The relations between metabolic variations and genetic evolution of different species

Metabonomics has been applied in many bio-related scientific fields. Nevertheless, some animal research works are shown to fail when they are extended to humans. Therefore, it is essential to figure out suitable animal modeling to mimic human metabolism so that animal findings can serve humans. In this study, two kinds of commonly selected body fluids, serum and urine, from humans and various experimental animals were characterized by integration of nuclear magnetic resonance (NMR) spectroscopy with multivariate statistical analysis to identify the interspecies metabolic differences and similarities at a baseline physiological status. Our results highlight that the dairy cow and pig may be an optimal choice for transportation and biodistribution studies of drugs and that the Kunming (KM) mouse model may be the most effective for excretion studies of drugs, whereas the Sprague-Dawley (SD) rat could be the most suitable candidate for animal modeling under overall considerations. The biochemical pathways analyses further provide an interconnection between genetic evolution and metabolic variations, where species evolution most strongly affects microbial biodiversity and, consequently, has effects on the species-specific biological substances of biosynthesis and corresponding biological activities. Knowledge of the metabolic effects from species difference will enable the construction of better models for disease diagnosis, drug metabolism, and toxicology research. (C) 2015 Elsevier Inc. All rights reserved.Metabonomics has been applied in many bio-related scientific fields. Nevertheless, some animal research works are shown to fail when they are extended to humans. Therefore, it is essential to figure out suitable animal modeling to mimic human metabolism so that animal findings can serve humans. In this study, two kinds of commonly selected body fluids, serum and urine, from humans and various experimental animals were characterized by integration of nuclear magnetic resonance (NMR) spectroscopy with multivariate statistical analysis to identify the interspecies metabolic differences and similarities at a baseline physiological status. Our results highlight that the dairy cow and pig may be an optimal choice for transportation and biodistribution studies of drugs and that the Kunming (KM) mouse model may be the most effective for excretion studies of drugs, whereas the Sprague-Dawley (SD) rat could be the most suitable candidate for animal modeling under overall considerations. The biochemical pathways analyses further provide an interconnection between genetic evolution and metabolic variations, where species evolution most strongly affects microbial biodiversity and, consequently, has effects on the species-specific biological substances of biosynthesis and corresponding biological activities. Knowledge of the metabolic effects from species difference will enable the construction of better models for disease diagnosis, drug metabolism, and toxicology research. (C) 2015 Elsevier Inc. All rights reserved

Observational study of surgical resection in small non-functional pancreatic neuroendocrine tumors: AS SEER-based study

Abstract The potential benefits of surgical resection for small non-functional pancreatic neuroendocrine tumors (NF-PNETs) in terms of survival remain uncertain. This study aimed to evaluate the impact of surgical treatment on patients with NF-PNETs. Using SEER data, we identified 1102 patients from 2004 to 2015 with well and moderately differentiated pancreatic neuroendocrine tumors (PNETs). The associations between continuous variables and receipt of surgery were assessed using Wilcoxon rank-sum tests. Kaplan–Meier survival curves for OS were compared using the log-rank test. We compared outcomes in patients who received surgical resection with those in patients who did not, using a univariable Cox model with inverse probability weighting according to the propensity score and propensity-score matching. Among the cohort of 1102 patients, a majority of 965 individuals (87%) underwent surgical intervention. Upon conducting univariate analysis, we observed that surgical treatment significantly prolonged patients' survival [HR = 0.41, 95% CI [0.26–0.65] P < 0.001]. However, the old [HR = 3.27, 95% CI (2.24–4.76), P 0.001], male gender [HR = 1.82, 95% CI (1.23–2.68), P = 0.003], and moderately well-differentiated factors [HR = 1.71, 95% CI (1.04–2.80), P = 0.034] were found to potentially decrease patients' survival time. In the multivariate analysis, male gender [HR = 1.73, 95% CI (1.15–2.61), P = 0.009] and the old factor [HR = 3.52, 95% CI (2.33–5.31), P < 0.001] emerged as influential predictors with higher hazard ratios. Notably, surgical treatment remained a significant factor associated with improved overall survival [HR = 0.53, 95% CI (0.33–0.84), P = 0.007]. Propensity-score matching and inverse probability weighting were employed as analytical techniques. The univariate analysis results showed favorable outcomes in the weight group [HR = 0.48, 95% CI (0.29–0.78), P = 0.003] and matched group [HR = 0.44, 95% CI (0.22–0.85), P = 0.015], respectively. Survival analysis further confirmed that surgical treatment contributed to increased overall survival (log rank, P < 0.05) in both the matching and weight groups. Patients diagnosed with small, non-functioning pancreatic neuroendocrine tumors who undergo surgical intervention exhibit improved overall survival (OS) outcomes. Therefore, surgery is strongly recommended for this patient population

A high serum creatine kinase (CK)-MB-to-total-CK ratio in patients with pancreatic cancer: a novel application of a traditional marker in predicting malignancy of pancreatic masses?

Abstract Background The finding that some benign pancreatic masses mimic the imaging appearance of carcinomas poses a challenge for pancreatic surgeons. Preoperative markers that assist in the diagnosis are critical under this circumstance. Abnormal serum creatine kinase (CK) isozyme levels were reported in cancer patients, and this study aimed to explore the potential value of the CK-MB-to-total-CK ratio (CK ratio) in differentiating pancreatic cancer (PC) from benign masses when combined with carbohydrate antigen 19-9 (CA19-9). Methods A total of 190 patients primarily diagnosed with pancreatic masses were retrospectively reviewed and assigned to the PC group and the benign pancreatic mass (BPM) group. Sixty-eight controls were enrolled for comparison. Levels of preoperative parameters, including total serum CK, CK-MB, absolute neutrophil count, absolute lymphocyte count, albumin, and CA19-9, were recorded as well as pathological information. A logistic regression model was established to assess the application value of the combination of CA19-9 and the CK ratio in diagnosis. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic value of the markers. Results The CK ratio was significantly elevated in the PC group compared with the BPM group (P < 0.001). In the multivariate analysis, a CK ratio greater than 0.220 was a statistically significant variable for predicting malignancy of pancreatic masses (P=0.001). Patients with stage III/IV PC had a higher CK ratio than those with stage I/II PC (P<0.01). Combined detection of CA19-9 and the CK ratio produced an increased Youden index (0.739 vs. 0.815) with improved sensitivity (82.2% vs. 89.8%). Conclusions The CK ratio is elevated in patients with pancreatic adenocarcinoma and is an independent factor predicting pancreatic adenocarcinoma. The CK ratio augments the diagnostic capacity of CA19-9 in detecting malignancy

NMR-Based Metabolomics Identify Metabolic Change in Spleen of Idiopathic Thrombocytopenic Purpura Patients

Idiopathic thrombocytopenic purpura (ITP) is a common hematological disease and the abnormal platelet destruction in the spleen is a critical pathological mechanism for ITP. However, the metabolomic change in the spleen caused by ITP is still unclear. In the present study, the metabolomic information of 18 ITP and 20 normal spleen samples were detected by using 1H high-resolution magic angle spinning NMR spectroscopy (1H MAS NMR). Compared with normal spleen, the concentrations of acetate, alanine, glutamine, glycerol, isoleucine, lysine, valine, phenylalanine, leucine, and methanol in ITP spleen tissue were elevated and 3-hydroxybutyric acid, ascorbate, asparagine, ethanol, glycogen, low-density lipoprotein, malonate, myo-inositol, glycerophosphocholine, pyroglutamate, and taurine were decreased. Amino acids metabolic pathways, such as branched-chain amino acids pathway, were identified as the main involved pathways based on enrichment analysis. The decrease in taurine level in the spleen was the most obvious metabolic signature involving ITP with high sensitivity and specificity to distinguish the spleen of ITP from the normal (CI: 0.825–0.982). Notably, the level of taurine in the spleen was negatively correlated with the efficacy of splenectomy (r = 0.622, p = 0.006). Collectively, the data from our study revealed previously unknown ITP-related metabolomic changes in the spleen and found a potential diagnostic and efficacy-predictive biomarker for ITP treatment

Interleukin-10 attenuates impairment of the blood-brain barrier in a severe acute pancreatitis rat model

Abstract Background Impairment of the blood-brain barrier (BBB) in severe acute pancreatitis (SAP) could result in life-threatening pancreatic encephalopathy. Interleukin-10 (IL-10) is a classical cytokine that is well-known for its strong immunoregulatory and anti-inflammatory abilities. However, whether and how IL-10 protects the BBB in SAP are still unclear. Methods This study includes in vivo experiments using a SAP rat model and in vitro experiments using an in vitro BBB model consisting of a monolayer of brain microvascular endothelial cells (BMECs). The study groups are divided into the control, SAP (in vivo)/TNF-α (in vitro), IL-10 treatment, IL-10 + signal transducer and activator of transcription 3 (STAT3) inhibitor S3I-201 treatment groups. Pancreatic pathological scores, serum amylase, serum TNF-α levels and BBB permeability by Evan’s blue assay in SAP rat models were evaluated. BMEC apoptosis in SAP rats or induced by TNF-αin vitro was detected by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and flow cytometry, separately. Expression levels of claudin-5 and proteins involved in the STAT3 signaling pathway were measured by Western blotting. Location and changes of junctional structure of claudin-5 on BMECs were assessed by immunohistochemistry and immunofluorescence. Results In vivo, IL-10 alleviated the severity of inflammation, attenuated the increased BBB permeability in SAP rat models by reducing BMEC apoptosis via the STAT3 pathway and ameliorated the down-regulation of claudin-5 expression in BMECs; in vitro, IL-10 improved BBB integrity against TNF-α by attenuating BMEC apoptosis via the STAT3 pathway, the impairment of tight junction structure and the down-regulation of claudin-5 expression in BMECs. Conclusions IL-10 improves BBB properties in SAP by attenuating the down-regulation of claudin-5 expression and the impairment of tight junctions and by STAT3 pathway-mediated anti-apoptotic effects on BMECs

Non-invasively predicting differentiation of pancreatic cancer through comparative serum metabonomic profiling

Abstract Background The differentiation of pancreatic ductal adenocarcinoma (PDAC) could be associated with prognosis and may influence the choices of clinical management. No applicable methods could reliably predict the tumor differentiation preoperatively. Thus, the aim of this study was to compare the metabonomic profiling of pancreatic ductal adenocarcinoma with different differentiations and assess the feasibility of predicting tumor differentiations through metabonomic strategy based on nuclear magnetic resonance spectroscopy. Methods By implanting pancreatic cancer cell strains Panc-1, Bxpc-3 and SW1990 in nude mice in situ, we successfully established the orthotopic xenograft models of PDAC with different differentiations. The metabonomic profiling of serum from different PDAC was achieved and analyzed by using 1H nuclear magnetic resonance (NMR) spectroscopy combined with the multivariate statistical analysis. Then, the differential metabolites acquired were used for enrichment analysis of metabolic pathways to get a deep insight. Results An obvious metabonomic difference was demonstrated between all groups and the pattern recognition models were established successfully. The higher concentrations of amino acids, glycolytic and glutaminolytic participators in SW1990 and choline-contain metabolites in Panc-1 relative to other PDAC cells were demonstrated, which may be served as potential indicators for tumor differentiation. The metabolic pathways and differential metabolites identified in current study may be associated with specific pathways such as serine-glycine-one-carbon and glutaminolytic pathways, which can regulate tumorous proliferation and epigenetic regulation. Conclusion The NMR-based metabonomic strategy may be served as a non-invasive detection method for predicting tumor differentiation preoperatively

The CA125 level postoperative change rule and its prognostic significance in patients with resectable pancreatic cancer

Abstract Background The relationship between postoperative CA125 level changes and early recurrence after curative resection of resectable PDAC is still unclear. Methods The electronic medical records and follow-up data of patients with resectable pancreatic cancer were evaluated. Dynamic CA125 detection was used to identify the rules for postoperative CA125 level change and its prognostic value in patients with resectable pancreatic cancer. Results The study included a total of 118 patients with resectable pancreatic cancer who underwent curative resection. Early postoperative CA125 levels were significantly higher than those before surgery (P 0.05). There was no correlation between early postoperative CA125 levels and early recurrence (P > 0.05). CA125 levels three months after surgery were associated with an increased risk of early recurrence (P = 0.038, 95% CI (1.001–1.025)). The cutoff CA125 level at 3 months after surgery for predicting early recurrence was 22.035. Patients with CA125 levels  22.035 at 3 months postoperatively (p  3 months postoperatively, rather than early postoperative elevation, were associated with a poor prognosis