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Processing bodies (P-bodies, PBs) are cytoplasmic foci formed by condensation of translationally inactivated messenger ribonucleoprotein particles (mRNPs). Infection with the protozoan parasite Trypanosoma cruzi (T. cruzi) promotes PB accumulation in host cells, suggesting their involvement in host mRNA metabolism during parasite infection. To identify PB-regulated mRNA targets during T. cruzi infection, we established a PB-defective human fibrosarcoma cell line by knocking out the enhancer of mRNA decapping 4 (EDC4), an essential component of PB assembly. Next-generation sequencing was used to establish transcriptome profiles for wild-type (WT) and EDC4 knockout (KO) cells infected with T. cruzi for 0, 3, and 24 h. Ingenuity pathway analysis based on the differentially expressed genes revealed that PB depletion increased the activation of several signaling pathways involved in the innate immune response. The proinflammatory cytokine IL-1β was significantly upregulated following infection of PB-deficient KO cells, but not in WT cells, at the mRNA and protein levels. Furthermore, the rescue of PB assembly in KO cells by GFP-tagged wild-type EDC4 (+WT) suppressed IL-1β expression, whereas KO cells with the C-terminal-deleted mutant EDC4 (+Δ) failed to rescue PB assembly and downregulate IL-1β production. Our results suggest that T. cruzi assembles host PBs to counteract antiparasitic innate immunity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Chagas disease, a neglected tropical disease caused by the protozoan Trypanosoma cruzi poses a significant health challenge in rural areas of Latin America. The current pharmacological options exhibit notable side effects, demand prolonged administration, and display limited efficacy. Consequently, there is an urgent need to develop drugs that are safe and clinically effective. Previously, we identified a quinone compound (designated as compound 2) with potent antiprotozoal activity, based on the chemical structure of komaroviquinone, a natural product renowned for its antitrypanosomal effects. However, compound 2 was demonstrated considerably unstable to light. In this study, we elucidated the structure of the light-induced degradation products of compound 2 and probed the correlation between the quinone ring's substituents and its susceptibility to light. Our findings led to the discovery of quinones with significantly enhanced light stability, some of which exhibiting antitrypanosomal activity. The most promising compound was evaluated for drug efficacy in a mouse model of Chagas disease, revealing where a notable reduction in blood parasitemia.

Background: Chagas disease can lead to life-threatening cardiac manifestations. Regional factors, including genetic characteristics of circulating Trypanosoma cruzi (T. cruzi), have attracted attention as likely determinants of Chagas disease phenotypic expression and Chagas cardiomyopathy (CCM) progression. Our objective was to elucidate the differential transcriptomic signatures of cardiomyocytes resulting from infection with genetically discrete T. cruzi strains and explore their relationships with CCM pathogenesis and progression., Methods: HL-1 rodent cardiomyocytes were infected with T. cruzi trypomastigotes of the Colombian, Y, or Tulahuen strain. RNA was serially isolated post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change ≥ 2 or ≤ 0.5) highlighted over-represented biological pathways. Intracellular levels of reactive oxygen species (ROS) were compared between T. cruzi-infected and non-infected HL-1 cardiomyocytes., Results: We found that oxidative stress-related gene ontology terms (GO terms), 'Hypertrophy model', 'Apoptosis', and 'MAPK signaling' pathways (all with P < 0.01) were upregulated. 'Glutathione and one-carbon metabolism' pathway, and 'Cellular nitrogen compound metabolic process' GO term (all with P < 0.001) were upregulated exclusively in the cardiomyocytes infected with the Colombian/Y strains. Mean intracellular levels of ROS were significantly higher in the T. cruzi-infected cardiomyocytes compared to the non-infected (P < 0.0001)., Conclusions: The upregulation of oxidative stress-related and hypertrophic pathways constitutes the universal hallmarks of the cardiomyocyte response elicited by T. cruzi infection. Nitrogen metabolism upregulation and glutathione metabolism imbalance may implicate a relationship between nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of Chagas cardiomyopathy., (© 2023. The Author(s).)

Purpose: The purposes of this study were to evaluate the low-contrast detectability of CT images assuming hepatocellular carcinoma and to determine whether dose reduction in abdominal plain CT imaging is possible., Methods: A Catphan 600 was imaged at 350, 250, 150, and 50 mA using an Aquilion ONE PRISM Edition (Canon) and reconstructed using deep learning reconstruction (DLR) and model-based iterative reconstruction (MBIR). A low-contrast object-specific contrast-to-noise ratio (CNR LO ) was measured and compared in a 5-mm module with a CT value difference of 10 HU, assuming hepatocellular carcinoma; a visual examination was also performed. Moreover, an NPS within a uniform module was measured., Results: CNR LO was higher for DLR at all doses (1.12 at 150 mA for DLR and 1.07 at 250 mA for MBIR). On visual evaluation, DLR could detect up to 150 mA and MBIR up to 250 mA. The NPS was lower for DLR at 0.1 cycles/mm at 150 mA., Conclusion: The low-contrast detection performance was better with DLR than with MBIR, indicating the possibility of dose reduction.

Reactive oxygen species are known to be involved in various diseases, and antioxidant ingredients are expected to essentially prevent diseases and contribute to improving health. However, antioxidants are easily degraded by enzymes before being absorbed in the intestine, so a means of transport that prevents their degradation in the body is necessary. Exosomes, which play an important role in communication between individual cells, have attracted attention as a new transport carrier of miRNA and DNA, but not yet fully exploited in food research. More recently, exosomes extracted from bovine milk began to be widely used as a cost-effective transport carrier not in clinical medicine but also in functional food materials. To develop practical applications as carriers for functional foods, systematic studies are necessary to clarify the introduction efficiency and the properties of encapsulated substances. In this study, we applied electroporation and incubation to encapsulate antioxidants into the exosomes and studied the encapsulation efficiency into the exosomes and the anticancer activity., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Objectives: To demonstrate the effect of an improved deep learning-based reconstruction (DLR) algorithm on Ultra-High-Resolution Computed Tomography (U-HRCT) scanners., Methods: Clinical and phantom studies were conducted. Thirty patients who underwent contrast-enhanced CT examination during the follow-up period were enrolled. Images were reconstructed using improved DLR [termed, New DLR, i.e., Advanced Intelligent Clear-IQ Engine (AiCE) Body Sharp] and conventional DLR (Conv DLR, AiCE Body) algorithms. Two radiologists assessed the overall image quality using a 5-point scale (5 = excellent; 1 = unacceptable). The noise power spectra (NPSs) were calculated to assess the frequency characteristics of the image noise, and the square root of area under the curve (√AUC NPS) between 0.05 and 0.50 cycle/mm was calculated as an indicator of the image noise. Dunnett's test was used for statistical analysis of the visual evaluation score, with statistical significance set at p < 0.05., Results: The overall image quality of New DLR was better than that of the Conv DLR (4.2 ± 0.4 and 3.3 ± 0.4, respectively; p < 0.0001). All New DLR images had an overall image quality score above the average or excellent. The √AUC NPS value of New DLR was lower than that of Conv DLR (13.8 and 14.2, respectively). The median values of reconstruction time required with New DLR and Conv DLR were 5.0 and 7.8 min, respectively., Conclusions: The new DLR algorithm improved the image quality within a practical reconstruction time., Advances in Knowledge: The new DLR enables us to choose whether to improve image quality or reduce the dose.

Background: Since the late twentieth century, Chagas disease gained global attention to suppress the vector burden as a main control strategy in endemic countries. In Central America, multi-national initiative successfully achieved significant reduction in the estimated disease prevalence as well as elimination of the region's principal vector species at the time in 2012. While the last decade has witnessed significant changes in ecosystem-such as urbanization and replacement of the main vector species-that can possibly affect the vector's habitation and residual transmission, the up-to-date vector burden in the region has not been evaluated thoroughly due to the cessation of active vector surveillance. The aim of this study was to update the risk of vector-borne Trypanosoma cruzi infection in El Salvador, the top Chagas disease-endemic country in Central America., Methods: A nationwide vector survey was conducted in the domestic environment of El Salvador from September 2018 to November 2020. The selection of the houses for inspection was based on expert purposeful sampling. Infection for T. cruzi was examined by microscopic observation of the insects' feces, followed by a species confirmation using PCR. The data were analyzed using R software version 4.1.3. Proportion estimates with 95% confidence intervals were inferred using the Jeffrey's method provided under the epiR package., Results: A total of 1529 Triatoma dimidiata was captured from 107 houses (infestation rate, 34.4%; 107/311) in all the fourteen departments of the country visited within the period; prevalence of T. cruzi infection was as high as 10% (153/1529). In the country, domestic T. dimidiata infestation was distributed ubiquitously, while T. cruzi infection rates varied across the departments. Five out of fourteen departments showed higher infection rates than the average, suggesting sporadic high-risk areas in the country., Conclusions: Our comprehensive study revealed substantial T. cruzi infection of T. dimidiata across the country, indicating potential active transmission of the disease. Therefore, strengthened surveillance for both vector and human infection is required to truly eliminate the risk of T. cruzi transmission in Central America., (© 2022. The Author(s).)

Background: The purpose of the present study was to evaluate the accuracy of the measurements associated with leg alignment on a teleoroentgenogram and an orthoroentgenogram., Methods: The models being irradiated were manufactured and represented 10° varus and 15° varus leg alignment, in which the true values of hip-knee-ankle angle (HKAA), mechanical axis (MA) length, and percentage of MA (%MA) were already known. HKAA, MA length, and %MA were measured in various radiographic conditions of the teleoroentgenogram and orthoroentgenogram. Then, the differences between the radiographic measurement values and the corresponding true values were analyzed., Results: Regarding HKAA, the teleoroentgenogram provided accurate angular measurements with minimal differences between the measurement and true value in both the 10° and 15° varus models, irrespective of the radiographic condition. In the orthoroentgenogram, the modified method measured accurate HKAA; however, the standard method showed significant angular measurement errors with a 0.6° and 1.0° difference from the true value in the 10° and 15° varus models, respectively. This angular measurement error of HKAA in the standard orthoroentgenogram became significantly larger with object-to-image distance. Regarding MA length, the orthoroentgenogram exhibited accurate length measurements. In contrast, the teleoroentgenogram showed a significant length measurement error for the MA length. Regarding %MA, significant differences from the true values of 2.0% and 2.4% were observed in the modified orthoroentgenograms of the 10° and 15° varus models, respectively. The teleoroentgenogram and standard orthoroentgenogram reproduced the accurate measurement value of %MA in the 10° and 15° varus models., Conclusion: A teleoroentgenogram is a reliable modality for accurate angular measurements such as HKAA and %MA. An orthoroentgenogram has the potential to measure both HKAA and length accurately if the radiographic condition was modified; however, measurement error in %MA may occur., Competing Interests: Declaration of competing interest The authors state that there are no conflicts of interest which might have influenced the preparation of this manuscript., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

A series of quinone derivatives with a variety of side chains were synthesized. These synthetic quinone compounds were evaluated for in vitro antitrypanosomal activity against trypomastigotes and amastigotes of Trypanosoma cruzi, the causative agent of Chagas disease. Measurement of solubility of quinones and their ability to permeate cell membranes were assessed to address their possible use as oral drugs. Some synthesized compounds exhibited potent antitrypanosomal activity. However, most compounds with a promising activity showed poor solubility that did not seem suitable for oral usage. Meanwhile, compound 5a, an N-tert-butoxycarbonylpiperidine derivative, exhibited good antitrypanosomal activity, ability to permeate membranes, and good solubility.

Objective: We aimed to establish correlations for the levels of follicle-stimulating hormone (FSH), estrone (E1) and estradiol (E2) between urine and serum in premenopausal and postmenopausal women using immunoassays., Methods: In this study of 92 women (61 postmenopausal, 31 premenopausal), both urine and blood specimens were collected on the same day and stored at 4 °C for analysis by chemiluminescent immunoassay, radioimmunoassay and/or electrochemiluminescent immunoassay., Results: There were correlations in the levels of FSH, E1 and E2 between urine and serum in both postmenopausal (r = 0.96 for FSH, r = 0.91 for E1, r = 0.80 for E2) and premenopausal (r = 0.98 for FSH, r = 0.92 for E1, r = 0.90 for E2) women. It is indicated that the correlations were stronger in the premenopausal group compared with the postmenopausal group, especially for FSH., Conclusion: The levels of FSH, E1 and E2 in urine correlated with those in the serum in premenopausal and postmenopausal women. Urine samples could be used instead of serum samples to measure hormone levels, which would reduce the difficulty of conducting large survey studies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Current data for the use of dimethyl fumarate (DMF) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) is limited., Objectives: To assess the efficacy of DMF in Japanese patients with RRMS., Methods: The phase 3, multinational APEX study (ClinicalTrials.gov identifier: NCT01838668) consisted of two parts: a 24-week double-blind part where subjects were randomized to receive DMF 240 mg or placebo twice daily in East Asian and Eastern European countries, and an open-label extension part where all subjects received DMF. The primary endpoint was the total number of new gadolinium-enhancing lesions in Weeks 12-24. In this interim analysis, we report efficacy data in the Japanese subgroup (DMF n  = 56; placebo n  = 58) over 72 weeks, including an extension phase., Results: DMF reduced the total number of new gadolinium-enhancing lesions in Weeks 12-24 by 85% versus placebo ( p  < 0.0001). At Week 24, the annualized relapse rate was also reduced by 48% with DMF, versus placebo. DMF reduced the probability of relapse from Week 8 and was sustained. The number of gadolinium-enhancing lesions was maintained through 72 weeks., Conclusions: DMF demonstrated sustained efficacy in this Japanese subgroup. The results were consistent with those observed in studies of DMF enrolling primarily Caucasian patients.

Background: The use of dimethyl fumarate has not been reported in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis., Objectives: The purpose of this study was to evaluate the efficacy and safety of dimethyl fumarate in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis., Methods: APEX was a phase 3, multinational trial, which consisted of a 24-week, randomized (1:1), double-blind study where patients received dimethyl fumarate 240 mg or placebo twice daily, followed by an open-label extension where all patients received dimethyl fumarate 240 mg. The primary endpoints were the total number of new gadolinium-enhancing (Gd+) lesions in Weeks 12-24 (Part I) and long-term safety (Part II). This post-hoc subgroup analysis evaluated the efficacy and safety of dimethyl fumarate in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis ( n =52) up to Week 72 (24 weeks Part I and 48 weeks Part II)., Results: Dimethyl fumarate reduced the mean total number of new gadolinium-enhancing lesions at Weeks 12-24 by 94% versus placebo; the number of patients who had a relapse over 24 weeks was reduced by 72%. Adverse events leading to discontinuation of the study drug were reported in 9% of patients receiving placebo/dimethyl fumarate and 4% of patients in dimethyl fumarate/dimethyl fumarate., Conclusions: Dimethyl fumarate demonstrated sustained efficacy and acceptable tolerability in treatment-naïve Japanese patients with relapsing-remitting multiple sclerosis for 72 weeks.

Background: The associations between ABO blood type and risk of diseases including cancer have been reported from epidemiological studies. Self-reporting is one of the most widely used methods of collecting the ABO blood type information. Verifying the accuracy of self-reporting is important to consider measurement errors. We aimed to conduct validation of self-reported ABO blood types in the Japan Nurses’ Health Study (JNHS), which is a large prospective cohort study. Methods: The concordance rate between self-reported and serologically or genetically inferred ABO blood groups was investigated for a subsample of 41 subjects from the Gunma Nurses’ Health Study, which was a pilot cohort study that preceded the JNHS. The presence of antibodies to A or B antigens in serum (serological test) and allele types of the ABO gene (genotyping test) were determined by using frozen blood samples that were preserved for approximately 7 years. ABO blood types were determined from these tests and compared with self-reported data. Results: All of the nurses reported that their ABO blood groups were concordant with those determined by a serological and/or genotyping test. Self-reported ABO blood types of 35 of 38 (92.1%) participants were consistent with the results from serological typing, while the answers of three participants were not. In these three participants, ABO genotypes that were inferred from genotyping of three single nucleotide polymorphisms in ABO loci perfectly matched with their self-reported ABO types, and all of these were O-type. Conclusions: Japanese health professionals report their blood type with a high degree of accuracy. Special attention should be paid to the O-type group in serological analysis of blood samples that have been preserved for several years in longitudinal studies., (Creative Commons Attribution License)

Results of studies on the associations of soy food intake with urinary estrogen levels in premenopausal women and in postmenopausal women have been inconsistent. We examined the associations of urinary isoflavone levels as well as soy food intake with estrone (E1) and estradiol (E2) in pre- and postmenopausal women. In addition, we compared the levels of isoflavones, E1 and E2 across current hormone users such as those receiving hormone replacement therapy and those using oral contraceptives and non-users among both pre- and postmenopausal women. Urinary levels of isoflavones, E1 and E2 in 498 women (36 hormone users and 462 non-users) were analyzed. Premenopausal women with a higher frequency of soy food intake had higher urinary isoflavone levels, but there were no significant associations between E1 and E2 levels and urinary isoflavone levels. Levels of E1 and E2 in hormone users were significantly lower than those in hormone non-users among premenopausal women, but levels of E1 and E2 in hormone users were significantly higher than those in hormone non-users among postmenopausal women. Postmenopausal women with a higher frequency of soy food intake had higher urinary isoflavone levels, and postmenopausal women with high urinary isoflavone levels had significantly higher E1 and E2 levels. In conclusion, the associations of urinary isoflavone levels with urinary estrogen levels differed with menopausal status. Urinary levels of E1 and E2 were high in postmenopausal women with high urinary isoflavone levels but not in premenopausal women with high urinary isoflavone levels., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The change in follicle-stimulating hormone (FSH) during the menopausal transition and associations of FSH with various diseases have been assessed by using blood samples. We examined cross-sectionally the variation of FSH levels, associations of estrone and estradiol with FSH, and associations of BMI with these hormones by using urinary samples from peri- and postmenopausal women in Japan. Of 4472 participants in the Urinary Isoflavone Concentration Survey of the Japan Nurses' Health Study, we analyzed urinary levels of estrone, estradiol and FSH in 547 women aged from 45 to 54 years. Urinary FSH levels varied widely in postmenopausal women and the pattern of change in urinary FSH levels seems to be similar to that in blood FSH levels in previous studies. There were no significant differences in age, body mass index (BMI), estradiol, estrone and estradiol/estrone ratio among three groups according to the tertile of FSH. In postmenopausal women, there were significant associations of BMI with levels of estrone and estradiol, but there was no significant association of BMI with FSH. Studies using urinary samples will allow us to establish a study project as a large-scale population-based study to determine associations between FSH and various diseases after menopause. J. Med. Invest. 66 : 297-302, August, 2019.

The purpose of this study is to compare the physical characteristics and visibility of high-resolution and conventional images acquired with the same X-ray dose, and to investigate the superiority of super high-resolution imaging. A Catphan phantom was scanned in the normal resolution (NR), high-resolution (HR), and super high-resolution (SHR) modes of ultra-high-resolution computed tomography at 120 kV and 75 mAs. All images were reconstructed into a 5-mm thick image slices with filtered back-projection (FBP) and hybrid image reconstruction (HIR), which included normal and enhanced adaptive iterative dose reduction 3D (AIDR and eAIDR, respectively). The modulation transfer function (MTF) and noise power spectrum (NPS) were measured using the circular edge method and radial frequency method, respectively. The signal-to-noise ratio (SNR) was then calculated. High-contrast resolution and low-contrast detectability were evaluated visually by five radiological technologists. The MTFs of HR eAIDR and HR FBP images were higher than those of NR FBP images. However, the NPSs of HR eAIDR and HR FBP images were larger than those of NR FBP images. The SNR of HR eAIDR images was higher than that of NR FBP and HR FBP images. The scores of high-contrast resolution of HR eAIDR , NR FBP , and HR FBP images were 13, 8, and 13 cycles/cm, respectively, and the scores of low-contrast detectability were 5, 5, and 6 mm, respectively. Hence, an improvement in high-contrast resolution of signal more than 400 HU in the axial section can be achieved without increasing the radiation dose and decreasing low-contrast detectability with 10 HU using the HR mode and eAIDR.

Introduction: The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS., Methods: Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded., Results: Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups., Conclusion: The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports., Trial Registration: ClinicalTrials.gov identifier NCT01838668., Funding: Biogen Japan Ltd.

Equol is one of the most active soy isoflavones. When the association between soy food intake in daily life and health outcomes is examined in epidemiological studies, it is important to define the equol-producing status of each individual. However, few studies have assessed equol-producing status without a soy challenge test. To determine a robust cutoff criterion for equol producer classification in observational studies, we conducted a urinary isoflavone concentration survey in daily life among women. Furthermore, we examined the association between eating habits regarding soy foods and equol-producing status. A total of 4,412 participants were included in the analyses. Urinary isoflavones were analyzed using a high-performance liquid chromatography method. We examined the distribution of the log10 equol/daidzein ratios, finding a mixture of two normal distributions, corresponding to equol producer and non-producer subpopulations. Applying a finite mixture model, we estimated the means, standard deviations, and mixing proportions of these two distributions. The estimation was carried out using the SAS NLIN procedure. The optimal cutoff point for the log10 equol/daidzein ratio in the study population was determined to be -1.42, according to the estimated parameters of the mixture distribution. Based on this criterion, 1,830 (41.5%) of the participants were identified as equol producers. Compared with non-consumers of soy foods, consumers of soy foods had significantly higher odds of being equol producers. Using log10-transformed equol/daidzein ratios ≥ -1.42 to define equol producers among Japanese women is reasonable and suitable for determining equol-producing status in epidemiological studies. We found that soy food eating habits were associated with equol-producing status. Further investigation is required to evaluate associations between equol-producing status in daily life and health outcomes. The results of this study suggest the best cutoff point to use in the definition of equol-producing status in daily life., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TU and SU are employees of Otsuka Pharmaceutical Co., Ltd. YI, KH, JNS, YO, and MK. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Autophagy has emerged as an essential component of the defense system against intracellular pathogens. We demonstrated that Trypanosoma cruzi, an intracellular protozoan parasite, was not eliminated by the host's autophagic machinery despite exposure to the host cell cytoplasm. Puncta of microtubule-associated protein 1 light chain 3 (LC3), an autophagy marker, and LC3-II, a lipidated form of LC3, were significantly increased after infection with T. cruzi, indicating that the parasite activated the early steps of host autophagy and induced autophagosome formation. However, autolysosomes were not observed in the infected cells. In addition, T. cruzi was not enwrapped by autophagosomes, suggesting that the parasite has mechanisms to allow it to evade autophagic capture. The results of this study indicate that host autophagy is incomplete following T. cruzi infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Processing bodies (PBs) are cytoplasmic granules containing mRNAs and proteins involved in translation and degradation of mRNAs. PBs are constitutively present in cells and are induced to accumulate when external stressors including microbial infection are applied to cells, followed by a rapid translational arrest. We have examined the impact of Trypanosoma cruzi (T. cruzi, Tc) infection on host cytoplasmic PB assembly. Within 24h post-infection, we found the average number of PB foci per cell increased by more than 2-fold. Protein levels of PB components were unaltered during infection. These results indicated that Tc infection caused accumulation of PBs by changing the localization pattern of PB protein components. To elucidate the role of the accumulated PBs on Tc infection, we knocked down PBs using a siRNA specific for PB components EDC4 and Lsm14A, which are involved in mRNA decapping and translational repression, respectively. We observed that the inhibition of PB accumulation significantly enhanced the infectivity and growth of intracellular amastigotes. Depletion of PBs did not affect nitric oxide (NO) production during Tc infection, indicating that the growth promotion was not caused by modulation of NO-mediated killing of Tc. Our results suggest that the accumulated PBs partially contribute to anti-parasitic responses by manipulating the host's mRNA metabolism., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Current chemotherapy drugs for Chagas' disease are insufficient due to their limited efficacy; however, anti-trypanosomal agents have recently shown promise. As such, synthetic intermediates of komaroviquinone were evaluated for anti-trypanosomal activity. Based on the results, a series of novel quinone derivatives were screened for anti-trypanosomal activity and mammalian cytotoxicity. Several quinone derivatives displayed higher antiprotozoal activity against Trypanosoma cruzi trypomastigotes than the reference drug benznidazole, without concomitant toxicity toward the host cell., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Chagas disease (human American trypanosomiasis), which is caused by the protozoan parasite Trypanosoma cruzi, is responsible for numerous deaths each year; however, established treatments for the disease are limited. Differentiation-inducing factor-1 (DIF-1) and DIF-3 are chlorinated alkylphenones originally found in the cellular slime mold Dictyostelium discoideum that have been shown to possess pharmacological activities. Here, we investigated the effects of DIF-3 derivatives on the infection rate and growth of T. cruzi by using an in vitro assay system utilizing host human fibrosarcoma HT1080 cells. Certain DIF-3 derivatives, such as butoxy-DIF-3 (Bu-DIF-3), at micro-molar levels strongly suppressed both the infection rate and growth of T. cruzi in HT1080 cells and exhibited little toxicity for HT1080 cells. For example, the IC50 of DIF-3 and Bu-DIF-3 versus the growth of T. cruzi in HT1080 cells were 3.95 and 0.72μM, respectively, and the LD50 of the two compounds versus HT1080 cells were both greater than 100μM. We also examined the effects of DIF-3 and Bu-DIF-3 on T. cruzi activity in C57BL/6 mice. Intraperitoneally administered Bu-DIF-3 (50mg/kg) significantly suppressed the number of trypomastigotes in blood with no apparent adverse effects. These results strongly suggest that DIF-3 derivatives could be new lead compounds in the development of anti-trypanosomiasis drugs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The authors developed a class of novel graphite-based field emitters, known as graphite field emitters inflamed at high temperature (GFEIHTs), which includes numerous edges and juts. The GFEIHT field emission characteristics are investigated in a vacuum tube (10 -7 Pa), and an anode current exceeding 2 mA is obtained. The authors also fabricated tipped-off x-ray tubes using GFEIHTs. No degradation in the anode current is observed under the operating conditions of 16.6 kV anode voltage and 160  μ A anode current. The current dispersion, defined as the standard deviation (σ)/mean over 24 h, is 2.8%. The authors successfully demonstrated radiography and x-ray fluorescence spectrometry using an x-ray tube with GFEIHT.

In this study, microdosimetric energy distributions of secondary charged particles from the (10)B(n,α)(7)Li reaction in boron-neutron capture therapy (BNCT) field were calculated using the Particle and Heavy Ion Transport code System (PHITS). The PHITS simulation was performed to reproduce the geometrical set-up of an experiment that measured the microdosimetric energy distributions at the Kyoto University Reactor where two types of tissue-equivalent proportional counters were used, one with A-150 wall alone and another with a 50-ppm-boron-loaded A-150 wall. It was found that the PHITS code is a useful tool for the simulation of the energy deposited in tissue in BNCT based on the comparisons with experimental results.

Objective: We evaluated the partial volume effect in PET/CT images and developed a simple correction method to address this problem., Methods: Six spheres and the background in the phantom were filled with F-18 and we thus obtained 4 different sphere-to-background (SB) ratios. Thirty-nine cervical lymph nodes in 7 patients with papillary thyroid carcinoma (15 malignant and 24 benign) were also examined as a preliminary clinical study. First, we developed recovery coefficient (RC) curves normalized to the maximum counts of the 37-mm sphere. Next, we developed a correction table to determine the true SB ratio using three parameters, including the maximum counts of both the sphere and background and the lesion diameter, by modifying the approximation formula of the RC curves including the point-spread function correction. The full width at half maximum in this formula is estimated with the function of the SB ratio., Results: In the phantom study, a size-dependent underestimation of the radioactivity was observed. The degree of decline of RC was influenced by the SB ratio. In preliminary clinical examination, the difference in the SUV(max) between malignant and benign LNs thus became more prominent after the correction. The PV correction slightly improved the diagnostic accuracy from 95 to 100%., Conclusions: We developed a simple table lookup correction method for the partial volume effect of PET/CT. This new method is considered to be clinically useful for the diagnosis of cervical LN metastasis. Further examination with a greater number of subjects is required to corroborate its clinical usefulness.

This study describes measurements on secondary particles produced by a 290 MeV/n Spread Out Bragg Peak (SOBP) carbon beam. Microdosimetric distributions of secondary fragments from the SOBP carbon beam have been measured by using a new tissue equivalent proportional counter (TEPC) system at the Heavy Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences. The new TEPC system consists of a TEPC, two solid-state detectors (SSD) and a scintillation counter (FSC: forward scintillation counter). The SSDs and FSC can separately identify charged fragments and secondary neutrons produced by the incident carbon ions. Microdosimetric distributions were measured for secondary particles including neutrons produced by a body-simulated phantom consisting of various PMMA plates (thickness: 0, 34.81, 55.2, 60.95, 64.83, 95.03, 114.79, 124.69, 135.2 and 144.98 mm, respectively) to cover the SOBP (at 60-125 mm depth). The new system can separately determine produced fragments from the incident SOBP carbon beam in a body-simulated phantom.

The purpose of this study was to obtain the neutron energy spectrum on the surface of the moderator of the Tokyo University reactor YAYOI and to investigate the origins of peaks observed in the neutron energy spectrum by use of the Monte Carlo Code PHITS for evaluating biological studies. The moderator system was modeled with the use of details from an article that reported a calculation result and a measurement result for a neutron spectrum on the surface of the moderator of the reactor. Our calculation results with PHITS were compared to those obtained with the discrete ordinate code ANISN described in the article. In addition, the changes in the neutron spectrum at the boundaries of materials in the moderator system were examined with PHITS. Also, microdosimetric energy distributions of secondary charged particles from neutron recoil or reaction were calculated by use of PHITS and compared with a microdosimetric experiment. Our calculations of the neutron energy spectrum with PHITS showed good agreement with the results of ANISN in terms of the energy and structure of the peaks. However, the microdosimetric dose distribution spectrum with PHITS showed a remarkable discrepancy with the experimental one. The experimental spectrum could not be explained by PHITS when we used neutron beams of two mono-energies.

The purpose of this study was to develop a computerized method for estimation of the location of a lung tumor in cine images on an electronic portal imaging device (EPID) without implanted markers during stereotactic body radiotherapy (SBRT). Each tumor region was segmented in the first EPID cine image, i.e., reference portal image, based on a multiple-gray level thresholding technique and a region growing technique, and then the image including the tumor region was cropped as a 'tumor template' image. The tumor location was determined as the position in which the tumor template image took the maximum cross-correlation value within each consecutive portal image, which was acquired in cine mode on the EPID in treatment. EPID images with 512 x 384 pixels (pixel size: 0.56 mm) were acquired at a sampling rate of 0.5 frame s(-1) by using energies of 4, 6 or 10 MV on linear accelerators. We applied our proposed method to EPID cine images (226 frames) of 12 clinical cases (ages: 51-83, mean: 72) with a non-small cell lung cancer. As a result, the average location error between tumor points obtained by our method and the manual method was 1.47 +/- 0.60 mm. This preliminary study suggests that our method based on the tumor template matching technique might be feasible for tracking the location of a lung tumor without implanted markers in SBRT.

Microdosimetry study has been carried out at the education and research mini-reactor of Kinki University (UTR-KINKI) using a tissue equivalent gas proportional counter (TEPC). The microdosimetric single event spectra for 0.5, 1, 2, 3 and 5 microm site sizes were obtained in the lineal energy range from 1 to 1000 keV/microm. Neutron and gamma-ray fractional doses were estimated from the single event spectra. The neutron dose fraction was varied from 35 to 55% for 0.5 to 5 microm site size. The averaged lineal energy, y(D), for each site size was likewise estimated and found to be dependent on the site size. The averaged lineal energy for neutron was slightly larger than that of the fission neutrons from (252)Cf, and the averaged lineal energy for gamma-ray had similar site-size-dependence of 25 keV gamma-rays and 250 kV X-rays. Relative biological effectiveness was found to be 4.1 +/- 0.13 for UTR-KINKI using Tilikidis's 2 Gy-response function. The estimated RBE for UTR-KINKI neutrons is quite close to the previous biological experimental value of 4.3 +/- 0.6 for micronucleated cells in gill cell of Medaka and 4.6 +/- 0.5 for induction of lymphocyte apoptosis in the thymus of ICR mice.

Microdosimetric single event spectra as a function of depth in a phantom for the 290 MeV/nucleon therapeutic carbon beam at HIMAC were measured by using a tissue equivalent proportional counter (TEPC). Two types of geometries were used: one is a fragment particle identification measurement (PID-mode) with time of flight (TOF) method without a backward phantom, and the other is an in-phantom measurement (IPM-mode) with a backward phantom. On the PID-mode geometry, fragments produced by carbon beam in a phantom are identified by the DeltaE-TOF distribution between two scintillation counters positioned up- and down-stream relative to the tissue equivalent proportional counter (TEPC). Lineal energy distributions for carbon and five ion fragments (proton, helium, lithium, beryllium and boron) were obtained in the lineal-energy range of 0.1-1000 keV/microm at eight depths (7.9-147.9 mm) in an acrylic phantom. In the IPM-mode geometry, the total lineal energy distributions measured at eight depths (61.9-322.9 mm) were compared with the distributions in the PID-mode. Both spectra are consistent with each other. This shows that the PID-mode measurement can be discussed as the equivalent of the phantom measurement. The dose distribution of the carbon beam and fragments were obtained separately. In the depth dose curve, the Bragg peak was observed. Relative biological effectiveness (RBE) for the carbon beam in the acrylic phantom was obtained based on a biological response function as a lineal-energy. The RBE of carbon beam had a maximum of 4.5 at the Bragg peak. Downstream of the Bragg peak, the RBE rapidly decreases. The RBE of fragments is dominated by Boron particles around the Bragg peak region.

Absorbed doses from main charged-particle beams and charged-particle fragments have been measured with high accuracy for particle therapy, but there are few reports for doses from neutron components produced as fragments. This study describes the measurements on neutron doses produced by carbon beams; microdosimetric distributions of secondary neutrons produced by 290 MeV/nucleon carbon beams have been measured by using a tissue equivalent proportional counter at the Heavy Ion Medical Accelerator in Chiba, Japan at the National Institute of Radiological Sciences. The microdosimetric distributions of the secondary neutron were measured on the distal and lateral faces of a body-simulated acrylic phantom (300 mm height x 300 mm width x 253 mm thickness). To confirm the dose measurements, the neutron energy spectra produced by incident carbon beams in the acrylic phantom were simulated by the particle and heavy ion transport code system. The absorbed doses obtained by multiplying the simulated neutron energy spectra with the kerma factor calculated by MCNPX agree with the corresponding experimental data fairly well. Downstream of the Bragg peak, the ratio of the neutron dose to the carbon dose at the Bragg peak was found to be a maximum of 1.4 x 10(-4) and the ratio of neutron dose was a maximum of 3.0 x 10(-7) at a lateral face of the acrylic phantom. The ratios of neutrons to charged particle fragments were 11% to 89% in the absorbed doses at the lateral and the distal faces of the acrylic phantom. We can conclude that the treatment dose will not induce serious secondary neutron effects at distances greater than 90 mm from the Bragg peak in carbon particle therapy.

Microdosimetric single event spectra were determined as a function of depth in an acrylic phantom for the carbon beam at HIMAC using a tissue equivalent proportional counter (TEPC) coupled to a scintillation counter system. The fragments produced by the carbon beam were identified by the deltaE-time of flight distribution obtained from two scintillation counters which were positioned at the up- and down-stream of the TEPC. Lineal energy distribution for the carbon beam and its five fragments, namely, proton, helium, lithium, beryllium, and boron ions, were measured in the lineal-energy range of 5-1000 keV/microm at five phantom depths between 0 and 230 mm. The dose distribution for the carbon beam and its fragments were obtained separately. The relative biological effectiveness (RBE) of the carbon beam in the phantom was calculated using a response function. The maximum RBE for the carbon beam was found to be about 5 near the Bragg peak. It was observed to rapidly decrease for Bragg peaks occurring at deeper positions in the phantom. The dose from the beam fragments accounted for about 30% to the total dose, however, its contribution to the RBE was less than 17%.

Microdosimetric single event spectrum in a human body simulated by an acrylic phantom has been measured for the clinical BNCT field at the Kyoto University Reactor (KUR). The recoil particles resulting from the initial reaction and subsequent interactions, namely protons, electrons, alpha particles and carbon nuclei are identified in the microdosimetric spectrum. The relative contributions to the neutron dose from proton, alpha particles and carbon are estimated to be about 0.9, 0.07 and 0.3, respectively, four depths between 5 and 41 mm. We estimate that the dose averaged lineal energy, yD decreased with depth from 64 to 46 keV microm(-1). Relative biological effectiveness (RBE) of this neutron field using a response function for the microdosimetric spectrum was estimated to decrease from 3.6 to 2.9 with increasing depth.

Purpose: To evaluate the outcome according to treatment modality and prognostic factors in clinical Stage I and II intermediate- or high-grade B-cell lymphomas of the head and neck., Methods and Materials: We analyzed 155 patients treated between 1983 and 1997, excluding those with the Working Formulation low-grade lymphomas. Of these patients, 88 had Stage I and 67 had Stage II disease. Forty-one patients were treated with radiotherapy (RT) alone, and 114 patients were treated with a combination of RT and chemotherapy. Most of the chemotherapy regimens included anthracycline derivatives. More patients with Stage I disease and more patients with poor performance status were treated with RT alone. The treatment results were evaluated according to the new prognostic index B-ALPS, consisting of tumor bulk, age, lactate dehydrogenase level, performance status, and stage., Results: The 5-year overall and failure-free survival rate was 71.5% and 68.3%, respectively, for all 155 patients. The 5-year survival rate was 67% for those treated with RT alone and 73% for those treated with radiochemotherapy (p = 0.13). Among the various potential prognostic factors, age >60 years, World Health Organization performance status 2-4, and tumor size >or=6 cm were associated with poorer survival. The 5-year survival rate was 82% for those with no or one B-ALPS factor, 66% for those with two factors, and 49% for those with three or more factors (p <0.0001). The B-ALPS index appeared to predict the prognosis of these patients better than did the International Prognostic Index. No single prognostic factor was useful to identify patient groups more suitable to treatment with RT alone, but in patients with two B-ALPS risk factors, those treated with radiochemotherapy had a better survival rate and tended to have a better failure-free survival rate than those treated with RT alone., Conclusion: A proportion of patients with clinical Stage I or II head-and-neck B-cell lymphoma may be successfully treated with RT alone. B-ALPS is a useful prognostic index in this disease.

Single event spectra of a clinical carbon beam have been measured by an ultra-miniature tissue-equivalent proportional counter (UMC). In order to cover the energy range of the Bragg peak, the incident energy of the carbon beam was degraded by aluminium plates. Single event spectra for carbon-events incident to the UMC were analysed and selected at several carbon energies using thin scintillation counters. It was found that the dose weighted lineal energy distributions have a doublet peak structure due to incident carbon beam and fragment contributions.

Microdosimetric spectra were measured in order to gain the microdosimetric parameters of some epithermal neutron fields. Changes in dose mean lineal energy YD as a function of depth of heavy water showed a trend of softening with heavy water of the beam. The neutron absorbed dose was obtained by using the frequency mean lineal energy. Results show good agreement with measurements with the activation method using gold foil. This study demonstrated how microdosimetric parameters change in radiation quality as a function of heavy water depth.

We describe three cases of adult T-cell leukemia/lymphoma (ATLL) with duodenal involvement and provide a review of the literature. The first case, a 74-year-old woman with acute subtype of ATLL, had multiple polypoid lesions from the bulbus extending into the descending portion of the duodenum. The second case, a 70-year-old man with lymphoma subtype of ATLL, had a polypoid tumor in the descending portion of the duodenum and multiple protruded lesions in the small and large intestines. The third case, a 67-year-old man with lymphoma subtype of ATLL, had a flat-elevated lesion in the descending portion of the duodenum, as well as a gastric ulcerated lesion. Biopsies from these lesions showed mucosal invasion of ATLL cells in each case. All patients received combination chemotherapy, which was successful in the first and third cases, accompanied by the disappearance of gastroduodenal lesions.

Purpose: The incidence of gallbladder sludge or gallstone formation in bedridden patients with cerebrovascular disease (CVD) remains obscure. The aim of this study was to determine the incidence, relationship to feeding method, and mechanisms of gallbladder sludge and gallstone formation in elderly patients with CVD., Methods: Using ultrasonography, we determined the development of gallbladder sludge and gallstone over a 12-month period, the area of the gallbladder, the gallbladder contractile response to cerulein, and fasting levels of plasma cholecystokinin (CCK) in 40 bedridden elderly patients with CVD. The patients were divided into three groups based on the feeding method: oral ingestion (OI), nasogastric feeding (NF), and total parenteral nutrition (TPN)., Results: Gallbladder sludge and gallstone were not observed in any of the 14 OI patients, but occurred in 6 and 1 of the 11 NF patients, and in 14 and 3 of the 15 TPN patients, respectively. Fasting gallbladder areas were significantly larger in the TPN group than in the other two groups. The TPN group showed a marked decrease in cerulein-induced gallbladder contractility. Fasting plasma CCK levels were lower in the TPN group than in the OI group., Conclusions: Our results indicate that elderly patients with CVD confined to bed over long periods are not necessarily at risk of gallbladder sludge or gallstone formation, and the development of these features may be associated with the feeding method. The predisposition of CVD patients on TPN to gallbladder disease is probably caused by failure of gallbladder contraction, resulting from insufficient secretion of CCK and impaired sensitivity of the gallbladder to CCK.