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.

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.

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.

Safety and Diagnostic Yield of Radial Probe Endobronchial Ultrasound-Guided Biopsy for Peripheral Lung Lesions in Patients with Idiopathic Pulmonary Fibrosis: A Multicenter Cross-Sectional Study.

BACKGROUND: Radial probe endobronchial ultrasound-guided transbronchial lung biopsy (RP-EBUS-TBLB) is widely used for diagnosis of peripheral lung lesions (PLLs). To date, there have been no reports regarding the clinical outcomes of RP-EBUS-TBLB for PLLs in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: This study was performed between October 2017 and December 2019 to identify the safety and diagnostic performance of RP-EBUS-TBLB in IPF patients. METHODS: Patients were divided into the usual interstitial pneumonia (UIP) group (n = 39, 4%), the probable UIP group (n = 12, 1%), and the noninterstitial lung disease (non-ILD) group (n = 903, 95%). RESULTS: The diagnostic yield was significantly lower in the UIP group than in the non-ILD group (62% vs. 76%; p = 0.042), but there were no significant differences between the UIP and probable UIP groups (62% vs. 83%; p = 0.293) or the probable UIP and non-ILD groups (83% vs. 76%; p = 0.741). Multivariate logistic analysis showed that the mean diameter of PLLs, positive bronchus sign on CT, and "within the lesion" status on EBUS were independently associated with success of the procedure. Especially, the presence of the UIP pattern on CT (OR, 0.385; 95% CI: 0.172-0.863; p = 0.020) was independently associated with failed diagnosis. Among patients with UIP, "within the lesion" status on EBUS (OR, 25.432; 95% CI: 2.321-278.666; p = 0.008) was shown to be a factor contributing to a successful diagnosis. Overall, there were no significant differences in complication rates among the 3 study groups. CONCLUSION: RP-EBUS-TBLB can be performed safely with an acceptable diagnostic yield, even in patients with IPF.

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.

The role of Zur-regulated lipoprotein A in bacterial morphology, antimicrobial susceptibility, and production of outer membrane vesicles in Acinetobacter baumannii.

BACKGROUND: Zinc uptake-regulator (Zur)-regulated lipoprotein A (ZrlA) plays a role in bacterial fitness and overcoming antimicrobial exposure in Acinetobacter baumannii. This study further characterized the zrlA gene and its encoded protein and investigated the roles of the zrlA gene in bacterial morphology, antimicrobial susceptibility, and production of outer membrane vesicles (OMVs) in A. baumannii ATCC 17978. RESULTS: In silico and polymerase chain reaction analyses showed that the zrlA gene was conserved among A. baumannii strains with 97-100% sequence homology. Recombinant ZrlA protein exhibited a specific enzymatic activity of D-alanine-D-alanine carboxypeptidase. Wild-type A. baumannii exhibited more morphological heterogeneity than a ΔzrlA mutant strain during stationary phase. The ΔzrlA mutant strain was more susceptible to gentamicin than the wild-type strain. Sizes and protein profiles of OMVs were similar between the wild-type and ΔzrlA mutant strains, but the ΔzrlA mutant strain produced 9.7 times more OMV particles than the wild-type strain. OMVs from the ΔzrlA mutant were more cytotoxic in cultured epithelial cells than OMVs from the wild-type strain. CONCLUSIONS: The present study demonstrated that A. baumannii ZrlA contributes to bacterial morphogenesis and antimicrobial resistance, but its deletion increases OMV production and OMV-mediated host cell cytotoxicity.

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.

Short communication: First detection of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus ST30 in raw milk taken from dairy cows with mastitis in South Korea.

We identified 199 Staphylococcus aureus isolates from quarter milk samples of 1,289 dairy cattle between 2014 and 2018. About 66% of the isolates were resistant to at least 1 antimicrobial agent; the highest rate of resistance was to penicillin, followed by resistance to ampicillin, erythromycin, and sulfadimethoxine. We obtained 30 methicillin-resistant S. aureus (MRSA) strains from 6 farms in 3 provinces. The MRSA strains exhibited a significantly higher resistance rate to most of the tested antimicrobials than the oxacillin-susceptible strains. The MRSA strains represented 5 genotypes: ST72-t324-SCCmec IV (n = 14), ST30-t1752-SCCmec IV (n = 8), ST188-t189-SCCmec NT (n = 6), ST188-t2284-SCCmec NT (n = 1), and NT-NT-SCCmec IV (n = 1). One of the ST188 MRSA strains represented a novel staphylococcal protein A (spa) type (t2284). In addition, 7 of the 8 ST30 MRSA strains were Panton-Valentine leukocidin (PVL)-positive and carried various staphylococcal enterotoxin encoding genes. This is the first report of PVL-positive ST30 MRSA-t1752-SCCmec IV from bovine mastitis in Korea. All of ST72-t324-SCCmec IV MRSA strains carried staphylococcal enterotoxin and leukotoxin encoding genes. They were also sensitive to most of the tested non-ß-lactam antimicrobials. In contrast, ST188-t189 MRSA strains were resistant to multiple antimicrobials and predominantly carried the leukotoxin encoding gene. Taken together, these findings may indicate that dairy cows could be a major source for spreading MRSA strains, and contaminated milk could be a vehicle for transmission. Suitable hygienic measures should be established in dairy farms and processing plants to limit the likelihood of introducing MRSA into the food chain.

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.

18 F-labeled 1,2,3-triazole-linked Glu-urea-Lys-based PSMA ligands have good pharmacokinetic properties for positron emission tomography imaging of prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library. METHOD: 18 F-labeling was achieved in a two-step synthesis consisting of [18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [18 F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. RESULTS: Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (Ki ). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [18 F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [18 F]6c, [18 F]6f, and [18 F]6i. Additional microPET/CT experiments of [18 F]6c and [18 F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10-3 mSv/MBq. CONCLUSIONS: [18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

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.