Quantum melting of spin ice is proposed for pyrochlore-lattice magnets Pr2TM2O7 (TM=Ir, Zr, and Sn). The quantum superexchange Hamiltonian having a nontrivial magnetic anisotropy is derived on the ...basis of atomic non-Kramers magnetic doublets. The ground states exhibit a cooperative ferroquadrupole and pseudospin chirality, forming a magnetic analog of smectic liquid crystals. Our theory accounts for dynamic spin-ice behaviors experimentally observed in Pr2TM2O7.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Transport in an ideal two-dimensional quantum spin Hall device is dominated by the counterpropagating edge states of electrons with opposite spins, giving the universal value of the conductance, ...2e(2)/h. We study the effect on the conductance of a magnetic impurity, which can backscatter an electron from one edge state to the other. In the case of isotropic Kondo exchange we find that the correction to the electrical conductance caused by such an impurity vanishes in the dc limit, while the thermal conductance does acquire a finite correction due to the spin-flip backscattering.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Central sensitization-related symptoms (CSS) are associated with the severity and progression of pain. The relationship between the severity of pain/CSS and clinical progresses remains unclear. This ...multicenter, collaborative, longitudinal study aimed to characterize the clinical outcomes of patients with musculoskeletal pain by classifying subgroups based on the severity of pain/CSS and examining changes in subgroups over time. We measured the pain intensity, CSS, catastrophic thinking, and body perception disturbance in 435 patients with musculoskeletal pain. Reevaluation of patients after one month included 166 patients for pain intensity outcome and 110 for both pain intensity and CSS outcome analysis. We classified the patients into four groups (mild pain/CSS, severe pain/mild CSS, severe pain/CSS, and mild pain/severe CSS groups) and performed multiple comparison analyses to reveal the differences between the CSS severity groups. Additionally, we performed the adjusted residual chi-square to identify the number of patients with pain improvement, group transition, changing pain, and CSS pattern groups at baseline. The most characteristic result was that the mild and severe CSS groups showed worsening pain. Moreover, many of the group transitions were to the same group, with a few transitioning to a group with mild pain/CSS. Our findings suggest that the severity and improvement of CSS influence pain prognosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background & Aims Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single ...nucleotide polymorphisms in ADH1B and ALDH2 , which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer. Methods We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2 . Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells. Results A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5′ thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6 ) factors. Many tumors contained mutations in genes that regulate the cell cycle ( TP53, CCND1, CDKN2A , FBXW7 ); epigenetic processes ( MLL2, EP300, CREBBP , TET2 ); and the NOTCH ( NOTCH1 , NOTCH3 ), WNT ( FAT1 , YAP1 , AJUBA ) and receptor-tyrosine kinase−phosphoinositide 3-kinase signaling pathways ( PIK3CA , EGFR , ERBB2 ). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes. Conclusions We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.
Aim
Drug‐induced liver injury (DILI) is a severe and life‐threatening immune‐mediated adverse effect, occurring rarely among treated patients. We examined genomic biomarkers in the Japanese ...population that predict the onset of DILI after using a certain class of drugs, such as Kampo products (Japanese traditional medicines).
Methods
A total of 287 patients diagnosed as DILI by hepatology specialists were recruited after written informed consent was obtained. A genome‐wide association analysis and human leukocyte antigen (HLA) typing in four digits were performed.
Results
We found a significant association (p = 9.41 × 10−10) of rs146644517 (G > A) with Kampo product–related DILI. As this polymorphism is located in the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo‐DILI patients contained HLA‐B*35:01, whereas only 15.2% were positive for this HLA among healthy volunteers. The odds ratio was 9.56 (95% confidence interval 3.75–24.46; p = 2.98 × 10−6, corrected p = 4.17 × 10−5), and it increased to 13.55 compared with the DILI patients not exposed to Kampo products. The individual crude drug components in the Kampo products, including Scutellaria root (ougon in Japanese), rhubarb (daiou), Gardenia fruit (sanshishi), and Glycyrrhiza (kanzou), were significantly associated with HLA‐B*35:01.
Conclusions
HLA‐B*35:01 is a genetic risk factor and a potential predictive biomarker for Kampo‐induced DILI in the Japanese population.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Exercise motivation (EM) is related to individual capabilities and social support. However, in support facilities for people with disabilities, it is susceptible to a lack of social support. In this ...study, we classified EM into Autonomous Motivation (AM) and controlled motivation (CM) and then examined the influence of social support.
Thirty-three residents from a support facility for people with disabilities in Japan participated in this study. We conducted a hierarchical multiple regression analysis in which age, gender and time since admission were entered in Step 1, mobility and self-efficacy as individual capabilities in Step 2, and family support, facility support and peer support as social support in Step 3.
A significant increase in variance from Step 2 to Step 3 was found for both AM (ΔR
2
= 0.504, ΔF = 12.18, p < .001) and CM (ΔR
2
= 0.269, ΔF = 3.491, p = .031). The results also showed that AM was higher among those with high family and facility support, and CM was higher among those with low family and high peer support.
Social support was a more significant predictor of EM among participants than individual capabilities.
KEY MESSAGES
Among residents of support facilities for people with disabilities, assessing not only individual capabilities but also social support status can lead to better understandings of exercise motivation (EM).
To enhance facility residents' autonomous motivation (AM), it is necessary to intervene after evaluating family and facility support.
When family support is not readily available among facility residents, efforts should be made to encourage residents to interact with each other to increase peer support.
Fluvastatin is a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor that competitively inhibits human cytochrome P450 (P450) 2C9 in vitro. Drug interactions between a variety of P450 2C9 ...substrates/inhibitors and fluvastatin can increase the incidence of fluvastatin-related hepatic or skeletal muscle toxicity in vivo. In this survey, the prescribed dosage of fluvastatin was reduced or discontinued in 133 of 164 patients receiving fluvastatin alone, as recorded in the Japanese Adverse Drug Event Report database of spontaneously reported events. The median days to onset of fluvastatin-related disorders were in the range 30–35 d in the 87 patients. Therefore, we aimed to focus on fluvastatin and, using the pharmacokinetic modeling technique, estimated the virtual plasma and hepatic exposures in subjects harboring the impaired CYP2C9*3 allele. The plasma concentrations of fluvastatin modeled after a virtual oral 20-mg dose increased in homozygotes with CYP2C9*3; the area under the plasma concentration curve was 4.9-fold higher than that in Japanese homozygotes for wild-type CYP2C9*1. The modeled hepatic concentrations of fluvastatin in patients with CYP2C9*3/*3 after virtual daily 20-mg doses for 7 d were 31-fold higher than those in subjects with CYP2C9*1/*1. However, heterozygous Chinese patients with CYP2C9*1/*3 reportedly have a limited elevation (1.2-fold) in plasma maximum concentrations. Virtual hepatic/plasma exposures in subjects harboring the impaired CYP2C9*3 allele estimated using pharmacokinetic modeling indicate that such exposure could be a causal factor for hepatic disorders induced by fluvastatin prescribed alone in a manner similar to that for interactions with a variety of co-administered drugs.
Background. Central sensitization (CS) and psychological factors are associated with pain intensity; however, the mediating role of CS on the relation between psychological factors and pain intensity ...remains unclear. Objectives. We performed mediation analysis to investigate how CS mediates relation between psychological factors and pain intensity. Methods. Twenty patients with musculoskeletal pain were included in this cross-sectional study. Central sensitization inventory (CSI), one pain intensity-related outcome measure (Short-Form McGill Pain Questionnaire 2 (SFMPQ2)), and three psychological outcome measures (Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale-4 (PCS), and Tampa Scale for Kinesiophobia-11 (TSK)) of all participants were assessed. The mediation analysis with a bootstrap sampling procedure was used to assess the indirect effects. The level of significance was set at 5%. Results. Mediation analysis showed that the HADS-anxiety, HADS-depression, and PCS had significant indirect effects on the pain ratings of CSI. Additionally, the direct effect was significant only for PCS. Conclusions. The relationship among anxiety symptoms, depression symptoms, and pain intensity was completely mediated by CS. Furthermore, the relationship between catastrophic thinking and pain intensity was partially mediated by CS. Our findings suggest that CS mediates relation between psychological factors and pain intensity, and CS-focused intervention may be important.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The combination of docetaxel, cisplatin, and 5‐fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase ...II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70–75 mg/m2) and cisplatin (70–75 mg/m2) on day 1, and continuous infusion of fluorouracil (750 mg/m2/day) on days 1–5. Antibiotic prophylaxis on days 5–15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty‐two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty‐one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment‐related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2‐year progression‐free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic ...drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 (NUDT15) polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the NUDT15 studies, mainly in Asian countries, and their implementation in several countries.
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