Surgical stress induced tumor immune suppressive environment.

Despite significant advances in cancer treatment over the decades, surgical resection remains a prominent management approach for solid neoplasms. Unfortunately, accumulating evidence suggests that surgical stress caused by tumor resection may potentially trigger postoperative metastatic niche formation. Surgical stress not only activates the sympathetic-adrenomedullary axis and hypothalamic-pituitary-adrenocortical axis but also induces hypoxia and hypercoagulable state. These adverse factors can negatively impact the immune system by downregulating immune effector cells and upregulating immune suppressor cells, which contribute to the colonization and progression of postoperative tumor metastatic niche. This review summarizes the effects of surgical stress on four types of immune effector cells (neutrophils, macrophages, natural killer cells and cytotoxic T lymphocytes) and two types of immunosuppressive cells (regulatory T cells and myeloid-derived suppressor cells), and discusses the immune mechanisms of postoperative tumor relapse and progression. Additionally, relevant therapeutic strategies to minimize the pro-tumorigenic effects of surgical stress are elucidated.

Red cell distribution width-a potential prognostic indicator for colorectal cancer patients after radical resection in China.

Background: Red cell distribution width (RDW) can signal poor prognosis in inflammatory medical conditions. The purpose of the study was to investigate the relationship between preoperative RDW and colorectal cancer (CRC) in a large cohort of patients. Methods: A total of 6,224 CRC patients who underwent radical resection at the Fudan University Shanghai Cancer Center were evaluated retrospectively. The prognostic significance of RDW for overall survival (OS) and disease-free survival (DFS) was analyzed using Cox proportional hazards models and Kaplan-Meier method. Propensity score matching (PSM) was used based on survival confounding factors. Results: The mean age of the study participants was 59.5±12.0 years and the study cohort was 44% female. The overall median and mean RDW values were 13.3% and 14.0%, respectively. Patients were stratified into three groups based on their RDW value (≤13.3%, 13.4-14.0%, and >14.0%). OS and DFS were shown to significantly deteriorate with increasing RDW category. In the PSM population, OS and DFS were significantly lower in the high RDW group compared with matched controls. However, the differences vanished in the comparisons between the middle RDW group and the control group. Conclusions: Our findings demonstrate that preoperative RDW may represent a simple and powerful prognostic factor for CRC patients after radical resection. Integrating RDW into clinical practice may better inform the prognosis and optimize therapeutic approaches for patients with CRC.

Enabling high-capacity Li metal battery with PVDF sandwiched type polymer electrolyte.

Polyvinylidene difluoride (PVDF) is one of the most attractive electrolyte materials for solid-state batteries due to its high ionic conductivity, however, the battery performance is limited by the high electrolyte-electrode interfacial resistance. Herein, PVDF polymer mixed with ceramic Li7La3Zr2O12 is coated on cellulose support membrane (PLCSM) through a simple slurry-casting method. The ionic transport of PLCSM is originated from dimethyl formamide (DMF)-Li+ solvation structure, which plays a critical role in conducting lithium ions. ß-PVDF after dehydrofluorination offers a high dielectric constant and enhances the dissociation of lithium salt. As a result, PLCSM with a total thickness of 85 µm presents an oxidation voltage of 4.9 V. Li-Li symmetric cells by employing PLCSM reveal that the critical current density (CCD) is increased to 1 mA cm-2. A full cell of LiFePO4 |PLCSM |Li with high mass loading (1.2 mA h cm-2) shows a first-cycle discharge capacity of 160 mA h g-1. With LiNi0.6Mn0.2Co0.2O2 as the cathode, the initial discharge capacity is 153 mA h g-1, and the capacity retention after 80 cycles is 80 %. The sandwiched PLCSM provides an effective strategy to achieve high-performance dendrite-free Li metal batteries.

Impact of operation duration on short-term and long-term prognosis in patients undergoing radical colorectal surgery.

Purpose: The objective of this study was to evaluate the impact of operation duration on short- and long-term outcomes of colorectal cancer patients following surgical resection. Methods: 6224 consecutive patients who underwent radical colorectal surgery were retrospectively assessed and were divided into short operation duration group (SOD) and long operation duration group (LOD) according to the operation duration cutoff value of 110 minutes. Results: Compared with patients in LOD group, patients in SOD group had significantly lower total costs in hospital, reduced expenses for drugs and antibiotics, shorter length of stay (LOS) in hospital and in the ICU. Moreover, 5-year overall survival (OS) and disease-free survival (DFS) for patients in the SOD group were markedly higher than for patients in the LOD group. Mutivariate regression analysis indicated that longer operation duration was associated with poor prognosis, with a hazard ratio of 1.004 (1.003, 1.005) for OS and 1.005 (1.003, 1.006) for DFS. Finally, surgeons' qualifications had meaningful correlation with operation duration (r= 0.450). Conclusions: Operation duration is an independent risk factor for patients' short-term and long-term outcome after radical colorectal surgery. Improve the surgical skills of the surgeon may shorten the operation duration, and further improve the outcome for patients.

KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1.

Kallikrein-related peptidase 8 (KLK8) acts as an oncogene or anti-oncogene in various tumours, and the abnormal expression of KLK8 is involved in the carcinogenesis of several tumours. However, the role of KLK8 in colorectal cancer (CRC) and the underlying mechanism remain largely unclear. In this study, the carcinogenic effect of KLK8 was determined via CCK-8 and colony formation assays in vitro and a xenograft model in nude mice in vivo. The metastasis-promoting effect of KLK8 was investigated with transwell migration and invasion assays and wound-healing assay in vitro and a metastasis model in nude mice in vivo. Bioinformatics analyses and mechanistic experiments were conducted to elucidate the molecular mechanism. Herein, we reported that KLK8 had a promotive effect on the proliferation, migration and invasion of RKO and SW480 cells. Epithelial-mesenchymal transition (EMT) played an important role in the promotive effects of KLK8 on CRC. In addition, protease-activated receptor-1 (PAR-1) antagonist SCH79797 but not protease-activated receptor-2 (PAR-2) antagonist FSLLRY-NH2 attenuated the proliferation, migration and invasion of KLK8-upregulated RKO and SW480 cells. PAR-1 antagonist SCH79797 reduced the tumour volume of xenograft model and decreased the metastatic nodules in the livers of metastasis model. Furthermore, SCH79797 could reverse the positive impact of KLK8 on the EMT process in CRC both in vitro and in vivo. Taken together, these findings demonstrated for the first time that KLK8 promoted EMT and CRC progression, and this effect might be, at least partly mediated by PAR1-dependent pathway.

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. We explored the relationship of KLK8 to clinicopathological features of PDAC based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. We found that KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch. Furthermore, overexpression of KLK8 in Mia-paca-2 and Panc-1 cells significantly increased epidermal growth factor (EGF) levels in the culture media. EGF receptor (EGFR) inhibitor could block KLK8-induced activation of PI3K/Akt/mTOR pathway and attenuate pro-proliferation and anti-apoptotic of KLK8 in Mia-paca-2 and Panc-1 cells. In conclusion, KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via EGF signaling-dependent activation of PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

Dynamic changes of plasma extracellular vesicle long RNAs during perioperative period of colorectal cancer.

Extracellular vesicles (EVs) long RNAs (exLRs) have been shown to be indicators for the diagnosis and prognosis of colorectal cancer (CRC); however, the dynamic changes of exLRs during perioperative period and their cellular sources in CRC remains largely unknown. In this study, exLR sequencing (exLR-seq) was performed on plasma samples from three CRC patients at four time points (before surgery [T0], after extubation [T1], 1 day after surgery [T2], and 3 days after surgery [T3]). Bioinformatics approaches were used to investigate the profile and biofunctions of exLRs and their cellular sources. Greater than 12,000 mRNAs and 2,000 lncRNAs were reliably detected in each exLR-seq sample. Compared with T0, there were 110 differentially expressed genes (DEGs) in T1, 60 DEGs in T2, and 50 DEGs in T3. A total of 11 DEGs were found at all three time points and were related to membrane potential. In addition, compared to T0, 22 differentially expressed lncRNAs (DELRs) were found in T1, 19 DELRs in T2, and 38 DELRs in T3. Moreover, only three DELRs were detected at all three time points. Interestingly, EVs from CD8 + T cells, CD4+ memory T cells and NK cells decreased after surgery and the absolute quantity of EVs from immune cells were reduced as well. In summary, this study was the first to characterize the dynamic changes of exLRs during perioperative period and the cellular sources. These findings established the foundation for further studies involving the effects of these dynamically changed exLRs on CRC.

Effects of general anesthesia versus local anesthesia in primary hepatocellular carcinoma patients presenting for thermal ablation surgery: a multiple center retrospective cohort study with propensity score matching.

BACKGROUND: Whether anesthesia methods affect the prognosis of tumor patients is controversial. With the aim of comparing the effects of general anesthesia (GA) and local anesthesia (LA) in primary hepatocellular carcinoma (HCC) patients presenting for elective thermal ablation (TA) surgeries, a multiple center retrospective cohort study was designed and implemented. METHODS: Patients who received elective TA surgery under GA or LA from Jan. 2014 to Dec. 2016 and met the eligibility criteria were included. Survival analysis was used to identify the influence of anesthesia methods on recurrence-free survival (RFS) and overall survival (OS). Propensity score matching (PSM) was used to minimize the bias between the GA group and the LA group. RESULTS: A total of 244 patients with GA and 245 with LA were eligible for analysis. After PSM, 178 patients remained in each group. In the matched groups, GA showed a significantly higher recurrence rate compared with LA by both the Kaplan-Meier survival analyses (P=0.011) and multivariable Cox regression analyses (P=0.002). The multivariable Cox regression model also revealed that GA had a hazard ratio (HR) of 1.746 (P=0.036) for death compared with the LA group. CONCLUSIONS: GA is associated with decreased RFS and OS after surgery compared with LA in HCC patients undergoing TA surgery. Prospective trials exploring the effects of different anesthetic methods on cancer outcome in these patients are warranted.

Surgical trauma-induced CCL18 promotes recruitment of regulatory T cells and colon cancer progression.

BACKGROUND: Surgical stress has been suggested to facilitate colon cancer growth and metastasis. However, the precise mechanisms by which surgical trauma promotes colon cancer progression remain poorly understood. METHODS: To unravel the mechanisms underlying surgery-induced colon cancer progression, a syngenic transplantation tumor model was established with CT26 cells, and the effect of laparotomy on tumor progression was investigated. Especially, the expression of several chemokines was assessed, and their roles in recruiting CD4+ CD25+ regulatory T cells (Tregs) after surgery were analyzed. RESULTS: Tregs population was significantly increased in the tumor tissue and peripheral blood of tumor-bearing mice after laparotomy. C-C motif chemokine ligand 18 (CCL18) expression was significantly upregulated after laparotomy in tumor tissue and the peritoneal cavity of tumor-bearing mice, and it was positively correlated with the recruitment of Tregs. Functionally, CCL18 knockdown significantly reduces tumor growth and angiogenesis compared with control. Through analysis of Tregs, we found an upregulated proportion of Tregs in tumor tissue, peritoneal cavity, and peripheral blood after laparotomy, but this enhancement was blocked after CCL18 knockdown. In patients with colon cancer, a higher Tregs proportion is positively correlated to more advanced clinical TNM stages and shorter survival. Furthermore, a positive correlation was found between the serum CCL18 level and the Treg proportion in clinical samples. CONCLUSION: Surgical trauma contributes to colon cancer progression by increasing CCL18 expression and hence promotes Treg recruitment, which leads to an immunosuppressive environment.

MiR-135a Protects Vascular Endothelial Cells Against Ventilator-Induced Lung Injury by Inhibiting PHLPP2 to Activate PI3K/Akt Pathway.

BACKGROUND/AIMS: Loss of endothelial barrier function plays an important role in the development of ventilator-induced lung injury (VILI). This study aimed to investigate the effects of miR135a on VILI in a model of mechanical stretch (MS)-induced human umbilical vein endothelial cell (HUVEC) injury. METHODS: HUVECs were randomly assigned to 7 groups: blank, negative control (NC), NC+MS, miR135a over-expression (mi-miR135a), mi-miR135a + MS, miR135a silencing (si-miR135a) and si-miR135a + MS groups. MS was induced by subjecting cells to cyclic stretch at 20% stretch for 4 h. After 24 h, levels of reactive oxygen species (ROS) were measured by DCFH-DA fluorescence intensity. Apoptosis was measured using annexin V-FITC/propidium iodide assay with flow cytometry. Inflammatory cytokine levels were determined by ELISA. Barrier integrity was determined using FITC-conjugated dextran assay. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2 and Bax were examined using western blotting. The interaction between miR135a and PHLPP2 was evaluated by dual-luciferase reporter assay. RESULTS: Our results showed that MS reduced cell numbers, increased the number of apoptotic cells, increased ROS, barrier dysfunction and inflammatory cytokines in HUVECs, and reduced p-PI3K and p-Akt expression; silencing of miR135a worsened MS-induced HUVEC injury. However, miR135a over-expression protected HUVECs against MS-induced increases in apoptotic cells, ROS, barrier dysfunction and inflammatory cytokines, which were accompanied by activation of the PI3K/Akt signaling pathway. Simultaneous silencing of miR135a and PHLPP2 partially salvaged the effects of miR135a silencing, and miR135a was found to interact with PHLPP2. CONCLUSION: miR135a may protect HUVECs from MS-induced injury by inhibiting PHLPP2 to activate PI3k/Akt signaling pathway.

Surgical trauma contributes to progression of colon cancer by downregulating CXCL4 and recruiting MDSCs.

Surgical stress has been shown to facilitate the tumor growth and metastasis of colon cancer. To unravel the mechanisms underlying surgery induced-colon cancer progression, a syngeneic transplantation tumor model was established with murine colon cancer CT26 cells and the effect of laparotomy on tumor progression was investigated. Especially the expression of several CXC chemokines was assayed, and its roles in regulating myeloid-derived suppressor cells (MDSCs) recruitment were analyzed. We found that laparotomy promoted in vivo tumor growth and angiogenesis. CXCL4 expression was significantly downregulated by laparotomy in the tumor tissue and the peritoneal cavity. Functionally, CXCL4 overexpression significantly reduces tumor volume compared to control. Through analysis of CD11b+/Gr1+ MDSCs cell, we found an upregulated proportion of MDSCs in the tumor tissues and peritoneal cavity following laparotomy, and this enhancement was blocked after CXCL4 overexpression. Further, a negative correlation was found between CXCL4 expression and MDSC amounts in clinical samples. Higher CXCL4 expression and lower MDSCs proportion is positively related to overall survival. CONCLUSION: Surgical trauma contributes to colon cancer progression by downregulating CXCL4 and hence promoting MDSC recruitment, which leads to an immunosuppressive environment.

Treatment with anti-programmed cell death 1 (PD-1) antibody restored postoperative CD8+ T cell dysfunction by surgical stress.

Millions of patients benefit from surgery and are exposed to surgical stress. However, ample studies suggest that surgical stress contributes to tumor recurrence or distant metastases. Surgical stress suppresses CD8+ T cells (CTL) function which is vital for eliminating the malignant cells. Anti-programmed cell death 1 (PD-1) therapy is an effective and safe treatment that increases survival rate of patients with multiple cancers, however, whether anti-PD-1 therapy is able to reverse the immunosuppression following surgery remains largely unknown. Using a surgical stress mice model, we found that surgical stress reduced CD8+ T cell total numbers in the spleen and impaired CTLs function. Surgical induced CD8+ T cells had impaired anti-tumor effects in a tumor bearing models. Blockade of PD-1 with specific antibody restored CD8+ T cell numbers and secretion ability. PGE2 expression was dramatically upregulated in the postoperative serum, and anti-PD-1 together with PGE2 inhibitor restored CTLs dysfunction induced by surgery. Collectively, blockade of PD-1 with monoclonal antibody may be an effective treatment during the postoperative period for restoring surgery-induced immunosuppression.

MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway.

Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) is a predicted oncoprotein that demonstrates tumorigenic activity in vivo; however, the mechanisms involved are unknown. Macrophages are divided into the pro-inflammatory M1 and anti-inflammatory/protumoral M2 subtypes. Tumor cells can induce M2 polarization of tumor-associated macrophages (TAMs) to promote metastasis; but the underlying pathways require to be elucidated. In this study, we detected a positive association between MFHAS1 expression in TAMs and human colorectal cancer (CRC) TNM stage. Supernatant of CT26 murine CRC cells induced MFHAS1 expression in RAW264.7 murine macrophages. Additionally, CT26 supernatant induced the M2 marker CD206 and activated the pro-M2 STAT6 and KLF4 signaling in control but not MFHAS1-silenced RAW264.7 macrophages. Moreover, supernatant of control, but not MFHAS1-silenced macrophages promoted CT26 cell proliferation, migration and epithelial-mesenchymal transition. Compared with control macrophages, MFHAS1-silenced macrophages showed significantly reduced protumoral effects in vivo. Together, these results suggested that CRC cells induce M2 polarization of TAMs through MFHAS1 induction and subsequent STAT6 and KLF4 activation to promote CRC progress. Finally, similar to CT26 supernatant stimulation, peroxisome proliferator-activated receptor-γ (PPARγ) activation by rosiglitazone induced M2 polarization of RAW264.7 macrophages through MFHAS1-dependent pathway. Our results highlight the role of MFHAS1 as a regulator of macrophages polarization and CRC progress.

Protective effects of oridonin on the sepsis in mice.

This study aimed to investigate the protective effects of oridonin (ORI) on cecal ligation and puncture (CLP)-induced sepsis in mice. Male C57BL/6 mice weighing 22-30 g and aged 8-10 weeks were randomly assigned to three groups: Sham group, CLP group, or CLP plus ORI group. In the CLP group and ORI group, CLP was induced, and intraperitoneal injection of normal saline and oridonin (100 µg/kg) was conducted, respectively. The survival rate was determined within the following 7 days. The blood, liver, and lung were collected at 24 hours after injury. Hematoxylin-eosin staining of the lung, detection of lung wet-to-dry ratio, and serum cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-6), and examination of intraperitoneal and blood bacterial clearance were conducted to evaluate the therapeutic efficacy. Results showed that ORI treatment significantly reduced the lung wet-to-dry ratio, decreased serum TNF-α and IL-6, and improved liver pathology compared with the CLP group (p < 0.05). Moreover, the intraperitoneal and blood bacterial clearance increased markedly after ORI treatment (p < 0.05). The 7-day survival rate in the ORI group was also dramatically higher than in the CLP group (p < 0.05). Our findings indicate that ORI can attenuate liver and lung injuries and elevate bacterial clearance to increase the survival rate of sepsis mice.

Surgical trauma induces postoperative T-cell dysfunction in lung cancer patients through the programmed death-1 pathway.

The programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway have been shown to be involved in tumor-induced and sepsis-induced immunosuppression. However, whether this pathway is involved in the surgery-induced dysfunction of T lymphocytes is not known. Here, we analyzed expression of PD-1 and PD-L1 on human peripheral mononuclear cells during the perioperative period. We found that surgery increased PD-1/PD-L1 expression on immune cells, which was correlated with the severity of surgical trauma. The count of T lymphocytes and natural killer cells reduced after surgery, probably due to the increased activity of caspase-3. Caspase-3 level was positively correlated with PD-1 expression. Profile of perioperative cytokines and hormones in plasma showed a significantly increased level of interferon-α, as well as various inflammatory cytokines and stress hormones. In ex vivo experiments, administration of anti-PD-1 antibody significantly ameliorated T-cell proliferation and partially reversed the T-cell apoptosis induced by surgical trauma. We provide evidences that surgical trauma can induce immunosuppression through the PD-1/PD-L1 pathway. This pathway could be a target for preventing postoperative cellular immunosuppression.

Long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF/NF-κB pathway and JAK/STAT3 pathway to inhibit TNF-α and IFN-γ in hepatocellular carcinoma.

HCC still has a poor prognosis in clinical due to high recurrence and metastasis rates worldwide nowadays. Indomethacin pretreatment is used as a potential chemopreventive agent in cancers for it could assist in anti-tumor functions of other agents and exert anti-tumor effect. Our study aims to discuss the effects and mechanisms of long-term use of indomethacin in HCC. The HepA mouse models were used to observe tumor recurrence, intrahepatic metastasis and remote metastasis. NK cell, αß T cell and γδ T cell were used to explore the underlying mechanisms for anti-tumor effect of indomethacin. The results showed that long-term use of indomethacin facilitated intrahepatic recurrence, intrahepatic dissemination and lung metastasis, and indomethacin inhibits TNF-α and IFN-γ in vivo and in vitro in a dose-dependent manner. Furthermore, long-term use of indomethacin increased the expression of PD-1 and PD-L2 in programmed death-1 pathway. Blockade of PD-1 and PD-L2 reversed the reduced production of TNF-α and IFN-γ induced by indomethacin in γδ T cells. In addition, long-term use of indomethacin activates TRIF/NF-κB and JAK/STAT3 pathways, and indomethacin promotes the expression of PD-1 and PD-L2 via TRIF/NF-κB pathway and JAK/STAT3 pathway respectively in γδ T cells. Given these findings, we drew a conclusion that long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF/NF-κB pathway and JAK/STAT3 pathway to inhibit TNF-α and IFN-γ in HCC.

Gene expression profiling reveals the defining features of monocytes from septic patients with compensatory anti-inflammatory response syndrome.

OBJECTIVES: To characterize the expression profiles of genes in purified monocytes from septic patients during systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS), and then to investigate the potential mechanism of monocyte deactivation. METHODS: Lipopolysaccharides (LPS)-induced cytokine responses, phagocytosis assay and migration assay were performed in monocytes from SIRS patients, CARS patients and healthy volunteers (n = 8). After functional assays, each pair of samples from the same group was pooled into one for gene expression analysis. All new samples (n = 4) were hybridized on NimbleGen human gene expression 12 × 135 K microarrays, and selected genes were validated by real-time polymerase chain reaction. Pathway analysis and Gene Ontology analysis were performed on differentially expressed genes using Agilent GeneSpring (version 11.0). RESULTS: A set of genes related to pro-inflammation, phagocytosis, chemotaxis, antigen presentation, and anti-apoptosis were significantly down-regulated, while some genes associated with pro-apoptosis and anti-inflammation were up-regulated instead on monocytes from CARS patients compared with SIRS patients and healthy volunteers. Monocytes from CARS patients showed impaired production of TNF-α and IL-6, and increased release of IL-10 when stimulated by LPS. Functional analysis confirmed reduced phagocytosis and migratory activity of monocytes from CARS patients. Human leukocyte antigen-DR (HLA-DR) measurements demonstrated decreased expression of HLA-DR on monocytes from CARS patients. CONCLUSION: Monocytes from CARS patients exhibited significant changes in mRNA expression of genes associated with phagocytosis, antigen presentation, inflammatory response, cell migration, and apoptosis, which might cause deactivation of monocytes during CARS.

STY39, a novel alpha-melanocyte-stimulating hormone analogue, attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice.

Various anti-inflammatory agents have been used to treat acute or chronic lung injury-induced pulmonary fibrosis (PF). However, the efficacy of the available treatments is disappointing, and new therapies are urgently needed. In the current study, we investigated the effect of a novel α-melanocyte-stimulating hormone analog, STY39, on bleomycin (BLM)-induced pulmonary inflammation and fibrosis in mice. C57BL/6 mice received an intratracheal injection of BLM before being treated with STY39 (0.625, 1.25, or 2.5 mg/kg, i.p.) once a day for 14 consecutive days. Various parameters, reflecting the inflammatory reaction, metabolism of extracellular matrix, myofibroblast proliferation, and degree of fibrosis in the lung, were evaluated. We found that STY39 significantly improved the survival of mice with lethal BLM-induced lung injury, limited body weight loss and the increase in the lung index, reduced the mRNA expression of types I and III procollagen and the production of hydroxyproline in the lung, diminished myofibroblast proliferation, and ultimately reduced BLM-induced lung damage. Further investigation revealed that, in a dose-dependent manner, STY39 treatment inhibited leukocyte migration into the lung; reduced the production of TNF-α, IL-6, macrophage inflammatory protein 2, and transforming growth factor ß1 in the lung; and altered the ratio of matrix metalloproteinase 1 to tissue inhibitors of metalloproteinase 1. These findings suggest that STY39 attenuates BLM-induced experimental PF by limiting the inflammatory reaction through the inhibition of proinflammatory and profibrosis cytokines and by accelerating the metabolism of extracellular matrix. Therefore, STY39 may be an effective therapy for preventing PF.

A metabonomic approach to early prognostic evaluation of experimental sepsis by (1)H NMR and pattern recognition.

This study proposes an NMR-based metabonomic approach to early prognostic evaluation of sepsis. Forty septic rats receiving cecal ligation and puncture (CLP) were divided into the surviving group and nonsurviving group on day 6, while 20 sham-operated rats served as the control group. Serum samples were collected from septic and sham-operated rats at 12 h after surgery and analyzed using (1)H NMR spectroscopy. Orthogonal partial least squares (OPLS) were applied and showed clustering according to predefined groups, indicating that NMR-based metabolic profiling could reveal pathologic characteristics in the serum of sham-operated, surviving, and nonsurviving septic rats. In addition, six characteristic metabolites including lactate, alanine, acetate, acetoacetate, hydroxybutyrate, and formate, which are mainly involved in energy metabolism, changed markedly in septic rats, especially in the nonsurvivors. Using these metabolites, a predictive model for prognostic evaluation of sepsis was constructed using a radial basis function neural network (RBFNN) with a prediction accuracy of about 87% by test samples. The results indicated that the NMR-based metabonomic approach is a potential technique for the early prognostic evaluation of sepsis.