Retinopathy of prematurity (ROP) is a vision-threatening disorder that leads to pathological growth of the retinal vasculature due to hypoxia. Here, we investigated the potential effects of alamandine, a novel heptapeptide in the renin-angiotensin system (RAS), on hypoxia-induced retinal neovascularization and its underlying mechanisms. In vivo, the C57BL/6J mice with oxygen-induced retinopathy (OIR) were injected intravitreally with alamandine (1.0 μmol/kg per eye). In vitro, human retinal microvascular endothelial cells (HRMECs) were utilized to investigate the effects of alamandine (10 μg/mL) on proliferation, apoptosis, migration, and tubular formation under vascular endothelial growth factor (VEGF) stimulation. Single-cell RNA sequencing (scRNA-seq) matrix data from the Gene Expression Omnibus (GEO) database and RAS-related genes from the Molecular Signatures Database (MSigDB) were sourced for subsequent analyses. By integrating scRNA-seq data across multiple species, we identified that RAS-associated endothelial cell populations were highly related to retinal neovascularization. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed a significant decrease in alamandine levels in both the serum and retina of OIR mice compared to those in the control group. Next, alamandine ameliorated hypoxia-induced retinal pathological neovascularization and physiologic revascularization in OIR mice. In vitro, alamandine effectively mitigated VEGF-induced proliferation, scratch wound healing, and tube formation of HRMECs primarily by inhibiting the hypoxia-inducible factor-1α (HIF-1α)/VEGF pathway. Further, coincubation with D-Pro⁷ (Mas-related G protein-coupled receptor D (MrgD) antagonist) hindered the beneficial impacts of alamandine on hypoxia-induced pathological angiogenesis both in vivo and in vitro. Our findings suggested that alamandine could mitigate retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway, providing a potential therapeutic agent for OIR prevention and treatment.
Animals ; Retinal Neovascularization/prevention & control* ; Mice, Inbred C57BL ; Vascular Endothelial Growth Factor A/metabolism* ; Humans ; Mice ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Oligopeptides/therapeutic use* ; Signal Transduction/drug effects* ; Cell Proliferation/drug effects* ; Endothelial Cells/drug effects* ; Retinopathy of Prematurity/drug therapy* ; Apoptosis/drug effects* ; Cell Movement/drug effects* ; Renin-Angiotensin System/drug effects* ; Cells, Cultured

The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.

Objective:To evaluate the therapeutic effect of electroacupuncture on acute gastrointestinal injury (AGI) in patients with severe traumatic brain injury (sTBI).Methods:A prospective randomized controlled trial was conducted. 126 consecutively hospitalized patients with AGI after sTBI admitted to intensive care unit (ICU) of the First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine from January 2018 to December 2019 were enrolled. The patients were divided into observation group and control group by random number table. All the patients of two groups were given conventional treatment of western medicine for consecutive 7 days, including the treatments of primary diseases, indwelling nasogastric tube to extract gastric contents every 6 hours to determine gastric residual volume (GRV). When vital signs were basically stable, enteral nutrition (EN) was implemented and EN feeding amount and speed were adjusted according to GRV. On the basis of conventional western medicine treatment, the observation group was treated with electroacupuncture at Zusanli, Tianshu, Shangjuxu, Xiajuxu and Zhongwan, once in the morning and once in the evening, 30 minutes each time. The gastrointestinal function parameters including intra-abdominal pressure (IAP), serum diamine oxidase (DAO) and gastrointestinal failure (GIF) scores were observed before treatment and at day 3 and day 7 of treatment. The incidence of ICU hospital-acquired pneumonia (HAP-ICU), duration of mechanical ventilation (MV), length of ICU stay, 28-day mortality and adverse reactions of electroacupuncture were also observed in the two groups. Kaplan-Meier method was used for 28-day survival analysis.Results:During the 7-day treatment and observation, 26 cases of 126 patients withdrew from the study, and 100 cases were actually enrolled, 50 cases in the observation group and 50 cases in the control group. IAP and DAO at day 3 of treatment in both groups were significantly lower than those before treatment [control group: IAP (cmH 2O, 1 cmH 2O = 0.098 kPa) was 13.75±2.76 vs. 18.11±3.97, DAO (U/L) was 129.88±24.81 vs. 158.01±22.64; observation group: IAP (cmH 2O) was 13.56±2.19 vs. 18.50±3.54, DAO (U/L) was 129.11±29.32 vs. 159.36±28.65; all P < 0.01]. The gastrointestinal function parameters of the two groups improved gradually with the extension of treatment time, and the IAP, DAO and GIF scores at day 7 of treatment in the observation group were significantly lower than those in the control group [IAP (cmH 2O): 11.28±3.61 vs. 12.68±3.23, DAO (U/L): 49.69±17.56 vs. 57.27±20.15, GIF score: 2.02±0.74 vs. 2.40±0.70, all P < 0.05). The duration of MV and the length of ICU stay in the observation group were significantly shorter than those in the control group [duration of MV (days): 15.72±4.60 vs. 18.08±4.54, length of ICU stay (days): 16.76±4.68 vs. 19.26±5.42, both P < 0.05], and the incidence of ICU-HAP and 28-day mortality were significantly lowered (12.0% vs. 30.0%, 22.0% vs. 32.0%, both P < 0.05). Survival analysis showed that the 28-day cumulative survival rate in the observation group was significantly higher than that in the control group (86.4% vs. 76.1%; Log-Rank test: χ 2 = 37.954, P < 0.001). The patients in the observation group had no significant adverse reaction of electroacupuncture treatment. Conclusion:Electroacupuncture at corresponding acupoints can effectively improve gastrointestinal function in patients with AGI after sTBI, which is beneficial to shortening the length of ICU stay, promoting the recovery of the patients, and reducing the 28-day mortality.

Objective:To explore the clinical value of procalcitonin (PCT) in predicting mortality of patients with acute biliary pancreatitis (ABP).Methods:The clinical data of 196 ABP patients admitted in the emergency department of Ruijin Hospital Affiliated to Shanghai Jiaotong University Medical College from January 2013 to June 2017 were analyzed retrospectively. The enrolled patients were divided into survival group ( n=176) and death group ( n=20) according to clinical outcome, and their clinical characteristics, laboratory results(including WBC, CRP, PCT), APACHEⅡ score, BISAP score, modified Marshall score, SOFA score and CTSI at admission were compared between two groups. The ROC curve and AUC were used to evaluate the effectiveness of PCT and multiple scoring systems in predicting mortality in ABP patients, and the Delong test was used to compare the predictive efficacy of various methods at 1-2 d, 3-4 d, and 5-7 d days after onset. Results:The PCT level, APACHEⅡ score, BISAP score, modified Marshall score, SOFA score, and CTSI of patients in the death group were significantly higher than those in the survival group [6.98(3.12, 13.64) μg/L vs 0.55(0.17, 1.74) μg/L, 12.00(6.00, 18.75) vs 6.00(3.00, 9.00), 3.20±1.47 vs 1.59±1.05, 2.85±0.37 vs 1.96±0.64, 5.50(4.00, 9.50) vs 2.00(1.00, 4.25), 5.05±2.33 vs 3.39±1.74], and all the differences were statistically significant (all P values <0.05). The AUC of PCT for predicting death was 0.881 (95% CI 0.820-0.938)and the cut-off value was 2.44. The predictive value of PCT was similar to that of the modified Marshall score, BISAP score and SOFA score, but higher than that of APACHEⅡ score and CTSI (all P values <0.05). The predictive AUC of PCT at 3-4 days after onset was higher than that of modified Marshall score, BISAP score and SOFA score, and were significantly higher than those at 1-2 days after onset. Conclusions:PCT can be used to predict the mortality of ABP within 7 days of onset. The predictive value of PCT was comparable to the modified Marshall score, BISAP score and SOFA score, and the best predictive time was 3-4 days after onset.

Objective To assess the predictive effect of myocardial injury biomarkers (proBNP, CK-MB, and cTnI) on the severity of acute pancreatitis (AP). Methods The records of 246 patients diagnosed with acute pancreatitis who were treated at Ruijin Hospital Emergency Department from January 2015 to December 2016 were retrospectively analyzed. According to the revised 2012 Atlanta guidelines, these patients were divided into the mild acute pancreatitis (MAP, n=47), moderately severe acute pancreatitis (MSAP, n=151) and severe acute pancreatitis (SAP, n=48) groups. The highest plasma levels of troponin I (cTnI), creatine kinase (CK)-MB, N-terminal B-type brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and procalcitonin (PCT) were recorded for comparison within 72 h after admission. The acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ ) score, sequential organ failure assessment (SOFA), bedside index for severity in acute pancreatitis (BISAP) and Balthazar computed tomography severity index (CTSI) were calculated at admission within 72 h. Whether there is an occurrence of organ dysfunction, and the organ types and persist time of organ dysfunction were recorded. The analysis of variance, SNK-q test and paired samples t test were used for the statistical analysis. Results The levels of proBNP, CK-MB, and cTnI were significantly higher in the SAP group than in the non-SAP group. The receiver operating characteristic (ROC) curve demonstrated cTnI had the maximum predictive power (AUC=0.872), while proBNP had the least predictive ability (AUC=0.763). The established model, which is to explore whether the myocardial injury markers had the predictive value, showed that the combination of myocardial injury indicators (CK-MB, cTnI) and traditional indicators had higher predictive value for SAP than traditional indicators alone (AUC=0.966 vs. AUC=0.945, P=0.04). Conclusions The elevated markers of myocardial injury had certain predictive value for severe acute pancreatitis.

Objective To investigate the related factors and preventive measures of delayed gastric emptying after operation for esophageal and cardiac carcinoma.Methods A total of 45 patients with delayed gastric emptying after operation for esophageal and cardiac carcinoma were selected as observation group,and 45 patients without delayed gastric emptying after operation for esophageal and cardiac carcinoma were selected as control group.Differences in the relevant factors were compared between the two groups.Results Single factor analysis showed that older age,high body mass index,short time education,malnutrition,poor mental state,rural residence,surgical incision,blood loss,long operation time,postoperative analgesia pump application,and the large amount of fluid volume were related risks of delayed gastric emptying (P ＜ 0.05).The Logistic regression analysis showed that older age (OR =4.15,95 ％ CI:1.89 ～ 26.30),bad psychological reaction (OR =3.96,95％ CI:1.38 ～ 25.38),long operation time (OR =3.40,95％ CI:1.11 ～ 20.28) and malnutrition (OR =3.02,95％ CI:1.09 ～ 19.35) were independent factors of delayed gastric emptying.Conclusion Delayed gastric emptying is one of the common complications after operation for esophageal and cardiac carcinoma,and the influencing factors are complex.

Objective To investigate the related factors and preventive measures of delayed gastric emptying after operation for esophageal and cardiac carcinoma.Methods A total of 45 patients with delayed gastric emptying after operation for esophageal and cardiac carcinoma were selected as observation group,and 45 patients without delayed gastric emptying after operation for esophageal and cardiac carcinoma were selected as control group.Differences in the relevant factors were compared between the two groups.Results Single factor analysis showed that older age,high body mass index,short time education,malnutrition,poor mental state,rural residence,surgical incision,blood loss,long operation time,postoperative analgesia pump application,and the large amount of fluid volume were related risks of delayed gastric emptying (P ＜ 0.05).The Logistic regression analysis showed that older age (OR =4.15,95 ％ CI:1.89 ～ 26.30),bad psychological reaction (OR =3.96,95％ CI:1.38 ～ 25.38),long operation time (OR =3.40,95％ CI:1.11 ～ 20.28) and malnutrition (OR =3.02,95％ CI:1.09 ～ 19.35) were independent factors of delayed gastric emptying.Conclusion Delayed gastric emptying is one of the common complications after operation for esophageal and cardiac carcinoma,and the influencing factors are complex.

Although links between cancer and inflammation were firstly proposed in the nineteenth century, the molecular mechanism has not yet been clearly understood. Epidemiological studies have identified chronic infections and inflammation as major risk factors for various types of cancer. NF-κB transcription factors and the signaling pathways are central coordinators in innate and adaptive immune responses. STAT3 regulates the expression of a variety of genes in response to cellular stimuli, and thus plays a key role in cell growth and apoptosis. Recently, roles of NF-κB and STAT3 in colon, gastric and liver cancers have been extensively investigated. The activation and interaction between STAT3 and NF-κB play vital roles in control of the communication between cancer cells and inflammatory cells. NF-κB and STAT3 are two major factors controlling the ability of pre-neoplastic and malignant cells to resist apoptosis-based tumor-surveillance and regulating tumor angiogenesis and invasiveness. Understanding the molecular mechanisms of NF-κB and STAT3 cooperation in cancer will offer opportunities for the design of new chemo-preventive and chemotherapeutic approaches.
Cell Transformation, Neoplastic ; Humans ; Inflammation ; metabolism ; NF-kappa B ; chemistry ; metabolism ; Neoplasms ; metabolism ; pathology ; Protein Structure, Tertiary ; STAT3 Transcription Factor ; chemistry ; metabolism ; Signal Transduction

Objective To evaluate the effect of Shenfu Decoction pretreatment on the function of intestinal mucosal barrier of endotoxemic rats.Methods Twenty-four adult male Sprague-Dawley rats,aged 4-6 months,weighing 180-220 g,were randomly divided into 3 groups (n =8 each):blank control group (group C),endotoxemia group (group E) and Shenfu Decoction pretreatment group (group S).Endotoxemia was induced by lipopolysaccharide 10 mg/kg injected intravenously in anesthetized rats in groups E and S.Normal saline and Shenfu Decoction 5 ml/kg were injected intraperitoneally at 30 min before the model of endotoxemia was established in groups E and S,respectively.At 2 h after the model of endotoxemia was estabhshed,blood samples were obtained from the abdominal aorta for measurement of the plasma concentrations of tumor necrosis factor-α (TNF-α),interleukin6 (IL-6),intestinal fatty acid binding protein (i-FABP) and diamine oxidase (DAO) by ELISA.The distal ileum was harvested for detection of the expression of tight junctional protein Zonula Occludens-1 (ZO-1) in the intestinal mucosa of epithelial cells by immunohistochemistry.The changes in pathological morphology of the intestinal mucosa were examined after one segment of the distal ileum was stained with haematoxylin and eosin.The pathological changes were assessed and graded according to Chiu's score.Results Compared withgroup C,the plasma TNF-α,IL-6,i-FABP and D-lac concentrations were significantly increased,Chiu's scores were increased,and the expression of ZO-1 was down-regulated in groups E and S (P ＜ 0.05).Compared with group E,the plasma TNF-α and IL-6 concentrations were significantly decreased,the plasma i-FABP and D-lac concentrations were decreased,Chiu's scores were decreased,and the expression of ZO-1 was up-regulated in group S (P ＜ 0.05).Conclusion Shenfu Decoction pretreatment can attenuate the damage to the intestinal mucosa and protect the function of intestinal mucosal barrier in endotoxemic rats and inhibition of systemic inflammatory responses is involved in the mechanism.

Objective To analyze and study the diagnosis of large granular lymphocyte leukemia(LGLL).Methods To report and discuss six cases weth LGLL we have found. Results 2 of T-LGLL and lof NK-LGLL had indolent process, mainly presenting with anemia and splenomegaly and good response to treatment, while; 1 of T-LGLL and 2 of NK-LGLL had aggressive process, their clinical characters are obviously general symptom, hepatomegaly,splenomegaly,these disease develop quickly and have bad prognosis. The immunophenotype of indolent LGLL is distinct from aggressive cases. Conclusion As a group of heterogeneous disease,its diagnosis should be based on clinical manifestation and immunophenotype and differentiated it carefully.