中枢神経系原発悪性リンパ腫の放射線治療個別化の妥当性と有用性：画像評価を用いた治療効果に基づく放射線治療計画

Background: To assess the feasibility and efficacy of individualized treatment selection in radiation therapy (RT) for primary central nervous system lymphoma (PCNSL) according to treatment response by radiographic assessment. Methods: The details of recurrence and change in performance status (PS) were assessed in 31 patients with histologically confirmed PCNSL treated between 2000 and 2016. During the treatment period, radiographic assessment was conducted, and RT planning (RTP) was determined individually by treatment response. Results: At a median follow-up of 28.2 months, 9 patients were alive and 7 of whom were relapse-free. Two-year overall survival (OS) and progression-free survival (PFS) rates were 69.3% and 52.7%, with median survival times (MSTs) of 36.5 months and 24.4 months, respectively. Two-year local recurrence rate was 40.5% and the median time to local recurrence from treatment initiation was 27.9 months. All patients were scheduled to receive whole-brain RT (WBRT) and subsequent partial-brain RT(PBRT), with a median total dose to the tumor bed of 46 Gy and median WBRT dose of 30 Gy. Eight patients received reduced-dose WBRT (rd-WBRT) (<30 GY), and 13 patients who could not achive a complete response (CR) during the RT period received additional boost radiation after WBRT and PBRT, with a median dose of 6 Gy. Over 70% of local recurrence occurred within areas in which only WBRT was conducted (median dose of 30.3 Gy). Two-year occurrence rate of neurotoxicity over grade 2 was 49.5%. PS at 24 months after RT was maintained in 12 patIents. Conclusions: lndividual RTP using radiographic assessment led to reasonable survival and disease control rates with mild treatment-related toxicity. For patients not receiving chemotherapy or lacking a CR after chemotherapy and WBRT, WBRT followed by PBRT and additional boost radiation for poor RT responders might be effective. However, even for patients with CR after chemotherapy, a WBRT dose of 30 Gy or higher might be necessary for local control.博士（医学）・甲第705号・平成31年3月15

A new genotype of bovine leukemia virus in South America identified by NGS-based whole genome sequencing and molecular evolutionary genetic analysis

Background: Bovine leukemia virus (BLV) is a member of retroviridae family, together with human T cell leukemia virus types 1 and 2 (HTLV-1 and -2) belonging to the genes deltaretrovirus, and infects cattle worldwide. Previous studies have classified the env sequences of BLV provirus from different geographic locations into eight genetic groups. To investigate the genetic variability of BLV in South America, we performed phylogenetic analyses of whole genome and partial env gp51 sequences of BLV strains isolated from Peru, Paraguay and Bolivia, for which no the molecular characteristics of BLV have previously been published, and discovered a novel BLV genotype, genotype-9, in Bolivia. Results: In Peru and Paraguay, 42.3 % (139/328) and over 50 % (76/139) of samples, respectively, were BLV positive. In Bolivia, the BLV infection rate was up to 30 % (156/507) at the individual level. In Argentina, 325/420 samples were BLV positive, with a BLV prevalence of 77.4 % at the individual level and up to 90.9 % at herd level. By contrast, relatively few BLV positive samples were detected in Chile, with a maximum of 29.1 % BLV infection at the individual level. We performed phylogenetic analyses using two different approaches, maximum likelihood (ML) tree and Bayesian inference, using 35 distinct partial env gp51 sequences from BLV strains isolated from Peru, Paraguay, and Bolivia, and 74 known BLV strains, representing eight different BLV genotypes from various geographical locations worldwide. The results indicated that Peruvian and Paraguayan BLV strains were grouped into genotypes-1, -2, and -6, while those from Bolivia were clustered into genotypes-1, -2, and -6, and a new genotype, genotype-9. Interestingly, these results were confirmed using ML phylogenetic analysis of whole genome sequences obtained by next generation sequencing of 25 BLV strains, assigned to four different genotypes (genotypes-1, -2, -6, and -9) from Peru, Paraguay, and Bolivia. Comparative analyses of complete genome sequences clearly showed some specific substitutions, in both structural and non-structural BLV genes, distinguishing the novel genotype-9 from known genotypes. Conclusions: Our results demonstrate widespread BLV infection in South American cattle and the existence of a new BLV genotype-9 in Bolivia. We conclude that at least seven BLV genotypes (genotypes-1, -2, -4, -5, -6, -7, and -9) are circulating in South America.Facultad de Ciencias VeterinariasInstituto de Genética Veterinari

Genotype-Dependent Efficacy of a Dual PI3K/mTOR Inhibitor, NVP-BEZ235, and an mTOR Inhibitor, RAD001, in Endometrial Carcinomas

The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235—a dual PI3K/mTOR inhibitor—and RAD001—an mTOR inhibitor—in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas

Validation of ozone data from the Superconducting Submillimeter-Wave Limb-Emission Sounder (SMILES)

The Superconducting Submillimeter-Wave Limb-Emission Sounder (SMILES) onboard the International Space Station provided global measurements of ozone profiles in the middle atmosphere from 12 October 2009 to 21 April 2010. We present validation studies of the SMILES version 2.1 ozone product based on coincidence statistics with satellite observations and outputs of chemistry and transport models (CTMs). Comparisons of the stratospheric ozone with correlative data show agreements that are generally within 10%. In the mesosphere, the agreement is also good and better than 30% even at a high altitude of 73km, and the SMILES measurements with their local time coverage also capture the diurnal variability very well. The recommended altitude range for scientific use is from 16 to 73km. We note that the SMILES ozone values for altitude above 26km are smaller than some of the correlative satellite datasets; conversely the SMILES values in the lower stratosphere tend to be larger than correlative data, particularly in the tropics, with less than 8% difference below similar to 24km. The larger values in the lower stratosphere are probably due to departure of retrieval results between two detection bands at altitudes below 28km; it is similar to 3% at 24km and is increasing rapidly down below

A new genotype of bovine leukemia virus in South America identified by NGS-based whole genome sequencing and molecular evolutionary genetic analysis

Background: Bovine leukemia virus (BLV) is a member of retroviridae family, together with human T cell leukemia virus types 1 and 2 (HTLV-1 and -2) belonging to the genes deltaretrovirus, and infects cattle worldwide. Previous studies have classified the env sequences of BLV provirus from different geographic locations into eight genetic groups. To investigate the genetic variability of BLV in South America, we performed phylogenetic analyses of whole genome and partial env gp51 sequences of BLV strains isolated from Peru, Paraguay and Bolivia, for which no the molecular characteristics of BLV have previously been published, and discovered a novel BLV genotype, genotype-9, in Bolivia. Results: In Peru and Paraguay, 42.3 % (139/328) and over 50 % (76/139) of samples, respectively, were BLV positive. In Bolivia, the BLV infection rate was up to 30 % (156/507) at the individual level. In Argentina, 325/420 samples were BLV positive, with a BLV prevalence of 77.4 % at the individual level and up to 90.9 % at herd level. By contrast, relatively few BLV positive samples were detected in Chile, with a maximum of 29.1 % BLV infection at the individual level. We performed phylogenetic analyses using two different approaches, maximum likelihood (ML) tree and Bayesian inference, using 35 distinct partial env gp51 sequences from BLV strains isolated from Peru, Paraguay, and Bolivia, and 74 known BLV strains, representing eight different BLV genotypes from various geographical locations worldwide. The results indicated that Peruvian and Paraguayan BLV strains were grouped into genotypes-1, -2, and -6, while those from Bolivia were clustered into genotypes-1, -2, and -6, and a new genotype, genotype-9. Interestingly, these results were confirmed using ML phylogenetic analysis of whole genome sequences obtained by next generation sequencing of 25 BLV strains, assigned to four different genotypes (genotypes-1, -2, -6, and -9) from Peru, Paraguay, and Bolivia. Comparative analyses of complete genome sequences clearly showed some specific substitutions, in both structural and non-structural BLV genes, distinguishing the novel genotype-9 from known genotypes. Conclusions: Our results demonstrate widespread BLV infection in South American cattle and the existence of a new BLV genotype-9 in Bolivia. We conclude that at least seven BLV genotypes (genotypes-1, -2, -4, -5, -6, -7, and -9) are circulating in South America.Facultad de Ciencias VeterinariasInstituto de Genética Veterinari

Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney

Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor(+) (p75NTR(+)) fibroblasts and homeostatic chemokine-producing fibroblasts inside TLTs, and retinoic acid-producing fibroblasts around TLTs. Deletion of CD4(+) cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.</p

Socio-Economic Variations Determine the Clinical Presentation, Aetiology and Outcome of Infective Endocarditis: a Prospective Cohort Study from the ESC-EORP EURO-ENDO (European Infective Endocarditis) Registry.

peer reviewedBACKGROUND: Infective endocarditis (IE) is a life-threatening disease associated with high mortality and morbidity worldwide. We sought to determine how socio-economic factors might influence its epidemiology, clinical presentation, investigation and management, and outcome, in a large international multi-centre registry. METHODS: The EurObservationalProgramme (EORP) of the European Society of Cardiology (ESC) EURO-ENDO registry comprises a prospective cohort of 3113 adult patients admitted for IE in 156 hospitals in 40 countries between January 2016 and March 2018. Patients were separated in 3 groups, according to World Bank economic stratification (Group 1 - high income [75.6%]; Group 2 - upper-middle income [15.4%]; Group 3 - lower-middle income [9.1%]). RESULTS: Group 3 patients were younger (median age [IQR]: Group 1 - 66 [53-75] years; Group 2 - 57 [41-68] years; Group 3 - 33 [26-43] years; p<0.001) with a higher frequency of smokers, intravenous drug use and human immunodeficiency virus (HIV) infection (all p<0.001) and presented later (median [IQR) days since symptom onset: Group 1 - 12 [3-35]; Group 2 - 19 [6-54]; Group 3 - 31 [12-62]; p<0.001) with a higher likelihood of developing congestive heart failure (13.6%; 11.1%; and 22.6%, respectively; p<0.001) and persistent fever (9.8%; 14.2%; 27.9%; p<0.001). Among 2157 (69.3%) patients with theoretical indication for cardiac surgery, surgery was performed less frequently in Group 3 patients (75.5%, 76.8% and 51.3%, respectively p<0.001) who also demonstrated the highest mortality (15.0%, 23.0% and 23.7%, respectively; p<0.001). CONCLUSIONS: Socio-economic factors influence the clinical profile of patients presenting with IE across the world. Despite younger age, patients from the poorest countries presented with more frequent complications and higher mortality associated with delayed diagnosis and lower use of surgery