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Summary: The vagus nerve is proposed to enable communication between the gut microbiome and the brain, but activity-based evidence is lacking. We find that mice reared germ-free exhibit decreased vagal tone relative to colonized controls, which is reversed via microbiota restoration. Perfusing antibiotics into the small intestines of conventional mice, but not germ-free mice, acutely decreases vagal activity which is restored upon re-perfusion with intestinal filtrates from conventional, but not germ-free, mice. Microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate indirectly stimulate vagal activity in a receptor-dependent manner. Serial perfusion of each metabolite class activates both shared and distinct neuronal subsets with varied response kinetics. Metabolite-induced and receptor-dependent increases in vagal activity correspond with the activation of brainstem neurons. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate vagal afferent neurons, thereby enabling the microbial modulation of chemosensory signals for gut-brain communication.

Background and Aims: The Cancer Genome Atlas (TCGA) project has identified HER2 mutations or amplification in 7% of colon cancers. In addition to HER2 mutations, colon cancer patients also possess co-occurring mutations in genes such as APC. Here, we investigated the role of HER2 and APC mutations on the crypt-villus architecture of the intestinal epithelium, localization of secretory cells, and expression of intestinal stem cell markers. Methods: We generated a HER2 transgenic mouse (HER2V777L Tg) possessing an activating mutation commonly found in colorectal cancer patients, HER2V777L, using transcription activator-like effector nucleases–based gene editing technology. We expressed the HER2V777L transgene in mouse small intestine and colon using Lgr5-Cre and Villin-Cre recombinases. In addition, we analyzed Lgr5-Cre; APCmin; HER2V777L Tg mice by morphologic and gene expression assays on intestinal sections and organoids derived from the epithelium. Results: HER2V777L expression resulted in hypertrophic crypt formation with expanded zones of proliferation. Proximal intestinal villi showed increased abundance of multiple differentiated lineages including extensive intermediate cell differentiation, as evidenced by MUC2/MMP7 co-immunofluorescence and transmission electron microscopy. HER2V777L expression in the context of APC loss resulted in further enhancement and expansion of the proliferative crypt compartment. Conclusions: We established an epithelial intrinsic role for HER2V777L on enhanced cellular proliferation. Additionally, we determined that HER2 and APC mutations, when combined, promote enhanced proliferation of intestinal crypts.

This study examined the training needs of agricultural extension workers on agroforestry in Cross River State. The study was specifically aimed at ascertaining the types of agroforestry systems practiced in the state, determining extension workers’ level of knowledge of the various agroforestry practices, determining the areas of training required by extension workers on agroforestry and ascertaining the challenges hampering extension workers’ active involvement in agroforestry activities. The area of the study was Cross River State, and the study sample consisted of 66 purposively selected extension workers in the state. Data were obtained using a validated semi-structured questionnaire and analyzed using the mean, standard deviation, percentages and binary logistic regression. The results revealed that snail farming (ranked = 1st), shelter belt/windbreak (ranked = 2nd) and aquaforestry (ranked = 3rd) etc were some of the most popular agroforestry practices in the area. It was also observed that extension workers in the state were very conversant with taungya farming (66.7%), improved fallow/shifting cultivation (74.1%) and shelter belt/windbreak (70.4%) among other agroforestry practices, but not too conversant with alley cropping, aquaforestry and integrated taungya farming. The results further showed that extension workers needed training in various areas of agroforesy practices, including effective communication skills, technical knowledge/skills, ecosystem management, start-up procedures and processing operations, and policy formation etc. However, the study noted that extension workers faced funding, training, manpower shortages and lack of government support challenges among others in participating in agroforestry. The study recommended the provision of agroforesty training to extension workers, improved government funding of extension services and increase in monthly salaries and special allowances for extension workers among others. [ABSTRACT FROM AUTHOR]

Objectives: To investigate who needs a careful postoperative monitoring for prostate cancer (PCa) after holmium laser enucleation of the prostate (HoLEP). We examined characteristics and oncological outcomes of HoLEP-related PCa., Methods: Patients who underwent HoLEP during 2002-2017 in a Japanese tertiary center were retrospectively analyzed. Patients were divided into non-PCa, PCa with HoLEP specimen (PCa-Ope), and PCa diagnosed during follow-up (PCa-Post). Outcomes of all HoLEP-related PCa were monitored., Results: Of the total 758, 60 (7.9%) were diagnosed with PCa from resected specimen of HoLEP and 9 (1.2%) were diagnosed postoperatively. Preoperative prostate-specific antigen (iPSA), postoperative PSA (pPSA), and PSA density were significantly higher in both PCa groups than those in non-PCa group. While iPSA significantly correlated to prostate volume (PV), pPSA was not associated with PV. A receiver-operating-characteristics curve demonstrated that pPSA 1.2 ng/mL achieved the optimal cut-off (AUC 0.95) for the incidence of PCa-Post. In addition to the incidence of PCa and iPSA, lower enucleation efficiency (enucleated volume /PV) was significantly associated with pPSA >1.2 ng/mL. Among PCa-Ope, 51 were Grade Group (GG) ≤2 and 42 were followed-up with active surveillance, whereas 8 of 9 PCa-Post were GG ≥3 and 2 progressed to death., Conclusions: Patients undergoing HoLEP are associated with some risk of potential PCa. While oncological outcomes were favorable among PCa-Ope, postoperative PSA should be carefully monitored even if not diagnosed with PCa with HoLEP specimen. Enucleation efficiency should be also considered not to misread pPSA value., (© 2023 The Japanese Urological Association.)

Introduction: Anterior segment duplicity with two lenses is a rare event which pathogenesis is still unknown. Different ocular and systemic abnormalities might be associated with such event., Case Observations: Hereby we describe a case of a 6-months female child referred to our service due to signs of ocular malformation in the left eye. The ocular exam showed a double anterior segment with twin lenses in one single eye, associated with double lamellar opacity and persistence of the two hyaloid arteries. The patient underwent surgical treatment with lensectomy and vitrectomy aiming visual stimulation and prevention of definitive visual loss secondary to amblyopia., Conclusion: In any case of ocular malformation, efforts to provide adequate visual stimulus are necessary to avoid amblyopia. In our case, the opacified lenses were removed, the patient adapted contact lenses and will be followed-up for visual stimulation at the ophthalmic pediatric division aiming the best visual prognosis possible.

Objectives: To investigate how much minimal residual membranous urethral length (mRUL) and maximal urethral length (MUL) measured on MRI preoperatively affect postoperative urinary incontinence (PUI) and recovery in robot-assisted radical prostatectomy (RARP) and open radical prostatectomy (ORP)., Methods: The subjects were 190 and 110 patients undergoing RARP and ORP, respectively, in our institution. Patients underwent preoperative MRI for prostate cancer evaluation and completed the quality of life questionnaire of the Expanded Prostate Cancer Index Composite instrument before and 1, 3, 6, and 12 months after surgery. The parameters of mRUL and MUL were measured on MRI and analyzed along with other parameters including age, body mass index, and nerve sparing., Results: The median mRUL and MUL were 7.81 and 14.27 mm in the RARP group and 7.15 and 13.57 mm in the ORP group, respectively. Recovery rates from PUI were similar in the two groups. Multivariate analyses showed that mRUL was a predictor of baseline continence, whereas shorter MUL was a predictor of poor recovery from PUI. Patients with both shorter mRUL and MUL had significantly worse recoveries from PUI after RARP and ORP than patients with longer mRUL and MUL., Conclusions: Minimal residual membranous urethral length contributes to urethral function as basal urinary continence, whereas MUL represents the potential of recovery from PUI in RARP and ORP. The MUL measured by preoperative MRI can predict poor recovery from PUI after radical prostatectomy and combined evaluation of MUL and mRUL support to anticipate poor recovery of PUI., (© 2022 The Japanese Urological Association.)

Background: Multiple medication use among older patients is reported to increase fracture risk. But this association is unclear in different subgroups and has not been confirmed by a case-crossover study, which can eliminate measurable and unmeasurable time-invariant confounders., Objective: To estimate the fragility fracture risk associated with concurrent use of multiple central nervous system (CNS) agents in older patients using a case-crossover design., Methods: This study targeted almost all patients aged ≥65 years in Japan who incurred fragility fractures from May 2013 to September 2014, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB Japan). Conditional logistic regression analysis estimated the risk of fragility fracture associated with the daily number of CNS agents, including subgroup analyses stratified by sex, age, and fracture location., Results: For 446,101 patients, the adjusted odds ratios (ORs) of fragility fracture increased almost linearly with number of CNS agents; 0, 0-1, 1-2, 2-3, 3-4, 4-5, and >5: OR reference, 1.21 (95% confidence interval, 1.18-1.23), 1.40 (1.35-1.46), 1.58 (1.49-1.67), 1.89 (1.74-2.05), 1.80 (1.60-2.03), and 1.90 (1.61-2.23; trend p < 0.001), respectively. A similar trend was observed for several subgroups, especially in males and those aged ≥85 years, showing marked linearity., Conclusions: The increased risk of fragility fracture associated with the use of multiple CNS agents was robust in older people in Japan., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Basal cell carcinoma of the prostate is a rare prostate malignancy. Its diagnosis and treatment have not been well established yet., Case Presentation: An 80-year-old man was referred to our hospital for undergoing holmium laser enucleation of the prostate with persistent lower urinary tract symptoms. Ultrasonography showed enlarged prostate (41.3 cc) with mid-lobe hypertrophy. His prostate-specific antigen and testosterone levels were 0.437 ng/mL and 873 ng/dL, respectively. Histological examination of the enucleated tissue confirmed basal cell carcinoma. The cells were positive for bcl-2, 34βE12, p63, and cytokeratin 5/6. Ki-67 labeling index was 5%. Subsequent staging computed tomography scan and bone scintigram showed neither lymph node nor distant metastasis. Currently, the patient is under close follow-up with imaging, endoscopy, and urodynamic study., Conclusion: It is difficult for physicians to detect prostate basal cell carcinoma before benign prostatic hyperplasia surgery. In case of organ-confined disease, age and Ki-67 labeling index could be suggestive of subsequent treatment decision-making., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)

Aims/introduction: Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear., Materials and Methods: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m 2 and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated., Results: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption., Conclusions: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Central nervous system (CNS) agents cause fractures among the elderly, but fracture risks of a wide range of CNS agent classes have not been analyzed in a study with the same population and definitions of variables. This study aimed to estimate the degree of fragility fracture risk of a wide range of CNS agent classes in elderly Japanese people. A case-crossover design study, with a case window and three control windows of 3 d each, as well as longer windows up to 15 d, was conducted among opioid non-users who lived without hospitalization for ≥13 months and incurred fragility fractures at ≥65 years of age, using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Conditional logistic regression estimated adjusted odds ratios (ORs) of CNS agent classes for fragility fractures for groups including and excluding users of pro re nata CNS agents (PRN-CNS agents) and for windows of 3-15 d. Antiepileptic agents had the highest adjusted ORs, 2.4 (95% confidence interval 2.3-2.5) for the group including PRN-CNS agent users (n = 446101). The next-highest classes were anti-dementia agents 1.5 (1.5-1.6), antipsychotics 1.5 (1.4-1.6), anti-Parkinson agents 1.3 (1.2-1.5), and antidepressants 1.1 (1.1-1.2). Similar ORs were found when PRN-CNS agent users were excluded (n = 352828), and slightly higher ORs were found for longer windows, with almost the same order of classes. Elderly individuals who use antiepileptic agents or a combination of antiepileptic agents and CNS agent classes with the next-highest ORs should be carefully monitored.

A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m 2 . Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000-1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12.06% vs. -3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

In addition to autophagy, proteasomes are critical for regulating intracellular protein levels and removing misfolded proteins. The 20S proteasome (20SPT), the central catalytic unit, is sometimes flanked by regulatory units at one or both ends. Additionally, proteosomal activation has been associated with increased lifespan in many organisms. Our group previously reported that the gating (open/closed) of the free 20S proteasome is redox controlled, and that S-glutathionylation of two Cys residues (Cys76 and Cys221) in the α5 subunit promotes gate opening. The present study constructed site-directed mutants of these Cys residues, and evaluated the effects these mutations have on proteosome gate opening and yeast cell survival. Notably, the double mutation of both Cys residues (Cys76 and Cys221) rendered the cells nonviable, whereas the lifespan of the yeast carrying the single mutations (α5-C76S or α5-C221S) was attenuated when compared to the wild type counterpart. Furthermore, it was found that α5-C76S or α5-C221S 20SPT were more likely to be found with the gate in a closed conformation. In contrast, a random α5-subunit double mutation (S35P/C221S) promoted gate opening, increased chronological lifespan and provided resistance to oxidative stress. The 20SPT core particle purified from the long-lived strain degraded model proteins (e.g., α-synuclein) more efficiently than preparations obtained from the wild-type counterpart, and also displayed an increased chymotrypsin-like activity. Mass spectrometric analyses of the C76S, C221S, S35P/C221S, S35P and S35P/C76S mutants provided evidence that the highly conserved Cys76 residue of the α5-subunit is the key determinant for gate opening and cellular survival. The present study reveals a sophisticated regulatory mechanism that controls gate opening, which appears to be based on the interactions among multiple residues within the α5-subunit, and consequently impacts the lifespan of yeast., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fragility fractures associated with age-related bone loss are of urgent concern worldwide because they reduce QOL and pose financial burdens for health care services. Currently, national data in Japan are limited. This study provides quantitative data for older patients throughout Japan who, although otherwise relatively healthy, sustained fragility fractures and were hospitalized for them. The National Database of Health Insurance Claims and Specific Health Checkups of Japan was accessed to target patients aged 65 years or older who sustained fractures between May 2013 and September 2014 and were not hospitalized for at least 13 months prior to fracture. We investigated whether the first fracture sustained was fragility related at any of four locations (proximal humerus, distal radius, vertebra, or femoral neck) and whether it necessitated hospitalization. Fragility fractures were identified in 490138 of 1188754 patients (41.2%, 345980 patients/year; 1 : 4 male-to-female ratio). Regardless of gender, vertebral fractures were most common across the age cohorts studied (43286 males and 162767 females/year), and femoral neck fractures increased markedly with increased patient age. Approximately 80% of patients with femoral neck fractures were hospitalized (62.3% of males, 71.1% of females) compared with up to 10.4% of patients with other fragility fractures. Data provided in this study can be used as a baseline for evaluating the health economy and establishing health policy in Japan.

Aim: Pneumonia is a common disease that is often fatal, particularly in older persons. Dysphagia is known to be closely associated with aspiration pneumonia, and hospitalized patients with aspiration pneumonia often have difficulty with oral intake. However, the relationship between acquisition of oral intake and detailed swallowing data has not been explored. The purpose of the present study was to examine the predictors, including videofluoroscopic swallowing evaluation, for achieving oral intake in older patients with aspiration pneumonia., Methods: This study included older patients, aged ≥65 years, who were admitted to Kawasaki Municipal Hospital (Kawasaki, Japan) from April 2012 through March 2014 as a result of aspiration pneumonia. Factors likely related to oral intake, including swallowing, nutritional, metabolic, and functional status, pneumonia severity and comorbidities were extracted from the medical records. Multiple logistic regression analysis was carried out to identify independent predictors for acquisition of oral intake., Results: A total of 160 patients were assigned to either the "oral intake" group (n = 104) or the "non-oral intake" group (n = 56). Multiple regression analysis showed that a low penetration aspiration scale on videofluoroscopy using 3 mL of moderately thick liquid water with tilting 30-60°, high albumin values, short duration of non-oral intake and a high Food Intake Level Scale score before admission were significantly associated with achievement of oral intake., Conclusions: Aspiration on videofluoroscopy, swallowing status before admission, nutritional status and duration of non-oral intake are important factors for acquiring oral intake. These results might be helpful for the management of older patients with aspiration pneumonia. Geriatr Gerontol Int 2018; 18: 1469-1473., (© 2018 Japan Geriatrics Society.)

Because growth hormone (GH) secretion is reportedly decreased in obese patients, we examined not only the factors associated with the decreased GH secretion but also GH response to the GH-releasing peptide (GHRP)-2-load test before and after laparoscopic gastrectomy (LSG). The study comprised 28 individuals aged 19-65 years [mean body mass index (BMI), 39.4 ± 9.4 kg/m 2 ]. In the univariate analysis, GH secretion peaks correlated negatively with BMI (r = -0.59, p = 0.001), visceral adipose tissue (r = -0.47, p = 0.005), and subcutaneous adipose tissue (r = -0.40, p = 0.04). In the two obese patients, the response to the GHRP-2-load test markedly improved by weight loss 12 months after LSG. In conclusion, GH secretion was decreased in obese patients and improved by LSG.

Some patients do not inform healthcare professionals of adverse drug reactions (ADRs) because they fear termination of aggressive medication therapies. Preferences for aggressive medication therapies may differ between patients and pharmacists. The goal of this study was to estimate whether pharmacists were able to accurately assess patient preference for aggressive medication therapies with potentially stronger ADRs. A cross-sectional study was conducted of hospitalized patients (35 to 74 years of age) receiving oral medications for a chronic disease or systemic chemotherapy at three hospitals in Japan. We estimated the extent of agreement between patient responses and pharmacist predictions using a scenario-based investigation (1) to examine the choice between an aggressive medication therapy and the standard therapy, and (2) to assess increased life expectancy as a result of aggressive medication therapy. The extent of agreement was estimated using the kappa statistic. Of 113 patients, 43 (38.1%) chose the aggressive medication therapy. Pharmacists correctly predicted the choice of 25 (58.1%) of these patients [kappa 0.32 (95% confidence interval 0.15-0.50)]. Of 111 patients, 42 (37.8%) expected one additional life expectancy year. However, pharmacists predicted that as many as 36 (85.7%) of these patients would require more years of added life expectancy before choosing an aggressive medication therapy [kappa 0.24 (0.08-0.40)]. Agreement between patients and pharmacists on the choice of aggressive medication therapy was generally poor. Pharmacists should make an effort to identify patients who might prefer more aggressive medication therapies with potentially stronger ADRs in order to minimize ADR risk.

In 1988, the late Prof. Rikimaru Hayashi had first proposed "Use of High Pressure in Food", introducing his views, i.e., "heat and pressure are independently capable of transforming the state of a substance, and such state transforming factors are only heat and pressure in nature." Sc. D. Masaru Nakahara stated in his note that he had been impressed by the unique starting point of Prof. Hayashi's idea. Prof. Hayashi had explored some good method for food processing without using heat, so he alternatively thought of high-pressure treatment (Hayashi R (1989) Use of high pressure to food processing and preservation. In: Hayashi R (ed) Use of high pressure in food. San-Ei Publishing Co, Kyoto, pp 1-30; Nakahara M (1990) Water and ions at high pressure: their fundamental properties relevant to the pressure treatment to food. In: Hayashi R (ed) Pressure-processed food--research and development. San-Ei Publishing Co, Kyoto, pp 3-21). Since the start-up of Japanese research group of high pressure in biological field (the present "Japanese Research Group of High Pressure Bioscience and Biotechnology (JHPBB)") and "International Association of High Pressure Bioscience and Biotechnology (IAHPBB)", we have continued to research into the industrial use of high-pressure treatment over a period of 25 years to realize our dream, that is, the same as Prof. Hayashi's dream. Although heat and pressure were found to be independent factors capable of transforming the state of a substance, use of heat has been overwhelmingly more frequent in food processing up to now. However, the pressure treatment has the advantages of instantaneous transmission, uniform distribution in vessels, and ability of inducing uniform change in quality. The high-pressure treatment does not cause cleavage of the covalent bond in the substance, thereby lessening the decomposition of nutrients, the generation of offensive smell, and the production of abnormal materials when compared with the heat application. In addition, energy consumption in the high-pressure treatment is less than that in the heat treatment. For the reasons mentioned above, the high-pressure treatment has thus been regarded as suitable for future food processing, and much attention has been paid to the researches of high-pressure treatment again. Then, we reviewed the previous researches in which little interest had been taken because of imperfectness of non-heat sterilization. Surprisingly, we discovered some novel findings about the effect of high-pressure treatment, that is, pressure history on the subsequent event. Then, we decided to present two theses on the themes, "Application of High-pressure Treatment to Enhancement of Functional Components in Agricultural Products" and "Application of High-pressure Treatment to Development of Sterilized Foods".

Protein S-glutathionylation is a post-translational modification that controls many cellular pathways. Recently, we demonstrated that the α5-subunit of the 20S proteasome is S-glutathionylated in yeast cells grown to the stationary phase in rich medium containing glucose, stimulating 20S core gate opening and increasing the degradation of oxidized proteins. In the present study, we evaluated the correlation between proteasomal S-glutathionylation and the intracellular redox status. The redox status was controlled by growing yeast cells in distinct carbon sources which induced respiratory (glycerol/ethanol) or fermentative (glucose) metabolism. Cells grown under glycerol/ethanol displayed higher reductive power when compared to cells grown under glucose. When purified from cells grown in glucose, 20S proteasome α5-subunit exhibited an intense anti-glutathione labeling. A higher frequency of the open catalytic chamber gate was observed in the S-glutathionylated preparations as demonstrated by transmission electron microscopy. Therefore, cells that had been grown in glucose displayed an increased ability to degrade oxidized proteins. The results of the present study suggest that 20S proteasomal S-glutathionylation is a relevant adaptive response to oxidative stress that is capable to sense the intracellular redox environment, leading to the removal of oxidized proteins via a process that is not dependent upon ubiquitylation and ATP consumption., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Network polymers of cobaltporphyrin derivatives are prepared by a facile click reaction via the Michael addition of acetoacetate-substituted tetraphenyl cobaltporphyrin and tri- or tetra-acrylates. The conversion is saturated for 1 h in the presence of a catalyst, which almost reaches the same gelation point of the formed network polymers. Deeply and homogeneously red-colored membranes with a sub-micrometer thickness are yielded on a porous supporting membrane. They are still tough even with a very high content of the rigid porphyrin residue. The oxygen permeability is high, at 10-100 Barrer, and the oxygen/nitrogen permselectivity (PO2/PN2) is significantly enhanced with the porphyrin content reaching 30, for the membranes with ca. 70 wt% porphyrin content., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Radiation dose rates were evaluated in three areas neighboring a restricted area within a 20- to 50-km radius of the Fukushima Daiichi Nuclear Power Plant in August-September 2012 and projected to 2022 and 2062. Study participants wore personal dosimeters measuring external dose equivalents, almost entirely from deposited radionuclides (groundshine). External dose rate equivalents owing to the accident averaged 1.03, 2.75, and 1.66 mSv/y in the village of Kawauchi, the Tamano area of Soma, and the Haramachi area of Minamisoma, respectively. Internal dose rates estimated from dietary intake of radiocesium averaged 0.0058, 0.019, and 0.0088 mSv/y in Kawauchi, Tamano, and Haramachi, respectively. Dose rates from inhalation of resuspended radiocesium were lower than 0.001 mSv/y. In 2012, the average annual doses from radiocesium were close to the average background radiation exposure (2 mSv/y) in Japan. Accounting only for the physical decay of radiocesium, mean annual dose rates in 2022 were estimated as 0.31, 0.87, and 0.53 mSv/y in Kawauchi, Tamano, and Haramachi, respectively. The simple and conservative estimates are comparable with variations in the background dose, and unlikely to exceed the ordinary permissible dose rate (1 mSv/y) for the majority of the Fukushima population. Health risk assessment indicates that post-2012 doses will increase lifetime solid cancer, leukemia, and breast cancer incidences by 1.06%, 0.03% and 0.28% respectively, in Tamano. This assessment was derived from short-term observation with uncertainties and did not evaluate the first-year dose and radioiodine exposure. Nevertheless, this estimate provides perspective on the long-term radiation exposure levels in the three regions.

The proteasome is a multimeric and multicatalytic intracellular protease responsible for the degradation of proteins involved in cell cycle control, various signaling processes, antigen presentation, and control of protein synthesis. The central catalytic complex of the proteasome is called the 20S core particle. The majority of these are flanked on one or both sides by regulatory units. Most common among these units is the 19S regulatory unit. When coupled to the 19S unit, the complex is termed the asymmetric or symmetric 26S proteasome depending on whether one or both sides are coupled to the 19S unit, respectively. The 26S proteasome recognizes poly-ubiquitinylated substrates targeted for proteolysis. Targeted proteins interact with the 19S unit where they are deubiquitinylated, unfolded, and translocated to the 20S catalytic chamber for degradation. The 26S proteasome is responsible for the degradation of major proteins involved in the regulation of the cellular cycle, antigen presentation and control of protein synthesis. Alternatively, the proteasome is also active when dissociated from regulatory units. This free pool of 20S proteasome is described in yeast to mammalian cells. The free 20S proteasome degrades proteins by a process independent of poly-ubiquitinylation and ATP consumption. Oxidatively modified proteins and other substrates are degraded in this manner. The 20S proteasome comprises two central heptamers (β-rings) where the catalytic sites are located and two external heptamers (α-rings) that are responsible for proteasomal gating. Because the 20S proteasome lacks regulatory units, it is unclear what mechanisms regulate the gating of α-rings between open and closed forms. In the present review, we discuss 20S proteasomal gating modulation through a redox mechanism, namely, S-glutathionylation of cysteine residues located in the α-rings, and the consequence of this post-translational modification on 20S proteasomal function.

Bone marrow-derived mesenchymal stem cells (MSCs) are reported to contribute to formation of tumor-promoting stromal cells. We reported recently that, in an orthotopic nude mice model of colon cancer, MSCs traveled to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells. We also found that CAFs express platelet-derived growth factor receptor (PDGFR) at a high level and that imatinib therapy targeting PDGFR in CAFs inhibits growth and metastasis of human colon cancer. These findings led us to examine whether the tumor-promoting effect of MSCs is impaired by blockade of PDGFR signaling achieved with imatinib. Orthotopic transplantation and splenic injection of human MSCs along with KM12SM human colon cancer cells, in comparison with transplantation of KM12SM cells alone, resulted in significantly greater promotion of tumor growth and liver metastasis. The KM12SM + MSC xenograft enhanced cell proliferation and angiogenesis and inhibited tumor cell apoptosis. When tumor-bearing animals were treated with imatinib, there was no significant increase in primary tumor volume or total volume of liver metastases, despite the KM12SM+MSC xenograft, and survival in the mixed-cell group was prolonged by imatinib treatment. Moreover, the ability of MSCs to migrate to tumor stroma was impaired, and the number of MSCs surviving in the tumor microenvironment was significantly decreased. In in vitro experiments, treatment with imatinib inhibited migration of MSCs. Our data suggest that blockade of PDGF signaling pathways influences the interaction between bone marrow-derived MSCs and tumor cells in the tumor microenvironment and, hence, inhibits the progressive growth of colon cancer., (Copyright © 2012 UICC.)

A 53-year-old man was referred to our hospital with bloody stool. Barium enema study and colonoscopy revealed multiple small nodules on the anterior wall of the lower rectum. Biopsy specimens showed proliferation of atypical lymphoid cells forming the nodules. Mucosa-associated lymphoid tissue lymphoma was diagnosed on the basis of histologic and immunohistochemical examinations. No metastasis was detected in lymph nodes or distant organs, indicative of clinical stage I disease. Although the test results were negative for Helicobacter pylori, eradication therapy was performed. The lesion disappeared completely within 9 months after the triple antibiotic therapy. H. pylori eradication therapy may be a useful treatment option regardless of H. pylori status.