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Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters—diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel–Lindau (VHL) disease—and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of “neuroendocrine tumor” (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published. Supplementary Information The online version contains supplementary material available at 10.1007/s00535-021-01827-7.

Aims Abnormal compositional changes in low-density lipoprotein (LDL) particles, such as triglyceride (TG) enrichment and size reduction, are common in patients with diabetes. Several cohort studies have demonstrated that LDL-TG and sdLDL-cholesterol (C) are sensitive biomarkers for predicting atherosclerotic cardiovascular diseases beyond LDL-C. Although sdLDL has been extensively studied, little is known about the properties of LDL-TG. We investigated similarities or differences between LDL-TG and sdLDL-C. Methods Fasting plasma was obtained from 1,085 patients with type 2 diabetes who were enrolled in the diabetes regional cohort study (ViNA Cohort). LDL-TG and sdLDL-C concentrations were measured using a homogeneous assay established by us. In a subset of subjects, LDL-TG and sdLDL-C levels were measured postprandially or after treatment with lipid-lowering drugs. Results In a quartile analysis, higher LDL-TG quartiles were associated with higher frequency of female and fibrate users, whereas sdLDL-C quartiles were associated with frequency of men, drinking, and metabolic syndrome-related measurements. Higher quartiles of LDL-TG/LDL-C were associated with smoking, drinking, fibrate users, and statin users. LDL-TG was significantly correlated with TG, LDL-C, sdLDL-C, and apolipoprotein (apo) B, with apoB being the primary determinant. LDL-TG correlated to high sensitive C-reactive protein (CRP) independently of other lipids. Mean LDL-TG did not change with fasting/non-fasting. Statin treatment reduced LDL-TG, whereas fibrates increased it, but these drugs reduced sdLDL-C equally. Conclusions LDL-TG levels were more tightly regulated by the number of LDL particles than plasma TG levels were. SdLDL-C was closely associated with metabolic syndrome-related factors, whereas LDL-TG was associated with low-grade systemic inflammation.

Some patients with diabetic kidney disease (DKD) show a fast progression of kidney dysfunction and are known as a "fast decliner" (FD). Therefore, it is critical to understand pathomechanisms specific for fast decline. Here, we performed a comprehensive metabolomic analysis of patients with stage G3 DKD and identified increased urinary lysophosphatidylcholine (LPC) in fast decline. This was confirmed by quantification of urinary LPC using mass spectrometry and identified urinary LPC containing saturated fatty acids palmitic (16:0) and stearic (18:0) acids was increased in FDs. The upsurge in urinary LPC levels was correlated with a decline in estimated glomerular filtration rate after 2.5 years. To clarify a pathogenic role of LPC in FD, we studied an accelerated rat model of DKD and observed an increase in LPC (16:0) and (18:0) levels in the urine and kidney tubulointerstitium as the disease progressed. These findings suggested that local dysregulation of lipid metabolism resulted in excessive accumulation of this LPC species in the kidney. Our in vitro studies also confirmed LPC-mediated lipotoxicity in cultured proximal tubular cells. LPC induced accumulation of lipid droplets via activation of peroxisome proliferator-activated receptor-δ followed by upregulation of the lipid droplet membrane protein perilipin 2 and decreased autophagic flux, thereby inducing organelle stress and subsequent apoptosis. Thus, LPC (16:0) and (18:0) may mediate a fast progression of DKD and may serve as a target for novel therapeutic approaches.

Background: Insulin resistance is a well-known predictor and risk factor for Type 2 Diabetes Mellitus (T2DM). Higher hematocrit induced by higher insulin resistance affects blood rheology. Objective: This study intended to reveal the association between indices of insulin resistance and hemorheological parameters during a 75 g oral glucose tolerance test (75-g OGTT). Methods: A total of 575 healthy young Japanese participants took 75-g OGTT. We then analyzed the association between insulin resistance indices and hematological parameters. Results: The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was significantly correlated with hematocrit (Ht), hemoglobin (Hb), Red Blood Cell (RBC), White Blood Cell (WBC), platelet count, lipid parameters, and Body Mass Index (BMI). The Matsuda index was negatively correlated with RBC count, WBC count, platelet count, Total Cholesterol (TC), Low-Density Lipoprotein-Cholesterol (LDL-C), triglyceride (TG), and positively correlated with High-Density Lipoprotein-Cholesterol (HDL-C). The disposition index was negatively correlated with Hb, RBC count, LDL-C, and BMI, while remaining positively correlated with HDL-C. The Homeostasis Model Assessment of beta cell (HOMA- IR ) was positively correlated with WBC count, platelet count, TC, LDL-C, and TG. The insulinogenic index was positively correlated with WBC count, platelet count, and TC. Multiple regression analysis revealed that HOMA-IR was independently associated with TG, and the Matsuda index was independently associated with TG, WBC count, and platelet count. The insulinogenic index was independently associated with WBC count. Conclusion: Cardinal rheological parameters reflected insulin resistance and were released even in the young, healthy Japanese individuals within the physiological range of glycemic control.

Significance: In vivo assessment of paramagnetic and diamagnetic conversions of nitroxyl radicals based on cyclic redox mechanism can be an index of tissue redox status. The redox mechanism of nitroxyl radicals, which enables their use as a normal tissue-selective radioprotector, is seen as being attractive on planning radiation therapy. Recent Advances: In vivo redox imaging using nitroxyl radicals as redox-sensitive contrast agents has been developed to assess tissue redox status. Chemical and biological behaviors depending on chemical structures of nitroxyl radical compounds have been understood in detail. Polymer types of nitroxyl radical contrast agents and/or nitroxyl radical-labeled drugs were designed for approaching theranostics. Critical Issues: Nitroxyl radicals as magnetic resonance imaging (MRI) contrast agents have several advantages compared with those used in electron paramagnetic resonance (EPR) imaging, while support by EPR spectroscopy is important to understand information from MRI. Redox-sensitive paramagnetic contrast agents having a medicinal benefit, that is, nitroxyl-labeled drug, have been developed and proposed. Future Directions: A development of suitable nitroxyl contrast agent for translational theranostic applications with high reaction specificity and low normal tissue toxicity is under progress. Nitroxyl radicals as redox-sensitive magnetic resonance contrast agents can be a useful tool to detect an abnormal tissue redox status such as disordered oxidative stress. Antioxid. Redox Signal. 36, 95–121.

Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.

The aryl hydrocarbon receptor (AHR) pathway modulates the immune system in response to kynurenine, an endogenous tryptophan metabolite. IDO1 and TDO2 catalyze kynurenine production, which promotes cancer progression by compromising host immunosurveillance. However, it is unclear whether the AHR activation regulates the malignant traits of cancer such as metastatic capability or cancer stemness. Here, we carried out systematic analyses of metabolites in patient‐derived colorectal cancer spheroids and identified high levels of kynurenine and TDO2 that were positively associated with liver metastasis. In a mouse colon cancer model, TDO2 expression substantially enhanced liver metastasis, induced AHR‐mediated PD‐L1 transactivation, and dampened immune responses; these changes were all abolished by PD‐L1 knockout. In patient‐derived cancer spheroids, TDO2 or AHR activity was required for not only the expression of PD‐L1, but also for cancer stem cell (CSC)‐related characteristics and Wnt signaling. TDO2 was coexpressed with both PD‐L1 and nuclear β‐catenin in colon xenograft tumors, and the coexpression of TDO2 and PD‐L1 was observed in clinical colon cancer specimens. Thus, our data indicate that the activation of the TDO2‐kynurenine‐AHR pathway facilitates liver metastasis of colon cancer via PD‐L1–mediated immune evasion and maintenance of stemness., We carried out systematic analyses of metabolites in patient‐derived colorectal cancer spheroids, and identified high levels of kynurenine and TDO2 that were positively associated with liver metastasis. Our data indicate that the activation of the TDO2‐kynurenine‐AHR pathway may lead to emergence of immune‐evasive cancer stem cells (CSCs) promoting liver metastasis.

Background/aim We describe a pharmacological strategy for selectively targeting glioblastoma using a redox-active combination drug menadione/ascorbate (M/A), compared to the chemotherapeutic standard-of-care temozolomide (TMZ). Materials and methods Experiments were conducted on glioblastoma mice (GS9L cell transplants - intracranial model), treated with M/A or TMZ. Tumor growth was monitored by magnetic resonance imaging. Effects of M/A and TMZ on cell viability and overproduction of mitochondrial superoxide were also evaluated on isolated glioblastoma cells (GS9L) and normal microglial cells (EOC2). Results M/A treatment suppressed tumor growth and increased survival without adverse drug-related side effects that were characteristic of TMZ. Survival was comparable with that of TMZ at the doses we have tested so far, although the effect of M/A on tumor growth was less pronounced than that of TMZ. M/A induced highly specific cytotoxicity accompanied by dose-dependent overproduction of mitochondrial superoxide in glioblastoma cells, but not in normal microglial cells. Conclusion M/A differentiates glioblastoma cells from normal microglial cells, causing redox alterations and oxidative stress only in the tumor. This easier-to-tolerate treatment has a potential to support the surgery and conventional therapy of glioblastoma.

Ras genes are frequently mutated in many cancer types; however, there are currently no conclusively effective anticancer drugs against Ras-induced cancer. Therefore, the downstream effectors of Ras signaling need to be identified for the development of promising novel therapeutic approaches. We previously reported that oncogenic Ras induced the expression of NF-HEV/IL-33, a member of the interleukin-1 family, and showed that intracellular IL-33 was required for oncogenic Ras-induced cellular transformation. In the present study, we demonstrated that the c-Mer proto-oncogene tyrosine kinase (MerTK), a receptor tyrosine kinase, played essential roles in oncogenic Ras/IL-33 signaling. The expression of MerTK was enhanced in transformed NIH-3T3 cells by the expression of oncogenic Ras, H-Ras (G12V), in an IL-33-dependent manner. In human colorectal cancer tissues, MerTK expression also correlated with IL-33 expression. The knockdown of IL-33 or MerTK effectively attenuated the migration of NIH-3T3 cells transformed by H-Ras (G12V) and A549, LoVo, and HCT116 cells harboring an oncogenic K-Ras mutation. Furthermore, the suppression of Ras-induced cell migration by the knockdown of IL-33 was rescued by the enforced expression of MerTK. The present results also revealed that MerTK was effectively phosphorylated in NIH-3T3 cells transformed by Ras (G12V). Ras signaling was essential for the tyrosine phosphorylation of MerTK, and the kinase activity of MerTK was indispensable for accelerating cell migration. Collectively, the present results reveal a novel role for MerTK in cancer malignancy, which may be utilized to develop novel therapeutic strategies that target Ras-transformed cells.

AIMS/INTRODUCTION Diabetic kidney disease (DKD) exacerbates dyslipidemia and increases the incidence of atherosclerotic cardiovascular disease. DKD is a concept that includes typical diabetic nephropathy and an atypical phenotype without proteinuria. We investigated dyslipidemia in different DKD phenotypes that have not been fully studied. MATERIALS AND METHODS Fasting plasma was obtained from 1,073 diabetes patients enrolled in the regional diabetes cohort (ViNA cohort). Non-proteinuric and proteinuric DKD were defined as an estimated glomerular filtration rate 300 mg/g. Novel lipid risk factors, low-density lipoprotein (LDL) triglyceride (TG) and small dense LDL cholesterol were measured using our established homologous assay. RESULTS The proportion of atherosclerotic cardiovascular disease patients was higher in non-proteinuric DKD and even higher in proteinuric DKD than in non-DKD. Increased estimated glomerular filtration rate grade and albuminuric stage were independently correlated with higher TG, TG-rich lipoprotein cholesterol and apolipoprotein CIII. Therefore, proteinuric DKD had the highest of these levels. Small dense LDL cholesterol and LDL-TG were higher in the proteinuria without renal dysfunction group in the lipid-lowering drug-free subset. Lipoprotein(a) was higher in DKD regardless of proteinuria. CONCLUSIONS Proteinuria was associated with an atherogenic subspecies of LDL, whereas renal dysfunction was associated with increased lipoprotein(a). Proteinuria and renal dysfunction independently exacerbated TG-rich lipoprotein-related dyslipidemia. This is in good agreement with the results of large-scale clinical studies in which proteinuria and renal dysfunction synergistically increased the risk of atherosclerotic cardiovascular disease in populations with diabetes.

The adsorption properties of Pu(IV), Am(III), Cm(III), and U(VI) on desferrioxamine B-immobilized micropolymeric resin (DMPs) and adsorbed species were elucidated using thermodynamic constants and log β values. This allowed the determination of adsorption characteristics (91, 95, 88, and 97% for Pu(IV), Am(III), Cm(III), and U(VI), respectively) and individual pH-independent adsorption properties. Pu(IV) could be separated from Am(III), Cm(III), and U(VI) at pH 2. The separation of Pu(IV) from Am(III), Cm(III), and U(VI) was achieved by controlling the pH of the solution using a single resin.

Oral malignant melanoma, which frequently invades the hard palate or maxillary bone, is extremely rare and has a poor prognosis. Bone morphogenetic protein (BMP) is abundantly expressed in bone matrix and is highly expressed in malignant melanoma, inducing an aggressive phenotype. We examined the role of BMP signaling in the acquisition of an aggressive phenotype in melanoma cells in vitro and in vivo. In five cases, immunohistochemistry indicated the phosphorylation of Smad1/5 (p-Smad1/5) in the nuclei of melanoma cells. In the B16 mouse and A2058 human melanoma cell lines, BMP2, BMP4, or BMP7 induces morphological changes accompanied by the downregulation of E-cadherin, and the upregulation of N-cadherin and Snail, markers of epithelial-mesenchymal transition (EMT). BMP2 also stimulates cell invasion by increasing matrix metalloproteinase activity in B16 cells. These effects were canceled by the addition of LDN193189, a specific inhibitor of Smad1/5 signaling. In vivo, the injection of B16 cells expressing constitutively activated ALK3 enhanced zygoma destruction in comparison to empty B16 cells by increasing osteoclast numbers. These results suggest that the activation of BMP signaling induces EMT, thus driving the acquisition of an aggressive phenotype in malignant melanoma.

Summary Objective Low molecular weight compounds that reduce the expression of MMP13 at the mRNA level might serve as disease-modifying osteoarthritis (OA) drugs (DMOADs). The objective of this study was to identify a candidate DMOAD that targets MMP13 expression. Design High-throughput screening was performed to identify compounds that suppress inflammatory cytokine-induced MMP13 expression. Ingenuity pathway analysis (IPA) using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was conducted to identify signaling pathways related to cytokines. MMP13 expression in chondrocytes was evaluated through RT-qPCR and western blotting analyses. Additionally, 10-week-old mice were subjected to destabilization of the medial meniscus (DMM) surgery to induce OA and were sacrificed 12 weeks post-surgery for pathological examination. OA was evaluated using the OARSI scoring system. Results Colchicine was identified as a DMOAD candidate as it inhibited inflammatory cytokine-induced MMP13 expression in vitro, and the colchicine-administered mice with DMM presented significantly lower OARSI scores (adjusted P: 0.0242, mean difference: 1.6, 95% confidence interval (CI) of difference: 0.1651–3.035) and significantly lower synovial membrane inflammation scores (adjusted P: 0.0243, mean difference: 0.6, 95% CI of difference: 0.06158–1.138) than mice with DMM. IPA further revealed that components of the Rho signaling pathways are regulated by cytokines and colchicine. IL-1β and TNF-α activate RAC1 and SRC signals, respectively, leading to the phosphorylation of PLC-γ1 and synergistic induction of MMP13 expression. Most notably, colchicine abrogates inflammatory cytokine-induced phosphorylation of PLC-γ1, leading to the induction of MMP13 expression. Conclusions Colchicine is a potential DMOAD candidate that inhibits MMP13 expression and consequent cartilage degradation by disrupting the SRC/RAC1-phospho-PLCγ1-Ca2+ signaling pathway.

We investigated the amount of polyphenols present in three types of stone fruits (peaches, plums, and prunes) that were produced in Japan during 2018 and 2019 using reversed-phase high-performance ...

Metal string complexes, linearly aligned transition metal arrays coordinated with the multidentate organic ligands, have gained much attention both in unique electronic/structural properties and in potential applications as conductive molecular nanowires. Here we report on a dimerized NiII trinuclear complex, [Ni6Cl2(dpa)8](I5)2·0.25I2 (dpa- = 2,2'-dipyridylamide anion). X-ray structural analysis revealed that two trinuclear moieties are bridged by a Cl anion to form a dimerized string structure. This is the first example of two Ni string complexes that are connected. In the electronic absorption and Raman spectra, characteristic absorption bands and a vibration mode based on the dimer string structure were observed. In the solid state, dimer complexes align in one dimension in an MMMXMMMX (M = metal, X = halogen) manner, leading to the intra- and interdimer antiferromagnetic interactions.

Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naive T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.

This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. Ovarian, fallopian tube or primary peritoneal cancer patients with stage III–IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. Twenty-four patients were included in this study. The median age was 55.5 years (37–80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7–92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.

The exploration of mechanochemical reactions has brought new opportunities for the design of functional materials. We synthesized the novel organic peroxide mechanophore bis(9-methylphenyl-9-fluorenyl) peroxide (BMPF) and examined its mechanochromic properties. The mechanism behind its mechanofluorescence was clarified and harnessed in polymer networks that can release the small fluorescent molecule 9-fluorenone upon exposure to a mechanical stimulus. Additionally, polymer networks cross-linked with BMPF units are able to tolerate temperatures up to 110 °C without any change in optical properties or mechanical strength. As mechanophores based on organic peroxide have rarely been documented so far, these fascinating results suggest excellent potential for applications of BMPF in stress-responsive materials. The mechanochemical protocol demonstrated here may provide guiding principles to expand the field of mechanochromic peroxides.

Sericin, which is derived from the outer layer of silk thread proteins of the common silkworm (Bombyx mori), functions as a glue to fix fibers of developing cocoons. Although sericin has potential ...

Naoto Tani,1,2 Tomoya Ikeda,1,2 Tatsuya Hirokawa,1,2 Yayoi Aoki,1 Alissa Shida,1 Kei Ikeda,1 Fumiya Morioka,1 Takaki Ishikawa1,2 1Department of Legal Medicine, Osaka City University Medical School, Osaka, 545-8585, Japan; 2Forensic Autopsy Section, Medico-Legal Consultation and Postmortem Investigation Support Center, C/O Department of Legal Medicine, Osaka City University Medical School, Osaka, 545-8585, JapanCorrespondence: Naoto TaniDepartment of Legal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno, Osaka, 545-8585, JapanTel +81-6-6645-3767Fax +81-6-6634-3871Email tani.naoto@med.osaka-cu.ac.jpPurpose: The purpose of this study was to examine the social and medical background of alcohol dependence and to prevent the abuse of alcohol.Methods: Alcohol and deaths were retrospectively investigated based on the forensic postmortem data of 1694 decedents ≥ 20 years of age in 2008– 2017. Of these, the 999 cases that could be tested for alcohol within 48 h of death were examined.Results: The alcohol-positive and alcohol-negative groups included 179 (17.9%) and 820 (82.1%) cases, respectively. In terms of medical issues, compared with the alcohol-negative group, men in the positive group were mostly in their 40s to 60s, whereas women’s age peaked in the 70s. The causes of death included many blunt injuries in men, though there was no difference in women. Underlying diseases were more frequent in men than women, with many of them having heart or liver disease, and the percentage of cases with mental disorders was 16.8% in the alcohol-positive group. In 15 cases of the alcohol-positive group, phenothiazine and barbituric acids were detected in 53.3% and 46.7% of cases, respectively. The incidence of traffic accidents and homicides was higher in the alcohol-positive group than in the alcohol-negative group.Conclusion: Measures to address social issues based on risk factors for alcohol and deaths are required.Keywords: forensic autopsy, alcohol, medical issue, socioenvironmental issue, pharmacological issue

Background Nonalcoholic fatty liver disease, which is highly associated with obesity, includes nonalcoholic steatohepatitis. Lipopolysaccharides from the intestine would induce inflammation in the liver in nonalcoholic fatty liver disease. This study aimed to examine the role of the bilio-pancreatic limb in the effect of duodenal–jejunal bypass on nonalcoholic steatohepatitis, with respect to the gut–liver axis, using a rat model. Methods Nonalcoholic steatohepatitis model rats were randomly assigned into 3 groups as follows: 1 sham group and 2 duodenal–jejunal bypass groups. The 2 duodenal–jejunal bypass groups were defined according to the bilio-pancreatic limb length: 30 cm (30-DJB group) and 0 cm (0-DJB group). Pathology findings and blood biochemistry, inflammatory cytokine and lipopolysaccharides receptor mRNA in the liver and common channel, and lipopolysaccharide-binding protein level in the portal vein were assessed. Results The reduction in plasma alanine aminotransferase and nonalcoholic fatty liver disease activity score in the 30-DJB group was not observed in the 0-DJB group, similar to the sham group. In the liver tissue, mRNA of inflammatory cytokines and lipopolysaccharide receptors, the area occupied by CD68-positive macrophages, and the number of CD3-positive T-lymphocytes on immunostaining were lower in the 30-DJB group; however, these findings were not observed in the 0-DJB group, and lipopolysaccharide-binding protein levels in the portal vein and mRNA expressions of inflammation-related genes in the common channel showed similar tendencies. Conclusion The bilio-pancreatic limb plays an important role in the beneficial effect of duodenal–jejunal bypass for nonalcoholic steatohepatitis. The bilio-pancreatic limb may suppress lipopolysaccharides-related cascades in the liver by reducing intestinal inflammation.

Diabetic macular edema (DME) is the main cause of visual loss in patients with diabetic retinopathy. DME has been treated using intravitreal anti-vascular endothelial growth factor (VEGF) drugs, steroids, laser photocoagulation, vitreoretinal surgery, and their combinations. These modalities are generally effective in preserving vision, but they sometimes produce only limited responses in patients with persistent or refractory DME. The levels of various inflammatory factors, including cytokines, chemokines, and extracellular matrices, as well as VEGF in the vitreous fluid, are increased in patients with DME. Excessive fibrinogen/fibrin levels in the vitreous fluid or fibrin deposition in the retina also contribute to DME pathogenesis. Tissue plasminogen activator (t-PA) promotes the degradation of fibrinogen or fibrin. Intravitreal t-PA injection is a commonly used treatment for subretinal hemorrhage secondary to age-related macular degeneration. Intravitreal t-PA injections have previously been used to restore vision by inducing posterior vitreous detachment in patients with DME. Herein, we describe the visual outcomes of intravitreal t-PA injection in a 78-year-old woman with treatment-resistant DME in her vitrectomized eye after several previous treatments. Before the injection, her best-corrected visual acuity (BCVA) was 0.7 logMAR and central foveal retinal thickness (CRT) was 735 μm. At 1 month after the injection, her BCVA was 0.8 logMAR and CRT was 558 μm, and 3 months later, her BCVA was 0.8 logMAR and CRT was 207 μm. Her BCVA was sustained, and CRT showed gradual improvements. These findings suggested the effectiveness of intravitreal t-PA injections for DME in the vitrectomized eye.

tRNATyr of Nanoarchaeum equitans has a remarkable feature with an extra guanosine residue at the 5ʹ-terminus. However, the N. equitans tRNATyr mutant without extra guanosine at the 5ʹ-end was tyrosylated by tyrosyl-tRNA synthase (TyrRS). We solved the crystal structure of N. equitans TyrRS at 2.80 A resolution. By comparing the present solved structure with the complex structures TyrRS with tRNATyr of Thermus thermophilus and Methanocaldococcus jannaschii, an arginine substitution mutant of N. equitans TyrRS at Ile200 (I200R), which is the putative closest candidate to the 5ʹ-phosphate of C1 of N. equitans tRNATyr, was prepared. The I200R mutant tyrosylated not only wild-type tRNATyr but also the tRNA without the G-1 residue. Further tyrosylation analysis revealed that the second base of the anticodon (U35), discriminator base (A73), and C1:G72 base pair are strong recognition sites.

To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We also assessed regional neurochemical and functional statuses related to spontaneous neural firing by measuring MRS signals and neuronal activities in a mouse model of Dravet syndrome under a resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that the MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

Slippery liquid-infused porous surfaces (SLIPSs) can be formed by impregnating lubricants in porous surfaces with low surface energy. In this study, SLIPSs have been obtained on practically important aluminum with a porous anodic alumina layer by impregnating lubricants containing organic additives. The additive-containing lubricants change the surface slippery even without prior organic coating of the porous alumina surface. The additive-containing SLIPSs reveal a low water sliding angle of

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the β-amino ester derivative.

Objective The risks of ovarian hyperstimulation syndrome (OHSS) involve high estrogen (E2) levels. We report two breast cancer patients with polycystic ovarian syndrome who underwent fertility preservation and had severe OHSS; their E2 levels were lowered using aromatase inhibitors (AI). Case Reports A 36-year-old woman underwent controlled ovarian stimulation (COS) with AI and cryopreserved 10 blastocysts. She was hospitalized with OHSS (E2 = 139.1 pg/mL). She improved with infusion alone. A 31-year-old woman underwent COS with AI and cryopreserved 8 blastocysts. She was hospitalized for OHSS (E2: 429 pg/mL). Her vascular endothelial growth factor (VEGF) levels were high (62 pg/mL) at 8 days after the procedure. She needed hospitalization for 9 days. The planned adjuvant therapy was delayed for a week in both cases. Conclusion Elevated VEGF levels should be considered as a risk factor of OHSS even if E2 levels are low with AI treatment.

Purpose To evaluate the usefulness of the retinal sensitivity in branch retinal vein occlusion (BVO) with macular edema (ME) following the anti-vascular endothelial growth factor (anti-VEGF) treatment. Methods Best-corrected visual acuity (BCVA), microperimetry, and optical coherence tomography (OCT) measurements were carried out in 20 patients with BVO with ME, at baseline and 1 month after the anti-VEGF treatment. The relationships among BCVA, mean retinal sensitivity (MS), macular volume (MV), central retinal thickness (CRT), integrity of ellipsoid zone (EZ), mean retinal sensitivity in the most affected quadrant (qMS), and macular volume in the most affected quadrant (qMV) were investigated. In addition, the relationships among the change in BCVA at 1 month (ΔBCVA1m), mean sensitivity in the most affected quadrant at 1 month (ΔqMS1m), MV in the most affected quadrant at 1 month (ΔqMV1m), and CRT at 1 month (ΔCRT1m) were analyzed. The optimal model for BCVA at 3 months after the treatment (BCVA3m) was identified. Results There was not a significant difference in BCVA (paired Wilcoxon test, p = 0.058) between at baseline and after the treatment, but there were significant differences in MS, MV, CRT, qMS, and qMV (p Conclusion Retinal sensitivity was related to retinal structure, whereas this was not the case with BCVA. In addition, retinal sensitivity was useful to predict BCVA after anti-VEGF therapy.

Two common conjugated linoleic acids (LAs), cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid-β (Aβ) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of Aβ in mouse neurons. CLA treatment did not affect the level of β-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment, or Aβ protein precursor (APP) in cultured neurons. BACE1 and γ-secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA-containing phosphatidylcholine (CLA-PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane-associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent Aβ generation. Our findings suggest that the accumulation of c9,t11 CLA-PC/LPC in neuronal membranes suppresses the production of neurotoxic Aβ in neurons.

BACKGROUND: Chronic kidney disease (CKD) impairs the anti-inflammatory effects of high-density lipoprotein (HDL) and increases cardiovascular mortality. Though the potential role of dietary interventions to manage HDL is well studied, the clinical trials aimed to increase HDL levels have failed to reduce cardiovascular risk, rendering HDL function to be explored as a more relevant clinical parameter. This study investigates the effects of rice endosperm protein (REP), a plant-based protein, on the anti-inflammatory properties of HDL and renal injury-driven atherosclerosis in comparison with casein, an animal protein. MATERIALS AND METHODS: Ten-week-old apolipoprotein E-deficient hyperlipidemic mice underwent uninephrectomy. The mice (n = 6 each) were pair-fed a normal casein-based diet or a REP-based diet (both with 20.0% protein content) for seven weeks. Atherosclerotic lesions were detected by en face Sudan IV staining of the aorta. RESULTS: The number and sizes of the atherosclerotic lesions were significantly lower in the REP-based diet-fed group than the casein-based diet-fed group (p = 0.038). However, the REP-based diet neither elicited an ameliorative effect on kidney function or histology nor impacted the cholesterol profiles. Furthermore, HDL from the REP-based diet-fed mice significantly suppressed the inflammatory cytokine response of human umbilical vein endothelial cells than that from the casein-based diet-fed mice (MCP-1, p = 0.010; IL-6, p = 0.011; IL-1β, p = 0.028). CONCLUSIONS: The REP-based diet has a higher potential to lessen the atherosclerotic lesions accelerated by renal mass reduction than a casein-based diet, which could be associated with the anti-inflammatory effects of HDL.

Background Methylisothiazolinone (MI) and Methylchloroisothiazolinone (MCI) are among the most common skin sensitizers, yet the immunological events that occur during MCI/MI allergic contact dermatitis (ACD) are still poorly understood. Objectives To analyse dendrocytes, macrophage subtypes and T cells in skin during the elicitation phase of MCI/MI ACD. Methods Thirteen patients with positive patch test reactions to MCI/MI (ACD group) and 11 individuals with negative patch test results were selected. Skin biopsies were only performed at 48 hours of patch testing. Immunohistochemistry was conducted to assess T cells, dendrocytes (Factor XIIIa), M1 (p-Stat1, CD68) and M2 (c-Maf, CD163) macrophages. Transcriptional analyses were performed for cytokines and related factors, and further compared to atopic dermatitis samples (n=4). Immunofluorescence assays addressed T cells location, along with IL-4 or IL-13, within the skin. Results MCI/MI elicited dermal dendrocytes and macrophages, pronouncedly the M2 subtype. T cells, majorly CD4+ T cells, accumulated in the perivascular areas. Similarly, abundant IL-4 protein was detected in these areas. There was an upregulation of IL-4 and IL-13 mRNA expression, a mild increase in IFNG mRNA levels and a down-regulation of RORC in the ACD group. Immunofluorescence revealed dermal clusters of T cells co-localized with IL-4. Conclusions M2 macrophages and Th2 cells participate in the immunopathogenesis of MCI/MI ACD. Dermal dendrocytes and M2 macrophages may assist the formation of CD4+ T cells perivascular clusters. These findings render a mechanistic insight into the MCI/MI reaction. Further analysis at different timepoints of patch testing is required to fully comprehend this ACD kinetics.

The expansion of intratumoral stem-like/progenitor exhausted CD8+ T (Tstem/Tpex) cells provides a potential approach to improve the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, here we demonstrate a strategy to facilitate Tstem/Tpex cell expansion by combining an alarmin high-mobility group nucleosome binding domain 1 (HMGN1) peptide with programmed death-ligand 1 (PD-L1) blockade. The antitumor effects of HMGN1, anti–PD-L1, and their combined treatment were monitored in the B16F10, LLC, Colon26, or EO771 tumor–bearing mice. The comprehensive immunologic analyses, such as high-dimensional flow cytometry, transcriptome analysis, and single-cell RNA-sequencing (scRNA-seq), were used to investigate the cellular and molecular mechanisms of antitumor immune responses after treatments. We identified the immunostimulatory domain (EPKRR SARLS AKPPA KVEAK PKK) on HMGN1 and synthesized this domain as a therapeutic peptide (minP1). Combined treatment with minP1 and PD-L1 blockade induced durable tumor regression in tumor-bearing mice. minP1 increased the number of intratumoral mature DCs enriched in immunoregulatory molecules (mregDC) and enhanced their MHC class I antigen–presenting program. minP1 also synergized with PD-L1 blockade in augmenting intratumoral Tstem/Tpex cell number. Analysis of our scRNA-seq dataset by CellPhonDB suggested potential interactions between mregDCs and Tstem/Tpex cells in tumors. Our results indicate that HMGN1 peptide (minP1) serves as an immunoadjuvant to promote effective anti–PD-L1 immunotherapy with increased Tstem/Tpex cells in tumors.

Introduction The aim of this study was to determine the rates of trimethoprim/sulfamethoxazole (TMP/SMX)-associated pseudo-elevation and true nephrotoxicity by comparison of creatinine-estimated and cystatin C-estimated GFRs (glomerular filtration rates) before and after TMP/SMX administrations. Methods Patients in whom serum creatinine and cystatin C were simultaneously measured are the cohort of this study. A decreasing of creatinine-estimated GFR posterior to TMP/SMX by ≥ 20% and a decreasing of cystatine C-estimated GFR posterior to TMP/SMX by ≥ 20% were defined as true nephrotoxicity. A decreasing of creatinine-estimated GFR posterior to TMP/SMX by ≥ 20% and a decreasing of cystatine C-estimated GFR posterior to TMP/SMX by Results A total of 66 patients were enrolled. Within the 19 patients in whom serum creatinine and cystatin C were measured simultaneously both before and after TMP/SMX administrations, 10 patients (52.6%) had nephrotoxicity. Fewer random error and systematic bias between creatinine- and cystatine C-estimated GFR were observed after TMP/SMX than before TMP/SMX by Bland-Altman analysis. Conclusions Using cystatin C, we reveled TMP/SMX-associated nephrotoxicity is not uncommon. We should equally pay attention to TMP/SMX-associated nephrotoxicity and pseudo-elevation. In spite of pseudo-elevation, creatinine-estimated GFR after receiving TMP/SMX is ironically reliable as surrogate maker for renal clearance.

Aims/Introduction We recently reported the beneficial effect of the combination of sodium–glucose cotransporter 2 inhibitor and dipeptidyl peptidase‐4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. Materials and Methods The CALMER study was a multicenter, open‐label, prospective, randomized, parallel‐group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. Results All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2–82.7%, P

A large-scale demonstration test of a triaxial high-temperature superconducting (HTS) cable for a practical cable system was performed in a chemical plant of a private company. The 200 m-long HTS (REBCO: REBa2Cu3O7-δ) triaxial cable, which was manufactured by connecting 3 cables using 2 joints via a snake-shaped layout, was laid approximately 5 m higher than ground level, and the cable was cryocooled by circulating liquid nitrogen. For the preverification test, the rise-up test of the liquid nitrogen and the development of technology for bending the cable, joining it, as well as laying and installing it, were conducted. No leakage of liquid nitrogen at the terminal due to damage caused by heat shock or liquid nitrogen drop impact was observed. The pressure required for the liquid nitrogen to achieve a 5 m height was from 27.5 to 33 kPa, which is in good agreement with the calculated pressure of 33.6 kPa. The cooling rate was well controlled, and the desired level of 4 K/h was achieved. The economic challenges and methods of achieving market penetration were also discussed. The goal was to realize a superconducting cable for practical applications, and it was thought that the energy and costs necessary for cryocooling could be drastically reduced by using the existing cold system in the plant. In this way, it is expected HTS cables can achieve low costs and high energy-saving effects and penetrate markets in the future.

Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), a suppressor of colorectal cancer (CRC) metastasis, is transcriptionally downregulated when CRC cells undergo epithelial‐mesenchymal transition (EMT). Here we show that decrease of MYB mediates the downregulation of HNRNPLL during EMT. The promoter activity was attributed to a region from −273 to −10 base pairs upstream of the transcription start site identified by 5'‐RACE analysis, and the region contained potential binding sites for MYB and SP1. Luciferase reporter gene assays and knockdown or knockout experiments for genes encoding the MYB family proteins, MYB, MYBL1, and MYBL2, revealed that MYB was responsible for approximately half of the promoter activity. On the other hand, treatment with mithramycin A, an inhibitor for SP1 and SP3, suppressed the promoter activity and their additive contribution was confirmed by knockout experiments. The expression level of MYB was reduced on EMT while that of SP1 and SP3 was unchanged, suggesting that the downregulation of HNRNPLL during EMT was mediated by the decrease of MYB expression while SP1 and SP3 determine the basal transcription level of HNRNPLL. Histopathological analysis confirmed the accumulation of MYB‐downregulated cancer cells at the invasion front of clinical CRC tissues. These results provide an insight into the molecular mechanism underlying CRC progression., Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), a suppressor of colorectal cancer (CRC) metastasis, is transcriptionally downregulated when CRC cells undergo epithelial‐mesenchymal transition (EMT). Here we show that decrease of MYB mediates the downregulation of HNRNPLL during EMT.

Developing highly active and durable electro-catalysts, consisting of earth-abundant elements, for oxygen evolution reaction (OER) is pivotal for large-scale water splitting for hydrogen production. Herein, we report that the commercially available FeNiCo alloy can be converted to a highly active electrocatalyst for OER by galvanostatic anodizing in a fluoride-containing ethylene glycol electrolyte. Anodizing of the alloy develops a porous film consisting of the (FeNiCo)F-2 phase, which is readily converted to a highly active porous oxyhydroxide during anodic polarization in a KOH electrolyte. The anodized alloy exhibits high activity and high durability for OER with an overpotential as low as 0.26 V at a current density of 10 mA cm(-2). The present study demonstrates that a simple and cost-effective anodizing process can be used to form a highly active OER electrode from a low-cost, practical, iron-based alloy. In addition, we found that fluorides containing Fe, Ni, and Co are excellent precursors for the formation of oxyhydroxides exhibiting high OER activity and durability.

Noncovalent chemistry may offer diversity in the functions and applications for artificial polymers by allowing various ordered-disordered phase transitions in a precisely controlled manner. To verify this notion from a fundamental perspective, we examined an achiral poly(phenylacetylene) derivative with an α-helical structure as a helical-spring polymer for revealing phase changes through control of intramolecular hydrogen bonding with the chiral solvent and temperature. When an amine capable of hydrogen bonding was used as the chiral solvent, either an irreversible helix-helix or a reversible helix-coil phase change occurred in an optically dissymmetric manner according to the amount of the chiral solvent added and ambient temperature. Considering the hydrogen-bonding strength values of the solvent mixture and the thermodynamic parameters, we could predict if the optical-dissymmetry phase changes would occur and, if so, how they occur. Our results were similar to those see for the denaturation of proteins, induced by solvent and temperature, based on helix-coil phase transition.