Scaffold-Hopped Compound Identification by Ligand-Based Approaches with a Prospective Affinity Test.

Scaffold-hopped (SH) compounds are bioactive compounds structurally different from known active compounds. Identifying SH compounds in the ligand-based approaches has been a central issue in medicinal chemistry, and various molecular representations of scaffold hopping have been proposed. However, appropriate representations for SH compound identification remain unclear. Herein, the ability of SH compound identification among several representations was fairly evaluated based on retrospective validation and prospective demonstration. In the retrospective validation, the combinations of two screening algorithms and four two- and three-dimensional molecular representations were compared using controlled data sets for the early identification of SH compounds. We found that the combination of the support vector machine and extended connectivity fingerprint with bond diameter 4 (SVM-ECFP4) and SVM and the rapid overlay of chemical structures (SVM-ROCS) showed a relatively high performance. The compounds that were highly ranked by SVM-ROCS did not share substructures with the active training compounds, while those ranked by SVM-ECFP4 were mostly recombinant. In the prospective demonstration, 93 SH compounds were prepared by screening the Namiki database using SVM-ROCS, targeting ABL1 inhibitors. The primary screening using surface plasmon resonance suggested five active compounds; however, in the competitive binding assays with adenosine triphosphate, no hits were found.

Risk Factors Causing Hypothyroidism in Patients With Head and Neck Cancer After Radiotherapy Using SIB-VMAT.

BACKGROUND/AIM: We evaluated the incidence of radiation-induced hypothyroidism and its risk factors in patients with head and neck cancer who underwent radiotherapy using simultaneous integrated boost-volumetric-modulated arc therapy (SIB-VMAT). PATIENTS AND METHODS: This retrospective study included 86 patients who received definitive radiotherapy using SIB-VMAT for head and neck cancer. The incidence of ≥ grade 2 hypothyroidism was evaluated. We also evaluated the relationships between hypothyroidism development and clinical factors and thyroid dose-volume parameters. RESULTS: During a median follow-up period of 17 months (range=3-65 months), 31 patients (36.0%, 31/86) developed grade 2 hypothyroidism requiring hormone replacement therapy. No patients experienced ≥ grade 3 hypothyroidism. The cumulative incidences of hypothyroidism at 1 and 2 years after radiation therapy were 24.5% and 38.7%, respectively, with a median onset time of 10.0 months (range=3.0-35.0 months). Thyroid volume (p=0.003), volume of the thyroid spared at 60 Gy (VS60; cut-off value, 5.16 ml; p=0.009), VS70 (cut-off value, 8.0 ml; p=0.007), VS60 equivalent dose in 2 Gy fraction (EQD2; cut-off value, 7.78 ml; p=0.001), and VS70EQD2 (cut-off value, 10.59 ml; p=0.008) were significantly associated with the development of radiation-induced hypothyroidism. CONCLUSION: Radiation-induced hypothyroidism is not rare in patients with head and neck cancer undergoing radiotherapy using SIB-VMAT. Radiation dose-volume parameters detected in this study may be useful indicators to prevent this complication.

Clinical Experience of Percutaneous Radiofrequency Ablation Using an arfa RF ABLATION SYSTEMⓇ in Various Organs.

Purpose: To evaluate the feasibility, safety, and efficacy of radiofrequency (RF) ablation using an ablation system (arfa RF ABLATION SYSTEMⓇ; Japan Lifeline Co. Ltd.) for treating solid tumors in various organs. Material and Methods: Between October 2019 and August 2021, 80 patients (29 women, 51 men; median age, 70.0 yr) underwent 107 RF ablation sessions using the ablation system to treat 151 tumors in the liver (n = 86), lung (n = 51), adrenal gland (n = 4), pleura (n = 4), bone (n = 3), lymph node (n = 2), and kidney (n = 1). The maximum tumor diameter was 2-40 mm (median, 11 mm). This study evaluated technical success (defined as the completion of planned RF ablation), technique efficacy (defined as the complete tumor ablation on follow-up images), and adverse events. Local tumor progression in 146 curatively treated malignant tumors was evaluated. Results: The technical success rate was 100% (107/107). Ablation zones in two tumors were insufficient. Therefore, the primary technique efficacy rate was 98.1% (105/107). Grade 3 hepatic infarction (1.6%, 1/64) and grade 4 pleuritis (3.4%, 1/29) occurred respectively after liver and lung RF ablation. During the median follow-up period of 10.2 months (Interquartile range, 4.2 and 16.4 months), local tumor progression developed in two tumors (1.4%, 2/146). Conclusions: The arfa RF ABLATION SYSTEMⓇ is a feasible, safe, and effective RF ablation device for managing solid tumors in various organs.

Protective Effect of Polaprezinc and Hyperbaric Oxygen Therapy on Radiation-induced Small Intestinal Damage in Mice.

BACKGROUND/AIM: To investigate the effect of polaprezinc (antioxidant) administration and hyperbaric oxygen therapy on radiation-induced intestinal injury. MATERIALS AND METHODS: Forty-five C57BL/6J mice underwent total body radiation of 2 Gy. Polaprezinc was given in 12 mice, hyperbaric oxygen in 12 mice, and both in 12 mice. The other 9 mice did not undergo any treatment. Mice were sacrificed 2, 4, and 6 h after radiation, and 9 specimens (3 each from the duodenum, jejunum, and ileum) were harvested. Apoptotic intestinal crypt cells were histologically evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: Apoptotic cell number per 1,000 crypt cells was 31.0±6.7 at 2 h, 28.4±5.2 at 4 h, and 32.9±5.1 at 6 h in the mice group treated by radiation alone. Both polaprezinc administration and hyperbaric oxygen therapy significantly suppressed apoptosis. Although the effect of polaprezinc administration on suppressing apoptosis became less over time (4.9±5.7 and 19.4±13.2 at 2 and 6 h, respectively), that of hyperbaric oxygen therapy was stable regardless of time (23.6±4.8 and 25.8±4.1 at 2 and 6 h). Administration of both polaprezinc and hyperbaric oxygen showed a significant synergetic or additive effect on suppressing apoptosis at 6 h (11.4±10.5, p<0.0035 vs. polaprezinc, p<0.0001 vs. hyperbaric oxygen). CONCLUSION: Both polaprezinc administration and hyperbaric oxygen therapy are effective in relieving radiation-induced small intestinal damage, and a synergistic or additive effect is expected when using both.

Use of Microballoon Catheter in Transarterial Ethanol Embolization of Renal Angiomyolipoma: A Retrospective Comparative Study with Historical Control?

Purpose: To clarify the utility of microballoon catheter in renal arterial ethanol embolization of renal angiomyolipoma (AML). Material and Methods: A total of 20 patients (15 women, 5 men) with median age of 45 years (39-60 years) underwent embolization to treat 22 AMLs. A mixture of ethanol and iodized oil was injected into the feeding arteries of 13 tumors using balloon occlusion (the balloon embolization group) with a microballoon catheter and 9 tumors without using balloon occlusion (the non-balloon embolization group). Changes in the maximum tumor diameter, tumor volume, and adverse events were evaluated. Result: The median baseline maximum tumor diameters and volumes were 6.3 cm and 61.4 cm3 in the balloon embolization group, and 4.6 cm and 40.1 cm3 in the non-balloon embolization group, respectively. Tumor enhancement disappeared on postembolization angiography in all cases. All tumors shrunk after embolization. There were no statistically significant differences in the percent decrease in the maximum tumor diameter and volume at 10-12 month between balloon occlusion group (31.5% and 67.9%) and control group (34.8% and 62.6%). Fever was significantly more frequent when balloon occlusion was used: 38% vs. 0% (p = 0.03). No major complication was observed in either patient group. Conclusions: Balloon occlusion may not affect tumor shrinkage when embolizing AMLs with a mixture of ethanol and lipiodol.

CT Findings of Primary Renal Angiosarcoma.

Primary angiosarcomas of the kidney are very rare but highly aggressive tumors showing poor prognosis. We present a case of primary renal angiosarcoma occurring in a 60-year-old man with left flank pain. CT images depicted a huge exophytic mass (14 cm in diameter) in the left kidney, exhibiting central extensive hemorrhage or necrosis without contrast enhancement. The mass showed centripetal peripheral nodular enhancement on dynamic contrast-enhanced CT images. We suggest its inclusion in the differential diagnosis of cases of hemorrhagic renal tumors with prominent vasculature.

Metastasis-Directed Radiotherapy for Oligoprogressive Castration-Resistant Prostate Cancer Recurrence Revealed by Choline PET/CT.

We report a 49-year-old male with castration-resistant prostate cancer (CRPC) with oligometastasis diagnosed by 11C-choline positron emission tomography-computed tomography (PET/CT) and treated with target radiotherapy. In the diagnosis of CRPC (serum prostate-specific antigen [PSA] level of 6.53 ng/mL after maximum androgen blockade (MAB) therapy, high-dose brachytherapy, and external beam radiotherapy), 11C-choline PET/CT detected one tiny obturator lymph node metastasis which fluorodeoxyglucose PET/CT could not detect. He underwent intensity-modulated radiation therapy and MAB was restarted. The PSA value decreased and reached nadir (0.091 ng/mL) after 6 months. The time to PSA progression was 10 months. The choline PET/CT finding and the corresponding local treatment could play an important role in the management sequence of oligoprogressive CRPC.

Application of a New Scaffold Concept for Computational Target Deconvolution of Chemical Cancer Cell Line Screens.

Target deconvolution of phenotypic assays is a hot topic in chemical biology and drug discovery. The ultimate goal is the identification of targets for compounds that produce interesting phenotypic readouts. A variety of experimental and computational strategies have been devised to aid this process. A widely applied computational approach infers putative targets of new active molecules on the basis of their chemical similarity to compounds with activity against known targets. Herein, we introduce a molecular scaffold-based variant for similarity-based target deconvolution from chemical cancer cell line screens that were used as a model system for phenotypic assays. A new scaffold type was used for substructure-based similarity assessment, termed analog series-based (ASB) scaffold. Compared with conventional scaffolds and compound-based similarity calculations, target assignment centered on ASB scaffolds resulting from screening hits and bioactive reference compounds restricted the number of target hypotheses in a meaningful way and lead to a significant enrichment of known cancer targets among candidates.

Identification of novel microRNA targets based on microRNA signatures in bladder cancer.

MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate protein-coding genes. To identify miRNAs that have a tumor suppressive function in bladder cancer (BC), 156 miRNAs were screened in 14 BCs, 5 normal bladder epithelium (NBE) samples and 3 BC cell lines. We identified a subset of 7 miRNAs (miR-145, miR-30a-3p, miR-133a, miR-133b, miR-195, miR-125b and miR-199a*) that were significantly downregulated in BCs. To confirm these results, 104 BCs and 31 NBEs were subjected to real-time RT-PCR-based experiments, and the expression levels of each miRNA were significantly downregulated in BCs (p < 0.0001 in all). Receiver-operating characteristic curve analysis revealed that the expression levels of these miRNAs had good sensitivity (>70%) and specificity (>75%) to distinguish BC from NBE. Our target search algorithm and gene-expression profiling in BCs (Kawakami et al., Oncol Rep 2006;16:521-31) revealed that Keratin7 (KRT7) mRNA was a common target of the downregulated miRNAs, and the mRNA expression levels of KRT7 were significantly higher in BCs than in NBEs (p = 0.0004). Spearman rank correlation analysis revealed significant inverse correlations between KRT7 mRNA expression and each downregulated miRNA (p < 0.0001 in all). Gain-of-function analysis revealed that KRT7 mRNA was significantly reduced by transfection of 3 miRNAs (miR-30-3p, miR-133a and miR-199a*) in the BC cell line (KK47). In addition, significant decreases in cell growth were observed after transfection of 3 miRNAs and si-KRT7 in KK47, suggesting that miR-30-3p, miR-133a and miR-199a* may have a tumor suppressive function through the mechanism underlying transcriptional repression of KRT7.

MicroRNA-338-3p and microRNA-451 contribute to the formation of basolateral polarity in epithelial cells.

MicroRNAs are small noncoding RNA species, some of which are playing important roles in cell differentiation. However, the level of participations of microRNAs in epithelial cell differentiation is largely unknown. Here, utilizing an epithelial differentiation model with T84 cells, we demonstrate that miR-338-3p and miR-451 contribute to the formation of epithelial basolateral polarity by facilitating translocalization of beta1 integrin to the basolateral membrane. Among 250 microRNAs screened in this study, the expression levels of four microRNAs (miR-33a, 210, 338-3p and 451) were significantly elevated in the differentiated stage of T84 cells, when epithelial cell polarity was established. To investigate the involvement of these microRNAs in terms of epithelial cell polarity, we executed loss-of- and gain-of-function analyses of these microRNAs. The blockade of endogenous miR-338-3p or miR-451 via each microRNA-specific antisense oligonucleotides inhibited the translocalization of beta1 integrin to the basolateral membrane, whereas inhibition of miR-210 or miR-33a had no effect on it. On the other hand, simultaneous transfection of synthetic miR-338-3p and miR-451 accelerated the translocalization of beta1 integrin to the basolateral membrane, although the introduction of individual synthetic microRNAs exhibited no effect. Therefore, we concluded that both miR-338-3p and miR-451 are necessary for the development of epithelial cell polarity.