Active DNA damage eviction by HLTF stimulates nucleotide excision repair.

Nucleotide excision repair (NER) counteracts the onset of cancer and aging by removing helix-distorting DNA lesions via a "cut-and-patch"-type reaction. The regulatory mechanisms that drive NER through its successive damage recognition, verification, incision, and gap restoration reaction steps remain elusive. Here, we show that the RAD5-related translocase HLTF facilitates repair through active eviction of incised damaged DNA together with associated repair proteins. Our data show a dual-incision-dependent recruitment of HLTF to the NER incision complex, which is mediated by HLTF's HIRAN domain that binds 3'-OH single-stranded DNA ends. HLTF's translocase motor subsequently promotes the dissociation of the stably damage-bound incision complex together with the incised oligonucleotide, allowing for an efficient PCNA loading and initiation of repair synthesis. Our findings uncover HLTF as an important NER factor that actively evicts DNA damage, thereby providing additional quality control by coordinating the transition between the excision and DNA synthesis steps to safeguard genome integrity.

GPCR-IPL score: multilevel featurization of GPCR-ligand interaction patterns and prediction of ligand functions from selectivity to biased activation.

G-protein-coupled receptors (GPCRs) mediate diverse cell signaling cascades after recognizing extracellular ligands. Despite the successful history of known GPCR drugs, a lack of mechanistic insight into GPCR challenges both the deorphanization of some GPCRs and optimization of the structure-activity relationship of their ligands. Notably, replacing a small substituent on a GPCR ligand can significantly alter extracellular GPCR-ligand interaction patterns and motion of transmembrane helices in turn to occur post-binding events of the ligand. In this study, we designed 3D multilevel features to describe the extracellular interaction patterns. Subsequently, these 3D features were utilized to predict the post-binding events that result from conformational dynamics from the extracellular to intracellular areas. To understand the adaptability of GPCR ligands, we collected the conformational information of flexible residues during binding and performed molecular featurization on a broad range of GPCR-ligand complexes. As a result, we developed GPCR-ligand interaction patterns, binding pockets, and ligand features as score (GPCR-IPL score) for predicting the functional selectivity of GPCR ligands (agonism versus antagonism), using the multilevel features of (1) zoomed-out 'residue level' (for flexible transmembrane helices of GPCRs), (2) zoomed-in 'pocket level' (for sophisticated mode of action) and (3) 'atom level' (for the conformational adaptability of GPCR ligands). GPCR-IPL score demonstrated reliable performance, achieving area under the receiver operating characteristic of 0.938 and area under the precision-recall curve of 0.907 (available in gpcr-ipl-score.onrender.com). Furthermore, we used the molecular features to predict the biased activation of downstream signaling (Gi/o, Gq/11, Gs and ß-arrestin) as well as the functional selectivity. The resulting models are interpreted and applied to out-of-set validation with three scenarios including the identification of a new MRGPRX antagonist.

A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair.

XPA is a central scaffold protein that coordinates the assembly of repair complexes in the global genome (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER) subpathways. Inactivating mutations in XPA cause xeroderma pigmentosum (XP), which is characterized by extreme UV sensitivity and a highly elevated skin cancer risk. Here, we describe two Dutch siblings in their late forties carrying a homozygous H244R substitution in the C-terminus of XPA. They present with mild cutaneous manifestations of XP without skin cancer but suffer from marked neurological features, including cerebellar ataxia. We show that the mutant XPA protein has a severely weakened interaction with the transcription factor IIH (TFIIH) complex leading to an impaired association of the mutant XPA and the downstream endonuclease ERCC1-XPF with NER complexes. Despite these defects, the patient-derived fibroblasts and reconstituted knockout cells carrying the XPA-H244R substitution show intermediate UV sensitivity and considerable levels of residual GG-NER (~50%), in line with the intrinsic properties and activities of the purified protein. By contrast, XPA-H244R cells are exquisitely sensitive to transcription-blocking DNA damage, show no detectable recovery of transcription after UV irradiation, and display a severe deficiency in TC-NER-associated unscheduled DNA synthesis. Our characterization of a new case of XPA deficiency that interferes with TFIIH binding and primarily affects the transcription-coupled subpathway of nucleotide excision repair, provides an explanation of the dominant neurological features in these patients, and reveals a specific role for the C-terminus of XPA in TC-NER.

Two interaction surfaces between XPA and RPA organize the preincision complex in nucleotide excision repair.

The xeroderma pigmentosum protein A (XPA) and replication protein A (RPA) proteins fulfill essential roles in the assembly of the preincision complex in the nucleotide excision repair (NER) pathway. We have previously characterized the two interaction sites, one between the XPA N-terminal (XPA-N) disordered domain and the RPA32 C-terminal domain (RPA32C), and the other with the XPA DNA binding domain (DBD) and the RPA70AB DBDs. Here, we show that XPA mutations that inhibit the physical interaction in either site reduce NER activity in biochemical and cellular systems. Combining mutations in the two sites leads to an additive inhibition of NER, implying that they fulfill distinct roles. Our data suggest a model in which the interaction between XPA-N and RPA32C is important for the initial association of XPA with NER complexes, while the interaction between XPA DBD and RPA70AB is needed for structural organization of the complex to license the dual incision reaction. Integrative structural models of complexes of XPA and RPA bound to single-stranded/double-stranded DNA (ss/dsDNA) junction substrates that mimic the NER bubble reveal key features of the architecture of XPA and RPA in the preincision complex. Most critical among these is that the shape of the NER bubble is far from colinear as depicted in current models, but rather the two strands of unwound DNA must assume a U-shape with the two ss/dsDNA junctions localized in close proximity. Our data suggest that the interaction between XPA and RPA70 is key for the organization of the NER preincision complex.

Extremely Stable Ag-Based Photonics, Plasmonic, Optical, and Electronic Materials and Devices Designed with Surface Chemistry Engineering for Anti-Tarnish.

Silver (Ag) metal-based structures are promising building blocks for next-generation photonics and electronics owing to their unique characteristics, such as high reflectivity, surface plasmonic resonance effects, high electrical conductivity, and tunable electron transport mechanisms. However, Ag structures exhibit poor sustainability in terms of device performance because harsh chemicals, particularly S2- ions present in the air, can damage their structures, lowering their optical and electrical properties. Here, the surface chemistry of Ag structures with (3-mercaptopropyl)trimethoxysilane (MPTS) ligands at room temperature and under ambient conditions is engineered to prevent deterioration of their optical and electrical properties owing to S2- exposure. Regardless of the dimensions of the Ag structures, the MPTS ligands can be applied to each dimension (0D, 1D, and 3D). Consequently, highly sustainable plasmonic effects (Δλ < 2 nm), Fabry-Perot cavity resonance structures (Δλ < 2 nm), reflectors (ΔRReflectance < 0.5%), flexible electrodes (ΔRelectrical < 0.1 Ω), and strain gauge sensors (ΔGF < 1), even in S2- exposing conditions is achieved. This strategy is believed to significantly contribute to environmental pollution reduction by decreasing the volume of electronic waste.

Real-Time Visualizing Nucleation and Growth of Electrodes for Post-Lithium-Ion Batteries.

ConspectusUntil recently, most studies on nucleation and growth mechanisms have employed electrochemical transient measurements, and numerous models have been established on various metal electrode elements. Contrary to the conventional tip-induced nucleation and growth model, a base-induced nucleation and growth mode was discovered not so long ago, which highlighted the importance of direct real-time observations such as visualization. As analysis techniques developed, diverse in situ/operando imaging methods have spurred the fundamental understanding of complex and dynamic battery electrochemistry. Experimental observations of alkali Li and Na metals are limited and difficult because their high reactivity makes not only the fabrication but also the analysis itself challenging. Na metal has high reactivity to electrolytes. Accordingly, it is difficult to visualize the Na deposition in real-time due to gas evolution and resolution limitation. Only a few studies have examined the Na deposition and dissolution reactions in operando. It is generally believed that the Mg anode is free from the dendrite growth of Mg metal, and Mg deposition preferentially occurs along the surface direction. However, whether the Mg anode always follows the dendrite-free growth has currently become a controversial topic and is being discussed and redefined based on real-time imaging analyses. In addition, a variety of morphological evolutions in the metal anodes are required to be systematically distinguished by key parameters. Real-time imaging analysis can directly confirm the solid-liquid-solid multiphase conversion reactions of S and Se cathodes. S and Se elements belong to the same chalcogen group, but their crystal structures and morphological changes significantly differ in each electrode during deposition and dissolution reactions. Therefore, it is necessitated to discuss the nucleation and growth behaviors by examining intrinsic properties of each element in chalcogen cathodes. Considering that a mechanistic understanding of the Se cathode is in its infancy, its nucleation and growth behaviors must be further explored through fundamental studies. In this Account, we aim to discuss the nucleation and growth behaviors of metal (Li, Na, and Mg) anodes and chalcogen (S and Se) cathodes. To elucidate their nucleation and growth mechanisms, we overview the morphological evolutions on the electrode surface and interface by in situ/operando visualizations. Our recent studies covering Li, Na, Mg, S, and Se electrodes verified by operando X-ray imaging are used as critical resources in understanding their nucleation and growth behaviors. Overall, with validation of the complex and dynamic nucleation and growth behaviors of metal and chalcogen electrodes by in situ/operando visualization methods, we hope that this Account can contribute to supporting the fundamental knowledge for the development of high-energy-density metal and chalcogen electrodes.

Next-generation sequencing using tissue specimen collected with a 1.1 mm-diameter cryoprobe in patients with lung cancer.

BACKGROUND AND OBJECTIVE: Next-generation sequencing (NGS) analysis is considered standard for lung cancer diagnosis in clinical practice. Little is known about the feasibility of NGS using tumour tissue sampled with a 1.1 mm-diameter cryoprobe. We aimed to investigate the suitability of specimens obtained by transbronchial cryobiopsy (TBC) using a 1.1 mm-diameter cryoprobe for NGS analysis. METHODS: Patients with lung cancer who underwent TBC using a 1.1 mm-diameter cryoprobe for NGS testing between October 2020 and April 2023 were enrolled. A 4.0- or 3.0 mm-diameter bronchoscope with radial probe endobronchial ultrasound and virtual bronchoscopic navigation was used to detect peripheral lung lesions. All procedures were performed under fluoroscopic guidance. Data were analysed retrospectively. RESULTS: A total of 56 patients underwent TBC using a 1.1 mm cryoprobe for NGS testing, during the study period. Most patients (98%) were in the advanced stage of lung cancer (recurrent or inoperable disease of stages III or IV). The diagnostic yield of NGS for DNA and RNA sequencing was 95% each (53 of 56). Moderate bleeding was noted in three patients (5%) and none of the study patients developed life-threatening complications, such as pneumothorax or lung infection. CONCLUSION: TBC using a 1.1 mm-diameter cryoprobe is a useful and safe tool for NGS analysis, for both DNA and RNA sequencing.

Focal nodular enhancement on DCE MRI of the prostatectomy bed: radiologic-pathologic correlations and prognostic value.

OBJECTIVES: To determine the concordance of dynamic contrast-enhanced (DCE) imaging findings with clinico-pathologic characteristics and their prognostic impact for predicting biochemical recurrence (BCR) in patients who underwent radical prostatectomy (RP) for prostate cancer. METHODS: This retrospective study included patients who underwent MRI within 1 year after RP between November 2019 and October 2020. DCE findings and their concordance with the presence and location of positive surgical margin (PSM) were assessed using RP specimens. Kaplan-Meier and logistic regression analyses were used to evaluate the prognostic impact of DCE findings for BCR. RESULTS: Among the 272 men (mean age ± standard deviation, 66.6 ± 7.4 years), focal nodular enhancement was more frequently observed in those with PSM compared to those with negative margin (85.4% versus 14.6%; p < 0.001). The sites of focal nodular enhancement were 72.9% (35/48) concordant with the PSM locations. Focal nodular enhancement was associated with a higher Gleason score, higher preoperative PSA (≥ 10 ng/mL), higher Gleason grade at the surgical margin, and non-limited margin involvement (p = 0.002, 0.006, 0.032, and 0.001, respectively). In patients without BCR at the time of MRI, focal nodular enhancement was associated with a shorter time to BCR (p < 0.001) and a significant factor predicting 1-year BCR in both univariate (odds ratio = 8.4 [95% CI: 2.5-28.3]; p = 0.001) and multivariate (odds ratio = 5.49 [1.56-19.3]; p = 0.008) analyses. CONCLUSIONS: Focal nodular enhancement on post-prostatectomy MRI was associated with adverse clinico-pathologic characteristics of high risk for recurrence and can be a predictor for 1-year BCR in patients undergoing RP. KEY POINTS: • Focal nodular enhancement (PI-RR DCE score ≥ 4) was 72.9% (35/48) concordant with the site of positive resection margin by radiologic-histologic correlation. • Focal nodular enhancement (PI-RR DCE score ≥ 4) was associated with higher Gleason score ( ≥ 8), preoperative PSA ( > 10 ng/mL), and Gleason grade 4 or 5 at the surgical margin and non-limited margin involvement (p ≤ 0.032). • In patients without BCR at the time of MRI, focal nodular enhancement was a significant factor predicting 1-year BCR (odds ratio = 5.49; 95% CI: 1.56-19.3; p = 0.008).

Metal-free synthesis of dihydrofuran derivatives as anti-vicinal amino alcohol isosteres.

Dihydrofuran cores are commonly incorporated into synthetically and pharmacologically significant scaffolds in natural product and drug discovery chemistry. Herein, we report a concise and practical strategy to construct spiro-dihydrofuran and amino dihydrofuran scaffolds as anti-vicinal amino alcohol isosteres. Hypervalent iodine (PhI(OAc)(NTs2))-mediated C-H activation of alkynes resulted in two-bond formations with one pi bond cleavage: (i) C(sp2)-N(sp3) and O(sp3)-C(sp2); (ii) C(sp2)-N(sp3) and C(sp3)-C(sp2). The metal-free 5-endo-dig oxidative cyclization provided versatile amino 2,3- and 2,5-dihydrofurans bearing the C5 quaternary carbon. The non-toxicity of all synthesised dihydrofurans was verified via in vitro cell viability assay.

Relationship between protein intake and grip strength in qualitative and quantitative aspects among the elderly in Korea: results from the Korea National Health and Nutrition Examination Survey.

BACKGROUND: This study investigated the association between quantitative and qualitative protein intake and grip strength (GS) in the South Korean population to explore nutritional management for the prevention of sarcopenia. METHODS: This cross-sectional study was based on data from a nationally representative sample of the South Korean elderly population, consisting of 1,531 men and 1,983 women aged 65 years and older who participated in the Korean National Health and Nutrition Examination Survey from 2016 to 2019. Low GS was defined as GS < 28 kg in men and GS < 18 kg in women. Protein intake was assessed using 1-day 24-h recall, and we analyzed absolute protein intake, protein intake by food source, and protein intake compared to dietary reference intake with per body weight or absolute daily recommended value. RESULTS: The total and animal protein intake and protein intake from legumes, fish and shellfish were significantly lower in women with a low GS than in those with a normal GS. After adjusting for confounding factors, women who consumed more protein than the estimated average requirement (EAR, 40 g/day for women) were 0.528 times less likely to have low GS than women consuming less protein than the EAR (95% CI: 0.373-0.749), and consuming any amount of protein from legumes were 0.656 times less likely (95% CI: 0.500-0.860) to have low GS than women who did not consume any amount of legume protein. CONCLUSIONS: This study provides epidemiological evidence that adequate protein intake above EAR and protein intake from legumes should be guided for preventing low GS, especially in elderly women.

Fast T2-Weighted Imaging With Deep Learning-Based Reconstruction: Evaluation of Image Quality and Diagnostic Performance in Patients Undergoing Radical Prostatectomy.

BACKGROUND: Deep learning-based reconstruction (DLR) can potentially improve image quality by reduction of noise, thereby enabling fast acquisition of magnetic resonance imaging (MRI). However, a systematic evaluation of image quality and diagnostic performance of MRI using short acquisition time with DLR has rarely been investigated in men with prostate cancer. PURPOSE: To assess the image quality and diagnostic performance of MRI using short acquisition time with DLR for the evaluation of extraprostatic extension (EPE). STUDY TYPE: Retrospective. POPULATION: One hundred and nine men. FIELD STRENGTH/SEQUENCE: 3 T; turbo spin echo T2-weighted images (T2WI), echo-planar diffusion-weighted, and spoiled gradient echo dynamic contrast-enhanced images. ASSESSMENT: To compare image quality, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) and subjective analysis using Likert scales on three T2WIs (MRI using conventional acquisition time, MRI using short acquisition time [fast MRI], and fast MRI with DLR) were performed. The diagnostic performance for EPE was evaluated by three independent readers. STATISTICAL TESTS: SNR, CNR, and image quality scores across the three imaging protocols were compared using Friedman tests. The diagnostic performance for EPE was assessed using the area under receiver operating characteristic curves (AUCs). P < 0.05 was considered statistically significant. RESULTS: Fast MRI with DLR demonstrated significantly higher SNR (mean ± SD, 14.7 ± 6.8 vs. 8.8 ± 4.9) and CNR (mean ± SD, 6.5 ± 6.3 vs. 3.4 ± 3.6) values and higher image quality scores (median, 4.0 vs. 3.0 for three readers) than fast MRI. The AUCs for EPE were significantly higher with the use of DLR (0.86 vs. 0.75 for reader 2 and 0.82 vs. 0.73 for reader 3) compared with fast MRI, whereas differences were not significant for reader 1 (0.81 vs. 0.74; P = 0.09). DATA CONCLUSION: DLR may be useful in reducing the acquisition time of prostate MRI without compromising image quality or diagnostic performance. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 3.

In silico identification of prolyl hydroxylase inhibitor by per-residue energy decomposition-based pharmacophore approach.

Hypoxia is an effective preconditioning stimulus and many cellular responses to hypoxia are mediated through a transcription control complex termed the hypoxia-inducible factor (HIF). The stability and activation of HIF are governed by HIF prolyl-4-hydroxylases 2 (PHD2). Hence, the development of a small molecule inhibitor for prolyl hydroxylase has been suggested as a potentially useful therapeutic strategy for the treatment of oxidative/ischemic stress conditions. Thus, to unveil a novel human PHD2 inhibitor, a custom-based virtual screening was carried out to identify the potential inhibitors against PHD2 based on; (1) the per-residue energy decomposition (PRED)-based pharmacophore model, (2) molecular docking, and (3) MD approaches. The PRED analysis was performed to identify the common interaction pattern of HIF fragment (5L9B) and crystallized ligand (4JZR) to develop a relevant accurate allosteric pharmacophore model. The custom pharmacophore model (AAARR) was developed and further used to screen multiple databases. The docking was performed as a secondary strategy for screening the pharmacophore hits. Furthermore, the docked complexes were screened by molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM-GBSA) based binding free energy calculations to determine the binding energy of the inhibitors and to identify crucial interaction energy fingerprint. One hit has demonstrated good binding free energy and a better binding affinity for PHD2 compared to the other four selected ligands. Thus, the results obtained from pharmacophore, docking, and MD simulations depicted that linker length and metal binding in the scaffold could be effectively used as a potent inhibitor toward human PHD2 in AD therapeutics.

Ancillary imaging and clinical features for the characterization of prostate lesions: A proposed approach to reduce false positives.

The relatively low specificity and positive predictive value of the Prostate Imaging-Reporting and Data System (PI-RADS) can lead to considerable false-positive results and unnecessary biopsies. The aim of this study was to propose ancillary features (AFs) indicating clinically significant prostate cancer (csPCa) or benign tissues in PI-RADS category ≥3 lesions and determine the usefulness of these AFs in reducing false-positive assessments of suspicious lesions in men at csPCa risk. This was a retrospective study, which included 199 men. A 3T, including turbo spin echo T2 -weighted, echo-planar diffusion-weighted, and spoiled gradient echo dynamic contrast-enhanced (DCE) images, was used. Five AFs (prostate-specific antigen density ≥0.15 ng/mL2 ; size ≥10 mm; heterogeneous T2 signal intensity; circumscribed nodule in the junction of peripheral and transition zone; and DCE time curves) indicating csPCa or non-csPCa were evaluated by three independent readers. The sensitivity and specificity of each AF were calculated. Inter-reader agreement was evaluated using κ statistics. Univariate and multivariate logistic regression analyses were conducted to determine significant AFs. The reduction in positive call rates and csPCa detection rates with combined AF use were calculated and compared with the findings obtained with PI-RADS use alone. The sensitivities and specificities of the AFs indicating csPCa were 72.1%-96.5% and 27.4%-75.2% for reader 1, 66.3%-96.5% and 23.9%-62.0% for reader 2, and 67.4%-96.5% and 34.5%-78.8% for reader 3, with moderate to substantial inter-reader agreement (Fleiss κ, 0.551-0.643). The combined use of two or more AFs for assessing PI-RADS ≥3 lesions resulted in a 19.6%-30.7% reduction in positive calls (p < .05) compared to PI-RADS use alone while preserving the csPCa detection rates (p ≥ .06) for three readers. The use of AFs in combination with PI-RADS can reduce positive calls and false positives without csPCa under-detection.

Performance of Prostate Imaging Reporting and Data System Version 2.1 for Diagnosis of Prostate Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The Prostate Imaging Reporting and Data System (PI-RADS) was introduced in 2012 and updated to version 2.1 (v2.1) in early 2019 to improve diagnostic performance and interreader reliability. PURPOSE: To evaluate the diagnostic performance of PI-RADS v2.1 in comparison with v2. METHODS: A systematic review and meta-analysis of the literature was performed using MEDLINE, EMBASE, and Cochrane databases to identify studies evaluating the diagnostic performance of PI-RADS v2.1 for diagnosing clinically significant prostate cancer (csPCa). STUDY TYPE: Systematic review and meta-analysis. SUBJECT: One thousand two hundred forty-eight patients with 1406 lesions from 10 eligible articles. FIELD STRENGTH/SEQUENCE: Conventional MR sequences at 1.5 T and 3 T. ASSESSMENT: Two reviewers independently identified and reviewed the original articles reporting diagnostic performance of PI-RADS v2.1. STATISTICAL TESTS: Meta-analytic summary sensitivity and specificity were calculated using a bivariate random effects model. Meta-analytic sensitivity and specificity between PI-RADS v2 and v2.1 were compared. RESULTS: The pooled sensitivity and specificity of PI-RADS v2.1 were 87% (95% confidence intervals, 82-91%) and 74% (63-82%), respectively. In five studies available for a head-to-head comparison between PI-RADS v2.1 and v2, there were no significant differences in either sensitivity (90% [86-94%] vs. 88% [83-93%], respectively) or specificity (76% [59-93%] vs. 61% [39-83%], respectively; P = 0.37). The sensitivity and specificity were 81% (73-87%) and 82% (68-91%), respectively, for a PI-RADS score cutoff of ≥4, and 94% (88-97%) and 56% (35-97%) for ≥3. Regarding the zonal location, the sensitivity and specificity for the transitional zone only were 90% (84-96%) and 76% (62-90%) respectively, whereas for the whole gland they were 85% (79-91%) and 71% (57-85%). DATA CONCLUSION: PI-RADS v2.1 demonstrated good overall performance for the diagnosis of csPCa. PI-RADS v2.1 tended to show higher specificity than v2, but the difference lacked statistical significance. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 3.

Preoperative MRI-based estimation of risk for positive resection margin after radical prostatectomy in patients with prostate cancer: development and validation of a simple scoring system.

OBJECTIVES: To develop a simplified MRI-based model to predict the risk for positive surgical margins (PSMs) after radical prostatectomy (RP) in patients with prostate cancer (PCa). METHODS: Consecutive patients who underwent RP for PCa were retrospectively identified from a tertiary referral hospital. Patients who underwent RP between January 2014 and June 2014 were assigned as derivation cohort (n = 330) and those between January 2018 and February 2018 were assigned as validation cohort (n = 100). MRI-based predictors associated with PSM were assessed: tumor size, tumor-capsule contact length, the Prostate Imaging Reporting and Data System (PI-RADS) category, tumor location (tumor contact to the apex or posterolateral side near the neurovascular bundle), apical depth, and prostate volume. A prediction model was developed by using multivariable logistic regression, and then it was transformed into a scoring system. The prediction and calibration performance of this scoring system was evaluated using the C statistics and Hosmer-Lemeshow goodness-of-fit test. RESULTS: A total of 121 (36.7%) and 32 (32.0%) of patients in the derivation and validation cohorts had PSMs after RP. The scoring system consisted of the following variables: tumor-capsule contact length, PI-RADS category, tumor located at the apex and/or posterolateral side. This scoring system provided good prediction performance for PSM in the derivation (C statistics, 0.80 [95% CI: 0.76, 0.85]) and validation (C statistics, 0.77 [95% CI: 0.68, 0.87]) cohorts, and also showed good calibration in both cohorts (p = 0.83 and 0.86, respectively). CONCLUSIONS: An MRI-based scoring system can help estimate the risk of PSM after RP. KEY POINTS: • An MRI-based scoring system served as a tool to estimate the risk of positive surgical margin (C statistics, 0.80 and 0.77 in the derivation and validation cohorts, respectively) after radical prostatectomy. • Tumor with contact to the apex or posterolateral aspect, the tumor contact length to capsule, and higher PI-RADS category were independent predictors for the presence of positive resection margins after radical prostatectomy in men with prostate cancer. • High-risk patients as determined by the scoring system demonstrated adverse post-surgical outcomes compared with low- or intermediate-risk patients, in regard to longer length (mean length, 13.0 mm versus 3.9 mm in low risk or 6.2 mm in intermediate risk; p ≤ 0.001) and higher Gleason grade at the margin (grades 4 and 5 in 69.4% and 20.4% versus 16.7% and 16.7% in low risk or 46.7% and 5.4% in intermediate risk; p < 0.001).

Enantioselective Total Synthesis of Nitraria Alkaloids: (+)-Nitramine, (+)-Isonitramine, (-)-Isonitramine, and (-)-Sibirine via Asymmetric Phase-Transfer Catalytic α-Allylations of α-Carboxylactams.

Many optically active 2-azaspirocyclic structures have frequently been found in biologically active natural products. In particular, Nitraria alkaloids, (+)-nitramine, (+)-isonitramine, (-)-isonitramine, and (-)-sibirine, have stereogenicity on their quaternary carbon of the 2-azaspiro[5,5]undecane-7-ol structure. To synthesize Nitraria alkaloids, we developed a new enantioselective synthetic method for chiral α-quaternary lactams via the α-alkylation of α-tert-butoxycarbonyl lactams. α-Alkylation of α-tert-butoxycarboxylactams in the circumstances of phase-transfer catalytic (PTC) system (solid KOH, toluene, and -40 °C) by virtue of the catalytic action of (S,S)-NAS bromide (5 mol %) furnished the corresponding α-alkyl-α-tert-butoxycarbonyl lactams in very high chemical (<99%) and enantioselectivity (<98% ee). Our catalytic methodology was successfully applied for the enantioselective total synthesis of Nitraria alkaloids. (+)-Isonitramine was obtained in 12 steps (98% ee, 43% yield) from δ-valerolactam through enantioselective phase-transfer catalytic allylation, Dieckmann condensation, and diastereoselective reduction as the key reactions. (-)-Sibirine and (+)-nitramine were prepared from (-)-isonitramine or its intermediate. Switching the phase-transfer catalyst from (S,S)-NAS bromide to (R,R)-NAS bromide afforded (-)-isonitramine (98% ee, 41% yield). (-)-Sibirine was synthesized by N-ethoxycarbonylation of (-)-isonitramine followed by reduction (98% ee, 14 steps, 32% yield). Furthermore, the diastereoselective reduction of (R)-2-benzhydryl-2-azaspiro[5.5]undecane-1,7-dione [(R)-15] followed by reductive removal of the diphenylmethyl group successfully gave (+)-nitramine (98% ee, 11 steps, 40% yield).

Bosniak Classification of Cystic Renal Masses Version 2019: Comparison With Version 2005 for Class Distribution, Diagnostic Performance, and Interreader Agreement Using CT and MRI.

BACKGROUND. The Bosniak classification system for cystic renal masses (CRMs) was updated in 2019, requiring further investigation. OBJECTIVE. The purpose of this study was to compare versions 2005 and 2019 of the Bosniak classification system in terms of class distribution, diagnostic performance, interreader agreement, and intermodality agreement between CT and MRI. METHODS. This retrospective study included 100 patients (mean age, 52.4 ± 11.6 years; 68 men, 32 women) with 104 CRMs (74 malignant) who underwent CT, MRI, and resection between 2010 and 2019. Two radiologists independently evaluated CRMs in separate sessions for each combination of version and modality and assigned a Bosniak class. Diagnostic performance was compared using McNemar tests. Interreader and intermodality agreement were analyzed using weighted kappa coefficients. RESULTS. Across readers and modalities, the proportion of class IIF CRMs was higher for version 2019 than version 2005 (reader 1: 28.8-30.8% vs 6.7-12.5%; reader 2: 26.0-28.8% vs 8.7-19.2%), although 95% CIs overlapped for reader 2 on CT. The proportion of class III CRMs was lower for version 2019 than version 2005 (reader 1: 33.7-35.6% vs 49.0-51.9%; reader 2: 31.7-40.4% vs 37.5-52.9%), although 95% CIs overlapped for all comparisons. Version 2019 showed lower sensitivity for malignancy than version 2005 across readers and modalities (all p < .05); for example, using CT, sensitivity was 75.7% for both readers with version 2019 versus 85.1-87.8% with version 2005. However, version 2019 showed higher specificity than version 2005, which was significant (all p < .05) for reader 1. For example, using CT, specificity was 73.3% (reader 1) and 70.0% (reader 2) with version 2019 versus 50.0% (reader 1) and 56.7% (reader 2) with version 2005. Diagnostic accuracy was not different between versions (version 2005: 76.9-85.6%; version 2019: 74.0-78.8%). Interreader and intermodality agreement were substantial for version 2005 (κ = 0.676-0.782 and 0.711-0.723, respectively) and version 2019 (κ = 0.756-0.804 and 0.704-0.781, respectively). CONCLUSION. Use of version 2019 versus version 2005 of the Bosniak classification system results in a shift in CRM assignment from class III to class IIF. Version 2019 results in lower sensitivity, higher specificity, and similar accuracy versus version 2005. Interreader and intermodality agreement are similar between versions. CLINICAL IMPACT. Version 2019 facilitates recommending imaging surveillance for more CRMs.

Patterns of sensitization to aeroallergens and their effect on airway hyper-responsiveness in Busan, Korea.

BACKGROUND: Allergen sensitization and its influence on allergic disease can vary depending on ethnicity and geography. OBJECTIVE: To investigate aeroallergen sensitization patterns and their effect on airway hyper-responsiveness (AHR) in Busan, Korea. METHODS: We reviewed data for subjects who attended for evaluation of respiratory symptoms between 2011 and 2016. The skin test results of 16 allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, dog, Alternaria, Aspergillus fumigatus, early blossoming tree pollen mix, late blossoming tree pollen mix, alder, birch, oak, grass mix, mugwort, ragweed, and Japanese hop) were analyzed. Age was categorized as group I (15 to < 65 years) or group II (≥ 65 years). RESULTS: A total of 2,791 subjects were analyzed (mean age: 50.9 years, female 61.3%). AHR was demonstrated in 15.8%; sputum eosinophilia in 12.1%; and atopy in 31.2%. The most commonly sensitizing allergen was house dust mite (17.4% to D. pteronyssinus and 17.9% to D. farinae), followed by late blossoming tree pollen mix (8.8%) and early blossoming tree pollen mix (8.6%). AHR was associated with sensitization to D. pteronyssinus, D. farina, Alternaria, dog, cat, alder, birch, oak, and mugwort. However, group II did not show any associations between AHR and any of the aeroallergens except D. farina. Multiple logistic regression analyses showed that the independent factors for AHR were ever-smoker status, D. farina, and oak sensitization. CONCLUSIONS: Sensitization to house dust mites and tree pollen was found to be common in Busan. These aeroallergens significantly affected AHR, particularly in the younger group.

Ligand-based pharmacophore modeling and docking studies on vitamin D receptor inhibitors.

In recent years, pharmacophore modeling and molecular docking approaches have been extensively used to characterize the structural requirements and explore the conformational space of a ligand in the binding pocket of the selected target protein. Herein, we report a pharmacophore modeling and molecular docking of 45 compounds comprising of the indole scaffold as vitamin D receptor (VDR) inhibitors. Based on the selected best hypothesis (DRRRR.61), an atom-based three-dimensional quantitative structure-activity relationships model was developed to rationalize the structural requirement of biological activity modulating components. The developed model predicted the binding affinity for the training set and test set with R2(training) = 0.8869 and R2(test) = 0.8139, respectively. Furthermore, molecular docking and dynamics simulation were performed to understand the underpinning of binding interaction and stability of selected VDR inhibitors in the binding pocket. In conclusion, the results presented here, in the form of functional and structural data, agreed well with the proposed pharmacophores and provide further insights into the development of novel VDR inhibitors with better activity.

Extraprostatic Tumor Extension: Comparison of Preoperative Multiparametric MRI Criteria and Histopathologic Correlation after Radical Prostatectomy.

Background There are no standardized and well-validated criteria for assessing the risk of extraprostatic extension (EPE) of prostate cancer at preoperative multiparametric MRI. Purpose To compare diagnostic performance, intra- and interreader agreement, and correlations of MRI-based criteria for assessment of EPE after radical prostatectomy, including EPE grade, European Society of Urogenital Radiology (ESUR) score, Likert scale, and capsular contact length (CCL). Materials and Methods This retrospective study included consecutive men who underwent MRI and radical prostatectomy between July 2016 and March 2017. Two genitourinary radiologists independently estimated the probability of EPE by using four MRI-based scoring methods. The diagnostic accuracies and intra- and interobserver agreement were evaluated with area under the receiver operating characteristic curve (AUC) and κ statistics, respectively. Correlations between MRI-based score and histologic extent of EPE were analyzed by using the Spearman correlation coefficient (ρ). Results A total of 301 men (mean age ± standard deviation, 65 years ± 7) were evaluated. A total of 129 (42.9%) men had EPE. The AUC ranges of EPE grade, ESUR score, Likert scale, and CCL for assessment of EPE were 0.77-0.81, 0.79-0.81, 0.78-0.79, and 0.78-0.85, respectively, for the two readers. The Likert scale showed lower sensitivity (68.2% [88 of 129] for reader 1, 72.1% [93 of 129] for reader 2) than did EPE grade (77.5% [100 of 129] for reader 1, 79.8% [103 of 129] for reader 2; P ≤ .04). Intra- and interreader agreement were substantial (κ range, 0.61-0.74) for the four methods, with ESUR score showing the lowest values (κ = 0.61 and κ = 0.63, respectively). EPE grade showed highest correlation with histologic extent of EPE (ρ = 0.53 and ρ = 0.55 for circumferential length; ρ = 0.42 and ρ = 0.55 for radial length for readers 1 and 2, respectively; P < .001). Conclusion Extraprostatic extension (EPE) grade, European Society of Urogenital Radiology score, Likert scale, and capsular contact length showed good overall diagnostic performance; however, the EPE grade resulted in more reliable performance and had the highest correlation with histologic EPE extent. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Padhani and Petralia in this issue.