Background Adjuvant therapies such as radiation therapy, chemotherapy, and immunotherapy are usually given after cancer surgery to improve the survival of cancer patients. However, despite advances ...in several adjuvant therapies, they are still limited in the prevention of recurrences. Methods We evaluated the immunological effects of RNA-based adjuvants in a murine melanoma model. Single-stranded RNA (ssRNA) were constructed based on the cricket paralysis virus (CrPV) internal ribosome entry site (IRES). Populations of immune cells in bone marrow cells and lymph node cells following immunization with CrPV.sup.IRES-ssRNA were determined using flow cytometry. Activated cytokine levels were measured using ELISA and ELISpot. The tumor protection efficacy of CrPV.sup.IRES-ssRNA was analyzed based on any reduction in tumor size or weight, and overall survival. Results CrPV.sup.IRES-ssRNA treatment stimulated antigen-presenting cells in the drain lymph nodes associated with activated antigen-specific dendritic cells. Next, we evaluated the expression of CD40, CD86, and XCR1, showing that immunization with CrPV.sup.IRES-ssRNA enhanced antigen presentation by CD8a.sup.+ conventional dendritic cell 1 (cDC1), as well as activated antigen-specific CD8 T cells. In addition, CrPV.sup.IRES-ssRNA treatment markedly increased the frequency of antigen-specific CD8 T cells and interferon-gamma (IFN-gamma) producing cells, which promoted immune responses and reduced tumor burden in melanoma-bearing mice. Conclusions This study provides evidence that the CrPV.sup.IRES-ssRNA adjuvant has potential for use in therapeutic cancer vaccines. Moreover, CrPV.sup.IRES-ssRNA possesses protective effects on various cancer cell models. Keywords: Murine melanoma model, Adjuvant immunotherapy, CrPV.sup.IRES-ssRNA, RNA vaccine, Antigen-presenting cells
Laparoscopic distal gastrectomy is gaining popularity over open distal gastrectomy for gastric cancer because of better early postoperative outcomes. However, to our knowledge, no studies have proved ...whether laparoscopic distal gastrectomy is oncologically equivalent to open distal gastrectomy.
To examine whether the long-term survival among patients with stage I gastric cancer undergoing laparoscopic distal gastrectomy is noninferior to that among patients undergoing open distal gastrectomy.
The Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS) group, which includes 15 surgeons from 13 institutes, conducted a phase 3, multicenter, open-label, noninferiority, prospective randomized clinical trial (KLASS-01) of patients with histologically proven, preoperative clinical stage I gastric adenocarcinoma from January 5, 2006, to August 23, 2010. Survival and recurrence status of the patients was determined in December 2016.
Patients were randomly assigned (1:1) to laparoscopic distal gastrectomy (n = 705) or open distal gastrectomy (n = 711). Of these patients, 85 received a surgical approach opposite the one to which they were randomized (63 randomized to the open surgery group and 22 to the laparoscopic group).
Difference in 5-year overall survival between the laparoscopic and open distal gastrectomy groups. The noninferiority margin was prespecified as -5% (corresponding hazard ratio of 1.54), with an assumed survival of 90% after 5 years in the open surgery group.
Among the 1416 patients (mean SD age, 57.3 11.1 years; 940 66.4% male) included in the study, the 5-year overall survival rates were 94.2% in the laparoscopic group and 93.3% in the open surgery group (log-rank P = .64). Intention-to-treat analysis confirmed the noninferiority of the laparoscopic approach compared with the open approach (difference, 0.9 percentage points; 1-sided 97.5% CI, -1.6 to infinity). The 5-year cancer-specific survival rates were similar between the 2 groups (97.1% in the laparoscopic group and 97.2% in the open surgery group, log-rank P = .91; difference, -0.03 percentage points; 1-sided 97.5% CI, -1.8 to infinity). Per-protocol analysis results were consistent with the intention-to-treat results for overall and cancer-specific survival rates.
The KLASS-01 trial revealed similar overall and cancer-specific survival rates between patients receiving laparoscopic and open distal gastrectomy. Laparoscopic distal gastrectomy is an oncologically safe alternative to open surgery for stage I gastric cancer.
ClinicalTrials.gov identifier: NCT00452751.
This study analyzed the decision-making times (DMTs) of participants at T-type indoor intersections according to the horizontal/vertical installation locations and the arrow directions of escape ...route signs. A total of 120 university students participated in the study. We analyzed the DMTs and following rates (FRs) required for the participants to observe the visual stimuli of the signs installed in front of the T-type indoor intersections and then properly select a path according to the arrow direction of the signs. The results are as follows: (1) the participants exhibited shorter DMTs for the right arrow direction of the signs, (2) the Simon effect occurred when the horizontal installation location of the signs was more than 60 cm away from the center of the T-type indoor intersection on both sides, (3) the DMTs of participants increased when the vertical installation location of the signs was low. Finally, we proposed an optimal installation location of the signs to support the shortest DMTs at T-type indoor intersections. It is expected that the results of this study will provide a database of DMTs, based on the locations of the signs during emergency evacuations, and will be utilized to improve the installation guidelines and regulations of signs.
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Adipogenesis involved in hypertrophy and hyperplasia of adipocytes is responsible for expanding the mass of adipose tissues in obese individuals. Peroxisome proliferator-activated ...receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) are two principal transcription factors induced by delicate signaling pathways, including signal transducer and activator of transcription 5 (STAT5), in adipogenesis. Here, we demonstrated a novel role of ginkgetin, a biflavone from Ginkgo biloba leaves, as a STAT5 inhibitor that blocks the differentiation of preadipocytes into adipocytes. During the differentiation of 3T3-L1 cells, ginkgetin treatment during the first 2 days markedly inhibited the formation of lipid-bearing adipocytes. PPARγ and C/EBPα expression was decreased in 3T3-L1 cells during adipogenesis following ginkgetin treatment, whereas no change was observed in C/EBPβ or C/EBPδ expression. Inhibition of PPARγ and C/EBPα expression by ginkgetin occurred through the prevention of STAT5 activation during the initiation phase of adipogenesis. In addition, ginkgetin-mediated the inhibition of adipogenesis was recapitulated in the differentiation of primary preadipocytes. Lastly, we confirmed the inhibitory effects of ginkgetin on the hypertrophy of white adipose tissues from high-fat diet-fed mice. These results indicate that ginkgetin is a potential anti-adipogenesis and anti-obesity drug.
Clinical practice guidelines have been slowly and inconsistently applied in clinical practice, and certain evidence-based, guideline-driven therapies for heart failure (HF) have been significantly ...underused. The purpose of this study was to survey guideline compliance and its effect on clinical outcomes in the treatment of systolic HF in Korea.
The SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR) trial was a multi-center, retrospective, observational study on subjects with systolic HF (ejection fraction <45%) admitted to 23 university hospitals. The guideline adherence indicator (GAI) was defined as a performance measure on the basis of 3 pharmacological classes: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), beta-blocker (BB), and aldosterone antagonist (AA). Based on the overall adherence percentage, subjects were divided into 2 groups: those with good guideline adherence (GAI ≥50%) and poor guideline adherence (GAI <50%). We included 1319 regional participants as representatives of the standard population from the Korean national census in 2008. Adherence to drugs at discharge was as follows: ACEI or ARB, 89.7%; BB, 69.2%; and AA, 65.9%. Overall, 82.7% of the patients had good guideline adherence. Overall mortality and re-hospitalization rates at 1 year were 6.2% and 37.4%, respectively. Survival analysis by log-rank test showed a significant difference in event-free survival rate of mortality (94.7% vs. 89.8%, p = 0.003) and re-hospitalization (62.3% vs. 56.4%, p = 0.041) between the good and poor guideline-adherence groups.
Among patients with systolic HF in Korea, adherence to pharmacologic treatment guidelines as determined by performance measures, including prescription of ACEI/ARB and BB at discharge, was associated with improved clinical outcomes.
Background It is unclear whether statin treatment could reduce the risk of early vascular events when baseline low‐density lipoprotein cholesterol (LDL‐C) levels are already low, at <70 mg/dL, at the ...time of the index stroke. Methods and Results This study was an analysis of a prospective, multicenter, nationwide registry of consecutive patients with first‐ever acute ischemic stroke with baseline low‐density lipoprotein cholesterol levels <70 mg/dL and without statin pretreatment. An inverse probabilities of treatment weights method was applied to control for imbalances in baseline characteristics. The primary outcome was a composite of stroke (either hemorrhagic or ischemic), myocardial infarction, and all‐cause death within 3 months. A total of 2850 patients (age, 69.5±13.4 years; men, 63.5%) were analyzed for this study. In‐hospital statin treatment was used for 74.2% of patients. The primary composite outcome within 3 months occurred in 21.5% of patients in the nonstatin group and 6.7% of patients in the statin group ( P <0.001), but the rates of stroke (2.65% versus 2.33%), hemorrhagic stroke (0.16% versus 0.10%), and myocardial infarction (0.73% versus 0.19%) were not significantly different between the 2 groups. After inverse probability of treatment weighting analysis, the primary composite outcome was significantly reduced in patients with statin therapy (weighted hazard ratio HR, 0.54 95% CI, 0.42–0.69). However, statin treatment did not increase the risk of hemorrhagic stroke (weighted HR, 1.11 95% CI, 0.10–12.28). Conclusions Approximately three‐quarters of the patients with first‐ever ischemic stroke with baseline low‐density lipoprotein cholesterol levels <70 mg/dL received in‐hospital statin treatment. Statin treatment, compared with no statin treatment, was significantly associated with a reduced risk of the 3‐month primary composite outcomes and all‐cause death but did not alter the rate of stroke recurrence.
This study explores the influence of processing methods on the connectivity of a ceramic component and its effect on the dielectric and thermal properties in Li2MoO4-polytetrafluoroethylene ...(LMO-PTFE) composites. Three processing cases were examined: cold sintering (case 1), dry pressing and subsequent thermal annealing (case 2), and cold sintering and subsequent thermal annealing (case 3). The processing methods change the connectivity of ceramic grains, the crystallinity of PTFE, and the dielectric properties of these composites. The microstructure analysis shows that CSP increases the LMO domain size via the dissolution and precipitation steps. The connected LMO grains increases the transport length of Li ions under electric field and manifests the space charge polarization in the dielectric measurments. More connected LMO grains of the composites also enhance thermal transport, while phonon scattering of discrete LMO particles lowers the thermal conductivity of the composites.
•Processing methods change the connectivity of a ceramic component in a polymer matrix.•Cold sintering process increases the ceramic domain size in the ceramic-polymer composite.•The connected ceramics grains increase the transport length of Li ions under electric field.•Thermal conductivity can be enhanced by a chain of connected ceramic grains.•This study contributes to the rational design of high-performance dielectric composites.
As an essential aromatic amino acid, L-phenylalanine (L-Phe) has a lot of applications as precursors for pharmaceuticals, artificial sweetner,
etc.
Previously, through metabolic engineering, we ...developed an
Escherichia coli
strain (YHP05) capable of overproducing L-Phe. In this study, we further engineered
E. coli
strain to develop an economic bioprocess for L-Phe production in large scale bioreactor. First, we developed
E. coli
YHP06 harboring pYHP which cultivation does not require supplementation of amino acids for cell growth. Next, the strong and constitutive gene expression systems for L-Phe biosynthesis were sequentially introduced into chromosome of
E. coli
, which allowed the antibiotic-free and inducer-free cultivation. Among the engineered strains, the H-02 strain showed the highest production of L-Phe (3.6 g/L) in the flask cultivation. The production of L-Phe in the engineered H-02 strain was also evaluated in lab-scale (5 L), and L-Phe as high as 30.7 g/L could be produced with 0.81 g/L/h of productivity. Finally, the pilot-scale (30 L) fed-batch cultivation was performed, and we could achieve the production of L-Phe as high as 38.6 g/L with 1.07 g/L/h of productivity.
Abstract
Introduction
Cytokines of the common γ chain (γc) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, ...autoimmune diseases, allergies, and cancer. Although γc is considered an assistant receptor to transmit cytokine signals and is an indispensable receptor in the immune system, its regulatory mechanism is not yet well understood.
Objective
This study focused on the molecular mechanisms that γc expression in T cells is regulated under T cell receptor (TCR) stimulation.
Methods
The γc expression in TCR-stimulated T cells was determined by flow cytometry, western blot and quantitative RT-PCR. The regulatory mechanism of γc expression in activated T cells was examined by promoter-luciferase assay and chromatin immunoprecipitation assays. NFAT1 and NFκB deficient cells generated using CRISPR-Cas9 and specific inhibitors were used to examine their role in regulation of γc expression. Specific binding motif was confirmed by γc promotor mutant cells generated using CRISPR-Cas9. IL-7TgγcTg mice were used to examine regulatory role of γc in cytokine signaling.
Results
We found that activated T cells significantly upregulated γc expression, wherein NFAT1 and NFκB were key in transcriptional upregulation via T cell receptor stimulation. Also, we identified the functional binding site of the γc promoter and the synergistic effect of NFAT1 and NFκB in the regulation of γc expression. Increased γc expression inhibited IL-7 signaling and rescued lymphoproliferative disorder in an IL-7Tg animal model, providing novel insights into T cell homeostasis.
Conclusion
Our results indicate functional cooperation between NFAT1 and NFκB in upregulating γc expression in activated T cells. As γc expression also regulates γc cytokine responsiveness, our study suggests that γc expression should be considered as one of the regulators in γc cytokine signaling and the development of T cell immunotherapies.
After acute myocardial infarction (AMI), the replicated phenomenon of obesity paradox, i.e., obesity appearing to be associated with increased survival, has not been evaluated in stabilized (i.e., ...without clinical events within 1 month post AMI) Asian patients with diabetes mellitus (DM).
Among 1192 patients in the DIabetic Acute Myocardial InfarctiON Disease (DIAMOND) Korean multicenter registry between April 2010 and June 2012, 2-year cardiac and all-cause death were compared according to obesity (body mass index ≥25 kg/m(2)) in 1125 stabilized DM patients.
Compared with non-obese DM patients (62% of AMI patients), obese DM patients had: higher incidence of dyslipidemia (31 vs. 24%, P < 0.01); lower incidence of chronic kidney disease (26 vs. 33%) (P < 0.01); higher left ventricular ejection fraction after AMI (53 ± 11 vs. 50 ± 12%, P < 0.001); and lower 2-year cardiac and all-cause death occurrence (0.7 vs. 3.6% and 1.9 vs. 5.2%, both P < 0.01) and cumulative incidence in Kaplan-Meier analysis (P < 0.005, respectively). Likewise, both univariate and multivariate Cox hazard regression analyses adjusted for the respective confounders showed that obesity was associated with decreased risk of both cardiac HR, 0.18 (95% CI 0.06-0.60), P = 0.005; and 0.24 (0.07-0.78), P = 0.018, respectively and all-cause death 0.34 (0.16-0.73), P = 0.005; and 0.44 (0.20-0.95), P = 0.038.
In a Korean population of stabilized DM patients after AMI, non-obese patients appear to have higher cardiac and all-cause mortality compared with obese patients after adjusting for confounding factors.
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