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Background: Major depressive disorder (MDD) has become a leading cause of disability worldwide. However, the diagnosis of the disorder is dependent on clinical experience and inventory. At present, there are no reliable biomarkers to help with diagnosis and treatment. DNA methylation patterns may be a promising approach for elucidating the etiology of MDD and predicting patient susceptibility. Our overarching aim was to identify biomarkers based on DNA methylation, and then use it to propose a methylation prediction score for MDD, which we hope will help us evaluate the risk of breast cancer. Methods: Methylation data from 533 samples were extracted from the Gene Expression Omnibus (GEO) database, of which, 324 individuals were diagnosed with MDD. Statistical difference of DNA Methylation between Promoter and Other body region (SIMPO) score for each gene was calculated based on the DNA methylation data. Based on SIMPO scores, we selected the top genes that showed a correlation with MDD in random resampling, then proposed a methylation-derived Depression Index (mDI) by combining the SIMPO of the selected genes to predict MDD. A validation analysis was then performed using additional DNA methylation data from 194 samples extracted from the GEO database. Furthermore, we applied the mDI to construct a prediction model for the risk of breast cancer using stepwise regression and random forest methods. Results: The optimal mDI was derived from 426 genes, which included 245 positive and 181 negative correlations. It was constructed to predict MDD with high predictive power (AUC of 0.88) in the discovery dataset. In addition, we observed moderate power for mDI in the validation dataset with an OR of 1.79. Biological function assessment of the 426 genes showed that they were functionally enriched in Eph Ephrin signaling and beta-catenin Wnt signaling pathways. The mDI was then used to construct a predictive model for breast cancer that had an AUC ranging from 0.70 to 0.67. Conclusion: Our results indicated that DNA methylation could help to explain the pathogenesis of MDD and assist with its diagnosis.

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BACKGROUND: The hemodynamic variations of cardiac and cerebral blood monitoring during pneumoperitoneum and head-down tilt position in general anesthetized elderly patients remain unresolved. We evaluated the time course of cerebral tissue oxygen saturation (SctO2) and cardiac output (CO) and investigated how the changes in hemodynamic values during the surgery would affect cerebral perfusion in elderly patients. METHODS: In this prospective observational study of 47 elderly patients (≥65 years old, American Society of Anesthesiologists Physical status I to III) undergoing laparoscopic colorectal radical resection with head-down position, SctO2 by near-infrared spectroscopy and arterial pressure-based cardiac output (APCO), Cardiac index (CI), stroke volume (SV), and SV index (SVI) according to FloTrac/Vigileo were measured at 9 time points. Heart rate (HR), mean arterial blood pressure (MAP), end-tidal carbon dioxide (ETCO2), bispectral index (BIS), central venous pressure (CVP), and ventilator settings were recorded. Results are reported as medians [95% confidence interval (CI)]. RESULTS: Heart Rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP, CO, CI, SV, SVI, and SctO2 before incision decreased significantly compared with the waking state (P<0.05). SBP, CO, CI, SV, and SVI before incision decreased significantly compared with induction and intubation (P<0.05). SBP, DBP, MAP, and CVP increased significantly after pneumoperitoneum and head-down tilt, and then decreased during the following hour. CO and SVI decreased, while CI and SV increased after pneumoperitoneum and head-down tilt. CO, CI, SV and SVI decreased at the following 20, 40, and 60 minutes respectively. SctO2 increased after pneumoperitoneum and head-down tilt and remained stable during the following hour. CVP decreased while CO, CI, SV, and SVI increased significantly at the end of pneumoperitoneum and head-down tilt (P<0.05). HR and MAP increased significantly at the end of surgery compared to at the end of pneumoperitoneum and head-down tilt (P<0.05). CI was associated with SctO2 as indicated by a Pearson r of 0.035 (P<0.05). CONCLUSIONS: Anesthesia, pneumoperitoneum, and head-down tilt affect cardiac function and cerebral perfusion in elderly patients. cardiac index independently affects elderly patients' cerebral blood flow.

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There is a body of evidence that the aging immune system is linked to cancer. In this study, with aging- and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune-cell proportion in the circulating whole blood of individuals. The analyses for aging- and CD4+ T cell proportion-derived differential genes showed that ubiquitination plays an important role in the aging immune system and tumorigenesis. Therefore, starting from a set of pre-annotated ubiquitination genes, we found that among the differentially ubiquitinated genes, DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, was significantly associated with both aging (P-value = 3.86e-06) and CD4+ T cell proportion (P-value = 1.97e-05) in circulating blood. By collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we validated that the 1st exon DNA methylation of DZIP3 could predict the onset of early stage (AUC = 0.833, OR = 8.82) and all pTNM stages of colorectal cancer (AUC = 0.782, OR = 5.70). Thus, the epigenetically regulated ubiquitination machine plays an important role in immune aging and tumorigenesis.

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Immune checkpoint inhibitor (ICI) treatment could bring long-lasting clinical benefits to patients with metastatic cancer. However, only a small proportion of patients respond to PD-1/PD-L1 blockade, so predictive biomarkers are needed. Here, based on DNA methylation profiles and the objective response rates (ORRs) of PD-1/PD-L1 inhibition therapy, we identified 269 CpG sites and developed an initial CpG-based model by Lasso to predict ORRs. Notably, as measured by the area under the receiver operating characteristic curve (AUC), our model can produce better performance (AUC = 0.92) than both a model based on tumor mutational burden (TMB) (AUC = 0.77) and a previously reported TMB model (AUC = 0.71). In addition, most CpGs also have additional synergies with TMB, which can achieve a higher prediction accuracy when joined with TMB. Furthermore, we identified CpGs that are associated with TMB at the individual level. DNA methylation modules defined by protein networks, Kyoto Encylopedia of Genes and Genomes (KEGG) pathways, and ligand-receptor gene pairs are also associated with ORRs. This method suggested novel immuno-oncology targets that might be beneficial when combined with PD-1/PD-L1 blockade. Thus, DNA methylation studies might hold great potential for individualized PD1/PD-L1 blockade or combinatory therapy.

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PURPOSE: This study compared the potential of 2 nanoparticles, namely albumin and gold nanoparticles, for the specific delivery of 99mTC- resveratrol in colon cancer. The aim of adding radioactive tag (99mTC) to resveratrol was to utilize it for imaging purposes. METHODS: We compared the potential of albumin loaded 99mTC- resveratrol with gold nanoparticles loaded 99mTc-resveratrol for tumor specific delivery. Twenty male Wistar rats were used for the formation of colon cancer model. Both delivery molecules were tested for tumor specific delivery. RESULTS: The results showed efficient delivery of 99mTC-resveratrol with albumin in comparison to gold nanoparticles, as confirmed by single-photon emission computed tomography (SPECT). CONCLUSIONS: Albumin is a superior molecule for the efficient delivery of 99mTC- resveratrol at tumor sites in comparison to gold nanoparticles.

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BACKGROUND: Polyunsaturated omega-3 fatty acids may beneficially influence healing processes and patient outcomes. The aim of this research was to study the clinical efficacy of fish oil enriched total parenteral nutrition in elderly patients after colorectal cancer surgery. METHODS: Fifty-seven elderly patients with colorectal cancer were enrolled in this prospective, randomized, double-blind, controlled clinical trial. All patients received isocaloric and isonitrogenous total parenteral nutrition by continuous infusion (20 - 24 hours per day) for seven days after surgery. The control group (n = 28) received 1.2 g/kg soybean oil per day, whereas the treatment group (n = 29) received 0.2 g/kg fish oil and 1.0 g/kg soybean oil per day. Blood samples were taken pre-operatively, and at days one and eight after the operation. The plasma levels of CD4, CD8, CD4/CD8, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were measured. Clinical outcomes were then analysed. RESULTS: Patient characteristics were comparable between the two groups. At day eight post-surgery, IL-6, TNF-α and CD8 titres were lower in the treatment group when compared to the control group; these results reached statistical significance. In the treatment group, there were fewer infectious complications and incidences of systemic inflammatory response syndrome (SIRS), and shorter lengths of hospital stay were observed. The total cost of medical care was comparable for the two groups. No serious adverse events occurred in either group. CONCLUSIONS: Fish oil 0.2 g/kg per day administrated to elderly patients after colorectal surgery was safe and may shorten the length of hospital stay and improve clinical outcomes.

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OBJECTIVE: To study the effect of mycophenolic acid (MPA) on maturation, endocytotic capacity and allostimulatory properties of human myeloid dendritic cell (MDC). METHODS: The peripheral blood mononuclear cells were isolated freshly from healthy volunteers (n = 15). The study group was treated by MPA. Co-stimulatory and adhesion molecular on MDC were analyzed by flow cytometry. After isolation of blood dendritic cell antigen-1(+) (BDCA-1(+)), the cellular uptake of FITC-dextran was measured by flow cytometry. After mixed lymphocyte reaction, the percentage of allogenic CD(4)(+) T cell in G(0) phase was analyzed by flow cytometry. RESULTS: (1) Maturation: Compared to control group, MPA down-regulated the level of CD40, CD62L, HLA-DR, CD54, CD80, CD83 and CD86 on MDC significantly in study group (t = -3.713, P > 0.010). (2) Endocytotic capacity: MPA enhanced significantly the endocytotic capacity of MDC in study group (t = 10.171, P = 0.000). (3) Allostimulatory capacity: Compared to control group, MPA reduced the ability of MDC to stimulate markedly the T cell proliferation in study group. CONCLUSION: MPA may enhance the phagocytic capacity of human peripheral MDC, inhibit the maturity of MDC and impair its allostimulatory capacity of CD(4)(+) T lymphocyte.

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BACKGROUND: We sought to study the effect of a combination therapy comprised of hyperbaric oxygen (HBO) and ulinastatin on the plasma levels of endotoxin, soluble CD14 (sCD14), endotoxin neutralizing capacity (ENC) and cytokines in acute necrotizing pancreatitis (ANP) in rats. METHODS: We randomly allocated 90 Sprague-Dawley rats into 6 groups: group 1 (ordinary control), group 2 (sham operation), group 3 (ANP), group 4 (ANP with HBO), group 5 (ANP with ulinastatin) and group 6 (ANP with HBO and ulinastatin). We induced ANP by retrograde injection of 3.5% sodium taurocholate (2.5 mL/kg) via the pancreatic duct. Five minutes after induction, animals in groups 5 and 6 were infused with ulinastatin (20 000 U/kg) via the portal vein. Thirty minutes after induction, animals in groups 4 and 6 received HBO therapy. We collected samples 3, 6 and 10 hours after induction of ANP. RESULTS: We found that the plasma level of endotoxin in group 3 was significantly higher than in group 4 (3, 6 h, both p < 0.001), group 5 (3 h, p < 0.001; 6 h, p = 0.014) and group 6 (both p < 0.001). The level of plasma sCD14 in group 3 was significantly higher than in group 4 (3, 6 h, both p < 0.001), group 5 (3, 6 h, both p = 0.001) and group 6 (3 h, p < 0.001; 6 h, p = 0.001). The plasma endotoxin and sCD14 levels in group 6 were significantly lower than in groups 4 and 5. The plasma ENC level in group 6 was significantly higher than in groups 3, 4 and 5 (p < 0.001). The ENC level in groups 4 and 5 were higher than in group 3, but there was no significant difference. The plasma level of tumour necrosis factor-alpha (TNF-alpha) and IL-6 in group 6 were significantly lower than in groups 3, 4 and 5 (p < 0.001). The TNF-alpha and IL-6 levels in groups 4 and 5 were lower than in group 3, but there was no significant difference. CONCLUSION: The use of an early combination therapy of HBO and ulinastatin was more effective than either therapy alone in the treatment of ANP.

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BACKGROUND & OBJECTIVE: Aldose reductase like gene-1 overexpresses in hepatocellular carcinomas; it might be the drug resistance- associated gene to anti-tumor drugs containing carbonyl groups on hepatocellular carcinomas. This study was designed to establish human hepatocellular carcinoma cell line (HepG2) transfected with aldose reductase like gene-1 (ARL-1), then to observe the changes of drug resistance to anti-tumor drugs with carbonyl group and screen the drug resistance-associated genes through cDNA chip. METHODS: PBK/ARL-1 plasmid was transfected to HepG2 cells by liposome to establish HepG2 monoclonal cells with high expression of ARL-1. The HepG2 cells with high expression of ARL-1 were determined by reverse transcription-polymerase chain reaction (RT-PCR),flow cytometric analysis (FCA), and immunohistochemical staining. MTT assay and cell apoptosis analysis were performed to determine the drug resistance ability of the cells to Adriamycin (ADM) and mytomycin (MMC), which contain carbonyl group. 5-fluorouracil (5-FU) that has no carbonyl group was used as control. Then two kinds of cDNA probes were made from HepG2 cells and ARL-HepG2 cells and labeled with Cy3 and Cy5 dyes. The probes were hybridized to the human liver cDNA chip and differentially expressed genes from the two cells were screened. The genes could be involved in drug resistance were confirmed by RT-PCR and Western blot. RESULTS: Compared with HepG2 cells, HepG2 cells transfected with ARL-1 gene have an increase in expression of ARL-1. Drug resistance ability of HepG2 cells transfected with ARL-1 gene to ADM and MMC increased 2.6 and 3.47 folds, respectively (t=6.39, P< 0.05 in ADM group; t=30.06, P< 0.01 in MMC group). Drug resistance to 5-FU had no statistical difference between them (t=0.684,P >0.05 in 5-FU group). 15 genes down-regulated and 9 genes up-regulated after transfected with ARL-1 gene were found by cDNA chip scanned. Some differentially displayed genes such as ubiquitin and MDR confirmed by RT-PCR and Western blot were consistent to the results of cDNA chip. CONCLUSION: The HepG2 cells with high expression of ARL-1 have more drug resistance to anti-tumor drugs with carbonyl group. Up-regulated MDR expression and down-regulated ubiquitin expression may contribute to the drug resistance of HepG2 cells.

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OBJECTIVE: To study the difference of the gene expression profile and to identify the different expression after transfection of the ARL-1 gene. METHODS: The cDNA probes were synthesized from total RNA of study group and control group, which was differentially hybridized to cDNA chips and confirmed by a gene specific semiquantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Six kinds of gene expression were increased and 9 kinds of gene expression were decreased. The findings were correlated with protein metabolism, signal pathway, metastasis, and drug resistance. CONCLUSIONS: cDNA chips showed that gene expression profile of liver carcinoma cell was changed after transfection of the ARL-1 gene. It is a useful method in understanding the mechanism of drug resistance.

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