RNA editing of AZIN1 coding sites is catalyzed by ADAR1 p150 after splicing.

Adenosine-to-inosine RNA editing is catalyzed by nuclear adenosine deaminase acting on RNA 1 (ADAR1) p110 and ADAR2, and cytoplasmic ADAR1 p150 in mammals, all of which recognize dsRNAs as targets. RNA editing occurs in some coding regions, which alters protein functions by exchanging amino acid sequences, and is therefore physiologically significant. In general, such coding sites are edited by ADAR1 p110 and ADAR2 before splicing, given that the corresponding exon forms a dsRNA structure with an adjacent intron. We previously found that RNA editing at two coding sites of antizyme inhibitor 1 (AZIN1) is sustained in Adar1 p110/Aadr2 double KO mice. However, the molecular mechanisms underlying RNA editing of AZIN1 remain unknown. Here, we showed that Azin1 editing levels were increased upon type I interferon treatment, which activated Adar1 p150 transcription, in mouse Raw 264.7 cells. Azin1 RNA editing was observed in mature mRNA but not precursor mRNA. Furthermore, we revealed that the two coding sites were editable only by ADAR1 p150 in both mouse Raw 264.7 and human embryonic kidney 293T cells. This unique editing was achieved by forming a dsRNA structure with a downstream exon after splicing, and the intervening intron suppressed RNA editing. Therefore, deletion of a nuclear export signal from ADAR1 p150, shifting its localization to the nucleus, decreased Azin1 editing levels. Finally, we demonstrated that Azin1 RNA editing was completely absent in Adar1 p150 KO mice. Thus, these findings indicate that RNA editing of AZIN1 coding sites is exceptionally catalyzed by ADAR1 p150 after splicing.

Soil Aggregates and Fertilizer Treatments Drive Bacterial Interactions via Interspecies Niche Overlap.

Bacterial interactions play significant roles in ecological functions in responding to anthropogenic interference and soil structure changes. However, it remains largely unknown how fertilizer regimes and soil particle sizes drive bacterial interactions. To evaluate bacterial interaction patterns in soil aggregates under long-term fertilizer treatments, we sampled nine bacterial co-occurrence communities and compared the difference between interspecies resource consumption patterns and network structure. Despite the differences between fertilizer treatments, the negative correlation ratios of interaction networks in soil aggregates were macroaggregates > microaggregates > silt + clays. Likewise, NPK-supplement (chemical fertilizer) had also decreased the number of positive correlations of the interaction network than M-supplement (organic fertilizer), regardless of the size of soil aggregates. Linear model analysis revealed that interspecies trophic patterns, including niche overlap and nestedness, drove bacterial competition in the interaction networks. Most importantly, interspecies niche overlap may be the intrinsic factor in the effects of fertilizer treatments and soil aggregates on bacterial interactions. This study enhances our understanding of the potential for changes in species trophic patterns and might guide the promotion of land management. IMPORTANCE Despite that the influence of soil structure and fertilizer treatments on the bacterial community has been widely studied, how they drive interspecies interactions has not been largely explored. Connectance and nestedness were significantly correlated with bacterial interactions, but no differences were found in different soil aggregates and fertilizer treatments. However, interspecies niche overlap could respond to soil aggregates and fertilizer treatments and ultimately drive the bacterial interactions. This study enhances our understanding of the mechanism of microbial interactions and highlights the importance of trophic patterns in the bacterial community. Our findings extend knowledge for nutrient availability on interspecific interactions.

An Aicardi-Goutières Syndrome-Causative Point Mutation in Adar1 Gene Invokes Multiorgan Inflammation and Late-Onset Encephalopathy in Mice.

Aicardi-Goutières syndrome (AGS) is a congenital inflammatory disorder accompanied by overactivated type I IFN signaling and encephalopathy with leukodystrophy and intracranial calcification. To date, none of the mouse models carrying an AGS-causative mutation has mimicked such brain pathology. Here, we established a mutant mouse model carrying a K948N point mutation, corresponding to an AGS-causative K999N mutation, located in a deaminase domain of the Adar1 gene that encodes an RNA editing enzyme. Adar1K948N/K948N mice displayed postnatal growth retardation. Hyperplasia of splenic white pulps with germinal centers and hepatic focal inflammation were observed from 2 mo of age. Inflammation developed in the lungs and heart with lymphocyte infiltration in an age-dependent manner. Furthermore, white matter abnormalities with astrocytosis and microgliosis were detected at 1 y of age. The increased expression of IFN-stimulated genes was detected in multiple organs, including the brain, from birth. In addition, single-nucleus RNA sequencing revealed that this elevated expression of IFN-stimulated genes was commonly observed in all neuronal subtypes, including neurons, oligodendrocytes, and astrocytes. We further showed that a K948N point mutation reduced the RNA editing activity of ADAR1 in vivo. The pathological abnormalities found in Adar1K948N/K948N mice were ameliorated by either the concurrent deletion of MDA5, a cytosolic sensor of unedited transcripts, or the sole expression of active ADAR1 p150, an isoform of ADAR1. Collectively, such data suggest that although the degree is mild, Adar1K948N/K948N mice mimic multiple AGS phenotypes, including encephalopathy, which is caused by reduced RNA editing activity of the ADAR1 p150 isoform.

Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce Aicardi-Goutières-syndrome-like encephalopathy.

Mutations in the adenosine-to-inosine RNA-editing enzyme ADAR1 p150, including point mutations in the Z-RNA recognition domain Zα, are associated with Aicardi-Goutières syndrome (AGS). Here, we examined the in vivo relevance of ADAR1 binding of Z-RNA. Mutation of W197 in Zα, which abolished Z-RNA binding, reduced RNA editing. Adar1W197A/W197A mice displayed severe growth retardation after birth, broad expression of interferon-stimulated genes (ISGs), and abnormal development of multiple organs. Notably, malformation of the brain was accompanied by white matter vacuolation and gliosis, reminiscent of AGS-associated encephalopathy. Concurrent deletion of the double-stranded RNA sensor MDA5 ameliorated these abnormalities. ADAR1 (W197A) expression increased in a feedback manner downstream of type I interferons, resulting in increased RNA editing at a subset of, but not all, ADAR1 target sites. This increased expression did not ameliorate inflammation in Adar1W197A/W197A mice. Thus, editing of select endogenous RNAs by ADAR1 is essential for preventing inappropriate MDA5-mediated inflammation, with relevance to the pathogenesis of AGS.

Mandatory Mask-Wearing and Hand Hygiene Associated With Decreased Infectious Diseases Among Patients Undergoing Regular Hemodialysis: A Historical-Control Study.

Background: Infections are the second leading cause of death among patients undergoing hemodialysis. However, preventive measures against infectious diseases are limited and have not been made mandatory for patients. Objective: To investigate the incidence of infectious diseases before and during the coronavirus disease (COVID-19) pandemic. Design: A historical comparative study of a prospective cohort. Setting(s): February 1, 2015 to January 31, 2020 was defined as the period before the mitigative confrontation of the COVID-19 pandemic in China. The period from February 1 to June 29, 2020 was defined as the period of mitigative confrontation of the COVID-19 pandemic in China. Participants: A cohort of patients undergoing hemodialysis whose infectious disease episodes were documented prospectively in the hemodialysis unit of the Third Affiliated Hospital of Guangzhou Medical University since February 1, 2015. Methods: Mandatory mask-wearing and reinforced hand-hygiene education were implemented to prevent COVID-19 from January 23, 2020 in China. The incidence of infectious episodes, including catheter-related infection, digestive tract infection, upper respiratory tract infection (UTRI), pneumonia, and infection at other sites, were documented and compared in the periods before and during the pandemic. Results: The historical control group consisted of 157 patients, with 79 patients in the COVID-19 prevention group. The mask-wearing rate of patients increased from 1.5 to 100%. Hand sanitizer consumption increased significantly during the COVID-19 pandemic. The compliance rates of hand hygiene increased from 66, 75.5, to 55% in physicians, nurses, and other employees before the pandemic to 90.5, 92.5, and 76.5%, respectively. The incidences of UTRI and pneumonia decreased during the pandemic (p < 0.001). Notably, catheter-related and digestive tract infections also decreased during the pandemic (p = 0.003 and 0.034, respectively). A matched-pair study was conducted to further analyze the 79 individual changes in the incidences of infectious disease before and during the pandemic. As a result, the incidences of UTRI, pneumonia, catheter-related infections, digestive tract infections, and infections at other sites all decreased during the pandemic. Conclusions: The present study indicated an association between mandatory mask-wearing and reinforced hand hygiene education and decreased respiratory, catheter-related, and digestive tract infection episodes in the hemodialysis unit.

RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain.

Adenosine deaminase acting on RNA 1 (ADAR1), an enzyme responsible for adenosine-to-inosine RNA editing, is composed of two isoforms: nuclear p110 and cytoplasmic p150. Deletion of Adar1 or Adar1 p150 genes in mice results in embryonic lethality with overexpression of interferon-stimulating genes (ISGs), caused by the aberrant recognition of unedited endogenous transcripts by melanoma differentiation-associated protein 5 (MDA5). However, among numerous RNA editing sites, how many RNA sites require editing, especially by ADAR1 p150, to avoid MDA5 activation and whether ADAR1 p110 contributes to this function remains elusive. In particular, ADAR1 p110 is abundant in the mouse brain where a subtle amount of ADAR1 p150 is expressed, whereas ADAR1 mutations cause Aicardi-Goutières syndrome, in which the brain is one of the most affected organs accompanied by the elevated expression of ISGs. Therefore, understanding RNA editing-mediated prevention of MDA5 activation in the brain is especially important. Here, we established Adar1 p110-specific knockout mice, in which the upregulated expression of ISGs was not observed. This result suggests that ADAR1 p150-mediated RNA editing is enough to suppress MDA5 activation. Therefore, we further created Adar1 p110/Adar2 double knockout mice to identify ADAR1 p150-mediated editing sites. This analysis demonstrated that although the elevated expression of ISGs was not observed, only less than 2% of editing sites were preserved in the brains of Adar1 p110/Adar2 double knockout mice. Of note, we found that some sites were highly edited, which was comparable to those found in wild-type mice, indicating the presence of ADAR1 p150-specific sites. These data suggest that RNA editing at a very limited sites, which is mediated by a subtle amount of ADAR1 p150, is sufficient to prevents MDA5 activation, at least in the mouse brain.

Neutrophil-to-Apolipoprotein A1 Ratio Predicted Overall Survival in Hepatocellular Carcinoma Receiving Transarterial Chemoembolization.

PURPOSE: The purpose of this study was to investigate the predictive capability of neutrophil-to-apolipoprotein A1 ratio (NAR) for predicting overall survival (OS) among patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE). PATIENTS AND METHODS: We investigated the clinical features of 554 patients with HCC receiving TACE and assessed NAR's predictive value for OS with 222 patients (the discovery cohort) and 332 patients (the validation cohort). The association of NAR with circulation lectin-type oxidized low-density lipoprotein receptor-1-positive (LOX-1+ ) polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was illustrated. RESULTS: Multivariate Cox regression revealed that lymphocyte count; Tumor, Node, Metastasis (TNM) stage; and NAR were independent prognostic factors in the discovery cohort. The validation cohort confirmed the independent prognostic value of TNM stage and NAR. Patients with low NAR (<2.7) displayed significantly increased OS in the discovery cohort (59.8 months vs. 21 months), the validation group (38.0 months vs. 23.6 months), and the total cohort (44.1 months vs. 22.0 months). A Cox proportional hazards model was used to combine Cancer of the Liver Italian Program (CLIP) score with discretized NAR. C-index illustrated that NAR-integrated CLIP score was the best model compared with NAR and CLIP score. Furthermore, NAR-CLIP presented superior predictive capacity for 10-, 20-, 30-, 40-, 50-, and 60-month survival compared with CLIP score by survival receiver-operator characteristic analysis in the discovery cohort, validation cohort, and total cohort. NAR was significantly associated with LOX-1+ PMN-MDSCs by linear regression. CONCLUSION: This study identified NAR as an independent predictor for OS among patients with HCC receiving TACE. NAR reflected circulation LOX-1+ PMN-MDSC level. IMPLICATIONS FOR PRACTICE: The present study identified neutrophil-to-apolipoprotein A1 ratio (NAR) as an independent predictor for overall survival among patients with hepatocellular carcinoma receiving transarterial chemoembolization. NAR reflected circulation level of lectin-type oxidized low-density lipoprotein receptor-1-positive polymorphonuclear myeloid-derived suppressor cells.

Dexamethasone and lactoferrin induced PMN-MDSCs relieved inflammatory adverse events of anti-cancer therapy without tumor promotion.

In this era of immune checkpoint inhibitors, inflammatory adverse events of anti-cancer therapies continue to pose a major challenge. Glucocorticoids, as the mainstay, were limited by serious side effects. Glucocorticoids induce myeloid-derived suppressor cells (MDSCs), and lactoferrin-induced polymorphonuclear MDSCs (PMN-MDSCs) were shown to relieve inflammatory conditions. Combined treatment with dexamethasone (DXM) and lactoferrin increased the generation of PMN-MDSCs in vitro (DXM/lactoferrin PMN-MDSCs) compared to DXM or lactoferrin treatment alone. DXM/lactoferrin PMN-MDSCs were distinct from tumor PMN-MDSCs in vivo with regard to gene expression profiles. DXM upregulated the myeloid cell response to lactoferrin by inducing the lactoferrin receptor Lrp1. DXM/lactoferrin PMN-MDSCs presented anti-bacterial capability, increased PGE2 production, increased survival capability, and decreased tumor tissue homing. Transfer of DXM/lactoferrin PMN-MDSCs relieved cisplatin-induced acute kidney failure, bleomycin-induced interstitial pneumonia, and allergic pneumonitis effectively without promoting tumor development. Our study shows that DXM/lactoferrin PMN-MDSCs are a promising cell therapy for inflammatory adverse events of anti-cancer therapies.

Keystone species determine the "selection mechanism" of multispecies biofilms for bacteria from soil aggregates.

Soil aggregates are integral parts of soil structure and play paramount roles in supporting microbial diversity, nutrient cycling and water retention. The formation of multispecies biofilms is a survival strategy for bacterial adaptation to the environment and help microorganisms access more complex nutrient sources via labor sharing, especially in soil aggregates. However, very little is known about the effect of species richness and composition on bacterial multispecies biofilms formation in different size soil aggregates. A random partition design strategy was used to identify the relative importance of bacterial richness and composition in driving multispecies biofilms. The strategy can separate the effects of species richness and composition from the soil aggregates occurring bacterial assemblage. Increasing species richness was found to be always positively correlated with multispecies biofilms productivity for bacteria from the same aggregate fractions. General linear model analysis revealed that species composition contributed more than species richness to forming multispecies biofilms, suggesting that "selection mechanism" plays a more important role than "complementarity mechanism". This "selection mechanism" relies mainly on culturable keystone species that can significantly enhance the formation of multispecies biofilms. The co-occurrence network was investigated to explore whether the culturable keystone species from the random partitions experiment are consistent with the keystone taxa. Four out of 10 culturable keystone species isolated from soil aggregates were matched the keystone taxa. It is concluded that the culturable keystone species determine the multispecies biofilms formation for bacteria residing in soil aggregates. This study provides insights into the role of culturable keystone species in multispecies biofilms. Understanding the formation of multispecies biofilms is fundamental to decipher how microbes interact with each other in soil aggregates. Meanwhile, it will enhance our knowledge of the quorum behavior of complex bacterial communities.

Accumulation of LOX-1+ PMN-MDSCs in nasopharyngeal carcinoma survivors with chronic hepatitis B might permit immune tolerance to epstein-barr virus and relate to tumor recurrence.

Chronic hepatitis B (CHB) has been reported to be associated with impaired prognosis for patients with nasopharyngeal carcinoma (NPC). However, the latent mechanism is unclear. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) induce immune suppression in CHB and promote the development of hepatocellular carcinoma. Lectin-type oxidized LDL receptor-1 (LOX-1) was recently identified as a specific marker for PMN-MSDC. We found NPC survivors with CHB had high levels of LOX-1+ PMN-MDSCs. LOX-1+ PMN-MDSCs significantly reduced T cell proliferation and activation. Endoplasmic reticulum stress was induced in LOX-1+ PMN-MDSCs. In addition, LOX-1+ PMN-MDSCs increased their expression of NOX2, a key reactive oxygen species (ROS)-related genes, and levels of ROS illustrated by the DCFDA test. The ROS inhibitor N-acetylcysteine abrogated the suppression of LOX-1+ PMN-MDSCs on T cell activation. The EBV DNA-positivity rate was higher in NPC survivors with CHB than in NPC patients without CHB. Those presenting with positive EBV DNA displayed higher LOX-1+ PMN-MDSC levels. LOX-1+ PMN-MDSCs suppressed the CD8+ T cell response against EBV. This study revealed LOX-1+ PMN-MDSC accumulation and activation in NPC survivors with CHB. LOX-1+ PMN-MDSCs might suppress the host immune response to EBV through ER stress/ROS pathway. These results explained the association of CHB with unfavorable NPC prognosis.

Expansion of Group 2 Innate Lymphoid Cells in Patients with End-Stage Renal Disease and Their Clinical Significance.

Group 2 innate lymphoid cells (ILC2s) play an important role in the control of tissue inflammation and homeostasis. However, the role of ILC2s in patients with end-stage renal disease (ESRD) has never been illustrated. In this study, we investigated ILC2s in ESRD patients and their clinical significance. Results showed that the frequencies and absolute numbers of ILC2s, not group 1 innate lymphoid cells or innate lymphoid cell precursors, were significantly elevated in the peripheral blood of ESRD patients when compared with those from healthy donor controls. Moreover, ILC2s from ESRD patients displayed enhanced type 2 cytokine production and cell proliferation. Plasma from ESRD patients significantly increased ILC2 levels and enhanced their effector function after in vitro treatment. The expression of phosphorylation of STAT5 in ILC2s, as well as the amounts of IL-2 in plasma, were increased in ESRD patients when compared with those from healthy donors. Clinically, ESRD patients with higher ILC2 frequencies displayed lower incidence of infectious complications during a mean of 21 month follow-up study. The proportions of ILC2s were negatively correlated with the prognostic biomarkers of chronic kidney disease, including serum parathyroid hormone, creatinine, and phosphorus, whereas they were positively correlated with serum calcium. These observations indicate that ILC2s may play a protective role in ESRD.

Expansion of Monocytic Myeloid-Derived Suppressor Cells in Patients Under Hemodialysis Might Lead to Cardiovascular and Cerebrovascular Events.

Background: The specific mechanism of cardiovascular and cerebrovascular vasculopathy in the context of end-stage renal disease has not been elucidated. In the present study, we investigated the clinical impact of myeloid-derived suppressor cells (MDSCs) on hemodialysis patients and their mechanism of action. Methods: MDSCs were tested among 104 patients undergoing hemodialysis and their association with overall survival (OS) and cardiovascular and cerebrovascular events was determined. Results: Hemodialysis patients presented a significantly higher level of monocytic MDSCs (M-MDSCs) compared to healthy controls. M-MDSC were tested 3 months after first testing among 103 hemodialysis patients, with one patient not retested due to early death. The repeated results of M-MDSC levels were consistent with the initial results. Patients with persistent high level of M-MDSCs presented decreased OS, as well as increased stroke and acute heart failure events. As illustrated by multivariate Cox regression, M-MDSC was an independent predictor for OS and stroke events of hemodialysis patients. T cell proliferations were significantly abrogated by hemodialysis-related M-MDSCs in a dose-dependent manner. Besides, M-MDSCs presented higher levels of CXCR4 and VLA-4 compared to monocytes, which indicated their enhanced capability to be recruited to atherosclerotic lesions. The expression of arginase I and activity of arginase was also significantly raised in hemodialysis-related M-MDSCs. Human coronary arterial endothelial cells (HCAECs) presented increased capability to migration by coculture with M-MDSCs, compared with monocyte group. Arginase inhibitor and L-arginine abrogated the immune suppressive function and induction of HCAECs migration of hemodialysis related M-MDSC. Plasma IFN-γ, TNF-α and IL-6 were elevated in hemodialysis patients compared with healthy control. M-MDSC level was positively related to IL-6 level among hemodialysis patients. The plasma of hemodialysis patients induced M-MDSCs significantly compared with plasma from health donors. Besides, IL-6 neutralizing antibody significantly abrogated the induction. Neutralizing antibody of IFN-γ and TNF-α partially decreased the generation of arginase of the induced M-MDSC. Conclusions: M-MDSCs were elevated in ESRD patients under hemodialysis, and they exhibited a strong association with the risk of cardiovascular and cerebrovascular diseases. Hemodialysis related M-MDSC presented enhanced recruitment to atherosclerotic lesions, promoted the migration of endothelial cells through exhaustion of local L-arginine.

Pretransplant metabolic syndrome and its components predict post-transplantation diabetes mellitus in Chinese patients receiving a first renal transplant.

BACKGROUND: Post-transplantation diabetes mellitus (PTDM) remains a major clinical challenge following renal transplant. Identification of pretransplant modifiable risk factors may allow timely interventions to prevent PTDM. This study aims to determine whether pretransplant metabolic syndrome and its components are able to predict PTDM in Chinese patients receiving their first renal transplant. PATIENTS AND METHODS: We conducted a single-center retrospective study of 633 non-diabetic patients receiving a first kidney transplant. PTDM was diagnosed between 1 month and 1 year post-transplant. Multivariable logistic regression and Cox proportional hazards model were applied to detect potential pretransplant risk factors for PTDM. RESULTS: One year post-transplant, 26.2% of recipients had developed PTDM. PTDM patients had significantly higher fasting plasma glucose (FPG) (P=0.026) and body mass index (BMI) (P=0.006) than non-PRDM patients, and lower levels of high-density lipoprotein cholesterol (P=0.015). The presence of metabolic syndrome was an independent risk factor for PTDM, as assessed by multivariable logistic regression analysis (OR 1.28, 95% CI 1.04-1.51, P=0.038) and Cox proportional hazards model (OR 2.75, 95% CI 1.45-6.05, P=0.021). Moreover, both FPG >5.6 mmol/L and BMI >28 kg/m2 (obesity) were able to predict PTDM. CONCLUSION: Our results suggest that the presence of metabolic syndrome and its components, impaired fasting glycemia and obesity, are independent risk factors for PTDM in Chinese non-diabetic patients receiving a first renal transplant. Interventions aimed at improving pretransplant metabolic syndrome may reduce the incidence of PTDM.

Selection of glucocorticoid-sensitive patients in interstitial lung disease secondary to connective tissue diseases population by radiomics.

PURPOSE: The effect of glucocorticoid(s) on connective tissue disease (CTD)-related interstitial lung disease (ILD) is controversial. This multicenter study aimed to identify glucocorticoid-sensitive patients using a radiomics approach. METHODS: A total of 416 CTD-ILD patients who began glucocorticoid treatment at the discretion of the attending physician, with or without cyclophosphamide, were included in this study. High doses were defined as pulsed intravenous methylprednisolone, an initial dose of 1 mg/kg/day of prednisolone or 0.8 mg/kg/day of methylprednisolone. Low doses were defined as those less than high doses. Radiomics features were manually extracted from primary lung lesions delineated on computed tomography images, and selected by variance, univariate feature selection, and least absolute shrinkage and selection operator regression model. The prediction models were developed using data from 309 patients from two centers and externally validated in 107 patients from four other hospitals. RESULTS: Treatment response in the training and validation groups was 38.5% and 36.4%, respectively. Eleven radiomics features were selected from 1,029 features with predictive value. Random forest models built for radiomics features to predict treatment response yielded a sensitivity of 0.897. The calibration curve of a nomogram demonstrated good agreement between prediction and observation. Decision curve analysis indicated that glucocorticoid was beneficial if the predicted response rate was 50%-60% for an individual. High doses of glucocorticoids and cyclophosphamide yielded superior efficacy. CONCLUSION: Radiomics-based predictive models reliably identified glucocorticoid-sensitive CTD-ILD patients. Short-term, high-dose glucocorticoid with cyclophosphamide yielded promising results as a potential therapy.

Endoplasmic reticulum stress induced LOX-1+ CD15+ polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma.

A recent study indicated that Lectin-type oxidized LDL receptor-1 (LOX-1) was a distinct surface marker for human polymorphisms myeloid-derived suppressor cells (PMN-MDSC). The present study was aimed to investigate the existence LOX-1 PMN-MDSC in hepatocellular carcinoma (HCC) patients. One hundred and twenty-seven HCC patients, 10 patients with mild active chronic hepatitis B, 10 liver cirrhosis due to hepatitis B, 10 liver dysplastic node with hepatitis B and 50 health control were included. LOX-1+  CD15+ PMN-MDSC were significantly elevated in HCC patients compared with healthy control and patients with benign diseases. LOX-1+  CD15+ PMN-MDSC in circulation were positively associated with those in HCC tissues. LOX-1+  CD15+ PMN-MDSCs significantly reduced proliferation and IFN-γ production of T cells with a dosage dependent manner with LOX-1-  CD15+ PMNs reached negative results. The suppression on T cell proliferation and IFN-γ production was reversed by ROS inhibitor and Arginase inhibitor. ROS level and activity of arginase of LOX-1 + CD15+ PMN were higher in LOX-1+  CD15+ PMN-MDSCs than LOX-1-  CD15+ PMNs, as well as the expression of the NADPH oxidase NOX2 and arginase I. RNA sequence revealed that LOX-1+ CD15+ PMN-MDSCs displayed significantly higher expression of spliced X-box -binding protein 1 (sXBP1), an endoplasmic reticulum (ER) stress marker. ER stress inducer induced LOX-1 expression and suppressive function for CD15+ PMN from health donor. For HCC patients, LOX-1+  CD15+ PMN-MDSCs were positively related to overall survival. Above all, LOX-1+  CD15+ PMN-MDSC were elevated in HCC patients and suppressed T cell proliferation through ROS/Arg I pathway induced by ER stress. They presented positive association with the prognosis of HCC patients.

A multidisciplinary team approach for nutritional interventions conducted by specialist nurses in patients with advanced colorectal cancer undergoing chemotherapy: A clinical trial.

BACKGROUND & AIMS: Nutritional interventions for malnutrition in cancer patients can be helpful. However, concise intervention recommendations remain controversial. Thus, the aim of this study was to report on a nutrition intervention conducted by a multidisciplinary team of specialist nurses and to explore the effect of nutritional intervention on cancer patients. METHODS: This prospective clinical trial study enrolled 110 colorectal cancer patients undergoing chemotherapy. The patients were evaluated upon admission using the 2002 Nutritional Risk Screening system (NRS-2002). The patients were randomly divided into intervention and control groups including 55 patients each. Patients in the control group were administered a normal diet, while those in the intervention group received individual recipes developed by a team of professional nurses, clinical doctors, dietitian, family caregivers, and the patients themselves. Patient weight and serum albumin and prealbumin levels were compared between the 2 groups at different time points. RESULTS: There was a significant difference in patient weight and serum albumin and prealbumin levels before and after nutrition intervention in the intervention group (P < .05). In the control group, weight did not change during ordinary diet guidance. Serum albumin level was slightly improved after 12 cycles of chemotherapy, similar to the prealbumin results. There were statistically significant differences in serum albumin and prealbumin levels between the intervention and control groups after nutrition intervention (P < .05). However, there was no statistically significant difference in weight between the groups after nutrition intervention (P > .05). CONCLUSION: A multidisciplinary team approach for nutrition intervention conducted by specialist nurses improved prealbumin levels in colorectal cancer patients undergoing chemotherapy, with no weight change.

Advance directives: cancer patients' preferences and family-based decision making.

BACKGROUND: Advance directives are a sensitive issue among traditional Chinese people, who usually refrain from mentioning this topic until it is imperative. Medical decisions for cancer patients are made by their families, and these decisions might violate patients' personal will. OBJECTIVES: This study aimed to examine the acceptance of advance directives among Chinese cancer patients and their families and patient participation in this procedure and, finally, to analyze the moral risk involved. RESULTS: While 246 patients and their family members refused official discussion of an advance directive, the remaining 166 patients and their families accepted the concept of an advance directive and signed a document agreeing to give up invasive treatment when the anti-cancer treatment was terminated. Of these, only 24 patients participated in the decision making. For 101 patients, anti-cancer therapy was ended prematurely with as many as 37 patients not told about their potential loss of health interests. MATERIALS AND METHODS: Participants were 412 adult cancer patients from 9 leading hospitals across China. An advance directive was introduced to the main decision makers for each patient; if they wished to sign it, the advance directive would be systematically discussed. A questionnaire was given to the oncologists in charge of each patient to evaluate the interaction between families and patients, patients' awareness of their disease, and participation in an advance directive. CONCLUSIONS: Advance directives were not widely accepted among Chinese cancer patients unless anti-cancer therapy was terminated. Most cancer patients were excluded from the discussion of an advance directive.

Neutrophil count is associated with myeloid derived suppressor cell level and presents prognostic value of for hepatocellular carcinoma patients.

Myeloid Derived Suppressor Cell (MDSC) has been raised to be a novel target for multiple cancers. However, target agents on MDSC have not display promising efficacy. One of the critical reasons shall be less optimal patient selection. In the present study, we aimed to identify clinical parameters relevant to MDSC level in hepatocellular carcinoma (HCC) patients for future MDSC targeted therapy. In the present study, a series of 55 HCC patients (testing group) and 20 healthy donors were analyzed investigating frequencies of MDSC in peripheral blood mononuclear cells (PBMC). As a result, we found that MDSC level was increased in HCC patients compared to healthy donors (10.33% vs 1.54%, p < 0.0001). The monocytes (r2 = 0.2875, p < 0.0001), neutrophils (r2 = 0.3630, p < 0.0001) and platelet counts (r2 = 0.0828, p = 0.0331) in circulation was positively associated with MDSC level. Then, the prognostic value of the above predictors was determined in a retrospective database of 255 HCC patients (validation group). The baseline characteristics of testing and validation group were similar. Multivariate analysis by Cox regression revealed that neutrophil count was an independent predictor for overall survival (OS) (p = 0.000, HR 1.065, 95% CI 1.028-1.103), with the rest parameters failed to reach a significant result. In summary, the present study firstly identified blood neutrophil counts was a predictor of MDSC level in PBMC for HCC patients. And, patients with higher neutrophil count level might be the optimal patient subgroup for MDSC targeted therapy.