The utility of arterial spin labeling imaging for predicting prognosis after a recurrence of high-grade glioma in patients under bevacizumab treatment.

BACKGROUND AND PURPOSE: Currently, the antiangiogenic agent bevacizumab (BVZ) is used as a treatment option for high-grade glioma (HGG) patients. However, BVZ restores disruptions of the blood-brain barrier, which leads to the disappearance of contrast enhancement during radiological examinations and therefore complicates evaluations of treatment efficacy. This study aimed to investigate the radio-morphological features of recurrent lesions that newly appeared under BVZ therapy, as well as the utility of arterial spin labeling (ASL) perfusion imaging for evaluating treatment response and prognosis in HGG patients receiving BVZ. METHODS: Thirty-two patients (20 males, 12 females; age range, 35-84 years) with HGG who experienced a recurrence under BVZ therapy were enrolled. We measured the relative cerebral blood flow (rCBF) values of each recurrent lesion using ASL, and retrospectively investigated the correlation between rCBF values and prognosis. RESULTS: The optimal rCBF cut-off value for predicting prognosis was defined as 1.67 using receiver operating characteristic curve analysis. The patients in the rCBF < 1.67 group had significantly longer overall survival (OS) and post-progression survival (PPS) than those in the rCBF ≥ 1.67 group (OS: 34.0 months vs. 13.0 months, p = 0.03 and PPS: 13.0 months vs. 6.0 months, p < 0.001, respectively). CONCLUSION: The ASL-derived rCBF values of recurrent lesions may serve as an effective imaging biomarker for prognosis in HGG patients undergoing BVZ therapy. Low rCBF values may indicate that BVZ efficacy is sustainable, which will influence BVZ treatment strategies in HGG patients.

Hydroboration of vinylsilanes providing diversity-oriented hydrophobic building blocks for biofunctional molecules.

Hydroboration of vinylsilanes with BH3 affords two silylethanol regioisomers. Herein, we investigated the regioisomeric ratio of hydroboration products from various vinylsilanes, focusing on the characteristic reaction profile. All investigated vinylsilanes afforded both regioisomers, and greater bulkiness increased the proportion of the Markovnikov products. The obtained silylethanols were used as hydrophobic building blocks for constructing nuclear progesterone receptor (PR) modulators. Notably, structural conversions from an α-isomer (silylethan-1-oxy derivative) to a ß-isomer (2-silylethoxy derivative) caused complete activity-switching from a PR agonist to an antagonist. Our results indicate that silylethanols are useful for structural development, and vinylsilanes are a versatile source of hydrophobic building blocks for obtaining biofunctional molecules.

Utility of combining multiple parameters of 123I-IMP SPECT and voxel-based morphometry MRI using a multiparametric scoring system for differentiating dementia with Lewy bodies from Alzheimer's disease.

BACKGROUND: Brain magnetic resonance imaging voxel-based morphometry (VBM) and perfusion single-photon emission computed tomography (SPECT) are useful for differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). PURPOSE: To determine whether combining multiple parameters of VBM and SPECT using a multiparametric scoring system (MSS) improves diagnostic accuracy in differentiating DLB from AD. MATERIAL AND METHODS: In total, 23 patients with DLB and 57 patients with AD underwent imaging using a voxel-based specific regional analysis system for AD (VSRAD), an easy Z-score imaging system, and a Z-Graph using three-dimensional stereotactic surface projection. The cutoff values were determined using the receiver operating characteristic curve to differentiate DLB from AD for all parameters. Patients were scored 1 (DLB) or 0 (AD) for each statistically significant parameter, according to a threshold. The total score was determined for each case to obtain a cutoff value for the MSS. RESULTS: The mean Z-scores in the medial temporal lobes using the VSRAD were significantly lower in patients with DLB than in those with AD. Each Z-score of the summed Z-scores in all four segmented regions of the occipital lobes using the Z-Graph was significantly higher in patients with DLB than in those with AD. Among the five parameters, the highest accuracy was 80% for the Z-score of the summed Z-scores in the left medial occipital lobe. For the MSS, a cutoff value of four improved the diagnostic accuracy to 82%. CONCLUSION: MSS was more accurate than any single parameter of VBM or SPECT in differentiating DLB from AD.

Design, Synthesis, and Evaluation of B-(Trifluoromethyl)phenyl Phosphine-Borane Derivatives as Novel Progesterone Receptor Antagonists.

We previously revealed that phosphine-boranes can function as molecular frameworks for biofunctional molecules. In the present study, we exploited the diversity of available phosphines to design and synthesize a series of B-(trifluoromethyl)phenyl phosphine-borane derivatives as novel progesterone receptor (PR) antagonists. We revealed that the synthesized phosphine-borane derivatives exhibited LogP values in a predictable manner and that the P-H group in the phosphine-borane was almost nonpolar. Among the synthesized phosphine-boranes, which exhibited PR antagonistic activity, B-(4-trifluoromethyl)phenyl tricyclopropylphosphine-borane was the most potent with an IC50 value of 0.54 µM. A docking simulation indicated that the tricyclopropylphosphine moiety plays an important role in ligand-receptor interactions. These results support the idea that phosphine-boranes are versatile structural options in drug discovery, and the developed compounds are promising lead compounds for further structural development of next-generation PR antagonists.

Solvent-Dependent Conformational Switching of N-Methyl-N,N'-diarylsquaramide.

N,N'-Diarylsquaramide and N,N'-dialkylsquaramide are conformationally stable linkers with extended (trans, trans) and folded (cis, cis) structures, respectively, independently of external conditions. Here, we show that N-monomethylated N,N'-diarylsquaramides generally take a (trans, cis) structure in the crystal but show a solvent-dependent conformational equilibrium in solution. In particular, the stable conformer of N-methyl-N,N'-bis(1-naphthyl)squaramide (1f) changes depending upon the solvent. Thus, aromatic N-monomethylated squaramides could find application as components of environment-responsive molecular switches.

Bimanual finger coordination in professional and amateur darbuka players.

Professional hand percussionists who play the darbuka (a drum from the Middle East) show fast and stable bimanual finger coordination compared to amateur players. A cross-recurrence quantification analysis clarifies how stable bimanual coordination is achieved by dissociating stochastic noise and attractor strength in the dynamic system. This study employed a cross-recurrence quantification analysis to examine professional and amateur darbuka players' fast and stable bimanual finger coordination. Eight professional and eight amateur percussion players participated in the study and played a darbuka with their right and left ring fingers, alternating as fast as possible for 12 s. We then analyzed the finger position data and calculated the stochastic noise and attractor strength from the density and the longest diagonal line in the recurrence plot, respectively. We used linear mixed-effects models to test whether stochastic noise and attractor strength differed between professional and amateur players. The results indicate that professional darbuka players achieve fast and stable bimanual finger coordination by enhancing attractor strength rather than reducing stochastic noise in the dynamic system.

Anticipatory regulation of cardiovascular system on the emergence of auditory-motor interaction in young infants.

Humans develop auditory-motor interaction to produce a variety of rhythmic sounds using body movements, which are often produced and amplified with tools, such as drumming. The extended production of sounds allows us to express a wide range of emotions, accompanied by physiological changes. According to previous studies, even young infants enhance movements in response to auditory feedback. However, their exhibition of physiological adaptation on the emergence of auditory-motor interaction is unclear. We investigated the movement and cardiac changes associated with auditory feedback to spontaneous limb movements in 3-month-old infants. The results showed that infants increased the frequency of limb movements inducing auditory feedback, while they exhibited a more regular rhythm of the limb movements. Furthermore, heart rate increase associated with the limb movement was first inhibited immediately after the timing of the auditory feedback, which may reflect sustained attention to the auditory stimuli. Then, through auditory-motor experience, the heart rate increase was inhibited even prior to the auditory feedback, leading to suppression of the peak intensity of the heart rate increase. These findings suggest that young infants regulate the cardiovascular system as well as limb movements in anticipation of the auditory feedback. The anticipatory regulation associated with movement and attentional changes may contribute to reduced cardiovascular stress in auditory-motor interaction, and provide a developmental basis for more sophisticated goal-directed behavior of producing rhythmic sounds.

Design, synthesis and structure-activity relationship of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisoprop-2-yl)phenylsilane derivatives as liver X receptor agonists.

Liver X receptor (LXR) α and LXRß are nuclear receptors playing key roles in lipid metabolism, and LXR ligands are attractive drug candidates for metabolic disorders. Here we report the structural development of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenylsilane derivatives as LXR agonists bearing silyl functionalities as the hydrophobic pharmacophore, based on the structure of the known sulfonamide LXR agonist T0901317. Most of the synthesized compounds exhibit agonistic activity toward LXRs, but the LXR subtype-selectivity differs depending upon the substituents on the silicon atom. Among them, tri(n-propyl) derivative 12 shows potent LXR-agonistic activity with moderate α subtype-selectivity, while dimethylphenylsilyl derivative 19 shows modest ß-selectivity. These results indicate that silanes can serve as an alternative to the sulfonamide moiety of LXR agonists, and are promising structural options for the development of novel subtype-selective LXR agonists.

The safety and feasibility of retrograde balloon aortic valvuloplasty using the INOUE-BALLOON with severe aortic stenosis.

In the transcatheter aortic valve implantation (TAVI) era, the indications for balloon aortic valvuloplasty (BAV) are increasing. Previously, the INOUE-BALLOON® (IB) was used only for antegrade BAV, but recently, it has also been used for retrograde BAV. However, the safety and feasibility of retrograde BAV using an IB are not fully understood. In this study, we investigated the safety and feasibility of retrograde BAV using an IB in elderly Japanese patients with severe aortic stenosis (AS). We compared 39 cases of retrograde BAV using an IB performed from June 2018 to September 2020 and 34 cases of antegrade BAV using an IB performed from August 2013 to May 2018. The total number of complications was lower in retrograde BAV than in antegrade BAV (p = 0.020). The procedure time was significantly shorter in retrograde BAV than in antegrade BAV (p < 0.001), and the maximum balloon size and number of balloon inflations were smaller in retrograde BAV than in antegrade BAV (p = 0.002 and p < 0.001, respectively). There was no significant difference in the degree of improvement in the aortic valve area or ejection fraction between retrograde and antegrade BAV. In conclusion, the present study showed the safety and feasibility of retrograde BAV using an IB in elderly Japanese patients with severe AS compared with antegrade BAV using an IB.

Structure-property and structure-activity relationships of phenylferrocene derivatives as androgen receptor antagonists.

Ferrocene is a representative organometallic compound having a sandwich structure with high stability and hydrophobicity. In this study, we determined the physicochemical properties of a series of nitro- and cyanophenylferrocenes, and evaluated their biological activity as androgen receptor (AR) antagonists. Ferrocene derivatives exhibited hydrophobicity parameter π values in the range between 2.54 and 3.23, depending on the substituents, indicating that the hydrophobicity of ferrocene is suitable for its application as a hydrophobic core structure of nuclear receptor ligands. The synthesized ferrocene derivatives showed AR-antagonistic activity, and among them, 3-nitrophenylferrocene 14 exhibited the most potent activity with an IC50 value of 0.28 µM. The developed compounds may be candidates for further structural development as AR antagonists. These findings also support the utility of organometallic species as structural options for drug discovery.

Design, synthesis and antitumor activity of phthalazine-1,4-dione-based menaquinone analogs.

New chemotherapeutics are needed to treat hepatocellular carcinoma (HCC), and menaquinones, homologs of vitamin K consisting of a 1,4-naphthoquinone core and a (poly)isoprene chain, are potential candidates. In this study, we designed and synthesized a series of phthalazine-1,4-dione-based menaquinone analogs. Among them, compounds bearing the intact isoprene chain exhibited selective antiproliferative activity towards HCC cell line JHH7, as compared with normal hepatocytes. The geranyl derivative 10 showed submicromolar potency, and might be a promising lead compound for anticancer agents.

Low signal intensities of MRI T1 mapping predict refractory diplopia in Graves' ophthalmopathy.

OBJECTIVE: In Graves' ophthalmopathy (GO), fibrosis in extraocular muscles (EOMs) may be related to intravenous glucocorticoid (ivGC)-resistant diplopia. Signal intensity (SI) of magnetic resonance imaging (MRI) T1 mapping can quantify properties of EOM components, including fibrosis. We investigated EOM features of GO patients with diplopia using T1 mapping SI and the predictive value of T1 mapping SI in the response of diplopia to ivGCs. DESIGN: We performed a cross-sectional study that included 13 active GO patients, 34 inactive GO patients with history of diplopia, including 20 with a history of diplopia disappearance, 14 GO patients with refractory diplopia and 35 control subjects. In nine active GO patients, the relationship between T1 mapping SI at pretreatment and at diplopia outcome after ivGC treatment was prospectively investigated. METHODS: T1 mapping SI of left and right inferior rectus and medial rectus muscles was measured in all participants. RESULTS: T1 mapping SI in inactive GO patients with refractory diplopia was significantly lower than that of other groups in all evaluated EOMs. Diagnostic accuracy for refractory diplopia by T1 mapping SI in GO patients with a history of diplopia disappearance was excellent (AUC 0.89) compared with other assessments. Furthermore, among nine active GO patients, pretreatment T1 mapping SI in four patients with ivGC-resistant diplopia tended to be low compared with the other five patients with improved diplopia. CONCLUSIONS: Low intensity T1 mapping in EOMs is likely to be associated with refractory diplopia and may be useful in predicting the response of diplopia to ivGCs.

Structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK inhibitors blocking WNK kinase signaling.

We report here structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK (STE20/SPS1-related proline/alanine-rich kinase) inhibitors. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension, and therefore inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for antihypertensive drugs. Based on the structure of lead compound 2, we examined the SAR of N-(4-phenoxyphenyl)benzamide derivatives, and developed compound 20l as a potent SPAK inhibitor. Compounds 20l is a promising candidate for a new class of antihypertensive drugs.

Phosphine boranes as less hydrophobic building blocks than alkanes and silanes: Structure-property relationship and estrogen-receptor-modulating potency of 4-phosphinophenol derivatives.

Increasing structural options in medicinal chemistry is important for the development of novel and distinctive drug candidates. In this study, we focused on phosphorus-containing functionalities. We designed and synthesized a series of phosphinophenol derivatives and determined their physicochemical properties, including hydrophobicity parameter LogP, and their biological activity toward estrogen receptor (ER). Notably, the phosphine borane derivatives (9 and 14) exhibited potent ER-antagonistic activity, exceeding the potency of the corresponding alkane (15) and silane (16) derivatives, despite having a less hydrophobic nature. The determined physicochemical parameters will be helpful for the rational design of phosphorus-containing biologically active compounds. Our results indicate that phosphine boranes are a promising new chemical entry in the range of structural options for drug discovery.

Approach-oriented coping strategy level may be related to volume of the whole hippocampus in the elderly.

AIM: Stress-related disorders and severe stress exposure can cause atrophy of the whole hippocampus and its subfields. However, the impact of stress coping strategies on the hippocampus remains unclear. Therefore, we aimed to examine the relation between approach- and avoidance-oriented coping strategies and hippocampal volume in elderly persons. METHODS: A total of 1045 elderly persons living in Arakawa-ward, Tokyo (mean ± SD age: 72.8 ± 5.2 years; 569 females [54.4%]) were included in the study and completed several questionnaires and face-to-face interviews and underwent magnetic resonance imaging. Approach- or avoidance-oriented coping strategies were assessed with the Stress and Coping Inventory, while cognitive function and depressive symptoms were assessed with the Mini-Mental State Examination and Geriatric Depression Scale, respectively. The volume of the whole hippocampus on T1-weighted images was delineated and calculated using FreeSurfer 6.0. Multiple regression analyses were performed to examine the relation between Stress and Coping Inventory scores and whole hippocampal volume. RESULTS: Approach-oriented coping strategy scores were positively correlated with whole hippocampal volume. Furthermore, these relations remained significant after controlling for the influence of cognitive function and depressive symptoms on these volumetric variables. In contrast, avoidance-oriented coping strategy scores were not correlated with whole hippocampal volume. CONCLUSION: This study demonstrated that hippocampal volume may be associated with the approach-oriented coping strategy; therefore, this strategy may preserve hippocampal volume in the elderly.

Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore.

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (2a) and bicalutamide (3), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(N-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their N-methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b, which was comparable to hydroxyflutamide (2b). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans-amide bond, while the active N-methylated coumarinamides have a folded structure with a cis-amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.

A new LC-MS assay for the quantitative analysis of vitamin K metabolites in human urine.

Vitamin K (VK), in both its phylloquinone and menaquinone forms, has been hypothesized to undergo ω- and ß-oxidation on its hydrophobic side chain in order to generate the observed urinary metabolites, K acid I and K acid II, which are excreted primarily as glucuronide conjugates. Synthetic standards of K acid I, K acid II, and a putative intermediate metabolite, menaquinone (MK)1 ω-COOH, were used to develop and optimize a new atmospheric pressure negative chemical ionization LC-MS/MS assay for the quantitation of these compounds in urine from untreated individuals and subjects treated with a high dose VK supplement. VK catabolites were extracted from urine, deconjugated, and converted to their methyl ester derivatives using previously reported methodology. The assay showed a high degree of sensitivity, with limits of detection below 10-50 fmol of metabolite per milliliter of urine, as well as an inter-assay precision of 8-12%. Metabolite standards provided unambiguous evidence for MK1 ω-COOH as a new human urinary metabolite of VK. This assay provides a minimally invasive, highly sensitive, and specific alternative for monitoring VK status in humans.

Safety and Efficacy of Low-Dose Prasugrel as Part of Triple Therapy With Aspirin and Oral Anticoagulants in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention　- From the TWMU-AF PCI Registry.

BACKGROUND: Using the standard maintenance dose of prasugrel (10 mg/day) as part of triple therapy with aspirin and an oral anticoagulant (OAC) is not recommended in the current guidelines because it increases the risk of bleeding compared with clopidogrel. However, the safety and efficacy of low-dose prasugrel (3.75 mg/day) as part of triple therapy has not been reported. Methods and Results: We registered 816 consecutive patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) from January 2011 to June 2016 at 8 hospitals in Japan. We examined the clinical outcomes of patients who received either low-dose prasugrel (n=57) or clopidogrel (n=451) as part of triple therapy after PCI. The incidences of bleeding (TIMI major and minor) and major adverse cerebrocardiovascular events (MACCE; all-cause death, nonfatal myocardial infarction, stent thrombosis, unplanned revascularization, and stroke) were evaluated. The cumulative 1-year incidence of bleeding was not significantly different (prasugrel 5.6% vs. clopidogrel 8.1%, log-rank P=0.55). In addition, the cumulative 1-year incidence of MACCE was also not significantly different (prasugrel 11.5% vs. clopidogrel 12.3%, log-rank P=0.88). CONCLUSIONS: Low-dose prasugrel, as part of triple therapy, did not increase the risk of bleeding compared with clopidogrel. Therefore, it can be an alternative to clopidogrel for patients with AF undergoing PCI.

Development of novel lithocholic acid derivatives as vitamin D receptor agonists.

Lithocholic acid (2) was identified as the second endogenous ligand of vitamin D receptor (VDR), though its binding affinity to VDR and its vitamin D activity are very weak compared to those of the active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1). 3-Acylated lithocholic acids were reported to be slightly more potent than lithocholic acid (2) as VDR agonists. Here, aiming to develop more potent lithocholic acid derivatives, we synthesized several derivatives bearing a 3-sulfonate/carbonate or 3-amino/amide substituent, and examined their differentiation-inducing activity toward human promyelocytic leukemia HL-60 cells. Introduction of a nitrogen atom at the 3-position of lithocholic acid (2) decreased the activity, but compound 6 bearing a 3-methylsulfonate group showed more potent activity than lithocholic acid (2) or its acylated derivatives. The binding of 6 to VDR was confirmed by competitive binding assay and X-ray crystallographic analysis of the complex of VDR ligand-binding domain (LBD) with 6.