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• Acid catalyzed isoquinolin-1-ones synthesis was achieved under mild condition. • The substrates with various functional groups provided the products with high yield. • The developed method were successfully applied to the derivatizations of doryanine. We describe the simple and efficient synthesis of N -substituted isoquinolin-1-one derivatives. Initiating with the coupling of benzoic acids containing vinyl ethers with different amines, followed by rapid intramolecular cyclization under acidic conditions at room temperature, N -substituted isoquinolin-1-ones were furnished in high yields. The utility of this simple and mild cyclization method was demonstrated through the practical synthesis of natural product doryanine and its analogues. [ABSTRACT FROM AUTHOR]

Persistent trigeminal artery (PTA) is a rare condition that represents a remnant fetal anastomosis between the carotid artery and basilar artery. PTA typically arises from precavernous portion of the internal carotid artery (ICA) to the basilar artery. Variations of PTA extending from the ICA and directly terminating as cerebellar arteries without jointing basilar artery are particularly rare. We presented the extremely rare case of the variations of PTA, which directly terminate in the ipsilateral anterior inferior cerebellar artery. In addition, we reviewed the embryogenesis and clinical implication of this anomaly. [ABSTRACT FROM AUTHOR]

Primary mediastinal leiomyoma is an extremely rare benign tumor of smooth muscle. Most common radiographic appearance is a well circumscribed heterogeneous solid mass. We reported a case of giant cyst-like lesion at the middle mediastinum, which was pathologically confirmed as a primary mediastinal leiomyoma. [ABSTRACT FROM AUTHOR]

Purpose: Transrectal ultrasound (TRUS)-guided prostate biopsy is the most useful technique for the diagnosis of prostate cancer; however, many patients describe the procedure as uncomfortable and painful. We investigated the effect of the patient's position on pain scales during TRUS-guided prostate biopsy. Materials and Methods: Between July 2012 and June 2013, a total of 128 consecutive patients who underwent TRUS-guided prostate biopsy were included in this study. Seventy patients underwent the procedure in the lithotomy position performed by a urologist and the other patients (n=58) underwent the procedure in the left lateral decubitus (LLD) position performed by a radiologist. Pain was assessed by using visual analogue scale (VAS) scores from 0 to 10. Using a linear regression model, we analyzed the correlation between pain scale score and clinical variables with a focus on patient position. Results: No significant differences related to age, body mass index, prostate volume, prostate-specific antigen (PSA), hematuria, pyuria, International Prostate Symptom Score, or the cancer detection rate were observed between the lithotomy and the LLD groups. In the correlation analysis, VAS score showed a significant correlation with diabetes mellitus, PSA level, and lithotomy position (p<0.05). In the multiple linear regression model, VAS score showed a significant correlation with lithotomy position (β=-0.772, p=0.003) and diabetes mellitus (β=-.803, p=0.033). Conclusions: We suggest that the lithotomy position may be the proper way to reduce pain during TRUS-guided prostate biopsy. [ABSTRACT FROM AUTHOR]

Numerous biomarkers and risk tables can be used to predict recurrence or progression of patients with primary or recurrent non-muscle invasive bladder cancer (NMIBC) receiving Bacillus Calmette-Guerin (BCG). However, few are suitable for BCG-unresponsive disease (i.e., recurrence or progression after BCG treatment). Therefore, identification of a novel marker that allows accurate prediction of prognosis, particularly risk of recurrence, is critically important in clinical practice. In the current study, gene ontology and gene set enrichment analyses of microarray datasets (GSE13507, n = 47) revealed that differentially expressed genes in recurred NMIBC patients after BCG treatment were associated with virus and ribosomal pathways. Among the core-enrichment genes, the expression of RPL9, a putative tumor suppressor, was lower in recurred NMIBC patients after BCG therapy than in patients without recurrence (P = 0.033) from the E-MTAT-4321 European cohort (n = 84). Data from The Cancer Genome Atlas (n = 406) showed that bladder cancer patients with higher RPL9 expression had a longer overall survival probability than patients with lower RPL9 expression (P = 0.011). Moreover, we used the latest digital PCR platform to examine 59 NMIBC patients and identified downregulation of RPL9 in patients with recurrence after BCG therapy (P = 0.031). The Kaplan-Meier survival estimator showed that NMIBC patients with higher expression of RPL9 had longer recurrence-free survival (log-rank test, P = 0.015). Therefore, we conclude that RPL9 expression is a prospective predictor of recurrence after BCG therapy in NMIBC patients. [ABSTRACT FROM AUTHOR]

Persistent trigeminal artery (PTA) is one of the remnant fetal anastomoses between the carotid artery and basilar artery. PTAs are classified according to angiographic appearance and various connection. Among them, those directly terminating in the cerebellar arteries are rare subtype. In addition, aneurysms of the PTA are unusual in the literature and have not previously accompanied this subtype of PTA connecting cerebellar artery. We present the first case of an aneurysm of the PTA which is directly terminating in the cerebellar arteries and combined with multiple aneurysms. [ABSTRACT FROM AUTHOR]

Intercalated nanocomposites with poly(butylene terephthalate) (PBT) incorporated between the montmorillonite layers were synthesized from dimethyl terephthalate and 1,4-butane diol by using an in situ interlayer polymerization. The PBT nanocomposites were melt-spun at different organoclay contents to produce monofilaments. The samples were characterized by using wide angle X-ray diffraction, electron microscopy, thermal analysis, and tensile testing. The extent of the clay layer in the PBT was confirmed by using X-ray diffraction and electron microscopy, and the clay layer was found to be highly dispersed on a nanometer scale. The addition of only a small amount of organoclay was enough to improve the thermo-mechanical properties of the PBT hybrid fibers. The hybrids were extruded with various draw ratios (DRs) to examine the tensile mechanical property of the fibers. At DR=1, the ultimate tensile strength of the hybrid fibers increased with the addition of clay up to a critical content and then decreased. However, the initial modulus monotonically increased with increasing amount of organoclay in the PBT matrix. When the DR was increased from 1 to 6, for example, the strength and the initial modulus values of the hybrids containing 3 wt% organoclay decreased linearly. [Copyright &y& Elsevier]

Our study was to clarify the intercalation of polymer chains to organoclays and to improve the thermo-mechanical properties. Two organoclays were synthesized. One was a montmorillonite modified with hexadecylamine (C16-MMT); the other was a fluorinated-mica modified with hexadecylamine (C16-Mica). Dispersions of organoclays with poly(lactic acid) (PLA) were by using the solution intercalation method at different organoclay contents to produce nano-scale composites. The maximum ultimate tensile strength was observed for blends containing 4 wt% of either of the two organoclays and decreased with further increases in the organoclay content. The initial modulus increased with increasing organoclay content up to 4 wt% for C16-MMT. When the C16-MMT content was greater than this critical wt%, the modulus of the hybrids started to decrease. In contrast, the initial modulus of the hybrids using C16-Mica increased continually with increasing clay content from 2 to 8 wt%. The tensile properties of the C16-Mica hybrids were higher than those of the hybrids containing C16-MMT. The optical translucency was not affected by the organoclay content up to 6 wt%; however, the films containing 8 wt% organoclays were slightly more cloudy. [Copyright &y& Elsevier]

Mixed lead halide perovskites have shown remarkable performance in photovoltaic and optoelectronic applications. Pure hybrid halide perovskites undergo clear phase transitions, however, the phase transitions in mixed perovskites are less studied. We present a contrasting behavior of the phase transition dynamics of MAPbBr 3- x Cl x (MA = CH 3 NH 3 +) mixed halide perovskites compared to the pure MAPbX 3 (X = Cl, Br) counterparts, which typically exhibit order-disorder phase transitions through a series of distinct structural phases. We have employed several spectroscopic techniques including temperature-dependent PXRD, Raman, dielectric and Brillouin spectroscopy. The results demonstrate that the mixed halide perovskite MAPbBr 1.5 Cl 1.5 does not undergo any structural phase transition typically observed in pure halide perovskites. We observed signatures of glassy behavior in mixed compositions of this system. In addition, we also explored the effects of replacing A-site cation on the phase transition behaviors. The results contribute to the understanding of phase transition mechanisms in perovskites and have implications for their stability and optoelectronic properties. [ABSTRACT FROM AUTHOR]

Purpose: P21-activated kinase 4 (PAK4), a serine/threonine kinase that regulates a number of fundamental cellular processes, has been suggested as a prognostic factor for various human tumors. The aim of the present study was to evaluate the clinical implications of phospho-Ser474 PAK4 (pPAK4S474), an activated form of PAK4, in surgically treated renal cell carcinoma (RCC). Materials and Methods: Samples from 131 patients with surgically treated RCC were immunostained to detect PAK4 and pPAK4S474. Expression of PAK4 and pPAK4S474 was compared with clinicopathological characteristics and survival after nephrectomy. Results: PAK4 and pPAK4S474 were expressed predominantly in the nucleus. Overall, 57.3% (75/131) and 24.4% (29/119) of specimens exhibited high expression of pPAK4S474 and PAK4, respectively. High expression of pPAK4S474 was associated with adverse pathologic characteristics, including advanced tumor stage and grade (p=0.036 and p=0.002, respectively), whereas this association was not significant for PAK4 expression (each p>0.05). Kaplan-Meier estimates showed that high expression of pPAK4S474 was associated with shorter recurrence-free survival in a subgroup with localized RCC and with cancer-specific survival in the total RCC cohort (log-rank test: p=0.001 and p=0.005, respectively), whereas PAK4 expression was not. Multivariate Cox regression analysis identified that high pPAK4S474 expression was an independent predictor of recurrence in the subgroup with localized RCC. Conclusions: pPAK4S474 may be a more accurate prognostic factor than total PAK4 in RCC patients. This marker would be useful for identifying patients with pathologically localized disease who may require further interventions. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 NMIBC patients identified a signature-based subtype predictor, MSP888, along with three distinct molecular subtypes: DP.BCG+ (related to progression and response to BCG treatment), REC.BCG+ (related to recurrence and response to BCG treatment), and EP (equivocal prognosis). Patients with the DP.BCG+ subtype showed worse progression-free survival but responded to BCG treatment, whereas those with the REC.BCG+ subtype showed worse recurrence-free survival but responded to BCG treatment. Multivariate analyses revealed that MSP888 showed independent clinical utility for predicting NMIBC prognosis (each p = 0.001 for progression and recurrence, respectively). Comparative analysis of this classifier and previously established molecular subtypes (i.e., Lund taxonomy and UROMOL class) revealed that a great proportion of patients were similar between subtypes; however, the MSP888 predictor better differentiated biological activity or responsiveness to BCG treatment. Our data increase our understanding of the mechanisms underlying the poor prognosis of NMIBC and the effectiveness of BCG therapy, which should improve clinical practice and complement other diagnostic tools. [ABSTRACT FROM AUTHOR]

Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study. Image 1 • Induction of androgen receptor degradation mediated by cereblon E3 ligase. • Inhibition of cell growth in AR-dependent prostate cancer cells. • Good microsomal stability and in vivo PK properties. • Effectively inhibit tumor growth by treatment with TD-802. [ABSTRACT FROM AUTHOR]

Purpose: Volumetry is used in polycystic kidney and liver diseases (PKLDs), including autosomal dominant polycystic kidney disease (ADPKD), to assess disease progression and drug efficiency. However, since no rapid and accurate method for volumetry has been developed, volumetry has not yet been established in clinical practice, hindering the development of therapies for PKLD. This study presents an artificial intelligence (AI)-based volumetry method for PKLD. Materials and Methods: The performance of AI was first evaluated in comparison with ground-truth (GT). We trained a V-netbased convolutional neural network on 175 ADPKD computed tomography (CT) segmentations, which served as the GT and were agreed upon by 3 experts using images from 214 patients analyzed with volumetry. The dice similarity coefficient (DSC), interobserver correlation coefficient (ICC), and Bland-Altman plots of 39 GT and AI segmentations in the validation set were compared. Next, the performance of AI on the segmentation of 50 random CT images was compared with that of 11 PKLD specialists based on the resulting DSC and ICC. Results: The DSC and ICC of the AI were 0.961 and 0.999729, respectively. The error rate was within 3% for approximately 95% of the CT scans (error<1%, 46.2%; 1%=error<3%, 48.7%). Compared with the specialists, AI showed moderate performance. Furthermore, an outlier in our results confirmed that even PKLD specialists can make mistakes in volumetry. Conclusions: PKLD volumetry using AI was fast and accurate. AI performed comparably to human specialists, suggesting its use may be practical in clinical settings. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimeras (PROTACs) are an emerging strategy for promoting targeted protein degradation by inducing the proximity between targeted proteins and E3 ubiquitin ligases. Although successful degradation of numerous proteins by PROTACs has been demonstrated, the elements that determine the degradability of PROTAC-targeted proteins have not yet been explored. In this study, we developed von Hippel-Lindau-Cereblon (VHL-CRBN) heterodimerizing PROTACs that induce the degradation of CRBN, but not VHL. A quantitative proteomic analysis further revealed that VHL-CRBN heterodimerizing PROTACs induced the degradation of CRBN, but not the well-known immunomodulatory drug (IMiD) neo-substrates, IKAROS family zinc finger 1 (IKZF1) and −3 (IZKF3). Moreover, truncation of disordered regions of CRBN and the androgen receptor (AR) attenuated their PROTAC-induced degradation, and attachment of the disordered region to stable CRBN or AR facilitated PROTAC-induced degradation. Thus, these results suggest that the intrinsically disordered region of targeted proteins is essential for efficient proteolysis, providing a novel criterion for choosing degradable protein targets. [ABSTRACT FROM AUTHOR]

• Lewis acid-mediated synthesis of 3,3′-bis-7-azaindolylmethane derivatives. • The structure-activity relationship on 7-azaindole ring and methylene moiety. • Some synthetic products displaying potent cytotoxicity competitive with doxorubicin. The synthesis of 3,3′-bis-7-indolylmethane derivatives is important for their further development as pharmaceutical compounds and other synthetic purposes. Herein, we describe the zinc- or acid-mediated cross-coupling reaction of 7-azaindoles with aldehydes, such as paraformaldehyde, alkyl aldehydes, aryl aldehydes, enal, and α-ketoaldehyde, providing the corresponding C3-linked bis-7-azaindole derivatives, which are a crucial class towards the development of novel bioactive compounds. High levels of site selectivity and functional group tolerance were observed. Synthesized 3,3′-bis-7-azaindole derivatives were evaluated against human breast adenocarcinoma cells (MCF-7) and human ovarian carcinoma cells (SKOV-3), respectively. Notably, compounds 3s and 4e displayed promising anticancer properties competitive with anticancer doxorubicin as a positive control. [ABSTRACT FROM AUTHOR]

The ruthenium(II)-catalyzed C-H aminocarbonylation of N-(hetero)aryl-7-azaindoles with isocyanates is described. The excellent site selectivity at the ortho-position within the N-(hetero)aryl ring was observed to provide ortho-amidated N-(hetero)aryl-7-azaindoles under the mild reaction conditions. The resulting 7-azaindole derivatives can be readily transformed into 7-azaindoles containing carboxylic acid and alkyl amine functional groups. [ABSTRACT FROM AUTHOR]