Inherited KDM6AA649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes.

Childhood onset of colorectal signet-ring cell carcinoma (CR-SRCC) is extremely rare and featured as highly malignant with poor prognosis. Here we reported a CR-SRCC case of 11-year-old boy with a novel inherited X-linked KDM6AA694T mutation. The H3K27me3 demethylase KDM6A was frequently mutated in varieties of tumors and acts as a tumor suppressor. In vivo H3K27me3 demethylation assay demonstrated that KDM6AA694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6AA694T in SRCC cell line KATO3 promoted cell proliferation, invasion and migration, which were further confirmed in vivo by constructing orthotopic tumor growth and lung metastasis model. Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.

Unraveling the role of serum metabolites in the relationship between plant-based diets and bone health in community-dwelling older adults.

The potential adverse effects of the plant-based dietary pattern on bone health have received widespread attention. However, the biological mechanisms underlying the adverse effects of plant-based diets on bone health remain incompletely understood. The objective of this study was to identify potential biomarkers between plant-based diets and bone loss utilizing metabolomic techniques in the Taizhou Imaging Study (TIS) (N = 788). Plant-based diet indexes (overall plant-based diet index (PDI), healthy plant-based diet index (hPDI), and unhealthy plant-based diet index (uPDI)) were calculated using the food frequency questionnaire, and bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. A multinomial logistic regression was used to explore the associations of plant-based diet indexes with bone loss. Furthermore, mediation analysis and exploratory factor analysis (EFA) were performed to explore the mediated effects of metabolites on the association of plant-based diets with BMD T-score. Our results showed that higher hPDI and uPDI were positively associated with bone loss. Moreover, nineteen metabolites were significantly associated with BMD T-score, among them, seven metabolites were associated with uPDI. Except for cholesterol esters in VLDL-1, the remaining six metabolites significantly mediated the negative association between uPDI and BMD T-score. Interestingly, we observed that the same six metabolites mediated the positive association between fresh fruit and BMD T-score. Collectively, our results support the deleterious effects of plant-based diets on bone health and discover the potential mediation effect of metabolites on the association of plant-based diets with bone loss. The findings offer valuable insights that could optimize dietary recommendations and interventions, contributing to alleviate the potential adverse effects associated with plant-based diets.

Metabolomics Differences of the Donor Livers Between In Situ and Ex Situ Conditions During Ischemia-free Liver Transplantation.

BACKGROUND: Ischemia-free liver transplantation (IFLT) has been innovated to avoid graft ischemia during organ procurement, preservation, and implantation. However, the metabolism activity of the donor livers between in the in situ and ex situ normothermic machine perfusion (NMP) conditions, and between standard criteria donor and extend criteria donor remains unknown. METHODS: During IFLT, plasma samples were collected both at the portal vein and hepatic vein of the donor livers in situ during procurement and ex situ during NMP. An ultra-high performance liquid chromatography-mass spectrometry was conducted to investigate the common and distinct intraliver metabolite exchange. RESULTS: Profound cysteine and methionine metabolism, and aminoacyl-tRNA biosynthesis were found in both in situ and ex situ conditions. However, obvious D-arginine and D-ornithine metabolism, arginine and proline metabolism were only found in the in situ condition. The suppressed activities of the urea cycle pathway during ex situ condition were confirmed in an RNA expression level. In addition, compared with extend criteria donor group, standard criteria donor group had more active intraliver metabolite exchange in metabonomics level. Furthermore, we found that the relative concentration of p-cresol, allocystathionine, L-prolyl-L-proline in the ex situ group was strongly correlated with peak alanine aminotransferase and aspartate aminotransferase at postoperative days 1-7. CONCLUSIONS: In the current study, we show the common and distinct metabolism activities during IFLT. These findings might provide insights on how to modify the design of NMP device, improve the perfusate components, and redefine the criteria of graft viability.

Assessing the association between smoking and hypertension: Smoking status, type of tobacco products, and interaction with alcohol consumption.

Background: The association between tobacco use and hypertension risk has been extensively researched but remains controversial, and few existing studies have considered the role of tobacco type and dosage response in this association. In this context, this study aims to provide epidemiological evidence for the possible relationship between tobacco smoking and future hypertension risk, with the tobacco type and consumption dose into consideration. Methods: This study was based on 10-year follow-up data from the Guizhou Population Health Cohort conducted in southwest China. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals [95% confidence intervals (CIs)], and restricted cubic spline analyses were performed to visualize the dose-response association. Results: A total of 5,625 participants (2,563 males and 3,062 females) were included in the final analysis. Heavy smokers of machine-rolled cigarettes had an elevated hypertension risk compared with non-smokers (HR: 1.50, 95% CI: 1.05-2.16). The interaction effects of heavy smoking-heavy drinking patterns increased the future hypertension risk, with an adjusted HR of 2.58 (95% CI: 1.06-6.33). Conclusion: This study did not find a significant association between overall tobacco use status and the risk of hypertension. However, heavy machine-rolled cigarette smokers had a statistically significant increased risk of hypertension compared with non-smokers, and a J-shape association has been found between the average daily consumption of machine-rolled cigarettes and the risk of hypertension. Besides, tobacco and alcohol consumption jointly increased the long-term hypertension risk.

Central Adiposity Indicators Maintain a Stronger Association With the Risk of Hypertension: A Prospective Cohort Study in Southwest China.

Objectives: Studies have linked obesity to an increased risk of hypertension, but the optimal adiposity indicators to predict hypertension remains controversial. We comprehensively explored the correlation between body mass index, waist circumference (WC), waist-to-height ratio (WHtR), long-term weight and WC change, and hypertension in an adult population in Southwest China. Methods: We studied 9,280 participants from 48 townships of 12 districts with a follow-up of 10 years in the Guizhou Population Health Cohort Study. We used Pearson's correlation coefficients combined with Dunn and Clark's z test and Zou's confidence interval test, receiver operating characteristic (ROC) analyses, and multivariate Cox proportional hazards regressions adjusting for demographic characteristics, lifestyle habits, disease history, and lipid information of participants. Results: Baseline central adiposity indicators (WC and WHtR) had closer associations with hypertension than BMI, and long-term WC change was more predictive of hypertension compared with weight change in the studied population. Conclusion: Central adiposity indicators maintain a stronger association with the risk of hypertension, hinting at the importance of WC management in the precaution of hypertension.

Abrogation of graft ischemia-reperfusion injury in ischemia-free liver transplantation.

BACKGROUND: Ischemia-reperfusion injury (IRI) is considered an inherent component of organ transplantation that compromises transplant outcomes and organ availability. The ischemia-free liver transplantation (IFLT) procedure has been developed to avoid interruption of blood supply to liver grafts. It is unknown how IFLT might change the characteristics of graft IRI. METHODS: Serum and liver biopsy samples were collected from IFLT and conventional liver transplantation (CLT) recipients. Pathological, metabolomics, transcriptomics, and proteomics analyses were performed to identify the characteristic changes in graft IRI in IFLT. RESULTS: Peak aspartate aminotransferase (539.59 ± 661.76 U/L versus 2622.28 ± 3291.57 U/L) and alanine aminotransferase (297.64 ± 549.50 U/L versus 1184.16 ± 1502.76 U/L) levels within the first 7 days and total bilirubin levels by day 7 (3.27 ± 2.82 mg/dl versus 8.33 ± 8.76 mg/dl) were lower in the IFLT versus CLT group (all p values < 0.001). The pathological characteristics of IRI were more obvious in CLT grafts. The antioxidant pentose phosphate pathway remained active throughout the procedure in IFLT grafts and was suppressed during preservation and overactivated postrevascularization in CLT grafts. Gene transcriptional reprogramming was almost absent during IFLT but was profound during CLT. Proteomics analysis showed that "metabolism of RNA" was the major differentially expressed process between the two groups. Several proinflammatory pathways were not activated post-IFLT as they were post-CLT. The activities of natural killer cells, macrophages, and neutrophils were lower in IFLT grafts than in CLT grafts. The serum levels of 14 cytokines were increased in CLT versus IFLT recipients. CONCLUSIONS: IFLT can largely avoid the biological consequences of graft IRI, thus has the potential to improve transplant outcome while increasing organ utilization.

Association of Perfusion Characteristics and Posttransplant Liver Function in Ischemia-Free Liver Transplantation.

It has been shown that normothermic machine perfusion (NMP), a novel preservation method, is able to assess and resuscitate liver grafts with risk factors. However, there is no consistent criteria for the assessment of liver grafts with NMP. Ischemia-free liver transplantation (IFLT) includes innovative surgical techniques and NMP, which can protect liver grafts from ischemia throughout organ procurement, preservation, and implantation. In our center, 28 human livers from donation after brain death donors were subjected to IFLT between July 2017 and October 2018. The correlation between posttransplant liver function tests with the perfusion parameters, blood gas analysis of perfusate, and bile biochemistry were analyzed. During the preservation phase, the vascular flow was stable, and the lactate level decreased rapidly. The transaminase release in the perfusate was low but stable, whereas the glucose level remained high. The perfusate lactate and aspartate aminotransferase (AST) levels at 1 hour of perfusion were correlated with the posttransplant peak AST level. There were negative correlations between the portal vein and hepatic artery flows at the end of perfusion and the peak transaminase levels within 7 days after transplantation. In conclusion, during IFLT, NMP is able to bridge the liver grafts from donors to recipients and can allow the assessment of liver function by perfusion characteristics.

First Preliminary Experience with Preservation of Liver Grafts from Extended-Criteria Donors by Normothermic Machine Perfusion in Asia.

BACKGROUND Normothermic machine perfusion (NMP) can provide access to evaluate and resuscitate high-risk donor livers before transplantation. The purpose of this study was to determine the efficacy of NMP in preservation and assessment of extended-criteria donor (ECD) livers in China. CASE REPORT From September 2018 to March 2019, 4 liver grafts from 3 transplant center defined as ECD were subjected to NMP, and then were transplanted successfully. During perfusion, perfusion parameters such as vascular flow, glucose level, lactate clearance, and bile production/composition were recorded to assess graft viability. All recipients were followed up 6 months after transplantation. CONCLUSIONS NMP provides a potential tool for preservation and assessment of ECD livers in China.

Volatile Oil from Acorus gramineus Ameliorates the Injury Neurons in the Hippocampus of Amyloid Beta 1-42 Injected Mice.

In recent years, the extraction fraction of volatile oil from Acorus gramineus has significant effects on anti-dementia and improving the learning and memory of animals. To date, limited studies have determined whether volatile oil from A. gramineus has the protective effect on neuronal damage. The aim of this study was to investigate the protective effects of volatile oil from A. gramineus on Alzheimer's disease (AD) mice, by means of behavior test, immunohistochemistry and western blot methods. In this study, mice were injected with Aß1-42 in the bilateral hippocampus to establish the AD model. On the seventh day after modeling, the mice with cognitive dysfunction were selected by the novel object recognition task. Subsequently, the volatile oil treatment groups underwent intragastric administration for per 10 g body weight 2.5 or 5 µL volatile oil from A. gramineus for 3 weeks. The control group and the AD group were given the same amount of saline. Our results showed that after treatment of volatile oil from A. gramineus, the number of Doublecortin and Nestin positive cells increased significantly, suggesting that the volatile oil from A. gramineus may induce the regeneration of hippocampal neurons in mice, and promote the growth of hippocampal neurons by upregulation of brain-derived neurotrophic factor, tyrosine protein kinase B, and neurotrophin-3 expression. These results might provide more experimental evidences for underlying mechanism about the neuroprotective effects of volatile oil from A. gramineus against AD relevant symptoms. Anat Rec, 302:2261-2270, 2019. © 2019 American Association for Anatomy.

Up-regulation of TREM2 accelerates the reduction of amyloid deposits and promotes neuronal regeneration in the hippocampus of amyloid beta1-42 injected mice.

Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and subsequently deposition of amyloid beta (Aß) within the brain. The immune cells of brain migrate to and invest their processes within Aß plaques and clear plaques from the brain. Previous studies have shown that treatment of myeloid cell with nuclear factor inhibitor increases expression of phagocytesis-related genes, such as triggering receptor expressed on myeloid cells 2 (TREM2). In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation as well as inflammatory response in vitro. The purpose of this study was to further investigate microglial proliferation, phagocytosis and the expression of brain derived neurotrophic factor (BDNF) induced by up-regulation of TREM2 in Aß1-42 injected mice. We first singly injected Aß1-42 into the hippocampus of mice to build the model of AD-like symptoms. Subsequently, ammonium pyrrolidinedithiocarbamate (PDTC) was injected into the lateral ventricle of mice. Various immunohistochemical techniques and Western blot analyses were applied to examine expressions of TREM2, microglia, Aß, Neuronal migration protein doublecortin (DCX) and BDNF in the hippocampus of mice. In the present study, we found the plaques-associated microglia lowly expressed TREM2 and BDNF in Aß1-42 intra-hippocampal injected mice. Treatment of the models with a nuclear factor inhibitor, PDTC, further induced the expression of TREM2 and enhanced microglial phagocytosis, coincident with the rapid reduction in plaque burden. The expression of BDNF was up-regulated and the expression of DCX was partly restored. This means that up-regulation of TREM2 might induce the microglia to express the BDNF. These findings further indicate that the level of TREM2 may affect the microglia response to pathological process induced by Aß.