Mu-opioid receptor alleviated ferroptosis in hepatic ischemia-reperfusion injury via the HIF-1α/KCNQ1OT1 axis.

Ferroptosis is the ideal therapeutic target for hepatic ischemia and reperfusion injury (HIRI). The µ opioid receptor (MOR) is associated with ferroptosis in HIRI. We aimed to determine the ferroptosis-related therapeutic mechanism of MOR in HIRI. A model of HIRI was established in BALB/c mice. Primary hepatocytes isolated from mice were stimulated by hypoxia/reoxygenation (H/R). Changes in histopathology were determined by H&E staining. Alterations in ferroptosis were evaluated by malondialdehyde (MDA), iron, glutathione (GSH), ACSL4, GPX4, and mitochondrial morphology. ALT and AST were used to determine hepatic function. First, we found that hepatic ischemia/reperfusion (I/R) induced the destruction of hepatic tissue structure and dead hepatocytes and determined that ferroptosis occurred in vivo and in vitro. During HIRI, the expression levels of HIF-1α and KCNQ1OT1 were significantly upregulated. We demonstrated that sufentanil improved the damage in the liver and hepatocytes undergoing I/R. Importantly, sufentanil inhibited ferroptosis in HIRI. In addition, sufentanil downregulated the expression levels of HIF-1α and KCNQ1OT1 in HIRI. Increases in HIF-1α and KCNQ1OT1 reversed the role of sufentanil in ferroptosis and HIRI. Subsequently, we determined that HIF-1α could activate the transcription of KCNQ1OT1 by binding to its promoter. In addition, KCNQ1OT1 was demonstrated to enhance ACSL4 stability by interacting with SRSF1. Finally, we observed that KCNQ1OT1 downregulation protected hepatocytes from hepatic I/R and inhibited ferroptosis. KCNQ1OT1 upregulation aggravated ferroptosis and hepatic injury during I/R. However, decreases in ACSL4 and SRSF1 reversed the harmful role of KCNQ1OT1 upregulation in HIRI. MOR alleviated ferroptosis in HIRI via the HIF-1α/KCNQ1OT1 axis.

Silencing lncRNA KCNQ1OT1 reduced hepatic ischemia reperfusion injury-induced pyroptosis by regulating miR-142a-3p/HMGB1 axis.

BACKGROUND: Based on pre-existing evidence, KCNQ1OT1 has been pointed out to be closely related to myocardial and cerebral ischemia reperfusion injury diseases. Herein, the objective of our study is to probe into the potential function as well as the underlying mechanism of KCNQ1OT1 on hepatic ischemia reperfusion injury (HIRI). METHODS: Using C57BL/6 J mice and primary mouse hepatocytes were conducted to establish HIRI model in vivo and in vitro. Cell viability was examined using CCK-8 assay and EdU assay. Flow cytometric analysis was performed to evaluate the pyroptosis. Dual-luciferase reporter assay was employed to verify the interaction relationships. qRT-PCR and Western blot were adopted to analyze the mRNA and protein level. Histopathological alteration of liver tissue was evaluated by HE staining. Immunohistochemistry (IHC) was performed to measure NLRP3 and caspase 1. RESULTS: Our data revealed that KCNQ1OT1 expression was ascending in hepatic tissue of HIRI mouse. Moreover, deprivation of KCNQ1OT1 mitigated I/R-induced hepatic injury and pyroptosis in vivo. Further experiments demonstrated that silencing KCNQ1OT1 promoted proliferation and inhibited pyroptosis in hypoxia/reoxygenation (H/R)-induced primary mouse hepatocytes. Mechanistically, KCNQ1OT1 functioned as a competing endogenous RNA which sponged miR-142a-3p, therefore promoted HMGB1 expression to activate TLR4/NF-κB signaling pathway in HIRI. CONCLUSION: LncRNA KCNQ1OT1 elevated HMGB1 expression through binding to miR-142a-3p, thereby promoting pyroptosis in HIRI.

Narrative medicine as a teaching strategy for nursing students to developing professionalism, empathy and humanistic caring ability: a randomized controlled trial.

BACKGROUND: Narrative medicine has become a solution to cultivate medical students' ability of empathy and humanistic care. However, the role of narrative medicine is lacking in the study of professionalism. The aim of this study was to analyze the effects of narrative medical theory learning and narrative writing on professionalism, empathy and humanistic care ability of nursing students. METHODS: This cluster randomized controlled trial was conducted between June 2021 and June 2022 in two universities in Jiangsu, China. The participants of this study were 85 nursing students who were randomly divided into the intervention group (n = 43) or the control group (n = 42). Participants in the intervention group were trained in narrative medical theory learning and narrative writing based on a Web-based platform, while those in the control group were not. Self-report questionnaires of professionalism, empathy and humanistic care ability were used before and after intervention. RESULTS: The results showed that the professionalism score of the intervention group was (68.7 ± 6.8 vs. 64.5 ± 7.5; P = 0.005), empathy (99.4 ± 15.7 vs. 92.2 ± 14.6; P = 0.014) and humanistic care ability (127.6 ± 20.0 vs. 113.3 ± 18.8; P = 0.004) were better than the control group. CONCLUSION: The results of this quantitative study suggest that narrative medical theory education and narrative writing based on the network platform can promote the development of professionalism, empathy and humanistic care ability of nursing undergraduates.

Octreotide ameliorates hepatic ischemia-reperfusion injury through SNHG12/TAF15-mediated Sirt1 stabilization and YAP1 transcription.

BACKGROUND: Hepatic ischemia-reperfusion (HIR) injury is a pathological condition initiated by interrupted hepatic blood supply and exaggerated after reperfusion, which is one of the most lethal risks in liver transplantation and other liver surgeries. We aimed to investigate the protective mechanism of octreotide (Oct) against HIR injury. METHODS: The function of Oct was evaluated in the in vivo mouse model of HIR injury. Histological examinations were performed to assess the pathological changes. Serum parameters including ALT and AST were measured to evaluate the liver damage. qRT-PCR and western blot analysis were employed to determine the levels of long non-coding RNA SNHG12 (SNHG12) and autophagy or apoptosis-related proteins. RNA pull-down and RIP assays were used to verify the interaction between SNHG12 and TAF15. The transcriptional regulation of TAF15 in YAP1 was validated by ChIP and luciferase reporter assays. RESULTS: In the in vivo HIR injury model, Oct efficiently alleviated HIR-caused hepatic damage by suppressing apoptosis and activating autophagy. However, silencing of SNHG12 abrogated the protective effects of Oct via inactivating autophagy. Further mechanism investigation revealed that SNHG12 promoted the stabilization of Sirt1 and increased YAP1 transcriptional activity via interacting with TAF15. Up-regulation of Sirt1 and YAP1 was essential for maintaining the protective effect of Oct against HIR injury through increasing autophagic flux and suppressing apoptosis. CONCLUSIONS: Oct-induced up-regulation of SNHG12 attenuated HIR injury via promoting Sirt1 stabilization and YAP1 transcription to activate autophagy and repress apoptosis.

Analysis of Symptom Characteristics, Influencing Factors, and Their Predictive Value for Posttraumatic Stress Disorder in Nurses: A Cross-Sectional Questionnaire Study.

ABSTRACT: Nurses often face a variety of nursing-related stresses, making them more prone to symptoms of posttraumatic stress disorder (PTSD). We aimed to explore symptom characteristics, influencing factors, and their predictive value for PTSD in nurses, so as to prevent the occurrence of PTSD in nurses. This was a cross-sectional study conducted in two tertiary hospitals in Yangzhou. A total of 1290 valid questionnaires were received in our study, and 190 nurses (14.7%) were positive for PTSD symptoms. The results show that individuals with higher scores on the Perceived Stress Scale-10 (PSS-10), Patient Health Questionnaire-15 (PHQ-15), Generalized Anxiety Disorder Scale-7 (GAD-7), and maladaptive cognitive emotion regulation strategies questionnaire (maladaptive CERS) were more likely to experience PTSD symptoms, whereas those with lower scores on the Perceived Social Support Scale (PSSS) were more likely to experience PTSD symptoms. Compared with the PSS-10, PHQ-15, and PSSS, GAD-7 and maladaptive CERS had higher predictive value. This study provided the optimal threshold of relevant factors that may have a positive effect on the prevention of PTSD symptoms. This has guiding implications for active prevention and intervention in some institutions.

Risk stratification and outcomes of intracranial hemorrhage in patients with immune thrombocytopenia under 60 years of age.

Intracranial hemorrhage (ICH) is a devastating complication of immune thrombocytopenia (ITP). However, information on ICH in ITP patients under the age of 60 years is limited, and no predictive tools are available in clinical practice. A total of 93 adult patients with ITP who developed ICH before 60 years of age were retrospectively identified from 2005 to 2019 by 27 centers in China. For each case, 2 controls matched by the time of ITP diagnosis and the duration of ITP were provided by the same center. Multivariate analysis identified head trauma (OR = 3.216, 95%CI 1.296-7.979, P =.012), a platelet count ≤ 15,000/µL at the time of ITP diagnosis (OR = 1.679, 95%CI 1.044-2.698, P =.032) and severe/life-threatening bleeding (severe bleeding vs. mild bleeding, OR = 1.910, 95%CI 1.088-3.353, P =.024; life-threatening bleeding vs. mild bleeding, OR = 2.620, 95%CI 1.360-5.051, P =.004) as independent risk factors for ICH. Intraparenchymal hemorrhage (OR = 5.191, 95%CI 1.717-15.692, P =.004) and a history of severe bleeding (OR = 4.322, 95%CI 1.532-12.198, P =.006) were associated with the 30-day outcome of ICH. These findings may facilitate ICH risk stratification and outcome prediction in patients with ITP.

Lidocaine pretreatment up-regulates aquaporin-5 expression in primary alveolar epithelium type II cells injured by lipopolysaccharides.

Acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) is associated with decreased aquaporin-5 (AQP5) expression. Lipopolysaccharides (LPS) can decrease AQP5 expression. The effects and mechanisms of lidocaine pretreatment on primary alveolar epithelium type II (AEC II) cells injured by LPS were investigated. Primary AEC II cells were isolated from rats previously injured with LPS as an ALI model. The groups of cells were evaluated: 1) pretreated with lidocaine (2, 20, 200µg/ml) and/or Infliximab, an anti-TNF-α neutralizing antibody, 2) uninjured cells; 3) solvent pretreated injured cells and 4) untreated injured cells as controls. TNF-α levels were evaluated by ELISA. AQP5 expression was determined by mRNA and protein expression (q-PCR and western blot).The release of TNF-α was increased significantly in AEC II cells following LPS injury. The release of TNF-α was decreased by 33%-100% as a result of lidocaine pretreatment in a dose-dependent fashion. This decrease was accompanied by up-regulated AQP5 expression in LPS injured AEC II cells, and Infliximab can greatly block AQP5 expression in LPS injured AEC II cells pretreated with lidocaine. Lidocaine pretreatment (2-200µg/ml) of LPS injured AEC II cells results in a decrease in TNF-α release, then up-regulates AQP5 expression, which maybe involved in the mechanism of its effects on AEC II cells injured by LPS.

Sufentanil postoperative analgesia reduce the increase of T helper 17 (Th17) cells and FoxP3+ regulatory T (Treg) cells in rat hepatocellular carcinoma surgical model: A randomised animal study.

BACKGROUND: Surgery-related pain and opioids might exacerbate immune defenses in immunocompromised cancer patients which might affect postoperativd overall survival. Sufentanil is a good postoperative pain control drug,the present study aimed to figure out whether it effect T cell immunity in rat hepatocellular carcinoma surgical model. METHODS: A rat hepatocellular carcinoma (HCC) models was established by N-nitrosodiethylamine. Forty-eight of them were randomly divided into 3 equal groups: surgery without postoperative analgesia (Group C), surgery with morphine postoperative analgesia (Group M), surgery with sufentanil postoperative analgesia (Group S). Each animal underwent a standard left hepatolobectomy, and intraperitoneally implanted with osmotic minipumps filled with sufentanil, morphine or normal saline according to the different group. The food and water consumptions, body weight changes, locomotor activity and mechanical pain threshold (MPT) were observed. The ratio of CD4+/CD8+, proportions of Th1, Th2, Th17 and Treg cells in blood were detected using flow cytometry. The liver function and the rats' survival situation of each group were observed. RESULTS: The food and water consumption, locomotor activity and MPT of group C declined than those of group S and M on d1, d2, d3 (P < 0.05). The CD4+/CD8+ ratio and the proportion of Th1 cells were significantly higher while the proportion of Th2, Th17 and Treg cells were significantly lower in group S and group M compared with group C. The rats of group S have higher CD4+/CD8+ ratio on d3, while lower proportion of Treg cells on d7 compared with group M. The plasma ALT and AST values in group C were significantly higher than that of group S and group M on both d3 and d7. There were not significant differences in mortality rate between 3 groups. CONCLUSIONS: Sufentanil and morphine postoperative analgesia in HCC rats accepted hepatectomy could relieve postoperative pain, promote the recovery of liver function after surgery, alleviate the immunosuppressive effect of pain. Furthermore, Compared to morphine, sufentanil might have a slighter effect on CD4+/CD8+ ratio and Treg frequencies. Therefore, sufentanil postoperative analgesia is better than morphine in HCC hepatectomy rats.

Discrimination between 5-Hydroxymethylcytosine and 5-Methylcytosine in DNA via Selective Electrogenerated Chemiluminescence (ECL) Labeling.

DNA methylation is used to dynamically reprogram cells in the course of early embryonic development in mammals. 5-Hydroxymethylcytosine in DNA (5-hmC-DNA) plays essential roles in the demethylation processes. 5-Methylcytosine in DNA (5-mC-DNA) is oxidized to 5-hmC-DNA by 10-11 translocation proteins, which are relatively high abundance in embryonic stem cells and neurons. A new method was developed herein to quantify 5-hmC-DNA based on selective electrogenerated chemiluminescence (ECL) labeling with the specific oxidation of 5-hmC to 5-fC by KRuO4. A thiolated capture probe (ssDNA, 35-mer) for the target DNA containing 5-hmC was self-assembled on a gold surface. The 5-hmC in the target DNA was selectively transformed to 5-fC via oxidation by KRuO4 and then subsequently labeled with N-(4-aminobutyl)-N-ethylisoluminol (ABEI). The ABEI-labeled target DNA was hybridized with the capture probe on the electrode, resulting in a strong ECL emission. An extremely low detection limit of 1.4 × 10-13 M was achieved for the detection of 5-hmC-DNA. In addition, this ECL method was useful for the quantification of 5-hmC in serum samples. This work demonstrates that selective 5-hmC oxidation in combination with an inherently sensitive ECL method is a promising tactic for 5-hmC biosensing.

Silibinin and indocyanine green-loaded nanoparticles inhibit the growth and metastasis of mammalian breast cancer cells in vitro.

AIM: To improve the therapeutic efficacy of cancer treatments, combinational therapies based on nanosized drug delivery system (NDDS) has been developed recently. In this study we designed a new NDDS loaded with an anti-metastatic drug silibinin and a photothermal agent indocyanine green (ICG), and investigated its effects on the growth and metastasis of breast cancer cells in vitro. METHODS: Silibinin and ICG were self-assembled into PCL lipid nanoparticles (SIPNs). Their physical characteristics including the particle size, zeta potential, morphology and in vitro drug release were examined. 4T1 mammalian breast cancer cells were used to evaluate their cellular internalization, cytotoxicity, and their influences on wound healing, in vitro cell migration and invasion. RESULTS: SIPNs showed a well-defined spherical shape with averaged size of 126.3±0.4 nm and zeta potential of -10.3±0.2 mV. NIR laser irradiation substantially increased the in vitro release of silibinin from the SIPNs (58.3% at the first 8 h, and 97.8% for the total release). Furthermore, NIR laser irradiation markedly increased the uptake of SIPNs into 4T1 cells. Under the NIR laser irradiation, both SIPNs and IPNs (PCL lipid nanoparticles loaded with ICG alone) caused dose-dependent ablation of 4T1 cells. The wound healing, migration and invasion experiments showed that SIPNs exposed to NIR laser irradiation exhibited dramatic in vitro anti-metastasis effects. CONCLUSION: SIPNs show temperature-sensitive drug release following NIR laser irradiation, which can inhibit the growth and metastasis of breast cancer cells in vitro.

Inhibition of Breast Cancer Metastasis by Pluronic Copolymers with Moderate Hydrophilic-Lipophilic Balance.

Metastasis is the primary cause resulting in the high mortality of breast cancer. The inherent antimetastasis bioactivity of Pluronic copolymers with a wide range of hydrophilic-lipophilic balance (HLB) including Pluronic L61, P85, P123, F127, F68, and F108 was first explored on metastatic 4T1 breast cancer cells. The results indicated that P85 and P123 could strongly inhibit the migration and invasion of 4T1 cells. The effects of the polymers on cell healing, migration, and invasion exhibited bell-shaped dependencies on HLB of Pluronic copolymers, and the better antimetastasis effects of Pluronic copolymers could be achieved with the HLB between 8 and 16. P85 and P123 themselves could significantly inhibit pulmonary metastasis in 4T1 mammary tumor metastasis model in situ. In addition, a synergetic antimetastasis effect could be achieved during drug combination of doxorubicin hydrochloride (DOX) and P85 or P123 intravenously. The metastasis effects of P85 and P123 both in vitro and in vivo were partially attributed to the downregulation of matrix metalloproteinase-9 (MMP-9). Therefore, Pluronic copolymers with moderate HLB 8-16 such as P85 and P123 could be promising excipients with therapeutics in drug delivery systems to inhibit breast cancer metastasis.

Clinical applications of the indirect immunofluorescence assay for detection of anticell membrane-associated DNA antibodies in juvenile systemic lupus erythematosus.

BACKGROUND: Juvenile-onset systemic lupus erythematosus (JSLE) has a higher mortality risk compared to adult-onset SLE. We compared the diagnostic value of anti-cmDNA antibodies with that of antinucleosome antibodies (AnuA), anti-Sm antibodies, and anti-dsDNA antibodies and human B lymphocyte Raji cells with that of human promyelocytic leukemia HL60 cells as substrates in an indirect immunofluorescence assay to detect anti-cmDNA antibodies in JSLE patients. METHODS: We recruited 92 JSLE patients and 71 patients with other juvenile-onset rheumatic diseases. Anti-cmDNA antibodies and antinuclear antibodies (ANA) were detected in patient sera using indirect immunofluorescence assays. Anti-dsDNA antibodies were detected by combining ELISA and indirect immunofluorescence. Anti-Sm antibodies were detected by double immunodiffusion assay and immunoblotting, while AnuA were detected by ELISA. RESULTS: The JSLE group had a significantly higher percentage of patients positive for anti-cmDNA compared to patients with other rheumatoid diseases. Using one antibody for diagnosis, anti-cm DNA antibodies had the highest accuracy at 84.0%; using two antibodies, the combination of anti-cm DNA and anti-dsDNA antibodies had 90.8% accuracy. Raji cells used as substrate demonstrated a stronger intensity of fluorescent patterns compared to HL60 cells. CONCLUSION: The high sensitivity, specificity, and accuracy of detection of anti-cmDNA antibodies make it a valuable diagnostic tool for JSLE.

[A study of the value of three molecular diagnostic techniques in the diagnosis of tuberculosis].

OBJECTIVE: To evaluate the diagnostic value of real-time fluorescent RNA isothermal amplification detection technology (simultaneous amplification and testing, SAT), Mycobacterium nucleic acid detection (PCR-fluorescence probe)method (TB-NTM-PCR) and Xpert MTB/RIF detection in the diagnosis of tuberculosis. METHODS: A total of 378 sputum specimens from pulmonary tuberculosis patients were collected between April to July 2014 in Xi'an Thoracic Tumor and Tuberculosis Hospital. The specimens were detected by 5 methods at the same time including acid-fast stain, SAT method, TB-NTM-PCR method, TB 960 rapid liquid culture and Xpert MTB/RIF. The sensitivity and specificity of SAT method, TB-NTM-PCR method and Xpert MTB/RIF were calculated according to the results of TB 960 rapid liquid culture and staining. The difference among all the 3 methods was analyzed by Chi-squared test. RESULTS: The positive rate of SAT-TB,TB-NTM-PCR and Xpert MTB/RIF were 37.6% (142/378), 37.8% (143/378) and 53.4% (202/378), respectively. In specimens both positive for acid-fast stain and culture, the positive rate of SAT method was 84.6% (77/91), that of TB-NTM-PCR was 91.2% (83/91), and that of Xpert MTB/RIF was 96.7% (88/91), the difference being significant (P=0.018 2). In specimens negative for acid-fast stain but positive for culture, the positive rate of SAT method was 61.9% (60 /97), that of TB-NTM-PCR was 44.3% (43/97), and that of Xpert MTB/RIF was 80.4% (78/97), the difference being significant (P<0.000 1). In specimens both negative for acid-fast stain and culture, the positive rate of SAT method was 1.6% (3/185), that of TB-NTM-PCR was 6.5% (12/185), and that of Xpert MTB/RIF was 16.8% (31/185), the difference being significant (P=0.018). In specimens positive for acid-fast stain but negative for culture, the number of positive samples of SAT,TB-NTM-PCR and Xpert MTB/RIF were 3 (3/5), 5 (5/5),and 5 (5/5), respectively. With the result of TB 960 rapid liquid culture and staining as the reference, Xpert MTB/RIF showed the highest sensitivity of 87.6% (163/186), the minimum rate of missed diagnosis of 12.4% (24/193), and the highest negative predictive value of 88.5% (185/209); SAT-TB showed the highest specificity of 98.2% (214/218), the minimum rate of misdiagnosis of 1.8%(4/218), the highest positive predictive value of 97.2% (138/142). With the result of TB 960 rapid liquid culture as the reference, the sensitivity and the specificity of Xpert MTB/RIF were 95.52% (128/134) and 95.24% (20/21). The accordance rate of Xpert MTB/RIF and TB 960 rapid liquid culture was 95.48%(148/155). CONCLUSION: The 3 molecular detection methods showed good results for the auxiliary diagnosis of tuberculosis. Xpert MTB/RIF had the best performance both in smear positive and negative specimens and it can detect rifampicin related rpoB gene mutations at the same time.

A Comparison of Fentanyl and Flurbiprofen Axetil on Serum VEGF-C, TNF-α, and IL-1ß Concentrations in Women Undergoing Surgery for Breast Cancer.

BACKGROUND: Vascular endothelial growth factor-C (VEGF-C), tumor necrosis factor-α (TNF-α), and interleukin-1ß(IL-1ß) have been shown to be associated with the recurrence and metastasis of breast cancer after surgery. This study tested the hypothesis that patients undergoing surgery for breast cancer, who received postoperative analgesia with flurbiprofen axetil combined with small doses of fentanyl (FA), exhibited reduced levels of VEGF-C, TNF-α, and IL-1ß compared with those patients receiving fentanyl alone (F). METHOD: Forty-women with primary breast cancer undergoing a modified radical mastectomy were randomized to receive postoperative analgesia with flurbiprofen axetil combined with fentanyl or fentanyl alone. Venous blood was sampled before anesthesia, at the end of surgery, and at 48 hours after surgery, and the serum was analyzed. The primary endpoint was changes in the VEGF-C concentrations in serum. RESULTS: Group FA patients reported similar analgesic effects as group F patients at 2, 24, and 48 hours. At 48 hours, mean postoperative concentrations of VEGF-C in group F patients were higher than in group FA patients, 730.9 versus. 354.1 pg/mL (P = 0.003), respectively. The mean postoperative concentrations of TNF-α in group F patients were also higher compared with group FA patients 27.1 vs. 15.8 pg/mL (P = 0.005). Finally, the mean postoperative concentrations of IL-1ß in group F were also significantly higher than in group FA 497.5 vs. 197.7 pg/mL (P = 0.001). CONCLUSION: In patients undergoing a mastectomy, postoperative analgesia with flurbiprofen axetil, combined with fentanyl, were associated with decreases in serum concentrations of VEGF-C, TNF-α, and IL-1ß compared with patients receiving doses of only fentanyl.

[Value of mean platelet volume and Gensini score on predicting short-term outcome in acute ST segment elevation myocardial infarction patient post emergency percutaneous coronary intervention].

OBJECTIVE: To explore the value of mean platelet volume (MPV) and Gensini score on predicting short-term prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) post emergency percutaneous coronary intervention (PCI). METHODS: From September 2011 to June 2013, 102 consecutive hospitalized STEMI patients undergoing emergency PCI were included. All patients routine blood test was made immediately after admission, and Gensini score was calculated according to the results of coronary angiography. Incidence of major adverse cardiac events (MACE) during hospitalization and 6 months after PCI was observed. RESULTS: MPV, Gensini score and percent of coronary artery three vessel lesions were significantly higher in MACE patients than in patients without MACE(P < 0.05 or 0.01). Area under the curve (AUC) of MPV plus Gensini score for predicting in hospital MACE and at 6 months post PCI was 0.836 (95%CI:0.706-0.966, P = 0.003) and 0.718 (95%CI:0.571-0.866, P = 0.006) , respectively. Kaplan-Meier survival analysis showed that incidence of without MACE at 6 months post PCI was significantly lower in patients with high MPV (>10.65 fl) than in patients with low MPV ( ≤ 10.65 fl) at admission (log-rank = 4.272, P = 0.039), and in patients with high Gensini score (>89) than in low Gensini score ( ≤ 89) (log-rank = 7.355, P = 0.007) at admission. CONCLUSIONS: High MPV and Gensini score are associated with lower MACE during hospitalization and at 6 months after PCI in acute STEMI patient. These two parameters could thus be used to predict short-term MACE in STEMI patients post PCI.

Simultaneous inhibition of tumor growth and angiogenesis for resistant hepatocellular carcinoma by co-delivery of sorafenib and survivin small hairpin RNA.

The development of multidrug resistance (MDR) in human hepatocellular carcinoma (HCC) is one of the major obstacles for successful chemotherapy of HCC. Co-delivery of sorafenib (SF) and survivin shRNA (shSur) was postulated to achieve synergistic effects in reversing MDR, suppressing tumor growth and angiogenesis. For this purpose, in this work, SF and shSur co-loaded pluronic P85-polyethyleneimine/d-α-tocopheryl polyethylene glycol 1000 succinate nanocomplexes (SSNs) were first designed and developed for the treatment of drug resistant HCC. The experimental results showed that SSNs could achieve effective cellular internalization and shSur transfection efficiency, induce significant downregulation of the survivin protein, and cause remarkable cell arrest and cell apoptosis. The tube formulation assay demonstrated that SSNs completely disrupted the enclosed capillary networks formed by human microvascular endothelial cells. The in vivo antitumor efficacy showed that SSNs were superior to that of other treatments on drug resistant hepatocellular tumor models. Therefore, it could be an efficient strategy to co-deliver SF and shSur for therapy of drug resistant HCC.

Genomic nursing science revealed the prolyl 4-hydroxylase subunit alpha 2 as a significant biomarker involved in osteosarcoma.

Backgrounds: This study aims to explore the clinical value of P4HA2 (prolyl 4-hydroxylase subunit alpha 2) in Osteosarcoma (OSC), and assess its potential to provide directions and clues for the practice of precision nursing. Methods: The GSE73166 and GSE16088 datasets were used to explore the P4HA2 expression in OSC. We then used the clinical data of patients obtaining from TARGET database to assess the prognostic value of P4HA2 in OSC. We also evaluated the predictive value of prognostic model based on P4HA2-related genes. Further, GSEA analysis was performed to explore related pathways. Results: The P4HA2 mRNA expression was higher in OSC than that in normal tissues and other bone cancer samples. Survival analysis found that P4HA2 high expression caused poor overall survival (OS) of patients with OSC and P4HA2 presented a favorable performance for predicting OS. Specifically, P4HA2 high expression statistically influenced the OS of patients with age≥15 years old and those with or without metastasis. Cox regression analysis indicated the independent prognostic value of P4HA2 in OSC, and nomogram analysis revealed its significant contribution to the survival probability of patients. We further established a prognostic model based on P4HA2-related genes, finding that prognostic model had a good prediction ability on OS. These results supported the clinical significance of P4HA2 in OSC. GSEA analysis suggested that P4HA2 was significantly related to the MAPK signaling pathway. In addition, P4HA2-associated natural killer cell-mediated cytotoxicity and T cell receptor signaling pathway were also predicted. Conclusions: This study revealed that P4HA2 can serve as an important prognostic biomarker for OSC patients, and it may become a promising therapeutic target in OSC treatment.

Fluorogenic RNA Aptamer-Based Amplification and Transcription Strategy for Label-free Sensing of Methyltransferase Activity in Complex Matrixes.

DNA methyltransferase is significant in cellular activities and gene expression, and its aberrant expression is closely linked to various cancers during initiation and progression. Currently, there is a great demand for reliable and label-free techniques for DNA methyltransferase evaluation in tumor diagnosis and cancer therapy. Herein, a low-background fluorescent RNA aptamer-based sensing approach for label-free quantification of cytosine-guanine (CpG) dinucleotides methyltransferase (M.SssI) is reported. The fluorogenic light-up RNA aptamers-based strategy exhibits high selectivity via restriction endonuclease, padlock-based recognition, and RNA transcription. By combining rolling circle amplification (RCA), and RNA transcription with fluorescence response of RNA aptamers of Spinach-dye compound, the proposed platform exhibited efficiently ultrahigh sensitivity toward M.SssI. Eventually, the detection can be achieved in a linear range of 0.02-100 U mL-1 with a detection limit of 1.6 × 10-3 U mL-1. Owing to these superior features, the method is further applied in serum samples spiked M.SssI, which delivers a recovery ranging from 92.0 to 107.0% and a relative standard deviation <7.0%, providing a promising and practical tool for determining M.SssI in complex biological matrices.

Efficacy and safety of sovleplenib (HMPL-523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM-01): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of ≥50 × 109/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open-label phase is ongoing. FINDINGS: Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 4·0, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<0·0001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study. INTERPRETATION: Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy. FUNDING: HUTCHMED and Science and Technology Commission of Shanghai Municipality.