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Background: Photoimmunotherapy is a treatment modality that induces targeted cell death by binding a molecular-targeted drug activated by infrared light to the tumor cells and subsequently illuminating the lesion with infrared light. For deep lesions, a needle catheter is used to puncture the tumor, and an illumination fiber (cylindrical diffuser) is inserted into the catheter lumen for internal illumination. However, it can be challenging to place the cylindrical diffusers in an appropriate position as the deep lesions cannot be often confirmed accurately during surgery. Materials and methods: We have developed "SlicerPIT", a planning simulation software for photoimmunotherapy. SlicerPIT allows users to place the cylindrical diffuser with its illumination range on preoperative images in 2D and 3D and export the planning data to external image-guided surgical navigation systems. We performed seven cycles of photoimmunotherapy with SlicerPIT in three patients with recurrent head and neck cancer. Results: Preoperative planning for photoimmunotherapy was conducted using SlicerPIT, which could be imported into the navigation system. During the operation, we punctured the needle catheters along with the treatment plan on the navigation screen. Subsequently, intraoperative CT imaging was performed and overlaid with the preoperative treatment plan to confirm the alignment of the cylindrical diffusers as planned, followed by infrared light illumination. Postoperative imaging showed necrosis and shrinkage of the entire tumor in all cycles. Conclusion: SlicerPIT allows for detailed preoperative treatment planning and accurate puncture. It may be a valuable tool to improve the accuracy of photoimmunotherapy for deep lesions and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Histone acetylation, which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a crucial role in the control of gene expression. HDAC inhibitors (HDACi) have shown potential in cancer therapy; however, the specific roles of HDACs in early embryos remain unclear. Moreover, although some pan-HDACi have been used to maintain cellular undifferentiated states in early embryos, the specific mechanisms underlying their effects remain unknown. Thus, there remains a significant knowledge gap regarding the application of selective HDACi in early embryos. Results: To address this gap, we treated early embryos with two selective HDACi (MGCD0103 and T247). Subsequently, we collected and analyzed their transcriptome data at different developmental stages. Our findings unveiled a significant effect of HDACi treatment during the crucial 2-cell stage of zygotes, leading to a delay in embryonic development after T247 and an arrest at 2-cell stage after MGCD0103 administration. Furthermore, we elucidated the regulatory targets underlying this arrested embryonic development, which pinpointed the G2/M phase as the potential period of embryonic development arrest caused by MGCD0103. Moreover, our investigation provided a comprehensive profile of the biological processes that are affected by HDACi, with their main effects being predominantly localized in four aspects of zygotic gene activation (ZGA): RNA splicing, cell cycle regulation, autophagy, and transcription factor regulation. By exploring the transcriptional regulation and epigenetic features of the genes affected by HDACi, we made inferences regarding the potential main pathways via which HDACs affect gene expression in early embryos. Notably, Hdac7 exhibited a distinct response, highlighting its potential as a key player in early embryonic development. Conclusions: Our study conducted a comprehensive analysis of the effects of HDACi on early embryonic development at the transcriptional level. The results demonstrated that HDACi significantly affected ZGA in embryos, elucidated the distinct actions of various selective HDACi, and identified specific biological pathways and mechanisms via which these inhibitors modulated early embryonic development. [ABSTRACT FROM AUTHOR]

Background: Carcinogenic risk assessment studies have been repeatedly improved and are still being debated to find a goal. Evaluation might be changed if new approaches would be applied to some chemicals which means that new approaches may change the final assessment. In this paper, the risk assessment of a chemical, in particular the proper carcinogenicity, is examined using the long-banned food additive, 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide, AF-2, as a case study. Results: First, Ames tests were carried out using strains TA1535, TA100, TA1538, and TA98 and their nitroreductase-deficient strains YG7127, YG7128, YG7129, and YG7130. The results showed that mutagenic activity was reduced by about 50% in the nitroreductase-deficient strains, indicating that part of the mutagenic activity shown in Ames test was due to bacterial metabolism. Second, in vivo genotoxicity tests were conducted, including the one that had not been developed in 1970's. Both a micronucleus test and a gene mutation assay using transgenic mice were negative. Third, assuming it is a genotoxic carcinogen, the virtual safety dose of 550 μg/day was calculated from the TD50 in rats with a probability of 10−5. Conclusion: AF-2 has been shown to be carcinogenic to rodents and has previously been indicated to be genotoxic in vitro. However, the present in vivo genotoxicity study, it was negative in the forestomach, a target organ for cancer, particularly in the gene mutation assay in transgenic mice. Considering the daily intake of AF-2 in the 1970s and its virtually safety dose, the carcinogenic risk of AF-2 could be considered acceptable. [ABSTRACT FROM AUTHOR]

Background: Superselective intra-arterial infusion of cisplatin and concomitant radiotherapy (RADPLAT) is a very promising treatment modality for locally advanced head and neck squamous cell carcinoma. However, there are some concerns regarding its potential for the control of neck lymph node metastasis. The objective of this study was to investigate whether RADPLAT provided inferior regional control compared to intravenous chemoradiotherapy (IV-CRT). Methods: A total of 172 patients with neck lymph node metastases, 66 of whom underwent RADPLAT and 106 IV-CRT, were enrolled in this study. We retrospectively compared regional control rates between RADPLAT and IV-CRT. Furthermore, to adjust for differences in factors related to patient background between the groups, we conducted inverse probability weighting (IPW) analysis using the propensity score. Results: A comparison between the two groups revealed that the regional control rates were almost equal under unadjusted conditions; however, after adjustment by IPW analysis, the RADPLAT group had a relatively better regional control rate than did the IV-CRT group (1 year regional control rate: 86.6% vs. 79.4%). In addition, the analysis of relative risk factors for regional control in the RADPLAT group showed that the absence of intra-arterial cisplatin infusion into metastatic lymph nodes was the only independent risk factor (Hazard ratio: 4.23, p = 0.04). Conclusion: This study showed that the regional control rate in patients treated with RADPLAT was noninferior to that for IV-CRT. Locally advanced head and neck cancers is a good indication for RADPLAT, even if the patients have neck lymph node metastases. [ABSTRACT FROM AUTHOR]

Next-generation RNA sequencing (RNA-Seq) has identified more differentially expressed protein-coding genes (DEGs) and provided a wider quantitative range of expression level changes than conventional DNA microarrays. JEMS·MMS·Toxicogenomics group studied DEGs with targeted RNA-Seq on freshly frozen rat liver tissues and on formalin-fixed paraffin-embedded (FFPE) rat liver tissues after 28 days of treatment with chemicals and quantitative real-time PCR (qPCR) on rat and mouse liver tissues after 4 to 48 h treatment with chemicals and analyzed by principal component analysis (PCA) as statics. Analysis of rat public DNA microarray data (Open TG-GATEs) was also performed. In total, 35 chemicals were analyzed [15 genotoxic hepatocarcinogens (GTHCs), 9 non-genotoxic hepatocarcinogens (NGTHCs), and 11 non-genotoxic non-hepatocarcinogens (NGTNHCs)]. As a result, 12 marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2, and Tubb4b) were proposed to discriminate GTHCs from NGTHCs and NGTNHCs. U.S. Environmental Protection Agency studied DEGs induced by 4 known GTHCs in rat liver using DNA microarray and proposed 7 biomarker genes, Bax, Bcmp1, Btg2, Ccng1, Cdkn1a, Cgr19, and Mgmt for GTHCs. Studies involving the use of whole-transcriptome RNA-Seq upon exposure to chemical carcinogens in vivo have also been performed in rodent liver, kidney, lung, colon, and other organs, although discrimination of GTHCs from NGTHCs was not examined. Candidate genes published using RNA-Seq, qPCR, and DNA microarray will be useful for the future development of short-term in vivo studies of environmental carcinogens using RNA-Seq. [ABSTRACT FROM AUTHOR]

Zinc is an essential micronutrient in human body and a vital cofactor for the function of numerous proteins encoded by the human genome. Zinc has a critical role in maintaining many biochemical and physiological processes at the molecular, cellular, and multiple organ and systemic levels. The alteration of zinc homeostasis causes dysfunction of many organs and systems. In the immune system, zinc regulates the differentiation, proliferation and function of inflammatory cells, including T cells, eosinophils, and B cells, by modifying several signaling pathways such as NFκB signaling pathways and TCR signals. An adequate zinc level is essential for proper immune responses and decreased zinc levels were reported in many allergic inflammatory diseases, including atopic dermatitis, bronchial asthma, and chronic rhinosinusitis. Decreased zinc levels often enhance inflammatory activation. On the other hand, the inflammatory conditions alter the intracellular homeostasis of zinc, often decreasing zinc levels. These findings implied that there could be a vicious cycle between zinc deficiency and inflammatory conditions. In this review, we present recent evidence on the involvement of zinc in atopic dermatitis, bronchial asthma, and chronic rhinosinusitis, with insights into the involvement of zinc in the underlying molecular and cellular mechanisms related to these allergic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Next Generation Sequencer (NGS) is a powerful tool for a high-throughput sequencing of human genome. It is important to ensure reliability and sensitivity of the sequence data for a clinical use of the NGS. Various cancer-related gene panels such as Oncomine™ or NCC OncoPanel have been developed and used for clinical studies. Because these panels contain multiple genes, it is difficult to ensure the performance of mutation detection for every gene. In addition, various platforms of NGS are developed and their cross-platform validation has become necessity. In order to create mutant standards in a defined background, we have used CRISPR/Cas9 genome-editing system in HEK 293 T/17 cells. Results: Cancer-related genes that are frequently used in NGS-based cancer panels were selected as the target genes. Target mutations were selected based on their frequency reported in database, and clinical significance and on the applicability of CRISPR/Cas9 by considering distance from PAM site, and off-targets. We have successfully generated 88 hetero- and homozygous mutant cell lines at the targeted sites of 36 genes representing a total of 125 mutations. Conclusions: These knock-in HEK293T/17 cells can be used as the reference mutant standards with a steady and continuous supply for NGS-based cancer panel tests from the JCRB cell bank. In addition, these cell lines can provide a tool for the functional analysis of targeted mutations in cancer-related genes in the isogenic background. [ABSTRACT FROM AUTHOR]

Four new homodinuclear lanthanoid(III) dithiocarbamato (RR ′dtc−) complexes bridged by 2,2′-bipyrimidine (bpm) of the form [{Ln(RR ′dtc) 3 } 2 (µ-bpm)] {Ln = Nd or Eu; RR ′ = dimethyl- (Me 2) or pyrrolidine- (pyr)} were prepared and their crystal structures and spectroscopic properties were characterized. Each LnIII (NdIII or EuIII) center in the dimer is 8-coordinated by three dithiocarbamato ligands (RR ′dtc−) and a 2,2′-bipyrimidine (bpm) having a κ2 N 1,1′:κ2 N 3,3′ bridging mode. Two pyrimidine rings of the bridging bpm ligand are almost planar and the mutually pseudo trans -positioned RR ′dtc ligands are also co-planar to each other. However, it was found for some of the pyrrolidine dithiocarbamato (pyrdtc−) complexes, [{Ln(pyrdtc) 3 } 2 (μ-bpm)], one of the coordinated pyrdtc ligands exhibits a severe structural distortion. Four new homodinuclear lanthanoid(III) dithiocarbamato (RR ′dtc−) complexes bridged by 2,2′-bipyrimidine (bpm) of the form [{Ln(RR ′dtc) 3 } 2 (µ-bpm)] {Ln = Nd or Eu; RR ′ = dimethyl- (Me 2) or pyrrolidine- (pyr)} were prepared and their crystal structures and spectroscopic properties were characterized. The crystallographic studies revealed that all of the complexes possess a similar structural motif with an 8:8-coordination geometry, in which the bpm ligand bridges two LnIII centers in the κ2 N 1,1′:κ2 N 3,3′ mode and three RR ′dtc− ligands coordinate to each LnIII center. The complexes exhibit weak but relatively sharp f–f transition bands in the absorption and magnetic circular dichroism (MCD) spectra recorded in the visible region. The MCD spectral studies demonstrated the magneto-optical behavior of the complexes. The spectral features of the dithiocarbamato complexes were distinctly different from those of their β-diketonato analogues, suggesting the coordination environment around the LnIII center influences the electronic structure and spectroscopic symmetry of the complexes in solution. [ABSTRACT FROM AUTHOR]

Complexation properties of U-shaped ligands, L1 and L2, which are Schiff bases of 5,5′-(9,9-dimethylxanthene-4,5-diyl)bis(salicylaldehyde) (H2xansal) with 3-amino-1-propanol or 2-hydroxybenzylamine, respectively, were investigated to construct polynuclear manganese complexes. In these ligands, two O,N,O-Schiff bases are bridged by a xanthene backbone. The reactions of H4L1 or H4L2 with manganese salts afforded tetra- and dinuclear manganese complexes, including the tetramanganese(II , II , III , III) complex [Mn4(L1)2(μ-OAc)2] with a Mn4O6 core exhibiting an incomplete double-cubane structure. In the Mn4O6 core, phenolate and alkoxide O atoms bridge the manganese ions. Deprotonated 3-hydroxypropyl groups were crucial to the assembly of four manganese ions because the phenolate-bridged dimanganese(III , III) complex [Mn2(H2L1)2]2+ was obtained in the absence of a base, and H4L2, which has 2-hydroxybenzyl groups instead of 3-hydroxypropyl groups in H4L1, afforded the cyclic dimanganese(IV , IV) complex [Mn2(L2)2]. We disclosed that [Mn4(L1)2(μ-OAc)2] was converted to the oxo-bridged tetramanganese(III , III , III , III) complex [Mn4(L1)(HL1)(μ3-O)(μ-OAc)2]+ by treating with NH4PF6 or NH4BF4: a triply bridging alkoxide was protonated and replaced by an oxide ligand. The cyclic voltammograms of [Mn4(L1)(HL1)(μ3-O)(μ-OAc)2]+ suggested that the reverse reaction forming [Mn4(L1)2(μ-OAc)2] occurred in the electrochemical processes and was assisted by protonation. [ABSTRACT FROM AUTHOR]

Highlights • We evaluated 12 mouse marker genes in rat toxicogenomics public data. • PCA is useful to discriminate genotoxic and nongenotoxic hepatocarcinogens. • PCA discriminated GTHC to NGTHC and NGTNHC at 24 h and 29 days. Abstract Previously, we proposed 12 marker genes (Aen , Bax , Btg2 , Ccnf , Ccng1 , Cdkn1a , Gdf15 , Lrp1 , Mbd1 , Phlda3 , Plk2 and Tubb4b) to discriminate mouse genotoxic hepatocarcinogens (GTHC) from non-genotoxic hepatocarcinogens (NGTHC). This was determined by qPCR and principal component analysis (PCA), as the aim of an in vivo short-term screening for genotoxic hepatocarcinogens. For this paper, we conducted an application study of the 12 mouse marker genes to rat data, Open TG-GATEs (public data). We analyzed five typical rat GTHC (2-acetamodofluorene, aflatoxin B1, 2-nitrofluorene, N -nitrosodiethylamine and N -nitrosomorpholine), and not only seven typical rat NGTHC (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital and WY-14643) but also 11 non-genotoxic non-hepatocarcinogens (NGTNHC; allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline and tolbutamide) from Open TG-GATEs. The analysis was performed at 3, 6, 9 and 24 h after a single administration and 4, 8, 15 and 29 days after repeated administrations. We transferred Open TG-GATEs DNA microarray data into log 2 data using the "R Project for Statistical Computing". GTHC-specific dose-dependent gene expression changes were observed and significance assessed with the Williams test. Similar significant changes were observed during 3–24 h and 4–29 days, assessed with Welch's t -test, except not for NGTHC or NGTNHC. Significant differential changes in gene expression were observed between GTHC and NGTHC in 11 genes (except not Tubb4b) and between GTHC and NGTNHC in all 12 genes at 24 h and 10 genes (except Ccnf and Mbd1) at 29 days, per Tukey's test. PCA successfully discriminated GTHC from NGTHC and NGTNHC at 24 h and 29 days. The results demonstrate that 12 previously proposed mouse marker genes are useful for discriminating rat GTHC from NGTHC and NGTNHC from Open TG-GATEs. [ABSTRACT FROM AUTHOR]

Graphical abstract The LnIII (NdIII or EuIII) center is 8-coordinated by three dithiocarbamato ligands (Xdtc) through two S donor atoms and a phenanthroline or bipyridine ligand through two N donor atoms. Both bidentate ligands of the dithiocarbamato (Xdtc) and diimine (NN) are almost planar, but the NN ligand plane and the pseudo trans -positioned Xdtc ligand plane is not coplanar. In the case of the [Eu(S -proOHdtc) 3 (phen)]·H 2 O (2e ·H 2 O) complex, a set of unsymmetrical coordination of the three S -proOHdtc− ligands around the EuIII center were observed. Highlights • Several NdIII and EuIII complexes with dithiocarbamato and diimine were prepared. • Chiral S -prolinol dithiocarbamato complexes of NdIII and EuIII were described. • Crystal structures of the LnIII dithiocarbamato complexes are reported. • The chiroptical properties of these complexes were investigated by CD and MCD. Abstract A series of NdIII and EuIII complexes containing achiral or chiral dithiocarbamato (dtc) ligands, [Ln(Xdtc) 3 (NN)] {Ln = Nd or Eu; X = dimethyl- (Me 2), pyrrolidine- (pyr), or (S)-prolinol- (S -proOH); NN = 1,10-phenanthroline (phen) or 2,2′-bipyridine (bpy)}, were prepared and their crystal structures and spectroscopic properties, in particular the natural circular dichroism (CD) and magnetic circular dichroism (MCD), were investigated. The crystal structures of the complexes analyzed by the X-ray diffraction method showed an 8-coordinate geometry around the LnIII center with comparable structural parameters to one another and to the related complexes reported previously. These complexes exhibited similar spectral patterns in their absorption, natural CD and MCD spectra in solution. Weak but characteristic sharp f–f transition bands were observed in the absorption and MCD spectra, but no CD signals associated with these transitions were observed even in the S -proOHdtc complexes. The MCD spectral pattern of the EuIII complexes revealed a local C 2v symmetry around the LnIII center in solution, in contrast to the aqua and the analogous β-diketonato EuIII complexes. [ABSTRACT FROM AUTHOR]

Lysine‐specific demethylase 1 (LSD1) is one of the flavin‐dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1‐selective inhibitors using target‐guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1‐selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1‐selective inhibitors. Lysine‐specific demethylase 1 (LSD1) is an attractive target for the therapy of cancer and other diseases. To date, we have reported several LSD1‐selective inhibitors with unique bioactivities by using target‐guided synthesis (TGS) strategies based on our original ideas. Our TGS approach could offer more potent LSD1‐selective inhibitors, which can be used as therapeutic agents. [ABSTRACT FROM AUTHOR]

Highlights • Fosphenytoin (F-PHT) is an antiepileptic drug for epilepsy and bipolar disorders. • F-PHT has the narrow therapeutic index. • Forensic practice often requires analysis of drugs and poisons in whole blood. • We developed a quantification method for F-PHT and its metabolites by UPLC-MS/MS. • This method appears to be suitable for forensic and clinical toxicology. Abstract A method for simultaneous quantification of fosphenytoin (F-PHT), phenytoin (PHT) and its main metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in whole blood was developed and validated using ultra-performance liquid chromatography-tandem mass spectrometry. Whole blood samples were pretreated by liquid–liquid extraction with acetonitrile and methanol. Chromatographic separation was performed using a CORTECS™ UPLC® C18 (2.1 × 50 mm i.d., particle size 1.6 μm) analytical column, and water containing 10 mM ammonium formate and acetonitrile as the mobile phase. Quantification of the analytes was carried out using mass chromatography with each product ion referenced against phenytoin-d 10 as an internal standard. Calibration curves exhibited good linear relationships in a range from 0.005 to 50 μg/ml with correlation coefficients exceeding 0.995. The limits of detection were estimated to be 0.002–0.01 μg/ml. The accuracies and precisions were 96.2–104.3% and 0.7–10.7%, respectively. The recovery efficiencies were in the range of 42.4–59.2%. Matrix effects were observed for PHT and HPPH, with signal suppression ranging from −6.6 to –32.2%. Matrix effect for F-PHT (−5.0 to 8.9%) was less than those for PHT and HPPH. All analytes were stable under different storage conditions. This method was successfully applied for the quantification of F-PHT, PHT and HPPH in rat whole blood samples taken after bolus intravenous administration of F-PHT. [ABSTRACT FROM AUTHOR]

Background: Mutagenicity, the ability of chemical agents to cause mutations and potentially lead to cancer, is a critical aspect of substance safety assessment for protecting human health and the environment. Metabolic enzymes activate multiple mutagens in living organisms, thus in vivo animal models provide highly important information for evaluating mutagenicity in human. Rats are considered suitable models as they share a similar metabolic pathway with humans for processing toxic chemical and exhibit higher responsiveness to chemical carcinogens than mice. To assess mutagenicity in rats, transgenic rodents (TGRs) are widely used for in vivo gene mutation assays. However, such assays are labor-intensive and could only detect transgene mutations inserted into the genome. Therefore, introducing a technology to directly detect in vivo mutagenicity in rats would be necessary. The next-generation sequencing (NGS) based error-corrected sequencing technique is a promising approach for such purposes. Results: We investigated the applicability of paired-end and complementary consensus sequencing (PECC-Seq), an error-corrected sequencing technique, for detecting in vivo mutagenicity in the rat liver samples. PECC-Seq allows for the direct detection of ultra-rare somatic mutations in the genomic DNA without being constrained by the genomic locus, tissue, or organism. We tested PECC-Seq feasibility in rats treated with diethylnitrosamine (DEN), a mutagenic compound. Interestingly, the mutation and mutant frequencies between PECC-Seq and the TGR assay displayed a promising correlation. Our results also demonstrated that PECC-Seq could successfully detect the A:T > T:A mutation in rat liver samples, consistent with the TGR assay. Furthermore, we calculated the trinucleotide mutation frequency and proved that PECC-Seq accurately identified the DEN treatment-induced mutational signatures. Conclusions: Our study provides the first evidence of using PECC-Seq for in vivo mutagenicity detection in rat liver samples. This approach could provide a valuable alternative to conventional TGR assays as it is labor- and time-efficient and eliminates the need for transgenic rodents. Error-corrected sequencing techniques, such as PECC-Seq, represent promising approaches for enhancing mutagenicity assessment and advancing regulatory science. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the differences between spinal metastasis and osteoporotic compression fractures on plain X-ray images, focusing on asymmetrical vertebral collapse and fracture level.Materials and Methods: This study included 180 patients with pathological collapse from spinal metastasis (188 vertebrae) who were treated at our institution and 70 patients (92 vertebrae) with osteoporotic compression fractures. Anteroposterior X-ray images of the lower thoracic and lumbar spine were evaluated for asymmetrical collapse deformity.Results: Asymmetrical collapse was found in 134 vertebrae (71.3%) with metastasis, and in 20 osteoporotic vertebrae (21.7%); this difference was significant (p < 0.0001). The asymmetrical collapse angle in spinal metastasis patients ranged from 0 to 18°, with a mean of 7.0 and a standard deviation (SD) of 4.5. In contrast, the asymmetrical collapse angle in patients with osteoporotic fractures ranged from 0 to 13°, with a mean of 3.1 and a SD of 2.8. The difference in collapse angle between the two groups was statistically significant (p < 0.001). The cutoff value to suspect spinal metastasis was determined to be 5° or more (sensitivity 0.67, specificity 0.74). Fracture at Th10 or below L3 was found in 20.2% of spinal metastasis patients; only 3% of osteoporotic fractures occurred at these levels.Conclusion: Asymmetrical collapse with an angle of 5° or more and fractures at atypical levels on plain radiographs can be useful clues to spinal metastasis. [ABSTRACT FROM AUTHOR]

Background: Although there is evidence about the beneficial effects of probiotics, their effects on aspirin-induced small bowel injuries have not been well examined. We evaluated the effects of the probiotic Lactobacillus gasseri OLL2716 (LG) on aspirin-induced small intestinal lesions, such as ulcers, erosions, reddened lesions, and bleeding. Summary: This study enrolled 64 patients who received aspirin for more than 1 month and provided written informed consent to be part of the study. The patients received 112 ml of yogurt containing LG or placebo twice daily for 6 weeks. Small bowel injuries were evaluated by capsule endoscopy before and after consuming the yogurt. The effect of LG on patient symptoms was also assessed using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires before and after 6 weeks of treatment. There was no significant difference in any baseline characteristics and the number of small bowel mucosal breaks between the 2 groups. In contrast with the placebo group, the LG group had significantly fewer small bowel mucosal breaks and reddened lesions after 6 weeks (p < 0 .01). The FSSG and GSRS scores were also significantly improved in the LG group but not in the placebo group. Key Messages: This double-blind, placebo-controlled study found that LG may be useful in reducing aspirin-induced small bowel injuries and in mitigating gastrointestinal symptoms. [ABSTRACT FROM AUTHOR]

We sought to evaluate the efficacy and feasibility of superselective intra-arterial infusion of high-dose cisplatin with concomitant radiotherapy (hereafter RADPLAT) for head and neck squamous cell cancer (hereafter HNSCC) patients with retropharyngeal lymph node (hereafter RPLN) metastasis. A retrospective case series review was conducted at University medical center in Japan. Ten HNSCC patients with RPLN metastasis treated by RADPLAT were analyzed. The ascending pharyngeal artery was targeted for the treatment of RPLN metastasis in 9 patients. The median total dose of cisplatin was 26.6 mg/m (mean 31.5 mg/m, range 11.7-87.9 mg/m). In the remaining patient, the RPLN was supplied by the ascending palatine artery. As grade 3 and 4 adverse effects, leukopenia was observed in three, mucositis in four and nausea in one patient. No neurological complications were observed in any patients. Metastatic RPLNs were evaluated as a complete response in all patients. There was no recurrence of RPLN metastasis in any patients. Four patients remain alive without any evidence of disease and six patients died of disease. The 5-year overall survival rate was 50 %. We have shown that superselective intra-arterial cisplatin infusion for RPLNs was a feasible and effective approach for HNSCC patients with RPLN metastasis. [ABSTRACT FROM AUTHOR]

Aim. The study assessed the usefulness of a recently developed method for respiratory rate (RR) monitoring in patients undergoing endoscopic submucosal dissection (ESD) under deep sedation. Methods. Study subjects comprised 182 consecutive patients with esophageal cancer or gastric cancer undergoing ESD. The usefulness of acoustic RR monitoring was assessed by retrospectively reviewing the patients’ records for age, gender, height, weight, past history, serum creatinine, RR before ESD, and total dose of sedative. Results. Respiratory suppression was present in 37.9% of (69/182) patients. Continuous monitoring of RR led to detection of respiratory suppression in all these patients. RR alone was decreased in 24 patients, whereas both RR and blood oxygen saturation were decreased in 45 patients. Univariate analysis showed female gender, height, weight, and RR before treatment to be significantly associated with respiratory suppression. Multivariate analysis showed RR before treatment to be the only significant independent predictor [odds ratio (OR) 0.83, 95% confidence interval (CI) 0.73–0.95, and P=0.006] of respiratory suppression. Conclusion. In this study, the difference in RR before treatment between patients with and without respiratory suppression was subtle. Therefore, we suggest that acoustic RR monitoring should be considered in patients undergoing ESD under sedation to prevent serious respiratory complications. [ABSTRACT FROM AUTHOR]

A reaction of [PdCl2(cod)] (cod = 1,5-cyclooctadiene) and an E/Z mixture of quinoline-2-carbaldehyde (pyridine-2-carbonyl)hydrazone (HL) gave two kinds of PdII mononuclear complexes, [PdCl(Z-L-κ3N,N′,N′′)] (1) and [PdCl2(E-HL′-κ2N,N′)] (2), where L− is the deprotonated hydrazonate anion and HL′ is the quinolinium–hydrazonate zwitterionic form of HL. Complex 2 is gradually converted to 1 in solution, and complex 1 is a good precursor to prepare a PdII/RuII heterodinuclear complex bridged by hydrazonate, trans(Cl,Cl)-[RuCl2(PPh3)2(μ-L)PdCl] (3). [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington’s disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nucleus. However, the precise functions of HDAC3 in the two cellular compartments are only vaguely known. HDAC3 directly binds to huntingtin (Htt) with short pQ and this interaction is important for suppressing neurotoxicity induced by HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, and this supposedly promotes neuronal death, indicating that HDAC3 would be a good therapeutic target for HD. However, the knockout of one HDAC3 allele did not show any efficacy in reducing neurodegenerative symptoms in a mouse model of HD. Therefore, the role of HDAC3 in the pathogenesis of HD has yet to be fully elucidated. We attempted to resolve this issue by focusing on the different roles of HDAC3 on cytoplasmic and nuclear Htt aggregates. In addition to supporting the previous findings, we found that HDAC3 preferentially binds to nuclear Htt over cytoplasmic ones. Specific HDAC3 inhibitors increased the total amount of Htt aggregates by increasing the amount of nuclear aggregates. Both cytoplasmic and nuclear Htt aggregates were able to suppress endogenous HDAC3 activity, which led to decreased nuclear proteasome activity. Therefore, we concluded that Htt aggregates impair nuclear proteasome activity through the inhibition of HDAC3. Our findings provide new insights regarding cross-compartment proteasome regulation. [ABSTRACT FROM AUTHOR]

Esophageal cancer is the most common second primary cancer (SPC) in patients with head and neck cancer (HNC). Esophageal SPC has a negative impact on survival. Elevated mean corpuscular volume (MCV) is an accepted predictor of esophageal cancer risk. The aim of this study was to elucidate the usefulness of elevated MCV as an indicator of a high risk for esophageal SPC. We retrospectively reviewed the medical records of patients with oropharyngeal, hypopharyngeal, and laryngeal squamous cell carcinoma who underwent chemoradiotherapy between 2003 and 2012. We excluded patients younger than 20 years or who had received treatment for esophageal cancer and who had a histologically unproven lesion. Patients were divided into two groups according to their MCV. The cut-off for MCV was defined by receiver operating characteristics curve analysis. The primary endpoint was the cumulative incidence of esophageal SPC. A total of 295 patients were included. The median follow-up period for surviving patients was 7.4 years and the optimal cut-off point was 99.0 fL. One hundred ninety-five patients (66%) had an MCV < 99.0 fL and 100 (34%) had an MCV ≥ 99.0 fL. The 5-year cumulative incidence in patients with an MCV < 99.0 fL and ≥ 99.0 fL was 8.7% and 27%, respectively. In the multivariate analysis, an MCV ≥ 99.0 fL (HR=2.2; 95%CI, 1.1-4.2) was an independent risk factor. MCV ≥ 99.0 fL was found to be a risk factor for esophageal SPC. We, therefore, recommend that patients with an MCV ≥ 99.0 fL should undergo intensive monitoring. [ABSTRACT FROM AUTHOR]

The reactions of quinoline-2-carbaldehyde (pyridine-2-carbonyl)hydrazone (HL) and [RuCl2(PPh3)3] in various solvents at different temperatures gave the three geometrical isomers trans(Cl,Cl)-, cis(Cl,Cl),trans(P,N)-, and trans(P,P)-[RuCl2(PPh3)2{HL-κ O(amide),κ N(imine)}] ( 1, 2, and 3, respectively) as well as a linkage isomer trans(P,P)-[RuCl2(PPh3)2{HL-κ N(imine),κ N(quin)}] ( 4). The molecular and crystal structures of 1- 4, together with both E and Z configurational isomers (with respect to the C=N double bond) of the free ligand HL, were determined by X-ray analysis. The ligand HL adopted a Z form and acted as a κ O(amide),κ N(imine) bidentate ligand in 1- 3, whereas it was an E isomer with a κ N(imine),κ N(quin) coordination mode in 4. The gradual thermal conversions of 1 to 2 and of 2 to 3 were observed in dichloromethane and ethanol, respectively, but an interconversion between 3 and 4 was not detected. In dichloromethane, all complexes have a reversible RuIII/II redox couple in the range 110-412 mV (vs. Ag/Ag+), and the redox potential was largely dependent on the coordination mode of HL and on the mutual configuration of the two PPh3 ligands. Such a potential shift can be interpreted as a combination of Cl-/amide O π-donor and PPh3/quinoline N π-acceptor orbital contributions to the RuII dπ orbitals [highest occupied molecular orbitals (HOMOs)]. Complexes 3 and 4 in acetonitrile showed a gradual spectral change, probably because of the substitution of the Cl- ligand by the acetonitrile solvent. In addition, 2- 4 showed solvatochromic behavior even in noncoordinating solvents that resulted from a blueshift of the metal-to-ligand charge-transfer (MLCT) transition band in polar solvents. These electrochemical and spectroscopic properties are also supported by DFT and time-dependent DFT (TD-DFT) calculations. [ABSTRACT FROM AUTHOR]

Several new iridium(iii) and rhodium(iii) complexes bearing 5-methyltetrazolate (MeCN4−) have been prepared, and their structures in the crystals and in solution have been determined by X-ray analysis and by NMR spectroscopy, respectively. In the crystals of the mononuclear complexes, κN2-coordination of MeCN4− was observed when the ancillary ligand was 2,2′-bipyridine (bpy): [Cp*M(bpy)(MeCN4-κN2)]PF6 (Cp* = η5-C5Me5; M = Ir: 1 and Rh: 2), while the corresponding complexes with 2-(2′-pyridyl)phenyl (ppy−) were confirmed to have the κN1-coordination of MeCN4−: [Cp*M(ppy)(MeCN4-κN1)] (M = Ir: 3 and Rh: 4). In solution, the IrIII complexes (1 and 3) were robust enough to maintain their molecular structures, but the RhIII complexes (2 and 4) existed as an equilibrium mixture of the κN1- and κN2-isomers. In addition to the IrIII–IrIII and RhIII–RhIII homodinuclear complexes bridged by MeCN4− (5–8), the corresponding heterodinuclear IrIII–RhIII complexes (9–12) were prepared using the mononuclear IrIII complexes (1 and 3) as precursors. The molecular structures of these dinuclear complexes were also characterised. Interestingly, both of the heterodinuclear complexes comprised of Cp*M(bpy)2+ and Cp*M′(ppy)+ fragments, [Cp*M(bpy)(μ-MeCN4)M′(ppy)Cp*](PF6)2 (M = Ir, M′ = Rh: 10 and M = Rh, M′ = Ir: 11), exhibited selective crystallisation of a specific μ-κN1(M′-ppy):κN3(M-bpy) isomer. In solution, the dinuclear complexes with a Rh–N(MeCN4) bond and more than one positive charge (6 and 9–11) showed a dissociation equilibrium, while monocationic MeCN4-bridged complexes (7, 8 and 12) were inactive for dissociation. Furthermore, the heterodinuclear complexes of 9–12, as well as the RhIII–RhIII complex of 8, exhibited a bridging isomerisation, which would proceed via a η2:η2-intermediate without dissociation of Cp*M(bpy or ppy) fragments. [ABSTRACT FROM AUTHOR]

Histone Nε-methyl lysine demethylasesKDM2/7 have been identified as potential targets for cancer therapies.On the basis of the crystal structure of KDM7B, we designed and prepareda series of hydroxamate analogues bearing an alkyl chain. Enzyme assaysrevealed that compound 9potently inhibits KDM2A, KDM7A,and KDM7B, with IC50s of 6.8, 0.2, and 1.2 μM, respectively.While inhibitors of KDM4s did not show any effect on cancer cellstested, the KDM2/7-subfamily inhibitor 9exerted antiproliferativeactivity, indicating the potential for KDM2/7 inhibitors as anticanceragents. [ABSTRACT FROM AUTHOR]

New ruthenium(II or III) complexes with general formula [Ru(0-N)(bpy)2]n+ (O-N = unsymmetrical bidentate phenolate ligand; bpy = 2,2'-bipyridine) were synthesized, and their crystal structures and electrochemical properties were characterized. RU11 complexes with 2-(2 imidazoliny1)phenolate (Himn-) or 2-(l,4,5,6-tetrahydropyrimidin-2- Y1)phenolate (Hthp-) could be deprotonated by addition of excess KOtBu, although the deprotonated species were easily reprotonated by exposure to air. Unlike these Ru11 complexes, their Ru111analogs showed interesting ligand oxidation reactions upon addition of bases. With [Ru111(Himn)(bpy)2]2+, two-electron oxidation of Himn- and reduction of the Ru111 center resulted in conversion of the 2-imidazolinyl group to a 2-imidazolyl group. On the other hand, the corresponding Hthp-1 complex exhibited four-electron oxidation of the ligand to form 2-(2-pyrimidyl)phenolate (pym-). These aromatization reactions of imidazolinyl and 1,4,5,6-tetrahydropyrimidyl groups were also achieved by the electrochemically generated Ru111 complexes. [ABSTRACT FROM AUTHOR]

The intermolecular interaction andaggregation of the neutral complex fac-tris(2-phenylpyridinato-C2,N)iridium(III) (fac-Ir(ppy)3) in solution was investigated. Intermolecularinteractionswere found to effectively decrease the luminescence lifetime via self-quenchingwith increasing fac-Ir(ppy)3concentrations.A Stern–Volmer plot for quenching in acetonitrile was linear,due to bimolecular self-quenching, but curved in toluene as the resultof excimer formation. 1H NMR spectra demonstrated a monomer–aggregateequilibrium which resulted in spectral shifts depending on solventpolarity. X-ray crystallography provided structural information concerningthe aggregate, which is based on a tetramer consisting of two Δ-fac-Ir(ppy)3–Λ-fac-Ir(ppy)3pairs. Offset π–π stackingof ppy ligands and electrostatic dipole–dipole interactionsbetween complex molecules play an important role in the formationof these molecular pairs. [ABSTRACT FROM AUTHOR]

To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using “click chemistry”, by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors. [ABSTRACT FROM AUTHOR]

Summary: Chemical biology is not a new discipline, as research at the interface of chemistry and biology has been growing for decades. However, the field still needs regional and global support in emerging countries. The meeting organized by Asian Chemical Biology Initiative in Bangkok, Thailand in January 2013, brought together regional communities of young and established researchers to nurture chemical biology research programs and highlight some of the newer developments. Here, we report on the meeting and some of the key research topics discussed. [Copyright &y& Elsevier]

Abstract: Four cobalt(III) complexes with the formula of [Co(Ln)2]− bearing tridentate amine-amidato-phenolato-type ligands (Ln: n =1–4) were synthesized. All of the complexes were characterized by 1H NMR spectroscopy and X-ray analysis. The geometrical selectivity was found to depend on the flexibility of the amine-amidato chelate in combination with the planar 2-oxybenzamido 6-membered chelate; that is, the amine-amidato 5-membered chelate took the mer-type geometry, and the 6-membered chelate took the fac-type geometry. In most of the mer-type complexes, intermolecular double hydrogen bonds via amidato(O) and amino group were selectively formed between their enantiomeric pairs of mononuclear complexes. In the case of two chiral ligands {L22– =2-amino-1-(2-oxybenzamido)propane; L32− = trans-1-amino-2-(2-oxybenzamido)cyclohexane}, [Co(L3)2]− showed diastereoselectivity while [Co(L2)2]− did not. Furthermore, PPh4[Co(L1)2] (L12− =2-amino-1-(2-oxybenzamido)-2-methylpropane) showed an apparent solvatochromic behavior in several solvents. Although the molecular structures of [Co(L2 or L3)2]− are quite similar to that of [Co(L1)2]−, these complexes did not exhibit such a solvatochromic behavior. [Copyright &y& Elsevier]

Abstract: X-ray crystallographic analyses revealed that the Pd–P and Pd–X bond lengths of [PdX2(P–P)] complexes (X− =Cl, Br and I and P–P=Ph2P(CH2) n PPh2; n =1: dppm, 2: dppe, 3: dppp, 4: dppb) are: Pd–P (dppm, dppe)Pd–X (dppp, dppb). The oxidation potentials values, E ½(ox), of the shorter Pd–P and longer Pd–X bond lengths in the dppm and dppe complexes are high and reflect strong dxy (dπ (Pd)) interaction with (dσ∗ (Pd)) and that this interaction is less dependent on X−. The longer Pd–P and shorter Pd–X bonds for the dppp and dppb complexes reflect that the (dσ∗ (Pd)) interaction is largely dependent on X−. The reduction potential, E ½(red), which reflects the (dσ∗ (Pd) LUMO energy, and the oxidation potential, E ½(ox), which reflects the (dxy (dπ (Pd) HOMO energy were, determined. The E ½(red) and E ½(ox) values indicate the σ-bonding properties and π-interaction in the system, respectively. Good linear relationships were observed between the potentials difference [E ½(ox)− E ½(red)] and the ligand-field transition energy (dπ (dxy )→dσ∗ ()) in the series of dihalogenopalladium(II) complexes. The linear relationship shows that the energies of the d–d transitions and ΔE(Redox) of the dppm and dppe complexes are less dependent on X− whilst those of the dppp and dppb are largely X− dependent. [Copyright &y& Elsevier]

To find HDAC8-selective inhibitors, we designed a libraryof HDAC inhibitor candidates, each containing a zinc-binding groupthat coordinates with the active-site zinc ion, linked via a triazolemoiety to a capping structure that interacts with residues on therim of the active site. These compounds were synthesized by usingclick chemistry. Screening identified HDAC8-selective inhibitors including C149(IC50= 0.070 μM), which was more potentthan PCI-34058 (6) (IC50= 0.31 μM),a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethylgroup of C149binds to a unique hydrophobic pocket ofHDAC8, and the orientation of the phenylthiomethyl and hydroxamatemoieties (fixed by the triazole moiety) is important for the potencyand selectivity. The inhibitors caused selective acetylation of cohesinin cells and exerted growth-inhibitory effects on T-cell lymphomaand neuroblastoma cells (GI50= 3–80 μM).These findings suggest that HDAC8-selective inhibitors have potentialas anticancer agents. [ABSTRACT FROM AUTHOR]

Abstract: Optically active (1S,2R)-NCL-1 and (1R,2S)-NCL-1 were synthesized and evaluated for their lysine-specific demethylase 1 inhibitory activity and cell growth inhibitory activity. In enzyme assays, the (1S,2R)-isomer was approximately four times more potent than the (1R,2S)-isomer. In cell growth inhibition assays, the two isomers showed similar activity in HEK293 cells and SH-SY5Y cells, whereas the (1S,2R)-isomer showed approximately four times more potent activity than the (1R,2S)-isomer in HeLa cells. [Copyright &y& Elsevier]

The tetrafluoroborate salt of bis{8-(diphenylphosphino)quinoline}copper(I), [Cu(Ph2Pqn)2]BF4, afforded orange prismatic (2O) or yellow columnar (2Y) crystals, dependent on the solvent and concentration of the recrystallization solution used. X-ray analysis revealed that crystals of 2O and 2Y had the same composition and exhibited different crystal systems: 2O was triclinic, with space group P1 and Z = 2, and 2Y was monoclinic with space group P21/c and Z = 4. In these crystals, the tetrahedral copper(I) complex exhibited a strong "rocking distortion" toward a trigonal pyramidal coordination geometry (by a slide translation of one of the unsymmetrical bidentate chelating ligands along the tetrahedral edge). In addition, both the 2O and 2Y complexes showed a "flattening distortion", meaning that the dihedral angle between the two chelate planes were off-perpendicular and oriented toward opposite directions, which resulted in a pair of distortion isomers: syn clinal (sc: 2O) and anti clinal (ac: 2Y). 31P CP-MAS NMR spectroscopy indicated that 2O and 2Y could be distinguished. Both isomers exhibited inequivalent P atoms, but a larger difference in chemical shift was observed in 2Y. TD-DFT calculations reproduced the difference in spectra between the orange- and yellow-colored complexes, which originated from metal-to-ligand charge-transfer transitions. [ABSTRACT FROM AUTHOR]

Abstract: A reaction of [Cp*IrCl2]2 {Cp*= η 5-C5(CH3)5} and 2-mercaptobenzimidazole (H2bimt) in methanol in a 1:2molar ratio gave a yellow complex of [Cp*IrCl2(H2bimt)]·CH3OH (1). In compound 1 the H2bimt acts as a monodentately S-donating (κS) ligand. A similar reaction of [Cp*IrCl2]2 and H2bimt in the presence of NaOCH3 (molar ratio of 1:2:2) gave an orange product (2) on addition of excess amount of NH4PF6. Compound 2 was composed of an unsymmetrical dinuclear complex cation, [(Cp*IrCl)2(μ-Hbimt)(μ-H2bimt)]+, a PF6 − anion, and water molecules of crystallization. In the complex cation, H2bimt bridges two IrIII centers by S atom in the μ-κS:κS mode, while the monodeprotonated Hbimt− ligand bridges via S and N atoms in the μ-κS:κN 1 mode. [ABSTRACT FROM AUTHOR]

The "solvent effect" on the solid-state luminescence of a neutral complex, [Ru(dbb)2(CN)2] (dbb = 4,4'-di-tert-butyl- 2,2'-bipyridine), was presented. The crystals of this complex showed a variety of luminescence color from orange to dark-red, depending on the acceptor number of the solvent included in the crystal as a solvent of crystallization. The luminescence change was very similar to the solvatochromism in solution, which was attributed to the local donor-acceptor interaction between the CN group and the solvent molecules. The dynamic shift observed in the transient emission spectrum of the crystalline powder was accounted for by the solvent molecule reorganization. X-ray crystallography of [Ru(dbb)2(CN)2]·3(CH3)2CO showed the complex molecule having an approximate C2 symmetry and very weak interactions between the acetone molecules and the CN groups. A three-dimensional networ) constructed by acetone molecules was observed in the hydrophobic space consisting of t-butyl groups in dbb ligands. A thin film of the complex showed vapochromic behavior such that the luminescence changed depending on the solvent of crystallization. This suggests a capability for organic molecule discrimination using the complex in the solid state. [ABSTRACT FROM AUTHOR]

Abstract: To identify novel non-nucleoside DNA methyltransferase (DNMT) inhibitors, we designed and synthesized a series of maleimide derivatives. Among this series, compounds 5–8 were found to be more potent DNMT1 inhibitors than RG108, a DNMT1 inhibitor reported previously by Siedlecki et al. The binding mode analysis of compound 5 is also reported. [Copyright &y& Elsevier]

Local hyperthermia has been widely used as physical therapy for a number of diseases such as inflammatory osteoarticular disorders, tendinitis, and muscle injury. Local hyperthermia is clinically applied to improve blood and lymphatic flow to decrease swelling of tissues (e.g., skeletal muscle). As for muscle repair following injury, the mechanisms underlying the beneficial effects of hyperthermia-induced muscle repair are unknown. In this study, we investigated the direct effects of continuous heat stress on the differentiation of cultured mammalian myoblasts. Compared with control cultures grown at 37°C, incubation at 39°C (continuous mild heat stress; CMHS) enhanced myotube diameter, whereas myotubes were poorly formed at 41°C by primary human skeletal muscle culture cells, human skeletal muscle myoblasts (HSMMs), and C2C12 mouse myoblasts. In HSMMs and C2C12 cells exposed to CMHS, mRNA and protein levels of myosin heavy chain (MyHC) type I were increased compared with the control cultures. The mRNA level of MyHC IIx was unaltered in HSMMs and decreased in C2C12 cells, compared with cells that were not exposed to heat stress. These results indicated a fast-to-slow fiber-type shift in myoblasts. We also examined upstream signals that might be responsible for the fast-to-slow shift of fiber types. CMHS enhanced the mRNA and protein levels of peroxisome proliferator-activated receptor-y coactivator (PGC)-1α in HSMMs and C2C12 cells but not the activities of MAPKs (ERK1/2 and p38 MAPK) in HSMMs and C2C12 cells. These data suggest that CMHS induces a fast-to-slow fiber-type shift of mammalian myoblasts through PGC-1α. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-anilinobenzamide derivatives were designed, synthesized and evaluated for their SIRT1-inhibitory activity. Among these, compounds 3 and 5 inhibited SIRT1 activity in enzyme assays and suppressed the growth of Daudi and HCT116 cells. [Copyright &y& Elsevier]

Abstract: Several (azido)iridium(III) complexes having a pentamethylcyclopentadienyl (Cp∗) group, [Cp∗Ir(N3)2(Ph2Ppy-κP)] (1: Ph2Ppy=2-diphenylphosphinopyridine), [Cp∗Ir(N3)(Ph2Ppy-κP,κN)]CF3SO3 (2), [Cp∗Ir(N3)(dmpm)]PF6 (3: dmpm=bis(dimethylphosphino)methane), [Cp∗Ir(N3)(Ph2Pqn)]PF6 CH3OH (4 CH3OH: Ph2Pqn=8-diphenylphosphinoquinoline), and [Cp∗Ir(N3)(pybim)] (5: Hpybim=2-(2-pyridyl)benzimidazole) have been prepared and their crystal structures have been analyzed by X-ray diffraction. In complex 1, the Ph2Ppy ligand is only coordinated via the P atom (-κP), while in 2 it acts as a bidentate ligand through the P and N atoms (-κP,κN) to form a four-membered chelate ring. Comparing the structural parameters of the chelate ring in 2 with those of a similar five-membered chelate ring formed by Ph2Pqn in 4, it became apparent that the angular distortion in the Ph2Ppy-κP,κN ring was remarkable, although the Ir–P and Ir–N bonds in the Ph2Ppy-κP,κN ring were not elongated very much from the corresponding bonds in the Ph2Pqn-κP,κN ring. In the pybim complex 5, the five-membered chelate ring was coplanar with the pyridine and benzimidazolyl rings. With the related (azido)iridium(III) complexes analyzed previously, comparison of the structural parameters of the Ir–N3 moiety in [Cp∗IrIII(N3)(L–L′)]+/0 complexes reveals an anomalous feature of the 2,2′-bipyridyl (bpy) complex, [Cp∗Ir(N3)(bpy)]PF6. [Copyright &y& Elsevier]

A new type of small-molecular sirtuin inhibitor was designed on the basis of the proposed catalytic mechanism for deacetylation of acetylated lysine substrates by sirtuins. Among the compounds thus designed and synthesized, we found that 2k, which contains an ethoxycarbonyl group at the a position to the acetamide of acetylated lysine substrate analogue 1, showed potent inhibitory activity in an in vitro assay using recombinant SIRT1, with high selectivity over SIRT2 and SIRT3. Mechanistic study by means of kinetic analysis, mass spectroscopy, and computation indicated that the enol form of compound 2k nucleophilically attacks NAD+ in the active site of SIRTs to afford the stable compound 2k-ADP-ribose conjugate 5, leading to inhibition of the enzyme activity. Compound 2k also caused a dose-dependent increase of p53 acetylation in human colon cancer HCT116 cells, indicating inhibition of SIRT1 in the cells. These results have implications for the development of selective sirtuin inhibitors by means of mechanism- based drug design. [ABSTRACT FROM AUTHOR]

Abstract: It has been observed that, at , [Co(NH3)6](ClO4)3, [Co(en)3](ClO4)3, [Co(bpy)3](ClO4)3, and [Co(phen)3](ClO4)3 in the regions of 1.25–5.00 mM aqueous solutions cause a significant surface tension reduction (STR) of water by the surfactants, sodium dodecylsulfate (SDS) and sodium dodecylbenzenesulfonate (SBS), suggesting the formation of the 1:1 and 1:2 association complexes, {[complex]3+(S−)}2+ and {[complex]3+(S−)2}+ where [complex]3+ =[Co(NH3)6]3+, [Co(en)3]3+, [Co(bpy)3]3+, or [Co(phen)3]3+, S− =DS− or BS−. The effect of [Co(en)3]3+ on STR in SDS–water system is the largest due to a strong hydrophilic interaction between amino protons of [Co(en)3]3+ and sulfate oxygen atoms of DS−. The effects of [Co(en)3]3+, [Co(bpy)3]3+, and [Co(phen)3]3+ on STR in SBS–water system are significant and almost same, meaning that the hydrophilic interaction between [Co(en)3]3+ and the sulfonate group is comparable to the hydrophobic interaction between [Co(bpy)3]3+ or [Co(phen)3]3+ and the phenyl group of BS−. The Co(III) complexes of 1.25–5.00 mM are precipitated as {[complex]3+(S−)3} at 0.0295–0.173 mM of S−. The precipitates, {[Co(bpy)3]3+(S−)3} and {[Co(phen)3]3+(S−)3} can be dissolved at higher molar ratio of [S−]/[complex3+] than 3.5 for SDS and 4.0 for SBS. This observation suggests that the aggregated premicelle [Co(bpy or phen)3]2(DS)− 7 or aggregated premicelle [Co(bpy or phen)3](BS)− 4 is formed. [Copyright &y& Elsevier]

Background and Aim: Cranberry is a fruit that originated in North America, and it has been used by Native Americans for bacterial infections. Recent studies have revealed it to be effective for preventing refractory urinary infections, while also suggesting that it plays a possible role in the eradication of Helicobacter pylori ( H. pylori). Methods: The H. pylori strains used in the present study were NCTC11637 and 11638. Sugar and organic acid-rich, and polyphenol-rich fractions were obtained from cranberry juice concentrate by Amberlite XAD7HP-column chromatography. The H. pylori growth inhibition was estimated by OD660 and titration in liquid culture, and by an agar dilution plate method. The shapes of the bacteria were analyzed by scanning electron microscopy. Results: Cranberry extract suppressed bacterial proliferation in a dose-dependent manner. In the comparison with other juices, polyphenol-rich fruits (cranberries, blueberries, and red grapes) showed similar growth inhibitory activity, whereas polyphenol-poor fruits (oranges, pineapples, apples, and white grapes) did not show any activity. The polyphenol-rich fraction of cranberry maintained the H. pylori-growth inhibitory activity. More bacteria in a coccoid form were observed after culture with cranberry. Conclusion: Cranberry extract inhibited H. pylori proliferation and it is suggested that polyphenols are responsible for this action. The morphological analysis suggested that cranberry induces H. pylori to develop a coccoid form, thereby inhibiting its growth bacteriostatically. Further basic studies to clarify these mechanisms in combination with in vivo studies are needed. [ABSTRACT FROM AUTHOR]

Background: Idiopathic thrombocytopenic purpura (ITP) is associated with the cytokine response and dysregulation of the cytokine network. Gene polymorphisms of proinflammatory cytokines are associated with several diseases including ITP. Recently, the successful eradication of Helicobacter pylori has been reported to improve the platelet counts in some patients with ITP. The aim of this study was to elucidate the relationship between cytokine gene polymorphisms and platelet recovery in ITP patients after the eradication of H. pylori. Materials and Methods: Gastric H. pylori infection was confirmed using a culture method or specific IgG antibodies against H. pylori in the serum. Thirty-six adult H. pylori-positive ITP patients received antibiotic therapy for H. pylori. The response to treatment was defined as complete response (CR) if the platelet count was above 150 × 103/μl and partial response (PR) if the platelet count increased by more than 50 × 103/μl above the pretreatment count. Genomic DNA was extracted from peripheral blood and polymorphisms in IL-1B (–31, –511), IL-1RN (long or short), TNFA (–308) and TNFB (+252) were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: Of the 36 ITP patients, twenty patients (responders) exhibited a platelet response after successful H. pylori eradication therapy, but the other patients (nonresponders) did not. There were no statistical differences in the frequencies of polymorphisms in IL-1B, IL-1RN and TNFA genes between responders and nonresponders. In contrast, the frequency of responders in ITP patients with the TNFB G/G or G/A genotype was significantly higher (69.6%) than that with the TNFB A/A genotype (30.8%). Conclusion: The TNFB (+252) G/G or G/A genotype may therefore be a good predictor of platelet recovery in ITP patients after the eradication of H. pylori. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The X-ray crystal structure of tetrakis (+)-hfbc Pr(III) complex, Na[Pr((+)-hfbc)4]·CH3CN, was compared with that of the corresponding Na–La complex with a pseudo-achiral dodecahedron, and the solution CD spectra were also discussed in the 4f–4f transition in consideration of the exciton CD couplet showing Δ-SAPR-8 configuration in CHCl3. [Copyright &y& Elsevier]

Abstract: The magnetic interactions in a new series of isostructural imino nitroxide radical lanthanide(III) complexes, [Ln(hfac)3(IM2py)] (Ln=Gd–Yb: IM2py=2-(2′-pyridyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazoline-1-oxy; hfac=1,1,1,5,5,5-hexafluoro-2,4-pentanedione), are examined by considering the intrinsic paramagnetic contribution of the Ln(III) ion from the corresponding [Ln(hfac)3(pybzim)] with a diamagnetic pybzim(2-(2-pyridyl)benzimidazole) ligand; the Ln(III)–IM2py interaction being antiferromagnetic for the 4f7 to 4f13 Ln(III) complexes and negligibly small for the other complexes. This series is the first example reverse to the previous cases for the series of Ln–Cu or Ln–aminoxyl(NIT) radical (4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazoline-3-oxide-1-oxy) complexes, other than only a few examples of semiquinone Ln complexes. This reverse nature of the magnetic interaction, as compared with the NIT complexes, validates the empirical approach by O. Kahn et al. [Inorg. Chem. 38 (1999) 3692; J. Am. Chem. Soc. 122 (2000) 3413] in the spin-coupled systems for a series of Ln(III) complexes. [Copyright &y& Elsevier]

Abstract: Aiming to develop selective anticancer drugs, we designed and synthesized three disulfides bearing a folic acid moiety as candidate folate receptor (FR)-targeted prodrugs of thiolate histone deacetylase inhibitors. Among them, compound 1 displayed growth-inhibitory activity toward folate receptor-positive MCF-7 breast cancer cells. The activity of 1 was significantly reduced by free folic acid, suggesting that cellular uptake of 1 is mediated by FR. [Copyright &y& Elsevier]

Abstract: Potassium bromate (KBrO3) is strongly carcinogenic in rodents and mutagenic in bacteria and mammalian cells in vitro. The proposed genotoxic mechanism for KBrO3 is oxidative DNA damage. KBrO3 can generate high yields of 8-hydroxydeoxyguanosine (8OHdG) DNA adducts, which cause GC>TA transversions in cell-free systems. In this study, we investigated the in vitro genotoxicity of KBrO3 in human lymphoblastoid TK6 cells using the comet (COM) assay, the micronucleus (MN) test, and the thymidine kinase (TK) gene mutation assay. After a 4h treatment, the alkaline and neutral COM assay demonstrated that KBrO3 directly yielded DNA damages including DNA double strand breaks (DSBs). KBrO3 also induced MN and TK mutations concentration-dependently. At the highest concentration (5mM), KBrO3 induced MN and TK mutation frequencies that were over 30 times the background level. Molecular analysis revealed that 90% of the induced mutations were large deletions that involved loss of heterozygosity (LOH) at the TK locus. Ionizing-irradiation exhibited similar mutational spectrum in our system. These results indicate that the major genotoxicity of KBrO3 may be due to DSBs that lead to large deletions rather than to 8OHdG adducts that lead to GC>TA transversions, as is commonly believed. To better understand the genotoxic mechanism of KBrO3, we analyzed gene expression profiles of TK6 cells using Affymetrix Genechip. Some genes involved in stress, apoptosis, and DNA repair were up-regulated by the treatment of KBrO3. However, we could not observe the similarity of gene expression profile in the treatment of KBrO3 to ionizing-irradiation as well as oxidative damage inducers. [Copyright &y& Elsevier]

Previously, we suggested that the phosphatidylinositol 3-kinase (PI3K)-p70 S6 kinase (p70 S6K) pathway plays an important role in granulocyte colony-stimulating factor (G-CSF)-dependent enhancement of the neutrophilic differentiation and proliferation of HL-60 cells. While atypical protein kinase C (PKC) has been reported to be a regulator of p70 S6K, abundant expression of PKCι was observed in myeloid and lymphoid cells. Therefore, we analyzed the participation of PKCι in G-CSF-dependent proliferation. The maximum stimulation of PKCι was observed from 15 to 30 min after the addition of G-CSF. From 5 to 15 min into this lag time, PKCι was found to translocate from the nucleus to the membrane. At 30 min it re-translocated to the cytosol. This dynamic translocation of PKCι was also observed in G-CSF-stimulated myeloperoxidase-positive cells differentiated from cord blood cells. Small interfering RNA for PKCι inhibited G-CSF-induced proliferation and the promotion of neutrophilic differentiation of HL-60 cells. These data indicate that the G-CSF-induced dynamic translocation and activation processes of PKCι are important to neutrophilic proliferation. J. Cell. Physiol. 211: 189–196, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: To identify prodrugs of a thiolate histone deacetylase inhibitor NCH-31 that show potent antiproliferative activity and are stable in human plasma, we synthesized several candidate prodrugs of NCH-31. Among these compounds, S-2-methyl-3-phenylpropanoyl compound 2 showed more potent antiproliferative activity and higher stability in human plasma than S-isobutyryl compound NCH-51. [Copyright &y& Elsevier]