWASs), single nucleotide polymorphisms (SNPs) on cyclin-dependent kinase inhibitor 2 A (CDKN2A), cyclin-dependent kinase inhibitor 2B (CDKN2B), and cyclin-dependent kinase inhibitor 2B antisense RNA1 (CDKN2B-AS1) were reported as risk loci for glioma, a subgroup of the brain tumor. To further characterize this association with the risk of brain tumors in a Korean population, we performed a fine-mapping association study of CDKN2A, CDKN2B, and CDKN2B-AS1. METHODS AND RESULTS: A total of 17 SNPs were selected and genotyped in 1,439 subjects which were comprised of 959 patients (pituitary adenoma 335; glioma 324; meningioma 300) and 480 population controls (PCs). We discovered that a 3'untranslated region (3'UTR) variant, rs181031884 of CDKN2B (Asian-specific variant), had significant association with the risk of pituitary adenoma (PA) (Odds ratio = 0.58, P = 0.00003). Also, rs181031884 appeared as an independent causal variant among the significant variants in CDKN2A and CDKN2B, and showed dose-dependent effects on PA. CONCLUSIONS: Although further studies are needed to verify the impact of this variant on PA susceptibility, our results may help to understand CDKN2B polymorphism and the risk of PA.

Factors that Predict Smoking Cessation among Older Koreans: Based on the Korea National Health and Nutrition Examination Survey 2016-2018.

BACKGROUND: Tobacco smoking is associated with several diseases and deaths in older Koreans. This study aimed to evaluate the factors associated with smoking cessation in older Koreans. METHODS: We selected 579 subjects who started smoking before the age of 65 years from the Korea National Health and Nutrition Examination Survey 2016-2018. We excluded the subjects who quit smoking before the age of 65 years, and then categorized the rest of subjects into those who stopped smoking after the age of 65 years and those who are constant smokers. Multivariable logistic analysis was performed to evaluate the factors related to smoking cessation among older Koreans. RESULTS: Among the participants, 66.1% were persistent smokers. After multivariable analysis, the factors significantly associated with smoking cessation were as follows: being in the age group of 75-79 years (adjusted odds ratio [aOR], 4.07; 95% confidence interval [CI], 2.12-7.83), being in the age group of 70-74 years (aOR, 3.10; 95% CI, 1.72-5.61), a family history of ischemic heart disease (aOR, 3.36; 95% CI, 1.09-10.35), and having had no cancer screening (aOR, 0.36; 95% CI, 0.18-0.70). CONCLUSION: Further efforts to identify the factors related to smoking cessation will help formulate a smoking cessation policy.

Clinical utility of current biomarkers for prostate cancer detection.

Although prostate-specific antigen (PSA) remains the most used test to detect prostate cancer (PCa), the limited specificity and an elevated rate of overdiagnosis are the main problems associated with PSA testing. Over the last three decades, a large body of evidence has indicated that PSA screening methods for PCa are problematic, although PSA screening significantly reduces PCa-specific mortality. A number of novel biomarkers have been introduced to overcome these limitations of PSA in the clinical setting. These biomarkers have demonstrated an increased ability to select patients for biopsy and identify men at risk for clinically significant PCa. Although a number of assays require further validation, initial data are promising. Forthcoming results will ultimately determine the clinical utility and commercial availability of these assays. Extensive efforts have recently been made to identify and commercialize novel PCa biomarkers for more effective detection of PCa, either alone or in combination with currently available clinical tools. This review highlights the role of existing and promising serum and urinary biomarkers for the detection and prognostication of PCa before prostate biopsy.

NOTCH1 Pathway is Involved in Polyhexamethylene Guanidine-Induced Humidifier Disinfectant Lung Injuries.

An outbreak of fatal humidifier disinfectant lung injuries (HDLI) occurred in Korea. Human studies on mechanisms underlying HDLI have yet to be conducted. This study aimed to investigate methylation changes and their potential role in HDLI after exposure to HDs containing polyhexamethylene guanidine-phosphate. DNA methylation analysis was performed in blood samples from 10 children with HDLI and 10 healthy children using Infinium Human MethylationEPIC BeadChip. Transcriptome analysis was performed using lung tissues from 5 children with HDLI and 5 controls. Compared to healthy controls, 92 hypo-methylated and 79 hyper-methylated CpG sites were identified in children with HDLI at the statistical significance level of |Δß|>0.2 and p<0.05. NOTCH1 was identified as a candidate network hub gene in cases. NOTCH1 transcripts significantly increased in lung tissues from HDLI cases compared to unexposed controls (p=0.05). NOTCH1 may play an important role in pulmonary fibrosis of HDLI.

Preoperative prostate health index and %p2PSA as the significant biomarkers of postoperative pathological outcomes of prostate cancer in Korean males: A prospective multi-institutional study.

Purpose: To evaluate the clinical utility of percentage of serum prostate-specific antigen (proPSA) to free PSA (%p2PSA) and the prostate health index (PHI) for predicting aggressive pathological outcomes of radical prostatectomy (RP) in Korean males. Materials and Methods: This prospective observational multicenter study included 160 Korean males who consecutively underwent RP. The predictive utility of preoperative %p2PSA and PHI for predicting the following pathological outcomes of RP including pT3 disease, pathologic Gleason sum ≥7, and Gleason sum upgrading was investigated using multivariate and decision-curve analyses. Results: The PHI and %p2PSA levels were significantly higher in patients with pT3 disease, pathologic Gleason sum ≥7, and Gleason sum upgrading. On univariate analysis, PHI was an accurate predictor of pT3 disease, pathologic Gleason sum ≥7, and Gleason sum upgrading. Multivariate and decision curve analyses revealed that inclusion of PHI to a base multivariate model including total PSA, percentage free PSA, PSA density, percentage of positive biopsy core, biopsy Gleason sum, and clinical stage factors significantly increased its predictive accuracy; %p2PSA showed a similar result. However, PHI was a more valuable predictor of pathological outcomes of RP. Conclusions: This study revealed PHI and %p2PSA as preoperative biomarkers of pathological outcomes in Korean males who underwent RP for prostate cancer.

Contemporary trends in radical prostatectomy and predictors of recovery of urinary continence in men aged over 70 years: comparisons between cohorts aged over 70 and less than 70 years.

We evaluated contemporary trends in radical prostatectomy (RP) in men aged >70 years and investigated associations of selected variables with recovery of urinary continence (UC) in two age groups: >70 and ≤ 70 years. A retrospective cohort of 2301 eligible patients attending our institution from 2004 to 2015 was reviewed. Patients were divided into two groups based on age at surgery (>70 years [n = 610] vs 70 years [n = 1691]) and four groups by year of surgery. Over the study period, the proportion of patients aged >70 years gradually increased up to 30.0%, and the rate of robot-assisted RP and neurovascular bundle (NVB) saving increased continually to 80.0% and 67.4% of older patients, respectively. Although the rate of recovery of UC within 12 months (3 months) in patients aged >70 years was lower than that in those aged ≤ 70 years (81.5% [52.6%] vs 88.6% [60.9%], respectively; both P < 0.001), the gap between age groups in the rate of recovery within 12 months narrowed from the second quarter of the study period. Among younger patients, age, robot-assisted RP, prostate volume, membranous urethral length (MUL), and NVB saving were predictors of recovery of UC within 3 or 12 months. In contrast, only age and MUL were predictors of recovery of UC within 3 and 12 months in patients aged >70 years. Therefore, unlike younger patients, only variables (age and MUL), possibly associated with the inherent function of the urinary sphincter, were predictors of recovery of UC in patients aged >70 years.

Dihydrotestosterone Increases Cytotoxic Activity of Macrophages on Prostate Cancer Cells via TRAIL.

Although androgen deprivation therapy (ADT) and immunotherapy are potential treatment options in men with metastatic prostate cancer (CaP), androgen has conventionally been proposed to be a suppressor of the immune response. However, we herein report that DHT activates macrophages. When the murine macrophage cell line (RAW 264.7), human monocyte cell line (THP-1), and human peripheral blood monocytes were cultured with androgen-resistant CaP cell lines, DHT increased cytotoxicity of macrophages in a concentration-dependent manner. Further studies revealed that DHT induced M1 polarization and increased the expression levels of TNF-related apoptosis-inducing ligand (TRAIL) in macrophages and that this effect was abrogated when TRAIL was neutralized with a blocking antibody or small interfering RNA. Subsequent experiments demonstrated that induction of TRAIL expression was regulated by direct binding of androgen receptor to the TRAIL promoter region. Finally, an in vivo mouse study demonstrated that castration enhanced the growth of an androgen-resistant murine CaP tumor and that this protumorigenic effect of castration was blocked when macrophages were removed with clodronate liposomes. Collectively, these results demonstrate that DHT activates the cytotoxic activity of macrophages and suggest that immunotherapy may not be optimal when combined with ADT in CaP.

Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly.

Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is therefore a serious public health problem. Infected patients are currently treated with nucleoside/nucleotide analogs and interferon α, but this approach is not curative. Here, we screen 978 FDA-approved compounds for their ability to inhibit HBV replication in HBV-expressing HepG2.2.15 cells. We find that ciclopirox, a synthetic antifungal agent, strongly inhibits HBV replication in cells and in mice by blocking HBV capsid assembly. The crystal structure of the HBV core protein and ciclopirox complex reveals a unique binding mode at dimer-dimer interfaces. Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.

A PHLDB1 variant associated with the nonfunctional pituitary adenoma.

PURPOSE: Previous studies have revealed that PHLDB1 single-nucleotide polymorphisms (SNPs) are associated with glioma risk. Nonetheless, the association between PHLDB1 SNPs and the risk of pituitary adenoma has not been studied. The present study evaluated the association of PHLDB1 SNPs with the risk of pituitary adenomas. METHODS: We genotyped 27 PHLDB1 tagging and exon SNPs in a case-control study that included 148 patients who got a diagnosis of nonfunctional pituitary adenoma (NFPA) and 375 normal controls within the Korean population. Statistical analyses of the association between PHLDB1 SNPs and the NFPA risk were conducted using logistic regression. RESULTS: We detected an association between a PHLDB1 SNP and the risk of NFPA in the Korean population. Rs67307131 in intron 2 was significantly associated with NFPA (odds ratio [OR] = 2.15, 95% confidence interval [CI] 1.44-3.20; P = 0.0002 in the dominant model). In the referent analysis, a higher OR and stronger association (lower P value) were observed among patients with the "C/T" genotype (OR = 2.39, 95% CI 1.60-3.58; P = 0.00002). In a functional analysis with a SNP annotation tool, this SNP was predicted to be a CpG site and copy number variant; these properties are associated with susceptibility to diseases. CONCLUSIONS: Our findings suggest that genetic variation of PHLDB1 may be associated with the risk of NFPA. This is the first report of an association between PHLDB1 variants and NFPA. Further research is needed to confirm the impact of this SNP on NFPA susceptibility.

Development and validation of a clinical nomogram predicting bladder outlet obstruction via routine clinical parameters in men with refractory nonneurogenic lower urinary tract symptoms.

We aimed to develop and validate a clinical nomogram predicting bladder outlet obstruction (BOO) solely using routine clinical parameters in men with refractory nonneurogenic lower urinary tract symptoms (LUTS). A total of 750 eligible patients ≥50 years of age who had previously not responded (International Prostate Symptom Score [IPSS] improvement <4 points) to at least three different kinds of LUTS medications (including a-blocker) for the last 6 months were evaluated as subcohorts for nomogram development (n = 570) and for split-sample validation (n = 180). BOO was defined as Abrams-Griffiths number ≥40, or 20-39.9 with a slope of linear passive urethral resistance ratio >2 cmH2O ml-1 s-1. A stepwise multivariable logistic regression analysis was conducted to determine the predictors of BOO, and b-coefficients of the final model were selected to create a clinical nomogram. The final multivariable logistic regression model showed that age, IPSS, maximum urinary flow rate, postvoid residual volume, total prostate volume, and transitional zone index were significant for predicting BOO; these candidates were used to develop the final nomogram. The discrimination performance of the nomogram was 88.3% (95% CI: 82.7%-93.0%, P < 0.001), and the nomogram was reasonably well-fitted to the ideal line of the calibration plot. Independent split-sample validation revealed 80.9% (95% CI: 75.5%-84.4%, P < 0.001) accuracy. The proposed BOO nomogram based solely on routine clinical parameters was accurate and validated properly. This nomogram may be useful in determining further treatment, primarily focused on prostatic surgery for BOO, without impeding the detection of possible BOO in men with LUTS that is refractory to empirical medications.

Association analysis of NOX5 polymorphisms with Hirschsprung disease.

BACKGROUND/PURPOSE: Hirschsprung disease (HSCR) is a developmental disease characterized by the absence of ganglion cells in the intestinal region. NADPH oxidase5 (NOX5) has been identified as one of the possible candidate genes for risk of Hirschsprung disease in our recent genome wide association study (GWAS). In this study, we performed a replication study to analyze the association of NOX5 polymorphisms with HSCR risk and conducted an extended analysis to investigate further associations for sub-groups and haplotypes. METHODS: A total of 23 NOX5 single nucleotide polymorphisms (SNPs) were genotyped in 187 HSCR patients and 283 unaffected controls. Statistical analysis was performed to examine the effects of genotype on risk of HSCR and HSCR subtype. RESULTS: Logistic regression analyses revealed that six SNPs (rs59355559, rs62010828, rs34990910, rs11856030, rs311905, and rs8024894) were associated with risk of HSCR (minimum p = 0.007 at rs62010828). Moreover, three SNPs (rs59355559, rs62010828, and rs8024894) were significantly associated with risk of long-segment HSCR (L-HSCR) subtype and 5 SNPs (rs59355559, rs62010828, rs34990910, rs11856030, and rs8024894) were found to be associated with risk of TCA subtype. CONCLUSION: Our results demonstrate that genetic variants in NOX5 have genetic effects on risk of HSCR, which may serve as useful preliminary information for further study. LEVELS OF EVIDENCE: Level III of prognosis study.

Could Peer Support Programs Be a Good Resource for Managing the Unmet Needs of Cancer Patients?

The number of cancer patients has been rapidly increasing, and while there have been wide variations, cancer survival rates also improved globally. Despite the improved survival rates, supportive care needs of cancer patients have been unmet in various domains. The current study aimed to investigate unmet needs that had potential to be managed by peer supports according to cancer trajectories. We used the comprehensive needs assessment tool in cancer (CNAT) and a modified CNAT to evaluate the unmet needs and peer support needs of cancer patients at the tertiary hospital of South Korea. Of the 402 participants, 335 (83.3%) needed peer support. For patients who had been diagnosed with cancer for more than 5 years, the highest proportion of peer support needs to unmet supportive care was reported in information domain (92.9%). Patients with advanced cancer reported peer support needs in the social/religious/spiritual (84.4%) and practical domains (81.1%). Most of stomach cancer patients needed peer supports to receive information (96.6%). The need for peer supports in the information domain was reported highest according to longer survival period and also according to advanced cancer stages. The proportion of peer support needs in unmet supportive care varied by cancer type. Further interventional studies are needed to investigate satisfaction with peer support in specific domains.