Myeloid-derived suppressor cells from tumour-bearing mice induce the population expansion of CD19hiFcγRIIbhi regulatory B cells via PD-L1.

Myeloid-derived suppressor cells (MDSCs) increase in number and gain immunosuppressive functions in tumours and many other pathological conditions. MDSCs are characterized by their strong T-cell immunosuppressive capacity. The effects that MDSCs may have on B cells, especially within the tumour microenvironment, are less well understood. Here, we report that either monocytic MDSCs or polymorphonuclear MDSCs can promote increases in interleukin (IL)-10-expressing CD19hiFcγRIIbhi regulatory B cells in vitro and in vivo. Splenic transitional-1, -2, and -3 cells and marginal zone B cells, but not follicular B cells, differentiate into IL-10-expressing CD19hiFcγRIIbhi regulatory B cells. The adoptive transfer of CD19hiFcγRIIbhi regulatory B cells via tail vein injection can promote subcutaneous 3LL tumour growth in mice. The expression of programmed death-ligand 1 on MDSCs was found to be strongly associated with CD19hiFcγRIIbhi regulatory B cell population expansion. Furthermore, the frequency of circulating CD19+FcγRIIhi regulatory B cells was significantly increased in advanced-stage lung cancer patients. Our results unveil a critical role of MDSCs in regulatory B-cell differentiation and population expansion in lung cancer patients.

Leukocyte Ig-like receptor A3 facilitates inflammation, migration and invasion of synovial tissue-derived fibroblasts via ERK/JNK activation.

OBJECTIVE: Leukocyte Ig-like receptor A3 (LILRA3) is a soluble receptor belongs to the immunoglobulin superfamily. Our previous studies demonstrated that LILRA3 is a common genetic risk for multiple autoimmune diseases, including RA. Functional LILRA3 conferred increased risk of joint destruction in patients with early RA. We undertook this study to further investigate the pathological role of LILRA3 in joint inflammation of RA. METHODS: Soluble LILRA3 was measured by ELISA. LILRA3 plasmids were transfected into human fibroblast-like synoviocytes (FLSs) using electroporation. Activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was determined by western blots. Cytokine transcripts were quantified by real-time PCR. Migratory and invasive capacities of FLSs were evaluated using transwell migration and Matrigel invasion assays. FLS apoptosis was analysed using flow cytometry. Colocalization of LILRA3, LILRB1 and HLA-G in RA-FLSs was visualized by immunofluorescence staining. RESULTS: Soluble LILRA3 was specifically expressed in synovial fluid and serum LILRA3 was significantly increased and positively correlated with disease activity/severity in RA patients. LILRA3 induced an increased expression of IL-6, IL-8 and MMP3 in RA-FLSs. In vitro LILRA3 stimulation or overexpression promoted RA-FLS migration and invasion, and enhanced phosphorylation of ERK/JNK. Inhibition of ERK/JNK resulted in suppression of IL-6/IL-8 expression in LILRA3-stimulated RA-FLSs. LILRA3 was co-localized with its homologue LILRB1 and shared ligand HLA-G in RA-FLSs. CONCLUSION: The present study provides the first evidence that soluble LILRA3 is a novel proinflammatory mediator involved in synovial inflammation by promoting RA-FLS activation, migration and invasion, probably through the ERK/JNK signalling pathways.

Spiritual care needs and their attributes among Chinese inpatients with advanced breast cancer based on the Kano model: a descriptive cross-sectional study.

BACKGROUND: Numerous previous research have established the need for spiritual care among patients with cancer globally. Nevertheless, there was limited research, primarily qualitative, on the spiritual care needs of Chinese inpatients with advanced breast cancer. Furthermore, the need for spiritual care was rarely explored using the Kano model. To better understand the spiritual care needs and attributes characteristics of inpatients with advanced breast cancer, this study examined the Kano model. METHODS: A descriptive cross-sectional design study was conducted in the oncology departments of three tertiary grade-A hospitals in China from October 2022 to May 2023. To guarantee high-quality reporting of the study, the Strengthening the Reporting of Observational Studies in Epidemiology Checklist was used. Data on the demographic characteristics questionnaire, the Nurse Spiritual Therapeutics Scale (NSTS), and the Kano model-based Nurse Spiritual Therapeutics Attributes Scale (K-NSTAs) were collected through convenience sampling. The Kano model, descriptive statistics, two independent samples t-tests, and one-way analysis of variance were used to analyze the data. RESULTS: The overall score for spiritual care needs was 31.16 ± 7.85. The two dimensions with the highest average scores, "create a good atmosphere" (3.16 ± 0.95), and the lowest average scores, "help religious practice" (1.72 ± 0.73). The 12 items were distributed as follows: three attractive attributes were located in Reserving Area IV; five one-dimensional attributes were distributed as follows: three one-dimensional attributes were located in Predominance Area I, and two were found in Improving Area II; two must-be attributes were located in Improving Area II; and two indifference attributes were located in Secondary Improving Area III. CONCLUSION: The Chinese inpatients with advanced breast cancer had a middle level of spiritual care needs, which need to be further improved. Spiritual care needs attributes were defined, sorted, categorized, and optimized accurately and perfectly by the Kano model. And "create a good atmosphere" and "share self-perception" were primarily one-dimensional and must-be attributes. In contrast, the items in the dimensions of "share self-perception" and "help thinking" were principally attractive attributes. Nursing administrators are advised to optimize attractive attributes and transform indifference attributes by consolidating must-be and one-dimensional attributes, which will enable them to take targeted spiritual care measures based on each patient's characteristics and unique personality traits.

Accelerated Oxygen Evolution Kinetics by Engineering Heterojunction Coupling of Amorphous NiFe Hydr(oxy)oxide Nanosheet Arrays on Self-Supporting Ni-MOFs.

Designing definite transition metal heterointerfaces is considered an effective strategy for the construction of efficient and robust oxygen evolution reaction (OER) electrocatalysts, but rather challenging. Herein, amorphous NiFe hydr(oxy)oxide nanosheet arrays (A-NiFe HNSAs) are grown in situ on the surface of a self-supporting Ni metal-organic frameworks (SNMs) electrode via a combination strategy of ion exchange and hydrolytic co-deposition for efficient and stable large-current-density water oxidation. The existence of the abundant metal-oxygen bonds on the heterointerfaces can not only be of great significance to alter the electronic structure and accelerate the reaction kinetics, but also enable the redistribution of Ni/Fe charge density to effectively control the adsorption behavior of important intermediates with a close to the optimal d-band center, dramatically narrowing the energy barriers of the OER rate-limiting steps. By optimizing the electrode structure, the A-NiFe HNSAs/SNMs-NF exhibits outstanding OER performance with small overpotentials of 223 and 251 mV at 100 and 500 mA cm-2 , a low Tafel slope of 36.3 mV dec-1 , and excellent durability during 120 h at 10 mA cm-2 . This work significantly provides an avenue to understand and realize rationally designed heterointerface structures toward effective oxygen evolution in water-splitting applications.

Spiritual care needs among Chinese elders hospitalized for severe chronic heart failure: An observational study.

OBJECTIVES: To investigate the spiritual care needs and their attributes among Chinese elders hospitalized for severe chronic heart failure (CHF) based on the Kano model, in order to provide a reference for improving the quality and satisfaction of spiritual care. METHODS: An observational design was implemented, and the STROBE Checklist was used to ensure quality reporting of the study. The demographic characteristics questionnaire, the Nurse Spiritual Therapeutics Scale, and the Kano model-based Nurse Spiritual Therapeutics Attributes Scale were used. A convenience sample of 451 patients were selected from 2 hospitals. Descriptive statistics, and Kano model were used to analyze the data. RESULTS: The total score of spiritual care needs was 29.95 ± 7.51. Among the 12 items, 3 items were attractive attributes, all of which were located in Reserving Zone IV; 5 items were one-dimensional attributes, of which 3 were located in Predominance Zone I and 2 were located in Improving Zone II; 2 items were must-be attributes, all of which were located in Improving Zone II; and 2 items were indifference attributes, all of which were located in Secondary Improving Zone III. SIGNIFICANCE OF RESULTS: The spiritual care needs among Chinese elders hospitalized for severe CHF were moderate. The must-be and one-dimensional attributes mainly focus on "creating a good atmosphere" and "sharing self-perception" dimensions, while attractive attributes mainly focus on "sharing self-perception" and "helping thinking" dimensions. It is suggested that hospital authority should develop and innovate attractive attributes on the basis of maintaining and perfecting must-be and one-dimensional attributes, and objectively analyze and optimize indifference attributes.

[Effects of Huangqin Tang on NLRP3/Caspase-1 pathway in mice model of ulcerative colitis].

The aim of this study was to explore the effects of Huangqin Tang(HQT) on the NLRP3/Caspase-1 signaling pathway in mice with DSS-induced ulcerative colitis(UC). C57BL/6J mice were randomly divided into a blank group, a model group(DSS group), and low-, medium-and high-dose HQT groups(HQT-L, HQT-M, and HQT-H), and western medicine mesalazine group(western medicine group). The UC model was induced in mice. Subsequently, the mice in the HQT-L, HQT-M, HQT-H groups, and the western medicine group were given low-, medium-, high-dose HQT, and mesalazine suspension by gavage, respectively, while those in the blank and DSS groups were given an equal volume of distilled water by gavage. After 10 days of administration, the body weight, DAI scores, and colonic histopathological score of mice in each group were determined. The levels of IL-6, IL-10, IL-1ß, and TNF-α in serum were determined by ELISA. The mRNA expression of NLRP3 and Caspase-1 in colon tissues was determined by RT-qPCR. The protein expression of NLRP3 and Caspase-1 in colon tissues was detected by immunohistochemistry. The results showed that compared with the blank group, the DSS group showed decreased body weight of mice and increased DAI scores and intestinal histopathological score. Compared with the DSS group, the HQT groups and the western medicine group showed improved DAI scores, especially in the HQT-M, HQT-H, and the western medicine groups(P<0.05). The intestinal histopathological scores of the HQT groups and the western medicine group significantly decreased, especially in the HQT-M, HQT-H, and the western medicine groups(P<0.05). In addition, compared with the blank group, the DSS group showed elevated expression of NLRP3 and Caspase-1 in colon tissues, increased serum levels of IL-6, IL-1ß, and TNF-α, and decreased IL-10 level. Compared with the DSS group, the HQT groups and the western medicine group displayed decreased expression of NLRP3 and Caspase-1 in colon tissues, reduced serum levels of IL-6, IL-1ß, and TNF-α, and increased IL-10 level. The improvement was the most significant in the HQT-H group and the western medicine group(P<0.01). In conclusion, HQT may reduce the expression of NLRP3 and Caspase-1 in colon tissues, reduce the se-rum levels of IL-6, IL-1ß, and TNF-α, and increase the expression of IL-10 by regulating the classic pyroptosis pathway of NLRP3/Caspase-1, thereby improving the symptoms of intestinal injury and inflammatory infiltration of intestinal mucosa in DSS mice to achieve its therapeutic effect.

XIST/miR-34a-5p/PDL1 axis regulated the development of lung cancer cells and the immune function of CD8+ T cells.

PURPOSE: Long non-coding RNA (lncRNA) XIST has been shown to be involved in the immune escape of breast cancer, but it is unclear whether it is involved in the immune escape of lung cancer, so it will be discussed in this study. METHODS: XIST and miR-34a-5p expression in lung cancer tissues and cells were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The targeting relationship between miR-34a-5p and XIST/programmed cell death receptor ligand 1 (PDL1) was predicted by bioinformatics website and verified by dual-luciferase report experiment. After co-transfection with XIST specific short hairpin RNA (sh-XIST) and miR-34a-5p inhibitors, the changes in PDL1 expression, and cell biological behavior were detected by qRT-PCR, cell counting kit 8, flow cytometry, and Transwell experiments. Similarly, after co-transfection of PDL1 specific small interfering RNA (siPDL1) and miR-34a-5p inhibitors, the changes in cell biological behavior were detected again. After CD8+ T cells were co-cultured with lung cancer cells transfected with sh-XIST and miR-34a-5p inhibitors, the expression of cytokines and immunosuppressive molecules was detected by western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: XIST was up-regulated in lung cancer tissues, while miR-34a-5p was the opposite. XIST up-regulated the expression of PDL1 by targeting miR-34a-5p, thereby affecting the viability, apoptosis, migration, and invasion of lung cancer cells. In the co-culture system, XIST targeted miR-34a-5p to inhibit cytokines secretion and promote the expression of immunosuppressive molecules. CONCLUSIONS: XIST/miR-34a-5p/PDL1 axis was involved in the malignant biological behavior of lung cancer cells and the immune function of CD8+ T cells.

Discovery of pyrroledione analogs as potent transient receptor potential canonical channel 5 inhibitors.

A deepening understanding of the relationship between transient receptor potential canonical channel 5 (TRPC5) and chronic kidney disease (CKD), has led to the emergence of several types of TRPC5 inhibitors displaying clear therapeutic effect. Herein, we report the synthesis and biological evaluation of a series of pyrroledione TRPC5 inhibitors, culminating in the discovery of compound 16g with subtype selectivity. Compared with GFB-8438, a potent TRPC5 inhibitor (Goldfinch Bio), compound 16g showed improved inhibition of TRPC5 and enhanced protective effect against protamine sulfates (PS)-induced podocyte injury in vitro. In addition, compound 16g did not induce cell death in primary cultured hepatocytes and immortalized podocytes in a preliminary toxicity assessment, indicating its utility as a potent and safe inhibitor for studying the function of TRPC5.

Synthesis of AC1903 analogs as potent transient receptor potential canonical channel 4/5 inhibitors and biological evaluation.

Transient receptor potential canonical (TRPC) channels are a class of non-selective cation channels expressed in a variety of tissues and organ systems where they functionally regulate physiological and pathological processes. TRPC5 has been shown to be a promising target for focal segmental glomerulosclerosis treatment. In this study, we report the synthesis and biological evaluation of a novel series of benzimidazole-based TRPC5 inhibitors. One compound, 8b, is 100-fold more potent than the parent compound, AC1903, in the suppression of TRPC5 channel activity. Interestingly, both AC1903 and 8b also suppressed TRPC4 channel activity with similar potency. Compound 8b also significantly blunts protamine sulfate-induced reorganization of podocyte cytoskeleton, interleukin (IL)-17-induced cell proliferation, and the expression of proinflammatory mediators in human keratinocyte HaCaT cells.

Mirabegron Ameliorated Atherosclerosis of ApoE-/- Mice in Chronic Intermittent Hypoxia but Not in Normoxia.

PURPOSE: It has been established that obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. Chronic intermittent hypoxia (CIH) activates sympathoadrenal system and upregulates ß3 adrenergic receptor (ß3 AR). However, the effect of selective ß3 AR agonist mirabegron in CIH-induced atherosclerosis remains unknown. METHODS: We generated a CIH-induced atherosclerosis model through exposing ApoE-/- mice to CIH (8 h per day, cyclic inspiratory oxygen fraction 5-21%, 60-s cycle) for 6 weeks after 4-week high-fat dieting and investigated the effects of mirabegron, a selective ß3 AR agonist, on CIH-induced atherosclerosis. The coronary endarterectomy (CE) specimens from coronary artery disease patients with OSA and without OSA were collected. RESULTS: The expression of ß3 AR was significantly elevated in CIH-induced atherosclerosis model. Furthermore, treatment with mirabegron (10mg/kg per day by oral administration for 6 weeks) ameliorated atherosclerosis in ApoE-/- mice in CIH but not in normoxia. Mechanistically, mirabegron activated ß3 AR and ameliorated intraplaque oxidative stress by suppressing p22phox expression and reactive oxygen species (ROS) level. In addition, in human CE specimens, ß3 AR was also upregulated associated with increased p22phox expression and ROS level both in the lumen and in the plaque of coronary artery in OSA subjects. CONCLUSION: This study first demonstrated that mirabegron impeded the progression of CIH-induced atherosclerosis, at least in part, via ß3 AR-mediated oxidative stress, suggesting a promising therapeutic strategy for protecting against atherosclerosis induced by CIH.

Novel Caspase-1 inhibitor CZL80 improves neurological function in mice after progressive ischemic stroke within a long therapeutic time-window.

Progressive ischemic stroke (PIS) is featured by progressive neurological dysfunction after ischemia. Ischemia-evoked neuroinflammation is implicated in the progressive brain injury after cerebral ischemia, while Caspase-1, an active component of inflammasome, exaggerates ischemic brain injury. Current Caspase-1 inhibitors are inadequate in safety and druggability. Here, we investigated the efficacy of CZL80, a novel Caspase-1 inhibitor, in mice with PIS. Mice and Caspase-1-/- mice were subjected to photothrombotic (PT)-induced cerebral ischemia. CZL80 (10, 30 mg·kg-1·d-1, i.p.) was administered for one week after PT onset. The transient and the progressive neurological dysfunction (as foot faults in the grid-walking task and forelimb symmetry in the cylinder task) was assessed on Day1 and Day4-7, respectively, after PT onset. Treatment with CZL80 (30 mg/kg) during Day1-7 significantly reduced the progressive, but not the transient neurological dysfunction. Furthermore, we showed that CZL80 administered on Day4-7, when the progressive neurological dysfunction occurred, produced significant beneficial effects against PIS, suggesting an extended therapeutic time-window. CZL80 administration could improve the neurological function even as late as Day43 after PT. In Caspase-1-/- mice with PIS, the beneficial effects of CZL80 were abolished. We found that Caspase-1 was upregulated during Day4-7 after PT and predominantly located in activated microglia, which was coincided with the progressive neurological deficits, and attenuated by CZL80. We showed that CZL80 administration did not reduce the infarct volume, but significantly suppressed microglia activation in the peri-infarct cortex, suggesting the involvement of microglial inflammasome in the pathology of PIS. Taken together, this study demonstrates that Caspase-1 is required for the progressive neurological dysfunction in PIS. CZL80 is a promising drug to promote the neurological recovery in PIS by inhibiting Caspase-1 within a long therapeutic time-window.

Spiritual care perceptions and empathy of Chinese nursing students: The mediating roles of spiritual well-being.

OBJECTIVE: To investigate spiritual care perceptions, spiritual well-being, and empathy, examine the correlations among spiritual care perceptions, spiritual well-being, and empathy, and explore the mediating role of spiritual well-being between other two variables of Chinese nursing students. METHODS: A cross-sectional design was implemented, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Checklist was used to ensure quality reporting of the study. A cluster sample of 2,718 nursing students was selected from 7 universities and colleges in China. The demographic characteristics questionnaire, the Chinese Version of the Spiritual Care-Giving Scale (C-SCGS), the Spiritual Health Scale Short Form (SHS-SF), and the Jefferson Scale of Physician Empathy-Nursing Student (JSPE-NS) were used. Descriptive statistics, correlation, and process plug-in mediation effect analyses were used to analyze the data. RESULTS: The total score of spiritual care perceptions, spiritual well-being, and empathy were 173.83 ± 25.62, 98.74 ± 12.87, and 105.04 ± 21.34, respectively. Spiritual care perceptions were positively correlated with spiritual well-being (r = 0.617, p < 0.01) and empathy (r = 0.528, p < 0.01). And spiritual well-being played a partial mediating role between the other two variables (accounting for 28.1%). SIGNIFICANCE OF RESULTS: Spiritual care perceptions, spiritual well-being, and empathy were quite moderate, which need in improving. It is suggested that nursing educators pay attention to the spiritual care education of nursing students, perfect the spiritual care education system, and take targeted measures according to nursing students' individual personality traits and differences, improve their spiritual well-being and empathy in multiple ways, so as to improve their spiritual care perceptions and competence.

Allicin attenuates myocardial apoptosis, inflammation and mitochondrial injury during hypoxia-reoxygenation: an in vitro study.

BACKGROUND: Myocardial ischemia-reperfusion (IR) injury is a damage due to an initial reduction in blood flow to the heart, preventing it from receiving enough oxygen, and subsequent restoration of blood flow through the opening of an occluded coronary artery producing paradoxical harmful effects. The finding of new therapies to prevent IR is of utmost importance. Allicin is a compound isolated from garlic having the ability to prevent and cure different diseases, and a protective effect on the myocardium was also demonstrated. Therefore, the aim of this study was to evaluate the in vitro protective effect of Allicin against myocardial IR injury on cardiomyocytes. METHODS: We established an in vitro hypoxia-reoxygenation (HR) model of primary porcine cardiomyocytes to simulate myocardial IR injury. Primary porcine cardiomyocytes were extracted from Mini-musk swines (1 day old). After a period of adaptation of at least 2-3 days, cardiomyocytes in good condition were selected and randomly divided into control group (normal oxygen for 5 h), HR group (2 h of hypoxia/3 h of reoxygenation), and HR + Allicin group (hypoxia/reoxygenation + Allicin treatment). RESULTS: After the induction of hypoxia/reoxygenation, Allicin treatment enhanced the cell viability. Moreover, Allicin treatment resulted in a reduction of apoptosis from 13.5 ± 1.2% to 6.11 ± 0.15% compared with the HR group (p < 0.05), and the apoptosis related proteins were regulated as well, with a decreased expression of Bax, cleaved caspase-3 and cytosolic cytochrome C and an increase in Bcl-2 expression in the HR + Allicin group (all p < 0.01). Pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor alpha were down-regulated by the treatment with Allicin (both p < 0.01). In addition, it significantly decreased intracellular reactive oxygen species generation (p < 0.01) and reduced the loss of mitochondrial membrane potential (p < 0.01). Furthermore, the expression of PPARγ coactivator-1α and endothelial nitric oxide synthase was up-regulated (both p < 0.01), while the expression of Endothelin-1, hypoxia inducing factor-1α and transforming growth factor beta was down-regulated (all p < 0.01) by Allicin treatment. CONCLUSIONS: These results suggested that Allicin protected the cardiomyocytes against HR damage by reducing apoptosis, inflammation and mitochondrial injury, thus providing a basis for its potential use in the treatment of myocardial IR.

Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury.

Melatonin receptors (MTs) are potential drug targets for stroke therapy. Ramelteon is a selective melatonin receptor agonist used to treat insomnia. In this study we investigated whether ramelteon could attenuate cerebral ischemia in mice. Acute focal cerebral ischemia was induced in mice via middle cerebral artery occlusion (MCAO). We found oral administration of ramelteon (3.0 mg/kg) significantly attenuated ischemic injury even when it was given 4 h after the onset of ischemia. We showed that administration of ramelteon (3.0 mg/kg) displayed comparable protective efficacy and length of effective time window as administration of edaravone (10 mg/kg, i.p.), which was used in clinic to treat ischemic stroke. Chronic ischemic brain injury was induced in mice using photothrombosis. Oral administration of ramelteon (3.0 mg · kg-1 · d-1) for 7 days after ischemia significantly attenuated functional deficits for at least 15 days. The neuroprotection of ramelteon was blocked by 4-P-PDOT, a specific MT antagonist. We further revealed that ramelteon significantly inhibited autophagy in the peri-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway. Intracerebroventricular injection of rapamycin, an autophagy activator, compromised the neuroprotection of ramelteon, suggesting ramelteon might attenuate ischemic injury by counteracting autophagic cell death. These data demonstrate for the first time the potential benefits of ramelteon in the treatment of both acute and chronic ischemic brain injury and provide the rationale for the application of ramelteon in stroke therapy.

Diagnostic Value of lncRNA ROR in Differentiating Ovarian Cancer Patients.

BACKGROUND: The current study aims to investigate the prognostic value of long non-coding RNA (lncRNA) ROR in ovarian cancer patients. METHODS: Sixty cases of ovarian cancer patients were collected from January 2017 to December 2017. The expression of lncRNA ROR in the plasma and tissues of ovarian cancer was detected by RT-qPCR. The relationship between the expression of lncRNA ROR and the clinicopathological characteristics was analyzed. RESULTS: The expression of lncRNA ROR in the plasma of ovarian cancer patients was significantly higher than that in healthy controls. Compared with that in the adjacent non-cancerous tissues, the level of lncRNA ROR was significantly enhanced in the ovarian cancer tissues. Further study showed that the expression of lncRNA ROR was closely related to FIGO stage, tumor grade, and lymph node metastasis. Pearson's correlation assay indicated that lncRNA ROR positively correlated with CA125 in ovarian cancer patients. Moreover, the combined detection of plasma lncRNA ROR and CA125 had the highest value in the diagnosis of ovarian cancer compared to that of lncRNA ROR or CA125 alone. CONCLUSIONS: The enhanced level of plasma lncRNA ROR could be used as a potential biomarker for the diagnosis of ovarian cancer.

Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population.

OBJECTIVE: The strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC. METHODS: We first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case-control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants. RESULTS: HLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10-36, OR=2.29). DRß1:37N had an independent protective effect (p=5.81×10-16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRß1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility. CONCLUSIONS: We provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.

A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/ß-Catenin Signaling Promotes Metastasis of Colon Cancer.

We previously demonstrated that long non-coding RNA cytoskeleton regulator RNA (CYTOR), also known as Linc00152, was significantly overexpressed in colon cancer and conferred resistance to oxaliplatin-induced apoptosis. At the same time, elevated CYTOR expression was also reported in gastric cancer and exerted influences on epithelial-mesenchymal transition (EMT) markers. However, the precise mechanism by which CYTOR promotes the EMT phenotype and cancer metastasis remains poorly understood. Here, we showed that loss of epithelial characteristics and simultaneous gain of mesenchymal features correlated with CYTOR expression. Knockdown of CYTOR attenuated colon cancer cell migration and invasion. Conversely, ectopic expression of CYTOR induced an EMT program and enhanced metastatic properties of colon cancer cells. Mechanistically, the binding of CYTOR to cytoplasmic ß-catenin impeded casein kinase 1 (CK1)-induced ß-catenin phosphorylation that enabled it to accumulate and translocate to the nucleus. Reciprocally, ß-catenin/TCF complex enhanced the transcription activity of CYTOR in nucleus, thus forming a positive feed-forward circuit. Moreover, elevated CYTOR, alone or combined with overexpression of nuclear ß-catenin, was predictive of poor prognosis. Our findings suggest that CYTOR promotes colon cancer EMT and metastasis by interacting with ß-catenin, and the positive feed-forward circuit of CYTOR-ß-catenin might be a useful therapeutic target in antimetastatic strategy.

Anti-SIRT1 autoantibody is elevated in ankylosing spondylitis: a potential disease biomarker.

BACKGROUND: Little is known about the presence of specific autoantibodies in ankylosing spondylitis (AS), an immune-mediated inflammatory disease. The object of this study was to explore potential autoantibody profiles in AS patients. RESULTS: Levels of anti-SIRT1 autoantibodies were significantly higher in AS (P < 0.001) and psoriatic arthritis (PsA) (P < 0.01) patients but not rheumatoid arthritis (RA) patients compared with healthy controls. Additionally, titers of anti-NAD-dependent protein deacetylase sirtuin-1(SIRT1) antibodies were significantly higher in AS patients than in RA (P < 0.05) and PsA (P < 0.05) patients. Moreover, levels of anti-SIRT1 (P < 0.001) antibodies were significantly higher during the first year in patients with hip joint involvement. The anti-SIRT1 antibody positivity rate was 18.9% in AS patients. CONCLUSIONS: Our findings indicate that anti-SIRT1 autoantibodies may serve as a marker for diagnosing AS and predicting hip joint involvement at an early stage.

Meta-analysis and systematic review of intravascular ultrasound versus angiography-guided drug eluting stent implantation in left main coronary disease in 4592 patients.

BACKGROUND: Although several meta-analyses have demonstrated the utility of intravascular ultrasound (IVUS) in guiding drug-eluting stent (DES) implantation compared to angiography-guidance, there has been a dearth of evidence in the left main coronary artery (LMCA) lesion subset. METHODS: We performed a meta-analysis to compare clinical outcomes of IVUS versus conventional angiography guidance during implantation of DES for patients with LMCA disease. Pubmed, Cochrane Library, Embase were searched. RESULTS: A total of 1002 publications were reviewed; and finally, seven clinical studies - one prospective randomized controlled trial and six observational studies with 4592 patients (1907 IVUS-guided and 2685 angiography-guided) - were included in the meta-analysis. IVUS guidance was associated with a significant reduction in major adverse cardiac events (relative ratio [RR] 95% CI 0.61; 95% confidence interval [CI] 0.53 to 0.70; P < 0.001), all-cause death (RR 0.55; 95% CI 0.42 to 0.71; P < 0.001), cardiac death (RR 0.45; 95% CI 0.32 to 0.62; P < 0.001), myocardial infarction (RR 0.66; 95% CI 0.55 to 0.80; P < 0.001), and stent thrombosis (RR 0.48; 95% CI 0.27 to 0.84; P = 0.01) compared with angiographic guidance. However, there was no significant difference regarding target lesion revascularization (RR 0.60; 95% CI 0.31 to 1.18; P = 0.099) and target vessel revascularization (RR 0.64; 95% CI 0.26 to 1.56; P = 0. 322). CONCLUSIONS: Compared to angiographic guidance, IVUS-guided DES implantation was associated with better clinical outcomes for patients with LMCA lesions, especially hard endpoints of death, myocardial infarction, and stent thrombosis.

Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry.

RATIONALE: Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH-7 in rats had a very short half-life (<30 min) after oral administration. As a result, the in vivo metabolic profile of MDH-7 should be investigated during early stages of drug development to better select drug candidates. METHODS: In this study, a rapid method was developed to identify the metabolites of MDH-7 in rat urine by means of ultra-performance liquid chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI-MS) using a triple quadrupole linear ion trap instrument. MDH-7 and its metabolites were detected and characterized by the combined use of the multiple reaction monitoring-information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) mode and the precursor scan information-dependent acquisition-enhanced product ion (PREC-IDA-EPI) mode. RESULTS: Ten novel metabolites of MDH-7 were identified and characterized in rat urine by LC/ESI-MS and collision-induced dissociation tandem mass spectrometry (CID-MS/MS) analyses. M1 was identified as 5-fluoro-N(4) -[(pentyloxy)carbonyl]cytosine; M2 and M3 were formed by hydroxylation products of M1. Metabolites M4-M10 were formed by a series of degradation reactions such as: deacetylation, hydroxylation, loss of the defluorocytosine base, oxidative-deamination, loss of the defluorouracil base, N-dealkylation and amide hydrolysis. CONCLUSIONS: Based on the profiles of the metabolites, possible metabolic pathways of MDH-7 in rats were proposed for the first time. This study provides new and available information on the metabolism of MDH-7 which is very useful to further understand its in vivo metabolic fate. Copyright © 2016 John Wiley & Sons, Ltd.