Rule Extraction by Genetic Programming with Clustered Terminal Symbols

When Genetic Programming (GP) is applied to rule extraction from databases, the attributes of the data are often used for the terminal symbols. However, in the case of the database with a large number of attributes, the search space becomes vast because the size of the terminal set increases. As a result, the search performance declines. For improving the search performance, we propose new methods for dealing with the large-scale terminal set. In the methods, the terminal symbols are clustered based on the similarities of the attributes. In the beginning of search, by reducing the number of terminal symbols, the rough and rapid search is performed. In the latter stage of search, by using the original attributes for terminal symbols, the local search is performed. By comparison with the conventional GP, the proposed methods showed the faster evolutional speed and extracted more accurate classification rules

Changes in mortality inequalities across occupations in Japan: a national register based study of absolute and relative measures, 1980-2010

Objective Changes in mortality inequalities across socioeconomic groups have been a substantial public health concern worldwide. We investigated changes in absolute/relative mortality inequalities across occupations, and the contribution of different diseases to inequalities in tandem with the restructuring of the Japanese economy.Methods Using complete Japanese national death registries from 5 year intervals (1980–2010), all cause and cause specific age standardised mortality rates (ASMR per 100 000 people standardised using the Japanese standard population in 1985, aged 30–59 years) across 12 occupations were computed. Absolute and relative inequalities were measured in ASMR differences (RDs) and ASMR ratios (RRs) among occupations in comparison with manufacturing workers (reference). We also estimated the changing contribution of different diseases by calculating the differences in ASMR change between 1995 and 2010 for occupations and reference.Results All cause ASMRs tended to decrease in both sexes over the three decades except for male managers (increased by 71% points, 1995–2010). RDs across occupations were reduced for both sexes (civil servants 233.5 to −1.9 for men; sales workers 63.3 to 4.5 for women) but RRs increased for some occupations (professional workers 1.38 to 1.70; service workers 2.35 to 3.73) for men and decreased for women from 1980 to 2010. Male relative inequalities widened among farmer, fishery and service workers, because the percentage declines were smaller in these occupations. Cerebrovascular disease and cancer were the main causes of the decrease in mortality inequalities among sexes but the incidence of suicide increased among men, thereby increasing sex related inequalities.Conclusions Absolute inequality trends in mortality across occupations decreased in both sexes, while relative inequality trends were heterogeneous in Japan. The main drivers of narrowing and widening mortality inequalities were cerebrovascular disease and suicide, respectively. Future public health efforts will benefit from eliminating residual inequalities in mortality by considering the contribution of the causes of death and socioeconomic status stratification

Risk assessment for hepatitis E virus infection from domestic pigs introduced into an experimental animal facility in a medical school

Hepatitis E virus (HEV) is known to cause zoonotic infections from pigs, wild boars and deer. Domestic pigs have been used as an experimental animal model in medical research and training; however, the risks of HEV infection from pigs during animal experiments are largely unknown. Here, we retrospectively investigated the seroprevalence and detection rates of viral RNA in 73 domestic pigs (average 34.5 kg) introduced into an animal experimental facility in a medical school during 2012-2016. We detected anti-HEV immunoglobulin G antibodies in 24 of 73 plasma samples (32.9%), though none of the samples were positive for viral RNA. Plasma samples of 18 pigs were sequentially monitored and were classified into four patterns: sustained positive (5 pigs), sustained negative (5 pigs), conversion to positive (6 pigs) and conversion to negative (2 pigs). HEV genomes were detected in 2 of 4 liver samples from pigs that were transported from the same farm during 2016-2017. Two viral sequences of the overlapping open reading frame (ORF) 2/3 region (97 bp) were identical and phylogenetically fell into genotype 3. A 459-bp length of the ORF2 region of an amplified fragment from a pig transported in 2017 was clustered with the wbJYG1 isolate (subgenotype 3b) with 91.5% (420/459 bp) nucleotide identity. Based on our results, we suggest that domestic pigs introduced into animal facilities carry a potential risk of HEV infection to researchers, trainees and facility staff. Continuous surveillance and precautions are important to prevent HEV infection in animal facilities

CD40 and IFN-γ dependent T cell activation by human bronchial epithelial cells

We examined whether freshly isolated human bronchial cells (HBEC) and bronchial epithelial cell line/ BEAS-2B cells expressed surface molecules required for APC function. These cells expressed CD40 and ICAM-1, but not B7-1, B7-2 or HLA-DR molecules. Treatment of these cells with IFN-γ resulted in enhanced expression of CD40 and ICAM-1 as well as induction of HLA-DR expression. Th2 cytokines such as IL-4 and IL-5, proinflammatory cytokine of GM-CSF and nonspecific activator endotoxin had no effect on these phenotypic expressions. Functional examinations showed that allogeneic lymphocytes purified from peripheral blood strongly proliferated in response to BEAS-2B cells cultured with IFN-γ, but only weakly compared with those without IFN-γ. When allogeneic lymphocytes were purified to CD4+ cells, the proliferative response against BEAS-2B cells was abolished. Blockade of CD40-CD40L interaction by anti-CD40 antibody also inhibited the proliferation of lymphocytes to BEAS-2B cells, although this treatment showed a minimum effect on the response to allogeneic MNC. Thus, bronchial epithelial cells have the ability to present allogeneic antigens to T cells in both CD40- and IFN-γ- dependent manners under the presence of third party cells that transduce co-stimulatory signals

Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into OH model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with GSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT

Pathological characteristics of reoperated regrowing clinically nonfunctioning pituitary tumor cases in comparison with initial surgical cases

ObjectivePostoperative nonfunctioning pituitary tumor (NFPT) regrowth is a significant concern, but its predictive factors are not well established. This study aimed to elucidate the pathological characteristics of NFPTs indicated for reoperation for tumor regrowth.MethodsPathological, radiological, and clinical data were collected from patients who underwent repeat operation for NFPT at Moriyama Memorial Hospital (MMH) between April 2018 and September 2023. For comparison, we also gathered data from patients who underwent initial surgery for NFPT during the same period at MMH.ResultsOverall, 61 and 244 NFPT patients who respectively underwent reoperation and initial operation were evaluated. The mean period between the previous operation and reoperation was 113 months. Immunonegativity for any adenohypophyseal hormone was significantly more frequent in the reoperation group than in the initial operation group. In addition, the rate of hormone-negative but transcription factor–positive (H-/TF+) tumors among silent gonadotroph tumors was significantly higher in the reoperation group than in the initial operation group. Furthermore, seven silent corticotroph tumors (SCTs) in the reoperation group were ACTH-negative but TPIT-positive. Because most of the previous surgeries were performed in other hospitals a long time ago, we could procure the previous pathological results with immunohistochemistry (IHC) only from 21 patients. IHC for TF had not been performed in all the previous specimens. IHC for adenohypophyseal hormone was almost the same as the current results, and many H-/TF+ tumors were previously diagnosed as NCT. In addition, the reoperated patients were classified into 3 groups on the basis of the condition of the previous operation: gross total resection (GTR), 12 patients; subtotal resection (STR), 17 patients; and partial resection (PR), 32 patients. The mean Ki-67 LI in the GTR, STR, and PR subgroups were 1.82, 1.37, and 0.84, respectively, with the value being significantly higher in the GTR subgroup than in the PR subgroup (P < 0.05).ConclusionsThe ratio of H-/TF+ tumors is significantly higher in symptomatically regrown tumors than in the initial cases, which used to be diagnosed as NCT. PR cases tend to grow symptomatically in a shorter period, even with lower Ki-67 LI than GTR cases

Efficiency of Peptide Nucleic Acid-Directed PCR Clamping and Its Application in the Investigation of Natural Diets of the Japanese Eel Leptocephali

Polymerase chain reaction (PCR)-clamping using blocking primer and DNA-analogs, such as peptide nucleotide acid (PNA), may be used to selectively amplify target DNA for molecular diet analysis. We investigated PCR-clamping efficiency by studying PNA position and mismatch with complementary DNA by designing PNAs at five different positions on the nuclear rDNA internal transcribed spacer 1 of the Japanese eel Anguilla japonica in association with intra-specific nucleotide substitutions. All five PNAs were observed to efficiently inhibit amplification of a fully complementary DNA template. One mismatch between PNA and template DNA inhibited amplification of the template DNA, while two or more mismatches did not. DNA samples extracted from dorsal muscle and intestine of eight wild-caught leptochephalus larvae were subjected to this analysis, followed by cloning, nucleotide sequence analysis, and database homology search. Among 12 sequence types obtained from the intestine sample, six were identified as fungi. No sequence similarities were found in the database for the remaining six types, which were not related to one another. These results, in conjunction with our laboratory observations on larval feeding, suggest that eel leptocephali may not be dependent upon living plankton for their food source

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients

Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.

Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD