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Although effective, immune checkpoint blockade induces response in only a subset of cancer patients. There is an urgent need to discover new immune checkpoint targets. Recently, it was found that a class of sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed on the surface of T cells in cancer patients inhibit T cell activation through their intracellular immunosuppressive motifs by recognizing sialic acid-carrying glycans, sialoglycans. However, ligands of Siglecs remain elusive. Here, we report sialylated IgG (SIA-IgG), a ligand to Siglec-7, that is highly expressed in epithelial cancer cells. SIA-IgG binds Siglec-7 directly and inhibits TCR signals. Blocking of either SIA-IgG or Siglec-7 elicited potent antitumor immunity in T cells. Our study suggests that blocking of Siglec-7/SIA-IgG offers an opportunity to enhance immune function while simultaneously sensitizing cancer cells to immune attack.

Background: Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM). Methods: This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine–Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30. Results: Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI < 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15–7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24–4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05–3.39; P = 0.035). Conclusions: Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM. Impact: This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT. See related commentary by Giri and Williams, p. 2002

The prognosis for cervical cancer (CC) patients with lymph node metastasis (LNM) is extremely poor. Lipid droplets (LDs) have a pivotal role in promoting tumor metastasis. The crosstalk mechanism between LDs and LNM modulated in CC remains largely unknown.This study aimed to construct a miRNA-dependent progonostic model for CC patients and investigate whether miR-532-5p has a biological impact on LNM by regualting LDs accumulation.LASSO-Cox regression was applied to establish a prognostic prediction model. miR-532-5p had the lowest P-value in RNA expression (P 0.001) and prognostic prediction (P 0.0001) and was selected for further study. The functional role of the prognostic miR-532-5p-correlated competing endogenous RNA (ceRNA) network was investigated to clarify the crosstalk between LDs and LNM. The underlying mechanism was determined using site-directed mutagenesis, dual luciferase reporter assays, RNA immunoprecipitation assays, and rescue experiments. A xenograft LNM model was established to evaluate the effect of miR-532-5p and orlistat combination therapy on tumor growth and LNM.A novel 5-miRNAs prognostic signature was constructed to better predict the prognosis of CC patient. Further study demonstrated that miR-532-5p inhibited epithelial-mesenchymal transition and lymphangiogenesis by regulating LDs accumulation. Interestingly, we also found that LDs accumulation promoted cell metastasis in vitro. Mechanistically, we demonstrated a miR-532-5p-correlated ceRNA network in which LINC01410 was bound directly to miR-532-5p and effectively functioned as miR-532-5p sponge to disinhibit its target gene-fatty acid synthase (Our findings highlight a LD accumulation-dependent mechanism of miR-532-5p-modulated LNM and support treatment with miR-532-5p/orlistat as novel strategy for treating patients with LNM in CC.

Despite an observed daytime front-seat seat belt use that exceeds 90%, nearly half of motor vehicle occupants who die in New York State (NYS) each year are not wearing a seat belt. Crash outcomes were examined by occupant, vehicle, environmental and traffic enforcement patterns related to the annual Click It or Ticket high visibility seat belt enforcement campaign. Three periods of enforcement were examined: pre-enforcement, peri-enforcement (during/immediately after), and post-enforcement. Of the 14.4 million traffic citations, 713,990 (5.0%) were seat belt violations. Relative risk with 95% CI was assessed using deaths from the Fatality Analysis Reporting System (FARS) and SAS Glimmix 9.4 software. Mortality was lower peri-enforcement (32.9%) compared to pre- (40.9%) or post-enforcement (37.1%) (p < 0.001) and tended to be elevated in low enforcement response areas (43.6%). Fatalities were 30% lower (0.7, 95% CI 0.6–0.9) during peri-enforcement in models adjusted for demographics, law coverage, enforcement response, rural, weekend, impairment, speeding, and vehicle type. Adjusted mortality was higher in rural (1.9, 1.6–2.6), alcohol-involved (1.8, 1.4–2.9), and speeding-involved (2.0, 1.7–2.5) crashes. Peri-enforcement alcohol- and speed-involved fatalities tended to be lower in restrained, unrestrained and occupants missing belt status. The finding of lower mortality in both belted and unbelted occupant’s peri-enforcement—in the context of fewer fatal speed and alcohol-involved crashes—suggests that the mechanism(s) through which high visibility seat belt enforcement lowers mortality is through impacting multiple risky driving behaviors.

Background: The purpose of this study was to examine the association between baseline skeletal muscle measurements, acute toxicity (immune effector cell–associated neurotoxicity syndrome [ICANS], cytokine release syndrome), and treatment efficacy in patients undergoing CAR T-cell therapy for B-lineage lymphoma. Patients and Methods: Skeletal muscle measurements were obtained from automated CT measurements in 226 consecutive patients who received CAR T-cell therapy between 2015 and 2021. The Kaplan-Meier method was used to examine progression-free survival (PFS) and overall survival (OS) at 1-year. Multivariable regression was used to calculate the hazard ratio (HR) with 95% confidence intervals, adjusted for covariates. Results: The median age of the cohort was 63.1 years (range, 18.5–82.4 years), and most patients were male (66%) and had primary refractory disease (58%). Patients with abnormally low skeletal muscle at baseline were at greater risk of ICANS (HR, 1.74; 95% CI, 1.05–2.87) and had longer length of hospitalization (mean 27.7 vs 22.9 days; PPConclusions: This information can be used for risk stratification prior to CAR T-cell therapy or to implement prehabilitation and nutritional optimization before lymphodepletion as well as thereafter. These efforts will be complementary to ongoing efforts toward sustained efficacy after CAR T-cell therapy.

Chunliang Shang,1 Yuan Li,1 Zhangxin Wu,1 Qin Han,1 Yuan Zhu,2 Tianhui He,1 Hongyan Guo1,3 1Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, People’s Republic of China; 2Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 3National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing 100191, People’s Republic of ChinaCorrespondence: Hongyan GuoDepartment of Obstetrics and Gynecology, Peking University Third Hospital, No. 49 Huayuan North Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel +86-17301281996Fax +86 1082267842Email bysyghy@163.comBackground: To depict the prognostic landscape of gynecological cancers from the perspective of DNA methylation, alternative splicing (AS) and polyadenylation (APA) events and investigate their correlation with immune infiltrates.Methods: Methylation and RNA-seq data and corresponding clinical information regarding gynecologic cancers were used to explore the relationships between changes in DNA methylation, AS and APA events and gynecologic cancer prognosis. QRT-PCR and multiple bioinformatics tools were employed to construct a gene interaction network and explore immune infiltrates.Results: Only the mRNA levels of CIRBP and INPP5K were simultaneously significantly decreased in gynecologic cancers and negatively associated with overall survival, which verified by qrt-PCR. We also identified that CIRBP or INPP5K DNA methylation, AS and APA events are prognostic indicators of gynecologic cancers. The activation of T cells might be the main signaling pathway by which these genes modulate cancer progression. CIRBP/INPP5K expression is positively associated with immune infiltration and is a major risk factor of survival, especially among uterine corpus endometrial carcinoma (UCEC) patients.Conclusion: According to these findings, the DNA methylation, AS and APA events of CIRBP and INPP5K may serve as important prognostic biomarkers and targets in gynecological cancers by modulating T cell infiltration.Keywords: DNA methylation, alternative splicing, alternative polyadenylation, activation of T cells, immune infiltration

Background Risk of nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT) is high. Patient-level clinical prediction models such as the HCT–comorbidity index (HCT-CI) help identify those at increased risk for NRM, but the independent contribution of social determinants of health on HCT outcomes is not well characterized. Methods This study included 1602 patients who underwent allogeneic HCT between 2013 and 2019 at City of Hope. Census tract–level social vulnerability was measured using the social vulnerability index (SVI). Fine-Gray multivariable regression evaluated the association between SVI and 1-year NRM. Subgroup analysis examined risk of NRM across combined SVI and HCT-CI categories and by race and ethnicity. Results Cumulative incidence of 1-year NRM after HCT was 15.3% (95% confidence interval [CI] = 13.6% to 17.1%). In multivariable analysis, patients in the highest SVI tertile (highest social vulnerability) had a 1.4-fold risk (subdistribution hazard ratio [sHR] = 1.36, 95% CI = 1.04 to 1.78) of NRM compared with individuals in the lower tertiles; patients in the highest SVI tertile who also had elevated (≥3) HCT-CI scores had the highest risk (sHR = 1.81, 95% CI = 1.26 to 2.58) of 1-year NRM (reference: lower SVI tertiles and HCT-CI < 3). High social vulnerability was associated with risk of 1-year NRM in Asian (sHR = 2.03, 95% CI = 1.09 to 3.78) and Hispanic (sHR = 1.63, 95% CI = 1.04 to 2.55) but not non-Hispanic White patients. Conclusions High social vulnerability independently associated with 1-year NRM after HCT, specifically among minority populations and those with a high comorbidity burden at HCT. These findings may inform targeted approaches for needs assessment during and after HCT, allowing for timely interventions to improve health outcomes in at-risk patients.

To investigate the risk factors that were associated with the death of elderly patients who were admitted to the intensive care unit (ICU) after elective abdominal surgery, and to find reliable and sensitive predictive indicators for early interventions and reducing the mortality.A retrospective case-control study was conducted. The clinical data of elderly (age ≥ 65 years old) patients after elective abdominal surgery admitted to the ICU of the Affiliated Hospital of Guizhou Medical University from January 1st 2016 to December 31st 2020 were collected, including the patient's gender, age, body mass index (BMI), medical history, American Society of Anesthesiologists (ASA) grades, surgical classification, intraoperative blood loss, duration of operation, interval time between end of operation and admission to the ICU, acute physiology and chronic health evaluation II (APACHE II) score and the worst laboratory examination results within 24 hours of ICU admission, the first blood gas analysis in ICU, the duration of invasive mechanical ventilation, and the length of ICU stay. Postoperative abdominal infection was evaluated by the pathogenic culture of peritoneal drainage fluid and clinical symptoms and signs. The patients were divided into death group and survival group based on clinical outcomes, and clinical data were compared between the two groups. Binary multivariate Logistic regression analysis was used to screen the risk factors of death, and the receiver operator characteristic curve (ROC curve) was plotted to analyze the predictive values of these risk factors.A total of 226 elderly patients with elective abdominal surgery were admitted to the ICU of our hospital during the past 5 years, of whom, two patients who did not undergo laboratory examinations within 24 hours of admission to the ICU were excluded. Finally, 224 patients met the criteria, with 158 survivors and 66 deaths. Univariate analysis showed that: compared with survival group, APACHE II score, blood lactate acid (Lac) and the proportion of postoperative abdominal infection were higher in death group [APACHE II score: 27.5 (25.0, 31.3) vs. 23.0 (18.0, 27.0), Lac (mmol/L): 2.9 (1.8, 6.6) vs. 1.8 (1.1, 2.8), the proportion of postoperative abdominal infection: 65.2% (43/66) vs. 35.4% (56/158), all P0.01], prothrombin time (PT), activated partial thromboplastin time (APTT) and interval time between end of surgery and admission to ICU were longer [PT (s): 17.20 (14.50, 18.63) vs. 14.65 (13.90, 16.23), APTT (s): 45.15 (38.68, 55.15) vs. 39.45 (36.40, 45.70), interval time between end of surgery and admission to ICU (hours): 39.2 (0.7, 128.9) vs. 0.7 (0.3, 2.0), all P0.01], postoperative hemoglobin (Hb), platelet count (PLT), prealbumin (PA), mean arterial pressure (MAP) and oxygenation index (PaOAPACHE II score, interval time between end of surgery and admission to ICU, and postoperative abdominal infection may be independent risk factors for the death of elderly patients who were admitted to the ICU after elective abdominal surgery, there would be far greater predictive values when the three variables were combined.

To explore the efficacy and safety of low- and medium-dose of glucocorticoids in adult patients with acute respiratory distress syndrome (ARDS) through Meta-analysis and trials sequential analysis (TSA).Databases associated with adult ARDS treatment with low- and medium-dose glucocorticoids both in English and in Chinese were searched from PubMed, Medline, China Biology Medicine (CBM), Cochrane Library, CNKI, Wanfang Data and VIP, of which the search duration was from the establishment of the database to December 2020. Low-dose glucocorticoids were defined as methylprednisolone ≤ 1 mg×kgA total of 996 patients in 7 literatures were finally included, including 515 patients in the low- and medium-dose glucocorticoid group (hormone group) and 481 patients in the conventional treatment group (control group). The research quality of 7 literatures was relatively high. The results of Meta-analysis and TSA showed that, compared with the control group, the hospital mortality in the hormone group was significantly decreased [relative risk (RR) = 0.77, 95% confidence interval (95%CI) was 0.66-0.89, P = 0.000 6], and mechanical ventilation free time in ICU for 28 days was significantly prolonged [standardized mean difference (SMD) = 0.50, 95%CI was 0.36-0.65, P0.000 1]. Although Meta-analysis showed that the ICU mortality of the hormone group was significantly lower than that of the control group (RR = 0.61, 95%CI was 0.38-0.99, P = 0.04), the TSA results showed that the cumulative Z value crossed the traditional threshold, but did not cross the TSA cut-off value, and the sample size did not reach required information size (RIS, n = 3 252), needed more research to confirm. Although Meta-analysis showed that PaOLow- and medium-dose of glucocorticoids therapy can reduce the hospital mortality of adult ARDS patients and shorten the mechanical ventilation duration in ICU for 28 days, and low- and medium-dose of glucocorticoids therapy does not increase the risk of infection and hyperglycemia.

To compare the effects of dexmedetomidine (DEX) and midazolam on the endogenous plasma catecholamine levels and the dosage of exogenous norepinephrine (NE) to maintain blood pressure in patients with septic shock.From January 2018 to December 2019, patients admitted to the department of critical care medicine of the Affiliated Hospital of Guizhou Medical University who needed invasive mechanical ventilation and had a stay of more than 48 hours in the intensive care unit (ICU) for septic shock and received DEX or midazolam for sedation were enrolled in this study. The hemodynamic data, arterial blood lactic acid (Lac) level, arterial blood gas analysis and vasoactive drug dose at 0, 12, 24, 48, 72 hours after entering the ICU were dynamically recorded, and the plasma catecholamine levels at 0, 24, 48 hours after entering the ICU were recorded. The acute physiology and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score on ICU-admission were calculated. The parameters of prognosis were collected.A total of 24 patients were enrolled, 12 in the DEX group and 12 in the midazolam group. There were similar dynamic trends in heart rate (HR), central venous pressure (CVP), venous-arterial carbon dioxide pressure difference (Pv-aCODEX can reduce plasma catecholamine levels in patients with septic shock more than midazolam, and does not increase the dose of exogenous NE, and has a smaller effect on hemodynamics in patients with septic shock than midazolam.

Total marrow irradiation (TMI) is an alternative to total body irradiation (TBI) as a component of the conditioning regimen for hematopoietic cell transplantation (HCT), offering the ability to deliver more targeted doses and facilitating organ-sparing. The organ-sparing effect of TMI is theorized to decrease the risk of complications associated with radiation, including subsequent malignant neoplasms (SMNs), while allowing for dosage escalation to improve oncologic outcomes. The purpose of this study was to compare SMNs rates among patients treated with TBI- or TMI-based conditioning regimens. We hypothesized that TMI would yield a rate of SMNs comparable to, if not lower than, TBI. A retrospective matched-pair analysis of patients who underwent allogeneic HCT and received either TBI- or TMI-based conditioning regimens to a total dose of 12 to 20 Gy was performed. A total of 171 patients received TMI-based conditioning and 171 received TBI-based conditioning, matched based on age, sex, diagnosis, and length of follow-up. SMNs were identified from an established long-term follow-up protocol, our institutional cancer registry, and the California Cancer Registry. There were no significant differences in patient and clinical characteristics between the TMI and TBI cohorts except for clinical response status at transplantation and radiation dose. As expected, patients in the TMI received higher radiation doses (median dose, 16.0 Gy for the TMI cohort versus 13.2 Gy for the TBI cohort; P.001). The median follow-up for both cohorts was 2.0 years (range, .5 to 12.3 years). There was no significant difference in the risk of developing SMNs between the 2 cohorts (P = .81). A total of 9 patients (5.3%) conditioned with TBI and 10 patients (5.8%) conditioned with TMI developed SMNs, at a median of 3.3 years and 1.7 years following HCT, respectively. Excluding nonmelanoma skin cancers and noninvasive neoplasms, 2 patients in the TBI cohort developed SMNs (both melanomas), and 1 patient in the TMI cohort developed an SMN (colon cancer). No patients developed a subsequent hematologic malignancy. TMI-based conditioning is not associated with a significant difference in the risk of developing SMNs compared with TBI-based conditioning during early post-HCT follow-up. Future studies with longer follow-up may be needed to further characterize the risk of SMNs associated with TMI-based conditioning regimens compared with TBI-based regimens.

Background: Evidence regarding the correlation between platelet count and all-cause mortality in critically ill patients with acute respiratory failure (ARF) is limited. Therefore, the aim of the study was to evaluate whether platelet count was associated with all-cause mortality in critical patients with ARF by using the electronic intensive care unit (eICU) Collaborative Research Database (eICU-CRD). Methods: In this retrospective multicenter cohort study, the data of 26961 patients with ARF hospitalized in ICUs between 2014 and 2015 were collected. The independent variable was log2 basal platelet count, and the dependent variables were all-cause in-hospital and ICU mortality. Covariates including demographic data, Acute Physiology and Chronic Health Evaluation (APACHE) IV score, supportive treatment, and comorbidities were collected. Results: In the fully adjusted model, log2 basal platelet count was negatively associated with all-cause mortality both in hospital [RR: 0.87, 95% CI: 0.84-0.91] and in ICU [RR: 0.87, 95% CI: 0.83-0.92]. A non-linear relationship between log2 basal platelet count and all-cause in-hospital and ICU mortality was identified by the nonlinearity test. The inflection points we got were 6.83 and 6.86 respectively (after inverse log2 logarithmic conversion, the platelet counts were 114×10(9)/L and 116×10(9)/L, respectively). On the right side of the inflection point, however, no association was observed between blood platelets and all-cause in-hospital (RR: 0.96, 95% CI: 0.88-1.03) and ICU mortality (RR: 0.97, 95% CI: 0.91-1.04). Conclusions: For patients with ARF in ICU, platelet count was negatively associated with all-cause in-hospital and ICU mortality when the platelet count was less than 114×10(9)/L and 116×10(9)/L respectively, but when the platelet count was higher, we failed to observe a correlation between them. The safe ranges of platelet count for hospital stay and ICU stay were 78×10(9)/L-145×10(9)/L and 89×10(9)/L-147×10(9)/L respectively.

High-energy, high-dose, microfocus X-ray computed tomography (HHM CT) is one of the most effective methods for high-resolution X-ray radiography inspection of high-density samples with fine structures. Minimizing the effective focal spot size of the X-ray source can significantly improve the spatial resolution and the quality of the sample images, which is critical and important for the performance of HHM CT. The objective of this study is to present a 9 MeV HHM CT prototype based on a high-average-current photo-injector in which X-rays with about 70μm focal spot size are produced via using tightly focused electron beams with 65/66μm beam size to hit an optimized tungsten target. In digital radiography (DR) experiment using this HHM CT, clear imaging of a standard 0.1 mm lead DR resolution phantom reveals a resolution of 6 lp/mm (line pairs per mm), while a 5 lp/mm resolution is obtained in CT mode using another resolution phantom made of 10 mm ferrum. Moreover, comparing with the common CT systems, a better turbine blade prototype image was obtained with this HHM CT system, which also indicates the promising application potentials of HHM CT in non-destructive inspection or testing for high-density fine-structure samples.

China Academy of Engineering Physics Terahertz Free Electron Laser (CTFEL) works in the range of 0.7~4.2 THz. To expand the range below 0.1 THz, we developed a super-radiation terahertz (THz) source based on sub-picosecond electron beam behind CTFEL. The sub-picosecond electron beam was generated by velocity compression and then injected into undulator to provide THz wave. In this proceeding, the preliminary experimental results of super-radiation terahertz source were reported.

The tunability, high power, high repetition rate and picoseconds-pulse time structure of terahertz (THz) radiation make the THz free-electron laser (FEL) a very attractive THz source of coherent radiation. China Academy of Engineering Physics terahertz free electron laser (CTFEL) is the first THz FEL user facility in China, which consists of a GaAs photocathode high-voltage DC gun, a superconducting RF linac, a planar undulator and a quasi-concentric optical resonator. The terahertz laser’s frequency is continuous adjustable from 0.7 THz to 4.2 THz. The average power is more than 10 W and the micro-pulse power is more than 0.3 MW. In addition, a super-radiation THz source based on CTFEL has also been built, with a frequency range of 0.1~0.7 THz. In the near future, by upgrading the electron energy, the frequency of facility will be extended to 0.1~125 THz, which will achieve full coverage of the THz band. The current status and future prospects of CTFEL THz radiation source are emphasized in this paper, and some important user experiments are introduced briefly.

Background: There is limited evidence on the correlation between platelet counts and all-cause mortality in critically ill patients with acute respiratory failure (ARF). The aim was to evaluate whether platelet count was associated with all-cause mortality in critical patients with ARF by using the eICU Collaborative Research Database.Methods: Using a retrospective multicenter cohort dataset, data of 26961 patients with ARF in ICU between 2014 and 2015 were collected. The independent variable was log2 basal platelet count, and the dependent variables were all-cause mortality in hospital and in ICU. Covariates included demographic data, Acute Physiology and Chronic Health Evaluation (APACHE) IV score, supportive treatment, and comorbidities.Results: In fully adjusted model, log2 basal platelet count was negatively associated with all-cause mortality both in hospital [ RR:0.87, 95% CI: 0.84 - 0.91] or in ICU [RR: 0.87, 95% CI:0.83, 0.92]. By nonlinearity test, the relationship between log2 basal platelet count and all-cause mortality in hospital and in ICU were nonlinear. The inflection point we got was 6.83 and 6.86 (after inverse log2 logarithmic conversion, the platelet count are 114×109/L and 116×109/L). There was no a correlation between blood platelets and all-cause mortality in hospital on the right side of the inflection point, (RR:0.96, 95% CI: 0.88-1.03) and in ICU (RR:0.97, 95% CI: 0.91-1.04).Conclusions: For patients with ARF in ICU, platelet count was negatively associated with all-cause mortality in hospital and in ICU when platelet count is less than 114 ×109/L and 116 ×109/L respectively, but when the platelet count was higher, we failed to observe a correlation between them. The safe ranges of platelet count we detected were 78×109/L -145×109/L and 89×109/L -147×109/L respectively.

Background Alveolar hypercoagulation and fibrinolytic inhibition are important characteristics during acute respiratory distress syndrome (ARDS), and NF-κB p65 signaling pathway is involved to regulate these pathophysiologies. We hypothesize that targeting NF-κB signal pathway could ameliorate alveolar hypercoagulation and fibrinolyitc inhibition, thus attenuating lung injury in ARDS. Purpose We explore the efficacy and the potential mechanism of andrographolide sulfonate (Andro-S) on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS in mice. Methods ARDS was made by lipopolysaccharide (LPS) inhalation in C57BLmice. Andrographolide sulfonate (2.5, 5 and 10 mg/kg) was intraperitoneally given to the mice (once a day for three consecutive days) before LPS administration. NEMO binding domain peptide (NBD), an inhibitor of NF-κB, was used as the positive control and it replaced Andro-S in mice of NBD group. Mice in normal control received saline instead of LPS. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis of alveolar coagulation, fibrinolytic inhibition as well as of pulmonary inflammatory response after 8 h of LPS inhalation. NF-κB signal pathway in lung tissue was simultaneously determined. Results Andro-S dose-dependently inhibited tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 expressions either in mRNA or in protein in lung tissue of ARDS mice, and it also decreased the concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) while promoting the production of activated protein C (APC) in BALF. Meanwhile, Andro-S effectively inhibited inflammatory response (interleukin 1β and myeloperoxidase) induced by LPS. LPS stimulation dramatically activated NF-κB signal pathway, indicated by increased expressions of phosphorylation of p65 (p-p65), p-IKKα/β and p-IκBα and the higher p65-DNA binding activity, which were all dose-dependently reversed by Andro-S. Andro-S and NBD presented similar efficacies. Conclusions Andro-S treatment improves alveolar hypercoagulation and fibrinolytic inhibition and attenuates pulmonary inflammation in LPS-induced ARDS in mice partly through NF-κB pathway inactivation. The drug is expected to be an effective choice for ARDS.

Background Alveolar hypercoagulation and fibrinolysis inhibition were associated with the refractory hypoxemia and the high mortality in patient with acute respiratory distress syndrome (ARDS), and NF-κB pathway was confirmed to contribute to the process. Triptolide (TP) significantly inhibited NF-κB pathway and thus depressed accessive inflammatory response in ARDS. We speculate that TP could improve alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS via NF-κB inactivation. Purpose The aim of this experiment was to explore the efficacy and potential mechanism of TP on alveolar hypercoagulation and fibrinolysis inhibition in LPS-induced ARDS in mice. Methods 50 μl of LPS (5 mg/ml) was inhalationally given to C57BL/6 mice to set up ARDS model. Male mice were randomly accepted with LPS, LPS + TP (1 μg/kg, 10 μg/kg, 50 μg/kg respectively), or with NEMO Binding domain peptide (NBD), an inhibitor of NF-κB. TP (1 μg/kg, 10 μg/kg, 50 μg/kg) were intraperitoneally injected or 10 μg/50 μl of NBD solution were inhaled 30 min before LPS inhalation. A same volume of normal saline (NS) substituted for TP in mice in control. The endpoint of experiment was at 8 hours after LPS stimulation. Pulmonary tissues were taken for hematoxylin-eosin (HE) staining, wet / dry ratio and for lung injury scores (LIS). Tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue were detected by Western-blotting and by quantitative Real-time PCR(qPCR) respectively. Concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) and activated protein C (APC) in bronchoalveolar lavage fluid (BALF) were measured by ELISA. NF-κB activation and p65-DNA binding activity in pulmonary tissue were simultaneously determined. Results LPS stimulation resulted in pulmonary edema, neutrophils infiltration, obvious alveolar collapse, interstitial congestion, with high LIS, which were all dose-dependently ameliorated by Triptolide. LPS also dramatically promoted the expressions of TF and PAI-1 either in mRNA or in protein in lung tissue, and significantly stimulated the secretions of TF, PAI-1, TAT, PⅢP but inhibited APC production in BALF, which were all reversed by triptolide treatment in dose-dependent manner. TP dose-dependently inhibited the activation of NF-κB pathway induced by LPS, indicated by the changes of phosphorylations of p65 (p-p65), p-IKKα/β and p-IκBα, and weakened p65-DNA binding activity. TP and NBD had same efficacies either on alveolar hypercoagulation and fibrinolysis inhibition or on NF-κB signalling pathway in ARDS mice. Conclusions TP dose-dependently improves alveolar hypercoagulation and fibrinolysis inhibition in ARDS mice through inhibiting NF-κB signaling pathway. Our data demonstrate that TP is expected to be an effective selection in ARDS.

To investigate the effect of NEMO binding domain peptide (NBDP) on lung inflammation and apoptosis in mice with acute respiratory distress syndrome (ARDS) and its mechanism.Thirty-six male BALB/c mice were divided into normal saline (NS) control group, ARDS model group, NBDP negative control group and 6, 12 and 18 μg NBDP pretreatment group by random number table method, with 6 mice in each group. ARDS mouse model was reproduced by aerosol inhalation lipopolysaccharide (LPS) 50 μL. An equivalent among of NS was inhaled in NS control group. The mice in NBDP negative control group were inhaled the materials similar to the non-functional NBDP 30 minutes before the aerosol inhalation LPS; 6, 12 and 18 μg of NBDP 50 μL were respectively inhaled in NBDP pretreatment groups. After inhalation of LPS for 6 hours, mice were sacrificed to get lung tissue and observe the degree of pathological injury and edema. Western blotting was used to detect the phosphorylation of nuclear factor-κB (NF-κB) pathway related proteins [NF-κB inhibitor (IκB) kinaseα/β(IKKα/β), IκBα and NF-κB p65; p-IKKα/β, p-IκBα, p-p65] and the expression of caspase-3 in lung tissue. The bronchoalveolar lavage fluid (BALF) was collected and the levels of inflammatory markers such as myeloperoxidase (MPO), interleukins (IL-1β, IL-8), and tumor necrosis factor-α (TNF-α) were detected by enzyme linked immunosorbent assay (ELISA).ARDS model group had severe edema and hemorrhage, alveolar structure destruction, pulmonary hemorrhage and hyaline membrane formation etc. under light microscope, consistent with the pathological characteristics of ARDS lung tissue, suggesting that the ARDS model was successfully reproduced. ELISA showed that MPO, IL-1β, IL-8 and TNF-α levels of BALF in ARDS model group were obviously higher than those in NS control group. There were no significant differences in the above inflammatory indicators between NBDP negative control group and ARDS model group. The levels of MPO, IL-1β, IL-8 and TNF-α in NBDP pretreatment groups were significantly lower than those in ARDS model group in a dose-dependent manner, especially in 18 μg NBDP, the differences were statistically significant as compared with ARDS model group [MPO (ng/L): 393.32±19.35 vs. 985.87±101.50, IL-1β (ng/L): 43.05±5.11 vs. 97.68±10.88, IL-8 (ng/L): 84.64±2.32 vs. 204.00±17.37, TNF-α (ng/L): 229.13±17.03 vs. 546.73±62.72, all P0.05]. Western blotting showed that p-IKKα/β, p-IκBα, p-p65 and caspase-3 protein expressions in ARDS model group were significantly higher than those in NS control group. There was no significant difference in above NF-κB pathway and apoptosis-related protein expression between the NBDP negative control group and ARDS model group. The p-IKKα/β, p-IκBα, p-p65 and caspase-3 protein expression in NBDP pretreatment groups were significantly lower than those in ARDS model group in a dose-dependent manner, especially in 18 μg NBDP, the differences were statistically significant as compared with ARDS model group [p-IKKα/β protein (p-IKKα/β/β-actin): 0.15±0.02 vs. 0.42±0.04, p-IκBα protein (p-IκBα/β-actin): 0.10±0.01 vs. 0.93±0.30, p-p65 protein (p-p65/β-actin): 0.22±0.05 vs. 1.37±0.21, all P0.05].NBDP can inhibit inflammatory response and apoptosis in ARDS lung tissue in a dose-dependent manner, and its mechanism is associated with interference NF-κB signaling pathway transduction.

The failure of T cells to eradicate tumour cells in the tumour microenvironment is mainly due to the dysfunction of T cells. Senescent T cells, with defects in proliferation and effector functions, accumulate in ageing, chronic viral infections, and autoimmune disorders where antigen stimulation persists. Increasing evidence suggests that inducing T cell senescence is a key strategy used by malignant tumours to evade immune surveillance. In this review, we summarize the general features, functional regulation, and signalling network of senescent T cells in tumour development and highlight their potential as prognostic biomarkers in multiple cancer treatments, including chemotherapy, radiotherapy, and immunotherapy. Moreover, we discuss possible therapeutic strategies for preventing or rejuvenating senescence in tumour-specific T cells. Understanding these critical issues may provide novel strategies to enhance cancer immunotherapy.

To determine the effect of andrographolide (AD) on the expression of procoagulant and fibrinolytic inhibitory factors in rat type II alveolar epithelial cells (AEC II) stimulated by lipopolysaccharide (LPS).The AEC II cells RLE-6TN in the logarithmic growth phase were divided into 5 groups: the normal control (NC) group, the LPS group, and the 6.25, 12.5, and 25 mg/L AD groups (AD 6.25 group, AD 12.5 group, AD 25 group). The NC group was cultured with RPMI 1640 conventional medium. In the LPS group, 5 mg/L LPS was added to the RPMI 1640 conventional medium for stimulation. Cells in the AD groups were treated with 6.25, 12.5, and 25 mg/L AD in advance for 1 hour and then given LPS to stimulate the culture. The cells and cell culture supernatant were collected 24 hours after LPS stimulation. The protein and mRNA expressions of tissue factor (TF), tissue factor pathway inhibitor (TFPI), and plasminogen activator inhibition-1 (PAI-1) in cells were detected by Western blotting and real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). The levels of procollagen III peptide (PIIIP), thrombin-antithrombin complex (TAT), antithrombin III (AT-III) and activated protein C (APC) in the cell supernatant were detected by enzyme linked immunosorbent assay (ELISA).Compared with the NC group, the protein and mRNA expressions of TF and PAI-1 in the LPS group were significantly increased, and the protein and mRNA expressions of TFPI were significantly reduced. At the same time, the levels of PIIIP and TAT in the cell supernatant were significantly increased, the levels of AT-III, APC were significantly reduced. Compared with the LPS group, the protein and mRNA expressions of TF and PAI-1 in AD 6.25 group, AD 12.5 group, AD 25 group were significantly reduced [TF/GAPDH: 0.86±0.08, 0.45±0.04, 0.44±0.04 vs. 1.32±0.10, TF mRNA (2Andrographolide in the dose range of 6.25-25 mg/L can dose-dependently inhibit the expression and secretion of procoagulant and fibrinolytic inhibitor-related factors in AEC II cells RLE-6TN stimulated by LPS, and promote the secretion of anticoagulant factors. 25 mg/L has the most obvious effect.

To observe the effects of berberine on procoagulant and fibrinolytic inhibitory factors produced by rat type II alveolar epithelial cell (AEC II) induced by lipopolysaccharide (LPS).AEC II cells (RLE-6TN cells) were cultured in vitro, and the cells in logarithmic growth phase were collected. The cytotoxicity text of berberine was detected by cell counting kit-8 (CCK-8) to determine the drug concentration range according to inhibition concentration of half cells (ICAccording to the inhibition rate curve, the ICBerberine could inhibit the LPS-induced expressions of procoagulant and fibrinolytic inhibitory factors in rat AEC II cells and promote the expressions of anticoagulant factors in a dose-dependent manner. Berberine may be a new therapeutic target for alveolar hypercoagulability and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS).

The effects of low-dose heparin and low molecular weight heparin on the efficacy and prognosis of patients with acute respiratory distress syndrome (ARDS) were systematically evaluated.Chinese and English databases such as Wanfang data, VIP database, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Service system (SinoMed), American National Medical Library database (PubMed), Netherlands Medical Abstracts database (Embase) and Cochrane library database were searched for the randomized controlled trials (RCTs) of heparin or low molecular weight heparin in the treatment of ARDS. The search time is from July 1999 to June 2020. The control group was given routine treatment, while the experimental group was given heparin 5-10 U×kgFourteen Chinese literatures were included, with a total of 894 cases, including 454 cases in the experimental group and 440 cases in the control group. The results of Meta-analysis showed that the 28-day fatality rate in the experimental group was significantly lower than that in the control group [relative risk (RR) = 0.54, 95% confidence interval (95%CI) was 0.38-0.76, P = 0.000 4], and 7-day SaOContinuous anticoagulation therapy with low dose heparin and low molecular weight heparin can improve the prognosis and reduce the mortality of patients with ARDS.

BackgroundPrevious studies have indicated coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate.MethodsWe conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariable logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes.ResultsWe included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the United Kingdom and Europe, followed by the United States and Canada (35.7%), and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (OR = 3.57, 95% CI = 1.80 to 7.06), male sex (OR = 2.10, 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00, 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariable analysis, only age greater than 65 years (OR = 3.16, 95% CI = 1.45 to 6.88) and being male (OR = 2.29, 95% CI = 1.07 to 4.87) were associated with increased risk of severe events.ConclusionsOur analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate compared with that of COVID-19 patients without cancer. Age and sex appear to be risk factors associated with a poorer prognosis.

Ovarian cancer (OC) is one of the most lethal malignant gynecologic tumors, characterized by an uncertain presentation and poor outcomes. With or without neoadjuvant chemotherapy, surgery followed by platinum-based chemotherapy and maintenance therapy are the basis for the treatment of ovarian cancer patients, but the outcome is still highly restricted by their advanced stage when diagnosed and high recurrence rate after chemotherapy. To enhance the anti-tumor effect and postpone recurrence, anti-VEGF agents and PARP inhibitors are suggested as maintenance therapy, but the population that can benefit from these treatments is small. Based on the interactions of immune cells in the tumor microenvironment, immunotherapies are being explored for ovarian cancer treatment. Disappointingly, the immune checkpoint inhibitors show relatively low responses in ovarian cancer. As shown in several studies that have uncovered a relationship between DC infiltration and outcome in ovarian cancer patients, dendritic cell (DC)-based treatments might have a potential effect on ovarian cancer. In this review, we summarize the functions of dendritic cells (DCs) in the tumor microenvironment, as well as the responses and drawbacks of existing clinical studies to draw a comprehensive picture of DC vaccine treatment in ovarian cancer and to discuss the promising future of immune biomarkers.

To explore the effect of small dose of low molecular weight heparin on the prognosis of elderly patients with severe pneumonia using systematic evaluation method.Databases including Wanfang data, VIP, CNKI, SinoMed, PubMed, Embase and Cochrane Library were searched for randomized controlled trial (RCT) studies about the comparison of conventional therapy and low molecular weight heparin on prognosis of elderly patients with severe pneumonia from the time of database establishment to August 2019. The patients in conventional treatment group were treated by improving ventilation, anti-infection, eliminating phlegm, relieving asthma and maintaining homeostasis while those in low molecular weight heparin group were subcutaneously injected with low molecular weight heparin of 4 000 U, once a day for 7 days. The patients' main outcomes included the oxygenation index (PaOA total of 14 RCT studies were enrolled involving 1 173 elderly patients with severe pneumonia, among whom 590 received low molecular weight heparin while the other 583 received conventional therapy. All the included studies were well designed and of high quality. The results of Meta-analysis showed that compared with conventional therapy, small dose of low molecular weight heparin significantly elevated PaOSmall dose of low molecular weight heparin can improve the prognosis of elderly patients with severe pneumonia and it has no obvious side-effect on coagulation function.

To explore the therapeutic effect of Xuebijing on patients with acute paraquat poisoning (APP) by using systematic evaluation method.PubMed, Cochrane Library, Embase, Wanfang database, China National Knowledge Infrastructure (CNKI), VIP database (VIP) and China Biology Medicine (CBM) were searched using the computers to find the literatures published about the Xuebijing injection for the treatment of APP. Randomized controlled trials (RCT) were retrieved from the establishment of the database to August 2019. Patients in experimental group were treated with Xuebijing injection combined with conventional treatment, while the patients in control group were only given conventional treatment. The patients' outcome included the 14-day mortality, arterial oxygen saturation (SaOTwenty-seven RCT studies in total were enrolled, of which 26 were in Chinese and 1 was in English. A total of 1 429 patients were enrolled, among whom 726 were in experimental group and another 703 were in control group. Meta-analysis showed that compared with the control group, the 14-day mortality [relative risk (RR) = 0.62, 95% confidence interval (95%CI) was 0.54 to 0.72, P0.000 01] and incidence of pulmonary fibrosis (RR = 0.67, 95%CI was 0.53 to 0.85, P = 0.000 9) of patients in the experimental group were significantly lowered, while SaOXuebijing injection can reduce the mortality of patients with APP, which may because that it can improve liver and kidney function, reduce inflammation and oxidative stress damage, inhibit pulmonary fibrosis and increase oxygenation level.

A 2 × 4 -cell superconducting linac module for the THz-FEL facility has been developed at the China Academy of Engineering Physics, which is expected to provide 6–8 MeV quasi-CW electron beams with an average current of 1–5 mA. The module consists of two 4-cell SRF cavities, two main couplers, two tuners and a cryostat. The design, fabrication and performance test of these components is presented in this paper. The test results reveal that all these components have reached their design goals and the module has also been assembled and horizontal tested at Chengdu. The gradients of both cavities at 2 K reach 10 MV/m, which meets our requirements. Currently beam-loading commissioning is underway.

Background Alveolar hypercoagulation and pulmonary inflammation are important characteristics and they regulate each other in acute respiratory distress syndrome (ARDS). NF-κB pathway has been confirmed to be involved in regulation of this crosstalk. Emodin, a traditional Chinese herb, shows potent inhibitory effect on NF-κB pathway, but whether it is effective in alveolar hypercoagulation and pulmonary inflammation in ARDS remains to be elucidated. Purpose The aim of this experiment was to evaluate the efficacy of emodin on LPS-provoked alveolar hypercoagulation and excessive pulmonary inflammation in ARDS, and its potential mechanism. Methods Mice ARDS was set up through LPS (40 μl, 4 mg/ml) inhalation. Male mice were randomly received with BPS, LPS only, LPS+ emodin (5 mg/kg, 10 mg/kg, 20 mg/kg, respectively) and BAY65-1942, an inhibitor of IKKβ. After 48 h of LPS stimulation, pulmonary pathological injury, expressions of Tissue factor (TF), plasminogen activator inhibitor (PAI)-1, activated protein C (APC), collagen Ⅰ, collagen III, interleukin (IL) 8, IL-1β and tumor necrosis factor (TNF)-α in lung tissues, as well as concentrations of antithrombin III (AT III), procollagen peptide type III (PIIIP), soluble thrombomodulin (sTM), thrombin antithrombin complex (TAT), myeloperoxidase (MPO) and the percentage of inflammatory cells in bronchoalveolar lavage fluid (BALF) were all determined. NF-κB pathway activation as well as NF-κB DNA binding activity in pulmonary tissue were simultaneously checked. Results LPS stimulation resulted in obvious lung injury, excessive inflammatory cells infiltration, which all were dose-dependently ameliorated by emodin. Expressions of TF, PAI-1, collagen Ⅰ and collagen III as well as IL-8, IL-1β and TNF-α in pulmonary tissue were all elevated while APC decreased under LPS provocation, which were all reversed by emodin treatment in dose-dependent manner. LPS promoted the secretions of PIIIP, sTM, TAT and inhibited AT III production in BALF, and resulted in high levels of MPO and the percentage of inflammatory cells in BALF, all of which were significantly and dose-dependently attenuated while AT III production was increased by emodin. Meanwhile, emodin effectively inhibited NF-κB pathway activation and attenuated p65 DNA binding activity induced by LPS inhalation. Emodin and BAY-65-1942 had similar impacts in this experiment. Conclusions Emodin improves alveolar hypercoagulation and fibrinolytic inhibition and depresses excessive pulmonary inflammation in ARDS mice in dose-dependent manner via NF-κB inactivation. Our data demonstrate that emodin is expected to be an effective drug in alveolar hypercoagulation and pulmonary inflammation in ARDS.

Microwave source system with high power and high stability is an important component of the superconducting accelerator in the free electron laser facility. This paper mainly presents the design of the 30 kW continuous wave (CW) microwave source system in the China Academy of Engineering Physics terahertz free electron laser (CAEP THz FEL, CTFEL) facility, the structure and the application of this system are also introduced.

CAEP (the China Academy of Engineering Physics) has developed a high average power THz radiation facility. A 1.3GHz RF buncher cavity is used to achieve short longitudinal bunch length. In order to regulate the amplitude and the phase of the accelerating voltage inside the buncher cavity, a digital LLRF (low-level radio-frequency) control system based on FPGA (field programmable gate array) technology was developed. This article mainly focuses on the fabrication and performance of the LLRF system, some test experiments have also been done and shows that the LLRF system works well and meets the design requirements.

A high average power Terahertz radiation facility has been developed by the China Academy of Engineering Physics. It is the first CW THz user facility based on free electron laser in China. A 1300 MHz RF buncher is a dispensable component of this facility, which provides a longitudinal manipulation of the electron beams. This paper mainly presents the RF measurement results of the buncher cavity and some test experiments has also been done. The bunch length of electron beams can be compressed to a minimum value at the field gradient of 1.2 MV/m. Further experimental optimization is under way.

China Academy of Engineering Physics tera-hertz free electron laser (CAEP THz FEL, CTFEL) is the first THz FEL oscillator in China, which was jointly built by CAEP, Peking university and Tsinghua university. This THz FEL facility consists of a GaAs photocathode high-voltage DC gun, a superconducting RF linac, a planar undulator and a quasi-concentric optical resonator. The terahertz lasers frequency is continuous adjustable from 2 THz to 3 THz. The macro-pulse average power is more than 10 W and the micro-pulse power is more than 0.5 MW.

Cold cathodes have attracted a lot of attention in the field of accelerators in recent years. While the development of suitable cold cathodes is in progress, attempts have been made to combine the cold cathode with a rf structure. Due to the strong dependence on the electric field, field emissions peak at the wave crest, which is not the best injection phase, during a rf cycle. To make the injection phase adjustable, a flexible double-frequency rf gun is designed. The addition of a 3rd-harmonic field to the fundamental one in the half cell will move the wave crest toward a better injection phase and make the initial bunch length shorter. The full cell is resonant at the fundamental frequency. Since only the half cell is resonant at two frequencies, the gun can be easily tuned. Simulations show that the time-dependent rf effects on the transverse and longitudinal phase spaces of the electron bunch can be reduced by choosing proper rf parameters and the space charge effects can be compensated for by using an external solenoid field. Therefore, the gun is able to provide low emittance, low energy spread and short electron bunches with high average current.