Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis.

Extensive studies demonstrate the importance of the STING1 (also known as STING) protein as a signaling hub that coordinates immune and autophagic responses to ectopic DNA in the cytoplasm. Here, we report a nuclear function of STING1 in driving the activation of the transcription factor aryl hydrocarbon receptor (AHR) to control gut microbiota composition and homeostasis. This function was independent of DNA sensing and autophagy and showed competitive inhibition with cytoplasmic cyclic guanosine monophosphate (GMP)-AMP synthase (CGAS)-STING1 signaling. Structurally, the cyclic dinucleotide binding domain of STING1 interacted with the AHR N-terminal domain. Proteomic analyses revealed that STING1-mediated transcriptional activation of AHR required additional nuclear partners, including positive and negative regulatory proteins. Although AHR ligands could rescue colitis pathology and dysbiosis in wild-type mice, this protection was abrogated by mutational inactivation of STING1. These findings establish a key framework for understanding the nuclear molecular crosstalk between the microbiota and the immune system.

Differences between resident self-assessments and faculty- assessments on Anesthesiology Milestones and associated factors: a cross-sectional study.

BACKGROUND: Accurate self-assessment is crucial for the professional development of physicians. There has been sparse data on the accuracy of self-assessments on Anesthesiology Milestones. The aim of this study was to investigate the differences between resident self-assessments and faculty-assessments on Anesthesiology Milestones and the associated factors. METHODS: This was a cross-sectional study conducted in a general tertiary university-affiliated hospital. We included anesthesia residents who were enrolled in the standardized residency training program in postgraduate year two and three at the time of the Milestone evaluation. We requested evaluations of competencies from both the Clinical Competency Committee faculty and the anesthesia residents themselves, utilizing the Chinese version of Anesthesiology Milestones in January 2023 and January 2024. The primary outcome was the differences between self- and faculty-assessments, calculated by subtracting the faculty-rated score from the self-rated score on each subcompetency. RESULTS: A total of 46 and 42 residents were evaluated in year 2023 and 2024, respectively. The self-rated sum score was significantly higher than that rated by faculty [mean (standardized deviation): 120.39 (32.41) vs. 114.44 (23.71), P = 0.008 in paired t test] with an intraclass correlation coefficient of 0.55 [95% confidence interval (CI): 0.31 to 0.70]. The Bland-Altman plots revealed significant overestimation in patient care (bias 0.32, 95% CI: 0.05 to 0.60), practice-based learning and improvement (bias 0.45, 95% CI: 0.07 to 0.84), and professionalism (bias 0.37, 95% CI: 0.02 to 0.72). Ratings from residents with master's degrees (mean difference: -1.06, 95% CI: -1.80 to -0.32, P = 0.005) and doctorate degrees (mean difference: -1.14, 95% CI: -1.91 to -0.38, P = 0.003) were closer to the faculty-assessments than residents with bachelor's degrees. Compared with patient care, the differences between self- and faculty- rated scores were smaller in medical knowledge (mean difference: -0.18, 95% CI: -0.35 to -0.02, P = 0.031) and interpersonal and communication skills (mean difference: -0.41, 95% CI: -0.64 to -0.19, P < 0.001) in the generalized estimating equation logistic regression model. CONCLUSIONS: This study revealed that residents tended to overestimate themselves, emphasizing the need to improve the accuracy of Milestones self-assessment. The differences between self- and faculty-assessments were associated with residents' degrees and domains of competency.

[Ultrasound-guided Radial Artery Cannulation].

Arterial cannulation can be used to monitor blood pressure in real time and facilitate frequent arterial blood gas analysis.It is one of the commonly used clinical techniques in anesthesia,emergency,and intensive care units.Studies have demonstrated that ultrasound guidance can increase the success rate of arterial cannulation and reduce the incidence of related complications.In recent years,ultrasound guidance technology has developed rapidly and is increasingly used in clinical practice.This article reviews the latest advances in the application of ultrasound guidance in radial artery cannulation.

Predictors of prolonged hypotension requiring vasopressor support after resection of pheochromocytoma and paraganglioma.

OBJECTIVE: Prolonged hypotension is a common complication after resection of pheochromocytoma (PCC) or paraganglioma (PGL). The objective of our study was to identify preoperative or intraoperative clinical factors that can predict prolonged hypotension after PCC/PGL resection. PATIENTS AND METHODS: A total of 414 patients who underwent resection of PCC or PGL at our institution between January 2013 and January 2020 were included. Patients were divided into two groups according to whether or not vasopressor support was required postoperatively. Associations between preoperative and intraoperative variables and prolonged hypotension were evaluated. RESULTS: Two hundred and one (48.6%) patients had postoperative hypotension that required vasopressor support with a median duration of 20 h. Multivariable analysis demonstrated that increased 24-h urinary norepinephrine (NE) levels (odds ratio [OR] = 1.091, 95% confidence interval [CI]: 1.052-1.132, p < .001), longer operative time (OR = 1.008, CI: 1.004-1.011, p < .001) and lower preoperative phenoxybenzamine dose (OR = 0.336, CI: 0.150-0.753, p = .008) were predictors of prolonged hypotension. Moreover, operative time, body mass index, 24-h urinary level of NE and preoperative phenoxybenzamine dose were significantly correlated with the duration of postoperative vasopressor support. CONCLUSIONS: Increased urine NE level, longer operative time and lower preoperative phenoxybenzamine dose were predictors of prolonged hypotension requiring vasopressor support. Clinicians can identify these factors to manage their patients better and prevent severe complications.

Plasminogen activator inhibitor-1 gene promoter 4G/5G polymorphism and risks of peripherally inserted central catheter-related venous thrombosis in patients with lung cancer: a prospective cohort study.

PURPOSE: This study investigated the influence of plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms and other contributing clinical factors on peripherally inserted central catheter-related venous thrombosis (PICC-RVT) in Chinese patients with lung cancer. METHODS: We conducted a prospective study of 237 participants. Blood samples were collected to detect the PAI-1 4G/5G genotype. Venous thromboembolism risk was calculated by the Caprini risk assessment model. Color Doppler ultrasonography was performed every 7 days for 3 weeks to confirm PICC-RVT. RESULTS: The rate of PICC-RVT was 13.50% (32/237). The 5G/5G, 4G/5G, and 4G/4G genotypes were found in 12.50% vs 17.56%, 59.38% vs 49.27%, and 28.12% vs 34.17% in the thrombus group and the non-thrombus group of the participants. No difference was observed in the distribution frequency of the three genotypes between the thrombus and non-thrombus groups. A higher fibrinogen level (OR 1.194, 95% CI 1.004-1.420, P = 0.045) and a higher Caprini score (OR 1.698, 95% CI 1.103-2.614, P = 0.016) were statistically significant risk factors for PICC-RVT. Compared with patients who underwent a pemetrexed/cisplatin regimen, those who were administered paclitaxel/cisplatin (OR 18.332, 95% CI 2.890-116.278, P = 0.002) or gemcitabine/cisplatin (OR 6.617, 95% CI 1.210-36.180, P = 0.029) were at increased risk of PICC-RVT. CONCLUSION: Our finding suggested that there is no statistically significant influence of the PAI-1 4G/5G gene variant on PICC-RVT in Chinese patients with lung cancer. However, patients with higher Caprini scores and higher fibrinogen levels are at increased risk for PICC-RVT, as are patients receiving chemotherapy. Clinical staff should carefully perform a risk assessment for patients with PICC. Those with the above risk factors should pay close attention and take timely and effective preventive measures.

Assessing the thrombosis risk of peripherally inserted central catheters in cancer patients using Caprini risk assessment model: a prospective cohort study.

PURPOSE: There was no optimal risk assessment tool to stratify the risk of peripherally inserted central catheter-related venous thromboembolism (PICC-RVT) in cancer patients. We currently use the Caprini risk assessment model for thrombotic risk assessment, but no evidence exists on the effectiveness of Caprini in such patients. This study was to assess the validity of the Caprini in Chinese cancer patients with PICCs. METHODS: We conducted a prospective study of 468 participants. Following calculating the Caprini score, color Doppler ultrasonography was performed every 7 days for 3 weeks to confirm PICC-RVT. RESULTS: There was a correlation between PICC-RVT and the Caprini score. Compared with scores of 5, the risk was 2.089-fold greater (95% CI 1.165-3.743, P = 0.012) in patients with a score of 6 and 7, and 7.156-fold greater (95% CI 3.157-16.217, P < 0.001) in patients with scores ≥8. The area under the receiver-operating characteristic curve was 0.636 (95% CI 0.590-0.680; P < 0.001). 6 was the best cutoff point for Caprini, with a sensitivity of 0.76 and a specificity of 0.44. CONCLUSIONS: The Caprini can be used for high-risk screening of the PICC-RVT in cancer patients, and classification of the highest risk level using a score of 6 can be more clinically significant compared to 5 as recommended. The results provide evidence for the practitioner's early use of the Caprini to assess the thrombotic risk in patients with PICCs and take timely prevention measures. But pharmacological prevention should be considered seriously for its low specificity.

Intractable mechanical hemolytic anemia complicating mitral valve surgery: a case series study.

BACKGROUND: Intractable, mechanical hemolytic anemia (IMHA) is a rare catastrophic complication following mitral valve surgery. We analyzed patient characteristics and IMHA management by reoperations after mitral valve surgery. METHODS: We collected medical records from mitral valve patients requiring reoperation due to IMHA. INCLUSION CRITERIA: hemoglobin < 100 g/L; positive hemolysis tests and echocardiography results; and exclusion of other hemolysis causes. RESULTS: Data from 25 IMHA cases included 10 (40%) early onset (1.3 (0.3,3.0) months) and 15 (60%) late onset (120 (24,204) months) cases. Early IMHA etiologies included surgical defects (6, 60%), uncontrolled infection (3, 30%) and Bechet's disease (1, 10%). Late IMHA etiologies included degeneration (13, 87%), new infection (1, 7%) and trauma (1, 7%). There were more mechanical valves (15, 88%) than bio-valves (2, 12%); the main valvular dysfunction was paravalvular leak (16, 64%). IMHA manifestations included jaundice (18, 72%), dark urine (21, 84%), heart failure (16, 64%), acute kidney injury (11, 44%), hepatomegaly (15, 60%), splenomegaly (15, 60%) and pancreatitis (1, 4%). Laboratory results showed decreased hemoglobin (70 ± 14 g/L) and increased bilirubin (72 ± 57 µmol/L), lactate dehydrogenase (2607 ± 2142 IU/L) and creatinine (136 ± 101 µmol/L) levels. Creatinine level negatively correlated with hemoglobin level (B = -3.33, S.E. B = 1.31, Exp(B) = 368.15, P = 0.018). Preoperative medications included iron supplements (20, 80%), erythropoietin (16, 64%) and beta-blocker (22, 88%). Two patients died of cardiac causes before reoperation. The other 23 underwent reoperation with long surgical times (aortic cross clamp 124 ± 50 min, cardiopulmonary bypass 182 ± 69 min) and blood transfusions (red blood cells 6 (6, 8) units, plasma 600 (400,800) ml, platelet 1(0,2) units). Postoperative complications included cardiac dysfunction (5, 22%), arrhythmia (10, 43%), sepsis (6, 26%), pulmonary infection (5, 22%), gastrointestinal bleeding (3, 13%), cerebral hemorrhage (2, 9%), chronic renal dysfunction (1, 4%) and surgical hemorrhage (1, 4%). Five (33%) patients died after reoperation from cardiac dysfunction (3, 60%), septic shock (1, 20%) and self-discharge (1, 20%). CONCLUSIONS: IMHA induces severe multi-organ dysfunction, contributing to high mortality. Perioperative management should focus on etiological treatment, organ protection, and blood management.

Anesthesia Considerations and Infection Precautions for Trauma and Acute Care Cases During the COVID-19 Pandemic: Recommendations From a Task Force of the Chinese Society of Anesthesiology.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. During the ongoing COVID-19 epidemic, most hospitals have postponed elective surgeries. However, some emergency surgeries, especially for trauma patients, are inevitable. For patients with suspected or confirmed COVID-19, a standard protocol addressing preoperative preparation, intraoperative management, and postoperative surveillance should be implemented to avoid nosocomial infection and ensure the safety of patients and the health care workforce. With reference to the guidelines and recommendations issued by the National Health Commission and Chinese Society of Anesthesiology, this article provides recommendations for anesthesia management of trauma and emergency surgery cases during the COVID-19 pandemic.

MiR-423-5p Regulates Cells Apoptosis and Extracellular Matrix Degradation via Nucleotide-Binding, Leucine-Rich Repeat Containing X1 (NLRX1) in Interleukin 1 beta (IL-1ß)-Induced Human Nucleus Pulposus Cells.

BACKGROUND Disc degeneration is characterized partly by the degradation in the extracellular matrix (ECM) and excess apoptosis of nucleus pulposus (NP) cells. NLRX1 (nucleotide-binding, leucine-rich repeat containing X1) is different from the other nucleotide-binding-domain and leucine-rich-repeat proteins and mainly located to the mitochondrial. It negatively regulates NF-κB (nuclear factor kappa B) and apoptosis inhibition. However, how NLRX1 is regulated and exerts effects in disc degeneration is unclear. Thus, the study aimed to analyze the effects of NLRX1 on NP cells. MATERIAL AND METHODS NLRX1 expression was detected in interleukin (IL)-1ß-induced NP cells by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Then, NLRX1 was overexpressed in IL-1ß-induced NP cells to detect apoptosis-related proteins and the extracellular matrix (ECM) by western blot, along with the detection of apoptosis levels using flow cytometry. StarBase predicted miR-423-5p target 3'UTR of NLRX1. Dual luciferase reporter assay showed that miR-423-5p could bind to the 3'UTR of NLRX1. Besides, miR-423-5p significantly affected NLRX1 levels detected by qRT-qPCR. RESULTS The miR-423-5p overexpression markedly, and negatively regulated the protective effects of NLRX1 on IL-1ß induced NP cells. Thus, our results suggested that miR-423-5p mediated the regulation of NLRX1 to affect apoptosis and ECM levels in IL-1ß induced NP cells. CONCLUSIONS miR-423-5p and NLRX1 could be potential therapeutic targets for patients with disc degeneration.

Dynamic needle tip positioning versus the angle-distance technique for ultrasound-guided radial artery cannulation in adults: a randomized controlled trial.

BACKGROUND: Ultrasound guidance can increase the success rate and reduce the incidence of complications of arterial cannulation. There are few studies on the utility of the dynamic needle tip positioning (DNTP) technique versus the angle-distance (AD) technique for ultrasound-guided radial arterial cannulation in adult surgical patients. We assessed and compared the success rates and incidences of complications of these two short-axis out-of-plane techniques. METHODS: A total of 131 adult surgical patients were randomized into DNTP and AD groups to undergo ultrasound-guided radial artery cannulation. The primary outcome was first-pass success without posterior wall puncture. The secondary outcomes included the first-pass success rate, 10-min overall success rate, cannulation time, posterior wall puncture, and the number of skin punctures. RESULTS: The first-pass success rates without posterior wall puncture were 53.8% in the DNTP group and 44.6% in the AD group (RR = 1.22, 95% CI: 0.86-1.72; P = 0.26). The cannulation time was significantly longer (P = 0.01) in the DNTP group [79.65 (54.3-109.4) seconds] than in the AD group [47.6 (24.9-103.8) seconds]. The posterior wall puncture rate was significantly lower (P = 0.002) in the DNTP group (29.2%) than in the AD group (56.1%; RR = 0.56, 95% CI: 0.42-0.82). CONCLUSIONS: There were no significant differences in the first-pass success rate, with or without arterial posterior wall puncture, or in the 10-min overall success rate between the DNTP and AD groups. However, the cannulation time was longer and the posterior wall puncture rate was lower in the DNTP group. TRIAL REGISTRATION: The trial was registered at www.clinicaltrials.gov (No: NCT03656978 ). Registered 4 September 2018.

Chinese Society of Anesthesiology Expert Consensus on Anesthetic Management of Cardiac Surgical Patients With Suspected or Confirmed Coronavirus Disease 2019.

The outbreak of a new coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) in China in December 2019 has brought serious challenges to disease prevention and public health. Patients with severe coronavirus disease 2019 (COVID-19) who undergo cardiovascular surgery necessitate extremely high demands from anesthesia personnel, and face high risks of mortality and morbidity. Based on the current understanding of COVID-19 and the clinical characteristics of cardiovascular surgical patients, the authors provide anesthesia management guidelines for cardiovascular surgery along with the prevention and control of COVID-19.

Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus.

OBJECTIVE: In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. DESIGN: We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. RESULTS: In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. CONCLUSIONS: Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.

Long-term low-dose morphine for patients with moderate cancer pain is predominant factor effecting clinically meaningful pain reduction.

PURPOSE: Patients with cancer often experience pain that affects their daily activities and quality of life. The analgesic ladder recommended by the World Health Organization has proved insufficient for many, and its scientific basis has been questioned. This retrospective study investigated factors related to adherence to long-term opioid therapy for patients with moderate cancer pain, including an evaluation of low-dose morphine relative to tramadol. METHODS: Clinical data were collected of patients with moderate cancer pain (n = 353) who received either low-dose morphine or tramadol and were followed for ≥ 27 weeks. Factors related to regime adherence were investigated, including the analgesia type, cancer therapy (antitumor therapy or palliative care), pain type (nociceptive, neuropathic, or mixed), and living distance to the hospital. Factors related to clinically meaningful pain reduction (≥ 30% reduction in pain from baseline) were also investigated. RESULTS: Patients taking tramadol, receiving antitumor therapy, experiencing neuropathic pain, and living far from the hospital were more likely to change analgesic strategy compared with, respectively, patients receiving low-dose morphine, palliative care, experiencing nociceptive pain, and living nearby. Factors that increased the likelihood of adherence to the analgesic regime were also associated with the likelihood of clinically meaningful pain reduction. Among adverse effects, a significantly higher percentage of patients experienced constipation in the tramadol group compared with those given morphine. CONCLUSIONS: Among patients with moderate cancer pain, long-term low-dose morphine was safe and more effective than tramadol for clinically meaningful pain reduction, and patients were less likely to change the analgesic strategy.

Interleukin-6 regulates expression of Fos and Jun genes to affect the development of mouse preimplantation embryos.

AIM: We investigated whether recombinant mouse interleukin-6 (IL-6) affects the development of preimplantation embryos and induces the -signal transducers and activators of transcription (JAK-STAT) signaling pathway by binding IL-6 signal transducer (IL-6st) and regulating Fos and Jun gene expression, thereby accounting for the negative effect of superovulation on embryo development. METHODS: We compared rates of blastocyst formation from embryos cultured with different concentrations of IL-6 or/and anti-interleukin 6 receptor antibody (anti-IL-6RAb) in superovulated experimental and normal control groups. IL-6 expression in preimplantation embryos was determined by immunofluorescence identification. Fos, Jun and IL-6st messenger RNA expression was detected by PCR and microarray experiments. RESULTS: Rates of blastocyst formation significantly decreased in superovulated embryos, whether or not they were incubated in 0.1, 1, 25 or 50 pg/mL IL-6, (P < 0.01) compared to embryos from naturally ovulated controls, whereas incubation in 5 and 10 pg/mL IL-6 reversed the negative effects of superovulation. The addition of anti-IL-6RAb to naturally ovulated embryos reduced blastocyst rates to those of superovulated embryos. Gene chip analysis indicated that the JAK-STAT signaling pathway contained differentially expressed IL-6, IL-6st, Jun and Fos genes. Both anti-IL-6RAb or ovarian stimulation downregulated IL-6st, Jun, and Fos messenger RNA expression, but expression of the same three genes increased in 5 pg/mL IL-6. CONCLUSION: Ovarian stimulation negatively impacts the development of preimplantation embryos by reducing IL-6 release. IL-6 affects the rate of development of zygotes to blastocyst by regulating IL-6st, Fos and Jun expression in the JAK-STAT signaling pathway.

Walnut oil promotes healing of wounds and skin defects in rats via regulating the NF-kB pathway.

The effects of walnut oil on wound healing and skin injury repair was observed in Sprague-Dawley (SD) rats, and mechanism of action was investigated. Normal SD rats were divided into an experimental group and a control group. Each group was observed at4 time points (day [D]3, D7, D14, and D21). In both groups, a skin wound was created on the back of the rats, with the spine as the central axis. In the experimental group, the wound was covered with walnut oil, and then bandaged and fixed with sterile gauze. In the control group, the wound was bandaged with vaseline gauze. At each corresponding time point, the wound area and wound healing time of each rat were examined. Epithelial cells of the wound tissues were observed using haematoxylin and eosin staining and immunohistochemical analysis,and the numbers of inflammatory cells and capillaries were counted. A western blot method was used to detect the expression of nuclear factor (NF)-κB and epidermal growth factor (EGF) in the wound tissues of both groups. Meanwhile, enzyme-linked immunosorbent analysis (ELISA) was used to detect the expression of transforming growth factor (TGF)-ß1 and matrix metalloproteinase (MMP)-1 in rat sera. A total of 48 SD rats completed the experiment. Healing time of residual wounds in the experimental group was 10.0±3.5 days, which was significantly shorter than that in the control group (18.0±6.0 days) (p<0.05). The wound healing rates in the experimental group were 54.14 % (D3) and 91.2 3% (D7), whereas those in the control group were 22.12% (D3) and 54.84% (D7 (p<0.05).Histological examinations revealed no epithelial cells on D3, D7, D14, and D21 in both the experimental and control groups. However, the number of inflammatory cells decreased significantly and the number of capillaries increased significantly in the experimental group compared to control (p<0.05). NF-κB expression was significantly lower, EGF expression significantly higher in the in the experimental group. Conversely, ELISA showed a significant increase in the expression of TGF-ß1 and MMP-1 in rat sera in the experimental group. So we conclude that walnut oil has significant effects in promoting the healing of skin defect wounds in SD rats.

Hypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD.

OBJECTIVE: In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs). DESIGN: Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2 weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs. We exposed human oesophageal squamous cell lines to acidic bile salts, and evaluated effects on HIF activation, p65 function, pro-inflammatory molecule production and immune cell migration. RESULTS: In patient biopsies, increased immunostaining for HIF-2α and phospho-p65, and increased pro-inflammatory molecule mRNA levels were seen when RO redeveloped 1 or 2 weeks after stopping PPIs. In oesophageal cells, exposure to acidic bile salts increased intracellular reactive oxygen species, which decreased prolyl hydroxylase function and stabilised HIF-2α, causing a p65-dependent increase in pro-inflammatory molecules; conditioned media from these cells increased T cell migration rates. HIF-2α inhibition by small hairpin RNA or selective small molecule antagonist blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts. CONCLUSIONS: In patients developing RO, increases in oesophageal HIF-2α correlate with increased pro-inflammatory molecule expression. In oesophageal epithelial cells, acidic bile salts stabilise HIF-2α, which mediates expression of pro-inflammatory molecules. HIF-2α appears to have a role in RO pathogenesis. TRIAL REGISTRATION NUMBER: NCT01733810; Results.

In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-box 2) expression.

OBJECTIVE: Barrett's metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, patients with GORD also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype. DESIGN: Oesophageal squamous cells from patients with Barrett's oesophagus were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor) and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically induced GORD which were fed diets with and without nitrite supplementation. RESULTS: In oesophageal squamous cells, NO profoundly decreased SOX2 protein and caused a significantly greater decrease in SOX2 mRNA than did acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed with nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed with normal diets. CONCLUSIONS: In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett's pathogenesis.

Knowledge, attitudes, and influencing factors of cancer patients toward approving advance directives in China.

PURPOSE: Many cancer patients do not have advance directives (ADs), which may lead to unwanted excessive or aggressive care when patients have lost decision-making capacity. The aim of this study was to investigate knowledge and attitudes of approving ADs and explore factors associated with willing to designate ADs among cancer patients in China. METHODS: We conducted semi-structured interview method investigating 753 in-patients with cancer in two cancer centers. RESULTS: Of those subjects, none of the cancer patients had an AD. Only 22.4 % (118 of 526) approved ADs. Comparing with the disapproved ADs group, the approved ADs group were more likely to discuss the AD with oncologist or nurse (χ (2) = 180.4, p < 0.001) in the cancer center (χ (2) = 244.1, p < 0.001), and they chose more comfort care (χ (2) = 18.8, p < 0.001). Most of cancer patients in the two groups wanted to die at home (72.8 %, 73.7 %, respectively). The older patients (OR, 1.04, 95 % CI, 1.02-1.07, p = 0.001), female (OR, 0.55, 95 % CI, 0.35-0.88, p = 0.013), with higher education levels (OR, 3.38, 95 % CI, 1.92-5.96, p < 0.001), with religious beliefs (OR, 2.91, 95 % CI, 1.71-4.94, p < 0.001), and with higher scores of ECOG (OR, 1.46, 95 % CI, 1.17-1.82, p = 0.001) were associated with desiring for ADs. CONCLUSIONS: Our findings indicate that there was a dearth of knowledge and different attitudes toward approving ADs among cancer patients, and some factors of demographic and clinical characteristics influenced their willing to designate ADs. This research highlights the importance of propagandizing the ADs to the public, especially to the patients, and further discussing with them when the time is ripe.

Predicting and Screening Dielectric Transitions in a Series of Hybrid Organic-Inorganic Double Perovskites via an Extended Tolerance Factor Approach.

Extended Goldschmidt tolerance factor t is applied to the hybrid double perovskites (MA)2 [B'B''(CN)6 ] (MA=methylammonium cation) to predict and screen dielectric transitions in 121 compounds through the correlations among t, the radius of the B component rB and the transition temperature Tc , based on experimental results from model compounds. For (MA)2 [B'Co(CN)6 ], it is concluded that: i) when t>0.873, the cubic phase would be stable below 298 K; ii) when 0.873>t>0.805, the cubic phase would be stable between 298 and 523 K; iii) the larger the rB , the higher the Tc of the perovskite (Tc (1/2) ∝rB ); and iv) the Tc of the hybrid perovskites can be well tuned by doping the B components.