Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors.

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 and TP53 (54.5%), followed by FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia [BilIN]), but a substantial proportion was subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. Combined analysis with metastatic tumors (n=11) identified branching evolution in nine patients (81.8%). Of these, eight patients (88.9%) had a total of 11 subclones expanded at least sevenfold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, six mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.

Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancers.

PURPOSE: Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). METHODS: Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. RESULTS: A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7 months, respectively, for PFS (p = 0.009), and median 21.1 months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. CONCLUSION: Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.

Amphiregulin can predict treatment resistance to palliative first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS wild-type metastatic colorectal cancer.

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

Correlation between tumor infiltrating immune cells and peripheral regulatory T cell determined using methylation analyses and its prognostic significance in resected gastric cancer.

Peripheral regulatory T cells (pTregs) are a highly immunosuppressive fraction of CD4+ T cells. We aimed to evaluate the clinical significance of pTregs in patients with gastric cancer and to determine the correlation between pTregs and immune cell infiltration in tumor microenvironment. pTregs status was determined by assessing the pTreg/total T-cell ratio (ratio of Foxp3 Treg-specific demethylated region (TSDR) to CD3G/CD3D demethylation, so-called Cellular Ratio of Immune Tolerance "ImmunoCRIT") using methylation analyses in 433 patients with gastric cancer who received curative surgery. Among 422 evaluable patients, 230 (54.5%) had high ImmunoCRIT (> 21.0). Patients with high ImmunoCRIT had significantly shorter disease-free survival (DFS) and overall survival (OS) than those with high ImmunoCRIT (p = 0.030, p = 0.008, respectively). In multivariate analysis, high ImmunoCRIT kept a prognostic role for shorter OS (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4-2.9; p = 0.005). CD3+ cell density and CD4+ cell density was significantly higher within the tumor in high ImmunoCRIT group than those in low ImmunoCRIT group (CD3+ cell, 202.12/mm2 vs. 172.2/mm2, p = 0.029; CD4+ cell, 56.5/mm2 vs. 43.5/mm2, p = 0.007). In conclusion, the peripheral ImmunoCRIT determined by epigenetic methylation analysis provides prognostic information in resected gastric tumors.

Risk factors of acute kindey injury in critical patients in emergency department / 中华急诊医学杂志

Objective:To investigate the incidence and risk factors of acute kidney injury in patients admitted to the resuscitation room of the Emergency Department.Methods:Patients were enrolled from the resuscitation room of our hospital from September to December 2018 by a retrospective cohort study. Patients were divided into AKI group and non-AKI group according to whether AKI occurred within seven days after admission. Demographic characteristics, APACHEⅡ score, whether to use nephrotoxic drugs,24-hour fluid volume, and patients survival time were collected. Multivariate regression analysis was used to explore the risk factors for AKI. Cox regression was used to study the effect of the occurrence of AKI on survival and to analyze the influence of AKI severity on the death risk of patients in the resuscitation room.Results:Among 238 critical patients who were finally included, 108 patients developed AKI(45.4%), 83 patients were in AKI stage 1 (34.9%), and 25 patients were in AKI stage 2-3 ( 10.5%).APACHEⅡ score>13( OR=1.11, 95% CI (1.08-1.16), P <0.01), vasoactive drugs ( OR=2.20, c95% CI (1.08-4.49), P=0.03), diabetes mellitus ( OR=2.33, 95% CI (1.23-4.42), P=0.01), and fluid load> 3 L( OR=3.10, 95% CI (1.17-8.25). P=0.02) were independent risk factors for AKI. After adjustment for APACHEⅡ score and age by multivariate COX regression, AKI remained an independent risk factor for death in emergency patients, and the severity of AKI significantly increased the risk of death in these patients(AKI 1: HR=1.45, 95% CI (1.08-2.03), P =0.04; AKI 2~3: HR=3.15, 95% CI (1.49-4.81), P=0.03). Conclusions:AKI occurred commonly in the resuscitation room of the emergency department. APACHE Ⅱ score>13, vasoactive drugs, diabetes, and fluid load>3 L were independent risk factors for AKI. The risk of death increased with the aggravation of AKI severity.

Application of liver three-dimensional visualized reconstruction technique in hepatectomy for children with complicated hepatoblastoma / 临床肝胆病杂志

Objective To investigate the application of liver three-dimensional (3D) visualized reconstruction technique in hepatectomy for children with complicated hepatoblastoma. Methods A retrospective analysis was performed for the clinical data of 30 children with hepatoblastoma who underwent hepatectomy for radical resection in PLA Rocket Force Characteristic Medical Center from January 2018 to October 2020, and according to whether liver 3D visualization with IQQA-Liver system was performed before surgery, the children were divided into 3D reconstruction group with 15 children and control group with 15 children. The two groups were compared in terms of perioperative parameters, short-term prognosis, and follow-up conditions. The independent samples t -test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the Fisher's exact test was used for comparison of categorical data between two groups. Results Compared with the control group, the 3D reconstruction group had a significantly higher mean age (55.7±10.2 years vs 28.2±2.7 years, P 0.05). The median follow-up after surgery was 9.5 months. In the 3D reconstruction group, 2 children experienced recurrence and were diagnosed at 10 and 12 months, respectively, after surgery, and they were treated with chemotherapy at the moment; in the control group, 4 children experienced recurrence, which was higher than that in the 3D reconstruction group ( P =0.651), and among these 4 children, 2 had recurrence at 7 months after surgery, received liver transplantation, and survived up to now, and the other 2 children died shortly after recurrence. Conclusion 3D visualized reconstruction technique helps to perform hepatectomy for children with complicated hepatoblastoma more safely and accurately, especially extended hepatectomy for patients with stage POST TEXT III/IV hepatoblastoma, thereby avoiding liver transplantation.

The influence of calling emergency medical services (EMS) on severity of disease among patients admitted to emergency room: A propensity-matched study / 中华急诊医学杂志

Objective:To evaluate the association between the use of emergency medical services (EMS) and the severity of disease among patients admitted to the emergency room, to analyze the characteristics of the patients, and to build prediction model providing evidence-based use of EMS resources.Methods:The data of patients admitted to the Emergency Room of the First Affiliated Hospital of University of Science and Technology of China from January 2020 to July 2021 were extracted from the Chinese Emergency Triage Assessment and Treatment (CETAT) database. Patients were divided into the EMS use group (AB+ group) and self-seeing group (AB-group) according to whether they used EMS. The patients’ general condition, vital signs and laboratory tests results were recorded. The severity of patients’ condition was judged based on whether the patient was admitted to the department of critical medicine, specialized care unit, emergency operation and/or emergency percutaneous intervention. A 9-variable model that did not require laboratory inspection and 22-variable model that required laboratory inspection were established to correct the propensity score to analyze the correlation between the severity of disease and the EMS use. In the subgroup analysis, the correlation between the EMS use and severity of the patients was analyzed according to the reason of the patient’s visit.Results:During the study period, 16 489 patients were admitted to the emergency room, and 6975 patients were finally enrolled in this study. There were 2768 patients (39.7%) in the AB+ group and 4207 patients (60.3%) in the AB-group. In the AB+ group 522 patients (18.9%) were in high risk, and in the AB-group 563 patients (13.4%) were in high risk. Compared with the AB-group, patients in the AB+ group were older and had a higher proportion of coma, a faster autonomic heart rate, and a lower diastolic blood pressure and peripheral oxygen saturation (SpO 2). In the 9-variable model, sex, consciousness, temperature, heart rate and diastolic blood pressure were associated with the EMS use. In the 22-variable model, consciousness, SpO 2, neutrophils, and albumin were the relevant factors for patients using EMS. Before the correction of propensity score, the EMS use was an independent risk factor for critically ill patients ( OR=1.5, 95% CI 1.32-1.72, P<0.001). After adjusted using 9-variable propensity score, the EMS use ratio decreased significantly compared with that without correction ( OR=1.24,95% CI 1.08-1.42, P<0.001). Interestingly, after adjusted with propensity score match with 22-variable model, there was no association between the severity of disease and t the EMS use ( OR=1.10,95% CI 0.95-1.28, P=0.195). In subgroup analysis, patients’ chief complaint of central nervous system, cardiovascular system, and trauma were the top three reasons at admission. Before the propensity score correction, the EMS calling patients with chief complaint of central nervous system, digestive system, and trauma were related to the severity of the patients. After adjusted with 9-variable model the EMS use was associated with the severity of the disease only in trauma patients, and after adjusted with 22-variable model there was no statistical difference considering the severity of the disease in all subgroups. Conclusions:The EMS use is common. However, the association of the EMS use with the severity of disease is decreased with variable models using propensity score. These findings indicate that the EMS use should be based on multivariable models, which may be important in detecting critically ill patients, optimizing the EMS use, and avoiding unnecessary call in the future.

PI3K p110α Blockade Enhances Anti-Tumor Efficacy of Abemaciclib in Human Colorectal Cancer Cells.

Targeting cell cycle regulation in colorectal cancer has not been fully evaluated. We investigated the efficacy of the CDK4/6 inhibitor, abemaciclib, and confirmed a synergistic interaction for PI3K p110α and CDK dual inhibition in colorectal cancer cell lines. Caco-2 and SNU-C4 cell lines were selected to explore the mechanism of action for and resistance to abemaciclib. In vitro and in vivo models were used to validate the anti-tumor activity of abemaciclib monotherapy and BYL719 combination therapy. Abemaciclib monotherapy inhibited cell cycle progression and proliferation in Caco-2 and SNU-C4 cells. CDK2-mediated Rb phosphorylation and AKT phosphorylation appeared to be potential resistance mechanisms to abemaciclib monotherapy. Abemaciclib/BYL719 combination therapy demonstrated synergistic effects regardless of PIK3CA mutation status but showed greater efficacy in the PIK3CA mutated SNU-C4 cell line. Growth inhibition, cell cycle arrest, and migration inhibition were confirmed as mechanisms of action for this combination. In an SNU-C4 mouse xenograft model, abemaciclib/BYL719 combination resulted in tumor growth inhibition and apoptosis with tolerable toxicity. Dual blockade of PI3K p110α and CDK4/6 showed synergistic anti-tumor effects in vivo and in vitro in human colorectal cancer cell lines. This combination could be a promising candidate for the treatment of patients with advanced colorectal cancer.

PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer.

PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA-mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G0/G1 phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA-mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA-mutant cells. Alpelisib partially reversed epithelial-mesenchymal transition markers in PIK3CA-mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA-mutant GC cells.

Gomisin N from Schisandra chinensis Ameliorates Lipid Accumulation and Induces a Brown Fat-Like Phenotype through AMP-Activated Protein Kinase in 3T3-L1 Adipocytes.

Obesity results from an imbalance between energy intake and energy expenditure, in which excess fat is stored as triglycerides (TGs) in white adipocytes. Recent studies have explored the anti-obesity effects of certain edible phytochemicals, which suppress TG accumulation and stimulate a brown adipocyte-like phenotype in white adipocytes. Gomisin N (GN) is an important bioactive component of Schisandra chinensis, a woody plant endemic to Asia. GN has antioxidant, anti-inflammatory and hepatoprotective effects in vivo and in vitro. However, the anti-obesity effects of GN in lipid metabolism and adipocyte browning have not yet been investigated. In the present study, we aimed to determine whether GN suppresses lipid accumulation and regulates energy metabolism, potentially via AMP-activated protein kinase (AMPK), in 3T3-L1 adipocytes. Our findings demonstrate that GN inhibited adipogenesis and lipogenesis in adipocyte differentiation. Also, GN not only increased the expression of thermogenic factors, including uncoupling protein 1 (UCP1), but also enhanced fatty acid oxidation (FAO) in 3T3-L1 cells. Therefore, GN may have a therapeutic benefit as a promising natural agent to combat obesity.

Korean Red Ginseng and Korean black ginseng extracts, JP5 and BG1, prevent hepatic oxidative stress and inflammation induced by environmental heat stress.

BACKGROUND: Continuous exposure to high temperatures can lead to heat stress. This stress response alters the expression of multiple genes and can contribute to the onset of various diseases. In particular, heat stress induces oxidative stress by increasing the production of reactive oxygen species. The liver is an essential organ that plays a variety of roles, such as detoxification and protein synthesis. Therefore, it is important to protect the liver from oxidative stress caused by heat stress. Korean ginseng has a variety of beneficial biological properties, and our previous studies showed that it provides an effective defense against heat stress. METHODS: We investigated the ability of Korean Red Ginseng and Korean black ginseng extracts (JP5 and BG1) to protect against heat stress using a rat model. We then confirmed the active ingredients and mechanism of action using a cell-based model. RESULTS: Heat stress significantly increased gene and protein expression of oxidative stress-related factors such as catalase and SOD2, but treatment with JP5 (Korean Red Ginseng extract) and BG1 (Korean black ginseng extract) abolished this response in both liver tissue and HepG2 cells. In addition, JP5 and BG1 inhibited the expression of inflammatory proteins such as p-NF-κB and tumor necrosis factor alpha-α. In particular, JP5 and BG1 decreased the expression of components of the NLRP3 inflammasome, a key inflammatory signaling factor. Thus, JP5 and BG1 inhibited both oxidative stress and inflammation. CONCLUSIONS: JP5 and BG1 protect against oxidative stress and inflammation induced by heat stress and help maintain liver function by preventing liver damage.

Spirulina maxima extract prevents activation of the NLRP3 inflammasome by inhibiting ERK signaling.

The blue-green alga Spirulina maxima is a microscopic filamentous cyanobacterium. Spirulina was recently reported to elicit beneficial effects such as reducing cholesterol and inducing weight loss; however, its effects on inflammation are unknown. To determine the effect of S. maxima extract (SME) on innate immunity, we investigated the NLRP3 inflammasome activation, which is a multiprotein scaffolding complex that plays important roles in innate immune responses to many pathogenic infections in macrophages. SME suppressed lipopolysaccharide (LPS)-induced upregulation of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-12, IL-1ß, and IL-18 in RAW264.7 cells. In addition, SME attenuated LPS-induced NLRP3 inflammasome activation, and thus pro-IL-1ß could not be cleaved to IL-1ß by activated caspase-1, which is activated by the NLRP3 inflammasome in RAW264.7 cells. Moreover, SME inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) in RAW264.7 cells, and attenuated the generation of ERK1 induced-reactive oxygen species (ROS), resulting in decreased expression of NF-κB. These findings suggest that SME suppresses the effects of the NLRP3 inflammasome via regulation of extracellular signal-regulated kinase (ERK). In summary, we demonstrated that SME prevents activation of the NLRP3 inflammasome by inhibiting ERK signaling.

Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement.

BACKGROUND: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. METHODS: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. RESULTS: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G1 phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to the parent cell line, whereas A549 and NCI-H460 did not show this change. The pan-HER inhibitor afatinib inhibited this alternative signaling pathway, resulting in a superior cytotoxic effect in pemetrexed-resistant NCI-H3122 cell lines compared to that in the parental cells line. CONCLUSION: The activation of EGFR-HER2 contributes to the acquisition of resistance to pemetrexed in EML4-ALK rearranged non-small cell lung cancer. However, the inhibition of this alternative survival signaling pathway with RNAi against EGFR-HER2 and with afatinib overcomes this resistance.

Korean ginseng extract ameliorates abnormal immune response through the regulation of inflammatory constituents in Sprague Dawley rat subjected to environmental heat stress.

BACKGROUND: Increases in the average global temperature cause heat stress-induced disorders by disrupting homeostasis. Excessive heat stress triggers an imbalance in the immune system; thus protection against heat stress is important to maintain immune homeostasis. Korean ginseng (Panax ginseng Meyer) has been used as a herbal medicine and displays beneficial biological properties. METHODS: We investigated the protective effects of Korean ginseng extracts (KGEs) against heat stress in a rat model. Following acclimatization for 1 week, rats were housed at room temperature for 2 weeks and then exposed to heat stress (40°C/2 h/day) for 4 weeks. Rats were treated with three KGEs from the beginning of the second week to the end of the experiment. RESULTS: Heat stress dramatically increased secretion of inflammatory factors, and this was significantly reduced in the KGE-treated groups. Levels of inflammatory factors such as heat shock protein 70, interleukin 6, inducible nitric oxide synthase, and tumor necrosis factor-alpha were increased in the spleen and muscle upon heat stress. KGEs inhibited these increases by down-regulating heat shock protein 70 and the associated nuclear factor-κB and mitogen-activated protein kinase signaling pathways. Consequently, KGEs suppressed activation of T-cells and B-cells. CONCLUSION: KGEs suppress the immune response upon heat stress and decrease the production of inflammatory cytokines in muscle and spleen. We suggest that KGEs protect against heat stress by inhibiting inflammation and maintaining immune homeostasis.

Influence factors analysis of mechanical compression and hands-only compression on restoration of spontaneous circulation and prognosis in patients with cardiac arrest / 中华危重病急救医学

OBJECTIVE@#To evaluate the influence factors of different compression modes on restoration of spontaneous circulation (ROSC) and outcomes in patients with cardiac arrest.@*METHODS@#Based on the national database of emergency cardiac arrest treatment, the clinical data of 517 patients with cardiac arrest admitted to 14 teaching hospitals in 7 provinces from July 2015 to July 2017 were enrolled. According to the way of compression, the patients were divided into mechanical compression group and hands-only compression group. The demographic data, resuscitation parameters [compression frequency, monitored ventilation frequency, duration of resuscitation, drug usage] and physiological parameters [end-expiratory partial pressure of carbon dioxide (PETCO2), pulse oxygen saturation (SpO2)] were collected. The ROSC rates and 24-hour, 7-day, 28-day survival rates were compared between the two groups. Multivariate Logistic regression model was used to analyze the influencing factors of ROSC according to whether the duration of resuscitation was longer than 60 minutes.@*RESULTS@#Of 517 patients, 24 were excluded because of incomplete data. A total of 493 patients were enrolled in the analysis with 214 patients in the mechanical compression group, and 279 in the hands-only compression group. Compared with hands-only compression group, the patients in mechanical compression group had higher age, proportion of chronic obstructive pulmonary disease (COPD) and PETCO2, fewer un-shockable rhythm, less compression rate, more epinephrine and sodium bicarbonate usage, and longer duration of cardiopulmonary resuscitation (CPR). Although the rate of ROSC in the mechanical compression group was higher than that in the hands-only compression group [36.9% (79/214) vs. 30.5% (85/279)], there was no significant difference in the rate of ROSC between the two groups [odds ratio (OR) = 1.10, 95% confidence interval (95%CI) = 0.68-1.76, P = 0.693], even after adjusted for con-variables by multivariate Logistic regression (OR = 1.21, 95%CI = 0.54-1.88, P = 0.054). Furthermore, 24-hour, 7-day, and 28-day survival rate also showed no significant difference in both univariate model and multivariate model. Comparisons of resuscitation parameters and physiological parameters between the two groups showed that when the duration of CPR < 60 minutes, the pressing frequency of the mechanical compression group was lower, ventilation frequency and adrenaline dosage were higher; and when the duration of CPR ≥ 60 minutes, the adrenaline dosage and PETCO2 of the mechanical compression group were higher. Multivariate Logistic regression analysis showed that among patients with a duration of CPR < 60 minutes, un-shockable rhythm (OR = 0.29, 95%CI = 0.05-0.75, P = 0.015), compression rate > 120 times/min (OR = 0.39, 95%CI = 0.24-0.64, P < 0.001), ventilation frequency > 40 times/min (OR = 0.50, 95%CI = 0.31-0.84, P = 0.034) were independent risk factors for ROSC; while PETCO2 ≥ 20 mmHg (1 mmHg = 0.133 kPa) was protective factor for ROSC (OR = 2.79, 95%CI = 1.88-4.49, P < 0.001). However, for patients with CPR duration ≥ 60 minutes, ≥ 65 years old (OR = 0.33, 95%CI = 0.15-0.67, P = 0.018), admission at night (OR = 0.74, 95%CI = 0.59-0.94, P = 0.035), un-shockable rhythm (OR = 0.38, 95%CI = 0.25-0.65, P = 0.001), non-cardiogenic cardiac arrest (OR = 0.35, 95%CI = 0.25-0.48, P = 0.013), previous history of diabetes mellitus (OR = 0.46, 95%CI = 0.27-0.82, P = 0.015) were independent risk factors for ROSC, and cardiac arrest occurred in emergency room (OR = 2.02, 95%CI = 1.02-2.92, P = 0.023), mechanical compression (OR = 1.41, 95%CI = 1.12-1.75, P = 0.043), PETCO2 ≥ 20 mmHg (OR = 2.94, 95%CI = 1.34-4.54, P = 0.012), previous history of acute coronary syndrome (ACS; OR = 2.47, 95%CI = 1.15-3.78, P = 0.043) were protective factors for ROSC.@*CONCLUSIONS@#Mechanical compression CPR had no significant differences in the rate of ROSC and 24-hour, 7-day, 28-day survival rates for cardiac arrest patients in the emergency departments compared with hands-only compression CPR. For those who undergone CPR duration more than 60 minutes, mechanical compression was associated with a higher rate of ROSC.

Questionnaires analysis on present status of ventilation therapy in cardiopulmonary resuscitation in Chinese emergency physicians / 中国中西医结合急救杂志

Objective To investigate the current practice of ventilation during cardiopulmonary resuscitation (CPR) in Chinese emergency physicians. Methods Self-designed questionnaires were used to survey mainly the present situation of CPR ventilation practice performed by 800 physicians who participated in the Peking Union International Summit for Emergency Medicine from April 17th to 19th, 2015. Results A total of 800 questionnaires were distributed and 638 (79.75%) valid questionnaires were taken back; the responders joining the survey came from 29 provinces and regions, including Beijing, Hebei, Shandong, Guangdong, Liaoning, etc. There were 331 males and 307 females; 91.54% (584 responders) were emergency physicians and 77.90% (497 responders) came from tertiary hospitals, 17.55% (112 responders) came from the secondary hospitals. Regarding ventilation during CPR, 86.4% (551 responders) declared the patients was routinely given endo-tracheal intubation; after intubation, 25.8% (142 responders) adopted bag-mask ventilation, and 74.2% (409 responders) applied mechanical ventilation. When a ventilator was used, 301 (73.6%) responders used the volume controlled ventilation mode, 334 (81.7%) responders set the respiratory rate (RR) lower than 15 bpm, while 89.2% (365 responders) used the tidal volume set at a range of 400-500 mL. When adopted the flow triggering sensitivity, 79.7% (326 responders) set the sensitivity at 1-6 L/min, while 16.4% (67 responders) selected the default parameter, not adjusting the flow triggering parameter; when adopted the pressure triggering sensitivity, 75.1% (307 responders) set the sensitivity between -1 to -6 cmH2O (1 cmH2O = 0.098 kPa) and 20.3% (83 responders) selected the default value, not adjusting the pressure triggering parameter. When the mechanical ventilation (MV) was adopted, 84.8% (347 responders) declared often experiencing problems with MV, such as airway high peak pressure alarms [39.6% (162/409)], lower ventilation volume per minute alarms [24.9% (102/409)], higher respiratory frequency alarms [21.3% (87/409)], but only 67.2% (275 responders) would again adjust the ventilation mode related parameters and only 59.2% (242 responders) would observe the actual respiratory frequency. Conclusions With regards to artificial ventilation during CPR, the majority of emergency physicians tend to adopt endotracheal intubation and commonly use the volume controlled mode of mechanical ventilation; among the ventilator parameter setting, the RR is not strictly in accordance with the CPR guidelines, and most of the inspiration triggering sensitivity setting was too low, very easily to induce hyperventilation; simultaneously, the emergency physicians often neglect the practical RR; although there are many problems with ventilation such as frequent alarms, only 67.2% of the emergency physicians would again adjust the ventilation parameters.

Influence factors analysis of mechanical compression and hands-only compression on restoration of spontaneous circulation and prognosis in patients with cardiac arrest / 中华危重病急救医学

Objective To evaluate the influence factors of different compression modes on restoration of spontaneous circulation (ROSC) and outcomes in patients with cardiac arrest. Methods Based on the national database of emergency cardiac arrest treatment, the clinical data of 517 patients with cardiac arrest admitted to 14 teaching hospitals in 7 provinces from July 2015 to July 2017 were enrolled. According to the way of compression, the patients were divided into mechanical compression group and hands-only compression group. The demographic data, resuscitation parameters [compression frequency, monitored ventilation frequency, duration of resuscitation, drug usage] and physiological parameters [end-expiratory partial pressure of carbon dioxide (PETCO2), pulse oxygen saturation (SpO2)] were collected. The ROSC rates and 24-hour, 7-day, 28-day survival rates were compared between the two groups. Multivariate Logistic regression model was used to analyze the influencing factors of ROSC according to whether the duration of resuscitation was longer than 60 minutes. Results Of 517 patients, 24 were excluded because of incomplete data. A total of 493 patients were enrolled in the analysis with 214 patients in the mechanical compression group, and 279 in the hands-only compression group. Compared with hands-only compression group, the patients in mechanical compression group had higher age, proportion of chronic obstructive pulmonary disease (COPD) and PETCO2, fewer un-shockable rhythm, less compression rate, more epinephrine and sodium bicarbonate usage, and longer duration of cardiopulmonary resuscitation (CPR). Although the rate of ROSC in the mechanical compression group was higher than that in the hands-only compression group [36.9% (79/214) vs. 30.5% (85/279)], there was no significant difference in the rate of ROSC between the two groups [odds ratio (OR) = 1.10, 95% confidence interval (95%CI) = 0.68-1.76, P = 0.693], even after adjusted for con-variables by multivariate Logistic regression (OR = 1.21, 95%CI = 0.54-1.88, P = 0.054). Furthermore, 24-hour, 7-day, and 28-day survival rate also showed no significant difference in both univariate model and multivariate model. Comparisons of resuscitation parameters and physiological parameters between the two groups showed that when the duration of CPR < 60 minutes, the pressing frequency of the mechanical compression group was lower, ventilation frequency and adrenaline dosage were higher; and when the duration of CPR ≥ 60 minutes, the adrenaline dosage and PETCO2 of the mechanical compression group were higher. Multivariate Logistic regression analysis showed that among patients with a duration of CPR < 60 minutes, un-shockable rhythm (OR = 0.29, 95%CI = 0.05-0.75, P = 0.015), compression rate > 120 times/min (OR = 0.39, 95%CI = 0.24-0.64, P < 0.001), ventilation frequency > 40 times/min (OR = 0.50, 95%CI = 0.31-0.84, P = 0.034) were independent risk factors for ROSC; while PETCO2≥20 mmHg (1 mmHg = 0.133 kPa) was protective factor for ROSC (OR = 2.79, 95%CI = 1.88-4.49, P < 0.001). However, for patients with CPR duration ≥ 60 minutes, ≥ 65 years old (OR = 0.33, 95%CI = 0.15-0.67, P = 0.018), admission at night (OR = 0.74, 95%CI = 0.59-0.94, P = 0.035), un-shockable rhythm (OR = 0.38, 95%CI = 0.25-0.65, P = 0.001), non-cardiogenic cardiac arrest (OR = 0.35, 95%CI = 0.25-0.48, P = 0.013), previous history of diabetes mellitus (OR =0.46, 95%CI = 0.27-0.82, P = 0.015) were independent risk factors for ROSC, and cardiac arrest occurred in emergency room (OR = 2.02, 95%CI = 1.02-2.92, P = 0.023), mechanical compression (OR = 1.41, 95%CI = 1.12-1.75, P = 0.043), PETCO2≥ 20 mmHg (OR = 2.94, 95%CI = 1.34-4.54, P = 0.012), previous history of acute coronary syndrome (ACS;OR = 2.47, 95%CI = 1.15-3.78, P = 0.043) were protective factors for ROSC. Conclusions Mechanical compression CPR had no significant differences in the rate of ROSC and 24-hour, 7-day, 28-day survival rates for cardiac arrest patients in the emergency departments compared with hands-only compression CPR. For those who undergone CPR duration more than 60 minutes, mechanical compression was associated with a higher rate of ROSC.

The effect of different ventilation modes on the ventilation rate and prognosis in patients with cardiac arrest after advanced airway placement / 中华急诊医学杂志

Objective To investigate the effect of different ventilation modes on the ventilation rate and prognosis in patients with cardiac arrest after advanced airway placement. Methods Based on the national database of emergency cardiac arrest treatment, patients treated with advanced airway placement during cardiopulmonary resuscitation (CPR) were enrolled in PUMCH Emergency Department from December 2013 to June 2018. The physiological parameters, such as electrocardiograph waveform, pulse oximetry plethysmographic waveform and capnography, were recorded at least 18 minutes. The demographic data and resuscitation parameters were collected. Waveform capnography was used for calculating ventilation rate (VR) and the VR between 8 to 12 breaths/min was defined as the qualified ventilation rate (QVR). According to the ventilation modes, patients were divided into the bag-mask group (BMG) and mechanical ventilation group (MVG). According to the VR, patients in the mechanical ventilation group were divided into two subgroups, the high-frequency ventilation subgroup (HFV subgroup) with the VR more than 20 breaths/min and the low-frequency VR subgroup (LFV subgroup) with the VR less than 20 breaths/min. VR, the qualified ventilation rate ratio (QVRR), the return of spontaneous circulation (ROSC), and 24-h and 7-day survival were compared between the two groups and subgroups. Result A total of 90 patients were enrolled in the analysis with 22 patients in the bag-mask group and 68 patients in the mechanical ventilation group. The total rate of ROSC was 35.6％, 24-h survival was 1.1％ and 7-day survival was 0. The first 18 minutes ventilation data were collected and added up to 1620 min. The median VR was 16.5 (12.0, 26.0) breaths/min and the QVRR was 30％. Compared with the mechanical ventilation group, the VR in the bag-mask group were lower (10 breaths/min vs 21 breaths/min) and the QVRR was higher (88.9％ vs 11.5％). The ROSC, 24-h survival and 7-day survival had no statistical differences between the two groups. In the mechanical ventilation group, the ratio of VR more than 20 breaths/min was 52.6％. Between the two subgroups, there was no statistical difference in ROSC, 24-h survival and 7-day survival. Conclusions Compared with the mechanical ventilation during CPR, the VR is lower with bag-mask ventilation, and the QVRR is higher. But there was no statistical difference on the outcomes. There was no difference on the outcomes between the two mechanical ventilation subgroups.

Preload in cardiopulmonary resuscitation-rethinking about high-quality CPR / 中国实用内科杂志

Cardiac arrest is one of the leading causes of death all over the world. Despite the progress in the researches of pathopgenesis and management of cardiopulmonary resuscitation,the survival rate of patients with cardiac arrest has remained disappointingly low over the past two decades with only about 7%. On the other hand, in the past decades researchs about CPR mainly focus on the quality of compression. It is largely unknown the relation of preload and flow during cardiac resuscitation, evidence to augment preload during CPR may be one of futher direction to improve the outcome of cardiac arrest patients.