Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice

We recently reported that Lactobacillus helveticus SBT2171 (LH2171) inhibited the proliferation and inflammatory cytokine production of primary immune cells in vitro, and alleviated collagen-induced arthritis (CIA) in mice, a model of human rheumatoid arthritis (RA). In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4+ T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity. The intraperitoneal administration of LH2171 significantly decreased the incidence and clinical score of EAE in mice. LH2171 also reduced the numbers of pathogenic immune cells, especially Th17 cells, in the spinal cord at the peak stage of disease severity. Interestingly, before the onset of EAE, LH2171 administration remarkably decreased the ratio of Th17 cells to CD4+ T cells in the inguinal lymph nodes (LNs), where pathogenic immune cells are activated to infiltrate the central nervous system, including the spinal cord. Furthermore, the expression of interleukin (IL)-6, an inflammatory cytokine essential for Th17 differentiation, decreased in the LNs of LH2171-administered mice. Moreover, LH2171 significantly inhibited IL-6 production in vitro from both DC2.4 and RAW264.7 cells, model cell lines of antigen-presenting cells. These findings suggest that LH2171 might down-regulate IL-6 production and the subsequent Th17 differentiation and spinal cord infiltration, consequently alleviating EAE symptoms

Chemosensitivity of Patient-Derived Cancer Stem Cells Identifies Colorectal Cancer Patients with Potential Benefit from FGFR Inhibitor Therapy

Some colorectal cancer patients harboring FGFR (fibroblast growth factor receptor) genetic alterations, such as copy number gain, mutation, and/or mRNA overexpression, were selected for enrollment in several recent clinical trials of FGFR inhibitor, because these genetic alterations were preclinically reported to be associated with FGFR inhibitor sensitivity as well as poor prognosis, invasiveness, and/or metastatic potential. However, few enrolled patients were responsive to FGFR inhibitors. Thus, practical strategies are eagerly awaited that can stratify patients for the subset that potentially responds to FGFR inhibitor chemotherapy. In the present study, we evaluated the sensitivity to FGFR inhibitor erdafitinib on 25 patient-derived tumor-initiating cell (TIC) spheroid lines carrying wild-type RAS and RAF genes, both in vitro and in vivo. Then, we assessed possible correlations between the sensitivity and the genetic/genomic data of the spheroid lines tested. Upon their exposure to erdafitinib, seven lines (7/25, 28%) responded significantly. Normal colonic epithelial stem cells were unaffected by the inhibitors. Moreover, the combination of erdafitinib with EGFR inhibitor erlotinib showed stronger growth inhibition than either drug alone, as efficacy was observed in 21 lines (84%) including 14 (56%) that were insensitive to erdafitinib alone. The in vitro erdafitinib response was accurately reflected on mouse xenografts of TIC spheroid lines. However, we found little correlation between their genetic/genomic alterations of TIC spheroids and the sensitivity to the FGFR inhibitor. Accordingly, we propose that direct testing of the patient-derived spheroids in vitro is one of the most reliable personalized methods in FGFR-inhibitor therapy of colorectal cancer patients

The Global Campaign (GC) to Reduce the Burden of Headache Worldwide. The International Team for Specialist Education (ITSE).

The social perception of headache, everywhere at low levels in industrialised countries, becomes totally absent in developing ones. Headache disorders came into the World Health Organization\u27s strategic priorities after publication of the 2001 World Health Report. Among the leading causes of disability, migraine was ranked 19th for adults of both sexes together and 12th for females. The Global Campaign (GC) to Reduce the Burden of Headache Worldwide was planned by the major international headache organizations together with WHO in order to identify and remove those cultural, social and educational barriers recognised as responsible factors for the inadequate treatment of headache disorders worldwide. Within the GC activities, the education of the medical body will represents a central pillar. An International Team for Specialist Education (ITSE) has been created to train physicians from all over the world through the acquisition of a university level Master Degree in Headache Medicine. Once trained as headache specialists, physicians will become trainers, offering education in this field to other health care providers in their own countries. In this way they will give life to a cultural chain raising awareness locally of headache, its burden and its medical control

Holographic Penta and Hepta Quark State in Confining Gauge Theories

We study a new embedding solutions of D5 brane in an asymptotic AdS${}_5\times S^5$ space-time, which is dual to a confining $SU(N_c)$ gauge theory. The D5 brane is wrapped on $S^5$ as in the case of the vertex of holographic baryon. However, the solution given here is different from the usual baryon vertex in the point that it couples to $k$-anti-quarks and $N_c+k$ quarks on the opposite two points of $S^5$, the north and south poles, respectively. The total quark number of this state is preserved as $N_c$ when minus one is assigned to anti-quark, then it forms a color singlet like the baryon. However, this includes anti-quarks and quarks, whose number is larger than that of the baryon. When we set as $N_c=3$, we find the so called penta and hepta-quark states. We study the dynamical properties of these states by solving the vertex and string configurations for such states. The mass spectra of these states and the tension of the stretched vertex are estimated, and they are compared with that of the baryon.Comment: 24 pages, 6 figure

An improved method for culturing patient-derived colorectal cancer spheroids

患者由来大腸がん幹細胞培養を用いた薬剤感受性試験を開発 --個別化医療の実現へ期待--. 京都大学プレスリリース. 2018-09-03.Recent advances allowed culturing and examination of patient-derived colorectal cancer (PD-CRC) cells as organoids or spheroids. To be applied to practical personalized medicine, however, current methods still need to be strengthened for higher efficiency. Here we report an improved method to propagate PD-CRC tumor initiating cells (TICs) in spheroid culture. We established > 100 cancer spheroid lines derived from independent colorectal cancer patients employing a serum-containing medium with additional inhibitors, Y27632 and SB431542. Because colorectal cancer spheroids showed wide-range growth rates depending on the patient tumors, we searched for supplementary factors that accelerated proliferation of slow-growing CRC-TIC spheroids. To this end, we introduced a convenient growth-monitoring method using a luciferase reporter. We found that epidermal growth factor (EGF) and/or basic fibroblast growth factor (bFGF) were critical for steady propagation of a subset of CRC-TIC spheroids carrying the wild-type RAS and RAF genes. We also identified 5′-(N-ethyl-carboxamido)-adenosine (NECA), an adenosine receptor agonist, as an essential supplement for another subset of spheroids. Based on these results, we propose to optimize culture conditions for CRC-TIC spheroids by adjusting to the respective tumor samples. Our method provides a versatile tool that can be applied to personalized chemotherapy evaluation in prospective clinical studies

Spontaneous supersymmetry breaking in matrix models from the viewpoints of localization and Nicolai mapping

In the previous work, it was shown that, in supersymmetric (matrix) discretized quantum mechanics, inclusion of an external field twisting the boundary condition of fermions enables us to discuss spontaneous breaking of supersymmetry (SUSY) in the path-integral formalism in a well-defined way. In the present work, we continue investigating the same systems from the points of view of localization and Nicolai mapping. The localization is studied by changing of integration variables in the path integral, which is applicable whether or not SUSY is explicitly broken. We examine in detail how the integrand of the partition function with respect to the integral over the auxiliary field behaves as the auxiliary field vanishes, which clarifies a mechanism of the localization. In SUSY matrix models, we obtain a matrix-model generalization of the localization formula. In terms of eigenvalues of matrix variables, we observe that eigenvalues' dynamics is governed by balance of attractive force from the localization and repulsive force from the Vandermonde determinant. The approach of the Nicolai mapping works even in the presence of the external field. It enables us to compute the partition function of SUSY matrix models for finite N (N is the rank of matrices) with arbitrary superpotential at least in the leading nontrivial order of an expansion with respect to the small external field. We confirm the restoration of SUSY in the large-N limit of a SUSY matrix model with a double-well scalar potential observed in the previous work.Comment: 45 pages, no figure; v2 references added; v3 discussions for general T moved to appendix, references added, typos fixed, version to be published in Nuclear Physics

Chronic Migraine Epidemiology and Outcomes – International (CaMEO-I) Study: Methods and multi-country baseline findings for diagnosis rates and care

BACKGROUND: The Chronic Migraine Epidemiology and Outcomes-International study provides insight into people with migraine in multiple countries. METHODS: This cross-sectional, observational, web-based cohort study was conducted in Canada, France, Germany, Japan, United Kingdom, and United States. An initial Screening Module survey solicited general healthcare information from a representative sample and identified participants with migraine based on modified International Classification of Headache Disorders-3 criteria; those with migraine completed a detailed survey based on validated migraine-specific assessments. RESULTS: Among 90,613 people who correctly completed the screening surveys, 76,121 respondents did not meet the criteria for migraine, while 14,492 did. Among respondents with migraine, mean age ranged from 40 to 42 years. The median number of monthly headache days ranged from 2.33 to 3.33 across countries, while the proportion of respondents with moderate-to-severe disability (measured by Migraine Disability Assessment) ranged from 30% (Japan) to 52% (Germany). The proportion of respondents with ≥15 monthly headache days ranged from 5.4% (France) to 9.5% (Japan). Fewer than half of respondents with migraine in each country reported having received a migraine diagnosis. CONCLUSION: These results demonstrated high rates of migraine-related disability and underdiagnosis of migraine across six countries. This study will characterize country-level burden, treatment patterns, and geographical differences in care

Two-Dimensional Compact N=(2,2) Lattice Super Yang-Mills Theory with Exact Supersymmetry

We construct two-dimensional N=(2,2) lattice super Yang-Mills theory, where the gauge and Higgs fields are all represented by U(N) compact variables, with keeping one exact supercharge along the line of the papers [1,2,3]. Interestingly, requirements of the exact supersymmetry as well as of the compact gauge and Higgs fields lead to the gauge group U(N) rather than SU(N). As a result of the perturbative renormalization argument, the model is shown to flow to the target continuum theory without any fine-tuning. Different from the case of noncompact Higgs fields, the path integral along the flat directions is well-defined in this model.Comment: 17 pages, no figure, LaTeX; v2:reference added, v3:minor corrections, v4:version to be published to Physics Letters

Exercise habituation is effective for improvement of periodontal disease status: a prospective intervention study

Background and purpose: Periodontal disease is closely related to lifestyle-related diseases and obesity. It is widely known that moderate exercise habits lead to improvement in lifestyle-related diseases and obesity. However, little research has been undertaken into how exercise habits affect periodontal disease. The purpose of this study was to examine the effect of exercise habits on periodontal diseases and metabolic pathology.Methods: We conducted a prospective intervention research for 12 weeks. The subjects were 71 obese men who participated in an exercise and/or dietary intervention program. Fifty subjects were assigned to exercise interventions (exercise intervention group) and 21 subjects were assigned to dietary interventions (dietary intervention group). This research was conducted before and after each intervention program.Results: In the exercise intervention group, the number of teeth with a probing pocket depth (PPD) ≥4 mm significantly decreased from 14.4% to 5.6% (P<0.001), and the number of teeth with bleeding on probing (BOP) significantly decreased from 39.8% to 14.4% (P<0.001). The copy counts of Tannerella forsythia and Treponema denticola decreased significantly (P=0.001). A positive correlation was found between the change in the copy count of T. denticola and the number of teeth with PPD ≥4 mm (P=0.003) and the number of teeth with BOP (P=0.010). A positive correlation was also found between the change in the copy count of T. denticola and body weight (P=0.008), low-density lipoprotein cholesterol (P=0.049), and fasting insulin (P=0.041). However, in the dietary intervention group the copy count of T. denticola decreased significantly (P=0.007) and there was no correlation between the number of periodontal disease-causing bacteria and PPD and BOP.Conclusion: Our results are the first to show that exercise might contribute to improvements in periodontal disease