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Abstract Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I polypeptide-related sequence A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2DLow T cell activation, and inhibited NKG2DHigh T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2DLow T cells was maintained. In vivo xenograft model revealed that NKG2DHigh T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2DLow T cells within the tumor microenvironment.

Abstract Background The relationship between the combination of platelet count and neutrophil‐lymphocyte ratio (COP‐NLR) and prognosis in patients with advanced non‐small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) combination therapy with chemotherapy remains unclear. Thus, we investigated prognostic factors, including the COP‐NLR, to identify patients who could benefit from the therapeutic efficacy of ICI combination therapy for advanced NSCLC. Furthermore, we evaluated the relationship between the COP‐NLR score during ICI combination therapy and treatment response. Methods We conducted a retrospective cohort study of 88 patients with NSCLC who initially received ICI combination therapy. The primary outcome was overall survival (OS). The prognostic factors were extracted using the Cox proportional hazards model. The relationship between COP‐NLR score at 3 weeks after starting ICI combination therapy and a good response (complete response [CR] and partial response [PR]) to treatment was analyzed using the chi‐square test. Results The median OS was 15.7 months. In the multivariable analysis, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2, distant metastatic sites ≥2, and baseline COP‐NLR scores of 1, 2 were extracted as significant poor prognostic factors. The proportion of patients with CR and PR in the 3‐week COP‐NLR score of 0 group was significantly higher than that in scores of 1, 2 group. Conclusions Baseline COP‐NLR, ECOG PS, and number of distant metastatic sites were prognostic factors in patients with NSCLC with ICI combination therapy. A lower 3‐week COP‐NLR was associated with a good response to treatment.

Calcium oscillations are rhythmic fluctuations of the intracellular concentration of calcium ions (Ca2+). As Ca2+ evokes various cellular processes, its intracellular concentration is tightly regulated. Ca2+ oscillations control biological events, including neuronal differentiation and proliferation of mesenchymal stem cells. The frequency and pattern of Ca2+ oscillations depend on cell type. Researchers have studied Ca2+ oscillations to better understand how cells communicate and regulate physiological processes. Dysregulation of Ca2+ oscillations causes health problems, such as neurodegenerative disorders. This review discusses the potential functions of Ca2+ oscillations in stem cells.

IntroductionImmune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for esophageal cancer (EC). Although ICIs enable long-term survival in some patients, the efficacy of ICIs varies widely among patients. Therefore, predictive biomarkers are necessary for identifying patients who are most likely to benefit from ICIs to improve the efficacy of the treatment. We retrospectively analyzed the outcomes of combination therapy, including nivolumab plus ipilimumab or chemotherapy plus anti-programmed cell death 1 (PD-1) antibodies in our institute to identify biomarkers.MethodsTwenty-seven patients received nivolumab plus ipilimumab, and thirty-six patients received chemotherapy plus anti-PD-1 antibodies were included in this study. We analyzed patient characteristics, efficacy, and safety. Multivariable analysis of biomarkers evaluated the correlation among overall survival (OS), progression-free survival (PFS), and the following variables: body mass index, performance status, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein level, and albumin level before treatment.ResultsIn multivariable analysis, albumin level was significantly correlated with PFS in the cisplatin plus 5-fluorouracil (CF) plus pembrolizumab group. NLR and albumin level were significantly correlated with OS in the nivolumab plus ipilimumab group. Other variables, including PS, BMI, and CRP did not correlate with any of the outcomes.ConclusionsHigh NLR in EC patients prior to treatment was significantly less effective for ICIs. In chemotherapy combined with ICIs, NLR before the treatment was not associated with treatment efficacy, suggesting combination chemotherapy may be beneficial for EC patients with high NLR. NLR may be an indicator of immunocompetence in anti-tumor immunity and a convenient predictive biomarker for selecting appropriate treatments including ICIs.

Abstract The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Abstract Protein arginine methyltransferase 5 (PRMT5) is a well-known epigenetic regulatory enzyme. However, the role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis is unknown. Here we show that fibroblast-specific deletion of PRMT5 significantly reduces pressure overload-induced cardiac fibrosis and improves cardiac dysfunction in male mice. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppress α-smooth muscle actin (α-SMA) expression induced by transforming growth factor-β (TGF-β) in cultured cardiac fibroblasts. TGF-β stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-β stimulation increases H3K4 tri-methylation mediated by the WDR5/MLL1 methyltransferase complex, which recognizes H3R2 dimethylation. Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction.

On 1 January 2024, a large earthquake occurred in Japan’s Noto region. Many buildings collapsed as a result of violent shaking. Electricity and water supplies were cut off, and communications were disrupted. On 5 January, four days after the earthquake, we visited Noto and conducted disaster-relief activities. This report integrates and discusses the results of the site visits, information broadcasts by public institutions, and previous research. Evacuation centers lacked water and proper sanitation, leading to health issues, including infectious diseases. Disaster Medical Assistance Teams (DMAT) were delayed in implementing infection control measures. Isolated evacuation centers faced communication and supply challenges. Infrastructure restoration, power supply, and toilet facilities at evacuation centers were delayed because of geographical challenges. It is important to have a team that can determine and carry out the necessary activities on site, even without instructions from the DMAT. It is believed to be effective to decide in advance how volunteer teams and the private sector will conduct their activities, assuming that they will be unable to contact public institutions during a disaster. In large-scale disasters, evacuees must operate evacuation centers autonomously. To achieve this, it is necessary for residents to regularly come together as a community. Systematically recording and accumulating these experiences will contribute to improved disaster prevention and mitigation planning. We hope that the experiences we obtained through the abovementioned disaster will be useful for preparing for future disasters.

Abstract Background Esophageal atresia (EA) in extremely low birth weight (ELBW) neonates is rare. This report aims to clarify EA’s clinical courses and prognosis in ELBW neonates and the clinical issues of long-term survival cases. Methods A retrospective analysis was conducted for 8 neonates diagnosed with esophageal atresia. Medical records of ELBW EA neonates treated at our institution were reviewed to assess patient demographics, clinical courses, and outcomes. Transferred patient data was obtained from their local physicians through questionnaires. Results EA in ELBW neonates were included in 8 of EA infants (7%). Fatal respiratory and cardiovascular complications of trisomy 18 and complications related to immaturity such as liver failure and pulmonary hypertension were associated with poor prognosis. During primary operations, gastrostomy and esophageal banding were performed together in 50% of the cases, while gastrostomy was performed alone in 25%. The esophageal anastomosis was not performed during any primary operation. All causes of death, except for 1 case, were due to non-surgical causes. A long-term survival case of 17 years postoperatively was included. Conclusion Although ELBW EA has a poor prognosis, long-term survival is possible in some cases, so aggressive therapeutic intervention is considered essential. It is important to share information about the prognosis with parents and multidisciplinary specialists and to select an appropriate treatment strategy for each case.

Abstract The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

IntroductionProgrammed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method.MethodsIn total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression.ResultsPD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group.ConclusionQuantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.

Abstract Background The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non–small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second‐line amrubicin (AMR) following first‐line platinum‐based chemotherapy and ICI combination therapy (chemo‐ICI) in SCLC. Patients and Methods We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second‐line following chemo‐ICI as first‐line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy‐enhancing variables of AMR. Results Overall, 89 patients treated with AMR after first‐line chemo‐ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1–39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27–3.65). Patients who relapsed more than 90 days after receiving first‐line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in

BackgroundCancer of unknown primary (CUP) is a malignant tumor without a known primary lesion with a frequency of 3−5%. It can be divided into favorable and unfavorable prognosis subsets. While recommended treatments are available for the former group, there is no established treatment for the latter. Here, we report the effective treatment of a 32-year-old woman with p16-positive squamous cell CUP with pembrolizumab plus 5-fluorouracil and cisplatin therapy.Case presentationA 32-year-old woman presented with metastatic lesions in the liver, lung, bone, cervical region, abdominal region, and pelvic lymph nodes. She was diagnosed with p16-positive squamous cell carcinoma of unknown primary origin. The patient received pembrolizumab plus 5-fluorouracil and cisplatin therapy, which markedly reduced the metastasis and improved her Eastern Cooperative Oncology Group performance status after two courses.ConclusionThis case report highlights the potential of pembrolizumab plus 5-fluorouracil and cisplatin therapy for treating CUP with an unfavorable prognosis. p16 positivity is worth examining for squamous cell carcinoma of unknown primary origin, and if present, this therapy should be considered a promising treatment option.

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC50 of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy.

In some non-mammalian eggs, the fusion of one egg and multiple sperm (polyspermy) induces a robust rise in intracellular calcium ion (Ca2+) concentration due to a shortage of inducers carried by a single sperm. Instead, one of the sperm nuclei is selected inside the egg for normal embryogenesis. Polyspermy also occurs during the in vitro fertilization of human eggs; however, the fate of such eggs is still under debate. Hence, the relationship between polyspermy and repetitive Ca2+ increases (Ca2+ oscillation) in mammals remains unknown. To address this issue, we used mouse sperm lacking extramitochondrial citrate synthase (eCS), which functions as a Ca2+ oscillation inducer; its lack causes retarded Ca2+ oscillation initiation (eCs-KO sperm). Elevated sperm concentrations normalize Ca2+ oscillation initiation. As expected, eCS deficiency enhanced polyspermy in both zona pellucida (ZP)-free and ZP-intact eggs despite producing the next generation of eCs-KO males. In conclusion, similarly to non-mammalian eggs, mouse eggs may develop normally under polyspermy conditions caused by problematic Ca2+ oscillation.

Abstract Recent increased development interest in millimeter-wave oscillator devices has necessitated realization of small oscillators with high frequency, wide frequency tunability, and room-temperature operation. Spin-torque oscillators (STOs) are fascinating candidates for such applications because of their nanometer size and suitability for room-temperature operation. However, their oscillation frequency and tunable range are limited to the order of 100 MHz–10 GHz. Here, we propose use of bilinear (J 1) and biquadratic (J 2) interlayer exchange couplings between ferromagnets in STOs to overcome these problems. The bilinear coupling contributes to oscillation frequency enhancement, whereas the biquadratic coupling facilitates frequency tunability via a current. Using micromagnetic simulation with parameters estimated from a material with small saturation magnetization, for J 1 = 0 and J 2 = − 1.0 mJ/m2, respectively, we find that the STO exhibits high frequency from 23 to 576 GHz and that its tunability reaches 61 GHz/(1011 A/m2) for current densities of − 0.5 to − 9.5 × 1011 A/m2. An analytical theory based on the macrospin model is also developed, which exhibits good quantitative agreement with the micromagnetic simulations. These results introduce new possibilities for spintronics applications in high-frequency devices such as next-generation mobile communications.

IntroductionImmune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. MethodsWe investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).ResultsThe genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs.DiscussionOur Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.

Abstract Background Dacomitinib is the second‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) for mutant non–small cell lung cancer (NSCLC). EGFR‐TKIs are often re‐administered in Japan after the disease progression prior EGFR‐TKI. There is little evidence of dacomitinib in rechallenge setting. This study evaluated clinical outcomes of dacomitinib in rechallenge setting. Methods Patients who received dacomitinib for advanced EGFR‐mutant NSCLC who had progressed after EGFR‐TKI in nine institutions in Japan were included in the analyses. Results In total, 43 patients were analyzed. The median progression‐free survival (PFS) was 4.3 months (95% confidence interval [CI], 2.5–5.6). The overall survival (OS) was 10.5 months (95% CI, 7.4–not reached). The overall response rate was 25.5% (95% CI, 13.1–33.7). Subset analysis indicated that patients with EGFR exon 21 L858R showed longer PFS than those with EGFR exon 19 deletion (5.8 vs. 4.1 months) (p = 0.018). The most common adverse events leading to dose modification were diarrhea, paronychia, rash, and oral mucositis. Conclusion In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR‐TKI. The benefit was especially pronounced in patients with the exon 21 mutation.

Background: The relationship between the combination of platelet count and neutrophil‐lymphocyte ratio (COP‐NLR) and prognosis in patients with advanced non‐small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) combination therapy with chemotherapy remains unclear. Thus, we investigated prognostic factors, including the COP‐NLR, to identify patients who could benefit from the therapeutic efficacy of ICI combination therapy for advanced NSCLC. Furthermore, we evaluated the relationship between the COP‐NLR score during ICI combination therapy and treatment response. Methods: We conducted a retrospective cohort study of 88 patients with NSCLC who initially received ICI combination therapy. The primary outcome was overall survival (OS). The prognostic factors were extracted using the Cox proportional hazards model. The relationship between COP‐NLR score at 3 weeks after starting ICI combination therapy and a good response (complete response [CR] and partial response [PR]) to treatment was analyzed using the chi‐square test. Results: The median OS was 15.7 months. In the multivariable analysis, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2, distant metastatic sites ≥2, and baseline COP‐NLR scores of 1, 2 were extracted as significant poor prognostic factors. The proportion of patients with CR and PR in the 3‐week COP‐NLR score of 0 group was significantly higher than that in scores of 1, 2 group. Conclusions: Baseline COP‐NLR, ECOG PS, and number of distant metastatic sites were prognostic factors in patients with NSCLC with ICI combination therapy. A lower 3‐week COP‐NLR was associated with a good response to treatment. [ABSTRACT FROM AUTHOR]

On 1 January 2024, a large earthquake occurred in Japan's Noto region. Many buildings collapsed as a result of violent shaking. Electricity and water supplies were cut off, and communications were disrupted. On 5 January, four days after the earthquake, we visited Noto and conducted disaster-relief activities. This report integrates and discusses the results of the site visits, information broadcasts by public institutions, and previous research. Evacuation centers lacked water and proper sanitation, leading to health issues, including infectious diseases. Disaster Medical Assistance Teams (DMAT) were delayed in implementing infection control measures. Isolated evacuation centers faced communication and supply challenges. Infrastructure restoration, power supply, and toilet facilities at evacuation centers were delayed because of geographical challenges. It is important to have a team that can determine and carry out the necessary activities on site, even without instructions from the DMAT. It is believed to be effective to decide in advance how volunteer teams and the private sector will conduct their activities, assuming that they will be unable to contact public institutions during a disaster. In large-scale disasters, evacuees must operate evacuation centers autonomously. To achieve this, it is necessary for residents to regularly come together as a community. Systematically recording and accumulating these experiences will contribute to improved disaster prevention and mitigation planning. We hope that the experiences we obtained through the abovementioned disaster will be useful for preparing for future disasters. [ABSTRACT FROM AUTHOR]

In the current study, the aim was to examine the toxicity of combined exposure to acrylamide and Staphylococcus aureus. We investigated the effect of staphylococcal enterotoxin A (SEA), a toxin produced by Staphylococcus aureus, on the oxidation induced DNA damaging potency of acrylamide in mouse spleen cells using an Formamidopyrimidine-DNA glycosylase-modified (FPG)-modified comet assay. Parameters like tail moment, tail length, and % tail DNA as indicators of DNA damage were significantly increased in the combined acrylamide and SEA treatment compared with SEA or acrylamide alone. Further, we examined the effects of acrylamide and its epoxide metabolite glycidamide on overall production of SEA, SEA mRNA gene expression, and on the formation of biofilm of S. aureus. Acrylamide significantly increased the SEA expression level and SEA production in S. aureus. Acrylamide also significantly increased biofilm formation in S. aureus without affecting its growth rate. Moreover, the addition of acrylamide significantly increased the expression of S. aureus virulence factors RNAIII and icaA in fetal bovine serum. Our results showed that combined exposure to acrylamide and S. aureus or its toxin enhanced their chemical and biological toxicities.

Abstract Background Peritoneal metastasis (PM) is one of the most common causes of noncurative surgery and the most frequent recurrence pattern in gastric cancer (GC). During the process of PM, GC cells detached from primary tumor interact with human peritoneal mesothelial cells (HPMC) overlapped with adipose tissues such as the omentum or mesentery. Although the interaction with HPMC promotes the malignancy of GC, the role of adipose tissues remains unclear. Aims We aimed to clarify how adipose tissue are affected by adjacent primary tumors during the expression of adipokines and to elucidate whether GC cells transform adipocytes into CAFs in vitro. In addition, we investigated whether GC cells are affected by adipocytes in their ability to infiltrate. Methods We investigated the phenotypic conversion of adipocytes during the malignant process of GC cells in vivo and in vitro. We evaluated the expression levels of adiponectin in the omental adipose tissue of gastric cancer patients by western blotting. Following adipocytes/gastric cancer cells coculture, adipocyte markers, adiponectin receptors, and inflammatory cytokine markers were detected by real‐time PCR and/or western blotting in the single‐cultured and co‐cultured adipocytes; cancer‐associated fibroblast (CAF) markers were detected by immunofluorescence and western blotting in the single‐cultured and co‐cultured adipocytes; invasion assays were performed in single cultured and co‐cultured MKN45 and OCUM. Results In omental adipose tissues that are situated close to the primary tumors, the expression of adiponectin tended to decrease in patients with subserosal or serosal invasion. By co‐culturing with GC cells, adipocytes were dedifferentiated and the expression levels of CAF marker FSP1 and inflammatory cytokines, PAI‐1 and IL‐6, significantly increased (p

Abstract Background Pleuroparenchymal fibroelastosis (PPFE) is characterised by predominant upper lobe pleural and subpleural lung parenchymal fibrosis. Radiological PPFE-like lesion has been associated with various types of interstitial lung diseases. However, the prevalence and clinical significance of radiological PPFE-like lesion in patients with idiopathic interstitial pneumonias (IIPs) are not fully understood. We aimed to determine the prevalence and clinical impact on survival of radiological PPFE-like lesion in patients with IIPs. Methods A post-hoc analysis was conducted using data from the Japanese nationwide cloud-based database of patients with IIPs. All the patients in the database were diagnosed as having IIPs by multidisciplinary discussion. Patients diagnosed with idiopathic PPFE were excluded. Clinical data and chest computed tomography (CT) image of 419 patients with IIPs were analysed. The presence of radiological PPFE-like lesion was independently evaluated by two chest radiologists blind to the clinical data. Results Of the 419 patients with IIPs, radiological PPFE-like lesions were detected in 101 (24.1%) patients, mainly in idiopathic pulmonary fibrosis (IPF) and unclassifiable IIPs, but less in idiopathic nonspecific interstitial pneumonia. Prognostic analyses revealed that radiological PPFE-like lesion was significantly associated with poor outcome in patients with IIPs, which was independent of age, IPF diagnosis and %FVC. In survival analyses, the patients with radiological PPFE-like lesions had poor survival compared with those without (log-rank, p

Fermented tea consumption has been reported to alleviate diabetes and dyslipidemia, inducing an antiobesity effect. Here, we investigated the effects of microbial fermented tea and microbial fermented twig tea, which are made from Camellia sinensis by fermentation with Aspergillus sp., on glucose tolerance and metabolic syndrome in prediabetic subjects in a randomized, double-blind study. They were asked to consume the tea three times a day for 12 weeks. Fasting blood glucose, HbA1c, and 2-h oral glucose tolerance test (OGTT) were measured as primary endpoints. After 12 weeks, fasting blood glucose level was significantly reduced in the microbial fermented twig tea group (n = 19) as compared with that in the microbial fermented tea group (n = 16, p = 0.017). There was no significant difference in the 2-hour OGTT and HbA1c values between the two groups. Triglyceride levels were significantly lower in the microbial fermented tea group than in the microbial fermented twig tea group at 12 weeks (p = 0.049).

Abstract Background An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. Methods Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as ‘early recurrence’, and recurrence more than 1 year after as ‘late recurrence’. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. Results Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026–1.087, p

Abstract Aquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.

Abstract Glial cells such as astrocytes and oligodendrocytes play crucial roles in the central nervous system. To investigate the molecular mechanisms underlying the development and the biological functions of glial cells, simple and rapid techniques for glial cell-specific genetic manipulation in the mouse cerebrum would be valuable. Here we uncovered that the Gfa2 promoter is suitable for selective gene expression in astrocytes when used with the piggyBac system and in utero electroporation. In contrast, the Blbp promoter, which has been used to induce astrocyte-specific gene expression in transgenic mice, did not result in astrocyte-specific gene expression. We also identified the Plp1 and Mbp promoters could be used with the piggyBac system and in utero electroporation to induce selective gene expression in oligodendrocytes. Furthermore, using our technique, neuron-astrocyte or neuron-oligodendrocyte interactions can be visualized by labeling neurons, astrocytes and oligodendrocytes differentially. Our study provides a fundamental basis for specific transgene expression in astrocytes and/or oligodendrocytes in the mouse cerebrum.

Hypertrophic stress-induced cardiac remodeling is a compensatory mechanism associated with cardiomyocyte hypertrophy and cardiac fibrosis. Continuation of this response eventually leads to heart failure. The histone acetyltransferase p300 plays an important role in the development of heart failure, and may be a target for heart failure therapy. The phenolic phytochemical 6-shogaol, a pungent component of raw ginger, has various bioactive effects; however, its effect on cardiovascular diseases has not been investigated. One micromolar of 6-shogaol suppressed phenylephrine (PE)-induced increases in cardiomyocyte hypertrophy in rat primary cultured cardiomyocytes. In rat primary cultured cardiac fibroblasts, 6-shogaol suppressed transforming growth factor-beta (TGF-β)-induced increases in L-proline incorporation. It also blocked PE- and TGF-β-induced increases in histone H3K9 acetylation in the same cells and in vitro. An in vitro p300-HAT assay revealed that 6-shogaol suppressed histone acetylation. The mice underwent transverse aortic constriction (TAC) surgery, and were administered 0.2 or 1 mg/kg of 6-shogaol daily for 8 weeks. 6-shogaol prevented TAC-induced systolic dysfunction and cardiac hypertrophy in a dose-dependent manner. Furthermore, it also significantly inhibited TAC-induced increases in histone H3K9 acetylation. These results suggest that 6-shogaol may ameliorate heart failure through a variety of mechanisms, including the inhibition of p300-HAT activity.