Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has ...assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines.
Hydraulic structures installed in rivers inevitably create a water level difference between upstream and downstream regions. The potential energy due to this difference in water level is converted ...into kinetic energy, causing high-velocity flow and hydraulic jumps in the river. As a result, problems such as scouring and sloping downstream may occur around the hydraulic structures. In this study, a FLOW-3D model was constructed to perform a numerical analysis of the Changnyeong-Haman weir in the Republic of Korea. The constructed model was verified based on surface velocity measurements from a field gate operation experiment. In the simulation results, the flow discharge differed from the measured value by 9–15 m3/s, from which the accuracy was evaluated to be 82–87%. The flow velocity was evaluated with an accuracy of 92% from a difference of 0.01 to 0.16 m/s. Following this verification, a flow analysis of the hydraulic structures was performed according to boundary conditions and operation conditions for numerous scenarios. Since 2018, the Changnyeong-Haman weir gate has been fully opened due to the implementation of Korea’s eco-environmental policy; therefore, in this study, the actual gate operation history data prior to 2018 was applied and evaluated. The evaluation conditions were a 50% open gate condition and the flow discharge of two cases with a large difference in water level. As a result of the analysis, the actual operating conditions showed that the velocity and the Froude number were lower than the optimal conditions, confirming that the selected design was appropriate. It was also found that in the bed protection section, the average flow velocity was high when the water level difference was large, whereas the bottom velocity was high when the gate opening was large. Ultimately, through the reviewed status survey data in this study, the downstream flow characteristics of hydraulic structures along with adequacy verification techniques, optimal design techniques such as procedures for design, and important considerations were derived. Based on the current results, the constructed FLOW-3D-based model can be applied to creating or updating flow analysis guidelines for future repair and reinforcement measures as well as hydraulic structure design.
The goal of this study was to determine the rat lens aldose reductase-inhibitory effects of 95% ethanol extracts from the leaves of C. esculenta and, its organic solvent soluble fractions, including ...the dichloromethane (CH2Cl2), ethyl acetate (EtOAc), n-butanol (BuOH) and water (H2O) layers, using dl-glyceraldehyde as a substrate. Ten compounds, namely tryptophan (1), orientin (2), isoorientin (3), vitexin (4), isovitexin (5), luteolin-7-O-glucoside (6), luteolin-7-O-rutinoside (7), rosmarinic acid (8), 1-O-feruloyl-d-glucoside (9) and 1-O-caffeoyl-d-glucoside (10) were isolated from the EtOAc and BuOH fractions of C. esculenta. The structures of compounds 1-10 were elucidated by spectroscopic methods and comparison with previous reports. All the isolates were subjected to an in vitro bioassay to evaluate their inhibitory activity against rat lens aldose reductase. Among tested compounds, compounds 2 and 3 significantly inhibited rat lens aldose reductase, with IC50 values of 1.65 and 1.92 μM, respectively. Notably, the inhibitory activity of orientin was 3.9 times greater than that of the positive control, quercetin (4.12 μM). However, the isolated compounds showed only moderate ABTS+ 2,29-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) activity. These results suggest that flavonoid derivatives from Colocasia esculenta (L.) Schott represent potential compounds for the prevention and/or treatment of diabetic complications.
Vitamin D deficiency is a worldwide health issue especially in women. Serum vitamin D concentrations vary depending on the weather. However, the ideal vitamin D supplementation strategy related to ...weather remains uncertain. We aimed to investigate the relationship between climate factors and serum 25-hydroxy vitamin D 25(OH)D concentrations. This study included 11,272 women aged 20-79 who visited a health promotion center for annual checkups between January 2013 and December 2015. We reviewed medical records and collected daily meteorological data. We analyzed the association between serum 25(OH)D concentration and climate factors using simple and multiple regression models and then predicted serum 25(OH)D concentration using multiple fractional polynomial models. The median age of the participants was 51 years (20-79 years), and the mean serum 25(OH)D level was 17.4 ± 8.6 ng/mL. The serum 25(OH)D concentration was lower in young women than in older women. The proportions of women with adequate 25(OH)D levels were 14.9% and 47.0% in the age groups 20-29 and 70-79, respectively. The maximum level of predicted log 25(OH)D was found in September, and the minimum was found in January. In multiple regression analysis, age and monthly mean temperature were associated with 25(OH)D concentrations. Serum 25(OH)D level was predicted using the following formula: log (25(OH)D) = 2.144 + 0.009 × age + 0.018 × ((temperature + 12.4)/10)2 (P < 0.001, adjusted R2 = 0.091). Serum 25(OH)D concentrations changed according to air temperature. An adequate strategy for vitamin D supplementation, based on air temperature, is necessary to maintain healthy serum 25(OH)D levels.
Although the association between apolipoprotein E (APOE) genotype and disease progression is well characterized in patients with Alzheimer's disease, such a relationship is unknown in patients with ...subcortical vascular cognitive impairment. We evaluated whether APOE genotype is associated with disease progression in subcortical vascular mild cognitive impairment (svMCI) patients. We prospectively recruited 72 svMCI patients (19 APOE4 carriers, 42 APOE3 homozygotes, and 11 APOE2 carriers). Patients were annually followed-up with brain MRI and neuropsychological tests for three years and underwent a second Pittsburgh compound B (PiB)-PET at a mean interval of 32.3 months. Amyloid-ß burden was quantified by PiB standardized uptake value ratio (SUVR), and the amount of small vessel disease was quantified by number of lacune and small vessel disease score on MRI. We also measured cortical thickness. During the three years of follow-up, compared to the APOE3 homozygotes, there was less increase in PiB SUVR among APOE2 carriers (p = 0.023), while the APOE genotype did not show significant effects on small vessel disease progression. APOE2 carriers also showed less cortical thinning (p = 0.023) and a slower rate of cognitive decline (p = 0.009) compared to those with APOE3 homozygotes. Our findings suggest that, in svMCI patients, APOE2 has protective effects against amyloid-ß accumulation, cortical thinning, and cognitive decline.
The purpose of this study was to analyze the treatment efficacy and safety of stereotactic ablative body radiotherapy (SABR) boost for cervical cancer patients not amenable to brachytherapy.
A ...retrospective review of the medical records from single institution of 25 eligible patients was performed. The patients underwent pelvic radiotherapy (RT) in 25 or 28 fractions with a median dose of 45 Gy (range 44-50.4 Gy). SABR boost was delivered after pelvic RT, with a median dose of 25 Gy (range 20-33 Gy), and a median fraction number of 5 (range 4-6). 21 patients with a follow-up period of more than one year were included in the toxicity analysis, and hematuria and hematochezia that occurred later than 3 months after the RT were graded.
The median follow-up period after radiotherapy was 2.85 years (range 0.33-6.60). The 3-year local control, locoregional control, disease-free survival, and overall survival rates were 80.9%, 75.8%, 40.9%, and 77.1%, respectively. 5 patients experienced grade 3 toxicity (3 genitourinary, 3 gastrointestinal), and no grade 4-5 toxicity was reported. Univariate analysis showed that cumulative D
in equivalent dose in 2 Gy fractions (EQD2) of rectum was marginally predictive for any grade of hematochezia (P = 0.051). Cumulative D
EQD2 of bladder was not predictive for hematuria. In the receiver operating characteristic (ROC) curve analysis, the optimal threshold of cumulative rectal D
EQD2 was 81.2 Gy for any grade of hematochezia.
SABR boost for cervical cancer was effective and tolerable. Although it cannot substitute brachytherapy, it can be a treatment option when brachytherapy is not possible.
We aimed to identify the effect of an extended number of neoadjuvant chemotherapy (NAC) cycles on prognosis and surgical morbidity after interval debulking surgery (IDS) in patients with newly ...diagnosed advanced ovarian cancer.
Medical records of patients with advanced ovarian cancer treated with NAC and having undergone IDS were retrospectively reviewed. Clinicopathological factors were compared between two groups: conventional (≤4 cycles) and extended (≥5 cycles) NAC groups. Kaplan-Meier analysis was performed to evaluate progression-free survival (PFS) and overall survival (OS).
A total of 156 patients were included, 112 patients in the conventional group and 44 patients in the extended NAC group. The extended NAC group had a significantly higher frequency of cancer antigen (CA)-125 normalization after NAC (59.1% vs. 33.9%, P = 0.004), a lower rate of bowel surgery (18.2% vs. 34.8%, P = 0.042), and a lower rate of transfusion during or after IDS (36.4% vs. 59.8%, P = 0.008) as compared to the conventional group. The complete cytoreduction rate after IDS was similar between the groups. In multivariate Cox regression analysis for PFS, radiologically stable and progressive disease after NAC (Hazard ratio HR, 1.983; 95% Confidence interval CI, 1.141-3.446; P = 0.015) and gross residual tumor after IDS (HR, 2.054; 95% CI, 1.414-2.983; P < 0.001) were independent risk factors for poor PFS. However, extended NAC cycles were not significantly associated with poor PFS. The median PFS was 19.5 and 16.9 months (P = 0.830), and the 5-year OS was 71.4 and 63.2% (P = 0.677) in the conventional and extended NAC groups, respectively.
Our study showed that extended NAC cycles were not inferior to conventional NAC cycles in terms of survival in patients with advanced ovarian cancer and reduced surgical morbidity such as bowel surgery and transfusion during or after IDS.
Efforts have been made to develop bromodomain inhibitors as cancer treatments. Sub-pathways, particularly in ovarian cancer, affected by bromodomain-containing protein (BRD) remain unclear. This ...study verified the antitumor effects of a new drug that can overcome OPT-0139-chemoresistance to treat ovarian cancer. A mouse xenograft model of human ovarian cancer cells, SKOV3 and OVCAR3, was used in this study. Cell viability and proliferation were assessed using MTT and ATP assays. Cell cycle arrest and apoptosis were determined using flow cytometry. BRD4 and c-Myc expression and apoptosis-related molecules were detected using RT-PCR and real-time PCR and Western blot. We confirmed the OPT-0139 effect and mechanism of action in epithelial ovarian cancer. OPT-0139 significantly reduced cell viability and proliferation and induced apoptosis and cell cycle arrest. In the mouse xenograft model, significant changes in tumor growth, volume, weight, and BRD4-related gene expression were observed, suggesting the antitumor effects of BRD4 inhibitors. Combination therapy with cisplatin promoted apoptosis and suppressed tumor growth in vitro and in vivo. Our results suggest OPT-0139, a BRD4 inhibitor, as a promising anticancer drug for the treatment of ovarian cancer by inhibiting cell proliferation, decreasing cell viability, arresting cell cycle, and inducing apoptosis.
The objective of this study was to estimate the accuracy of transcriptome-based classifier in differential diagnosis of uterine leiomyoma and leiomyosarcoma. We manually selected 114 normal uterine ...tissue and 31 leiomyosarcoma samples from publicly available transcriptome data in UCSC Xena as training/validation sets. We developed pre-processing procedure and gene selection method to sensitively find genes of larger variance in leiomyosarcoma than normal uterine tissues. Through our method, 17 genes were selected to build transcriptome-based classifier. The prediction accuracies of deep feedforward neural network (DNN), support vector machine (SVM), random forest (RF), and gradient boosting (GB) models were examined. We interpret the biological functionality of selected genes via network-based analysis using GeneMANIA. To validate the performance of trained model, we additionally collected 35 clinical samples of leiomyosarcoma and leiomyoma as a test set (18 + 17 as 1st and 2nd test sets).
We discovered genes expressed in a highly variable way in leiomyosarcoma while these genes are expressed in a conserved way in normal uterine samples. These genes were mainly associated with DNA replication. As gene selection and model training were made in leiomyosarcoma and uterine normal tissue, proving discriminant of ability between leiomyosarcoma and leiomyoma is necessary. Thus, further validation of trained model was conducted in newly collected clinical samples of leiomyosarcoma and leiomyoma. The DNN classifier performed sensitivity 0.88, 0.77 (8/9, 7/9) while the specificity 1.0 (8/8, 8/8) in two test data set supporting that the selected genes in conjunction with DNN classifier are well discriminating the difference between leiomyosarcoma and leiomyoma in clinical sample.
The transcriptome-based classifier accurately distinguished uterine leiomyosarcoma from leiomyoma. Our method can be helpful in clinical practice through the biopsy of sample in advance of surgery. Identification of leiomyosarcoma let the doctor avoid of laparoscopic surgery, thus it minimizes un-wanted tumor spread.
The prognostic significance of positive peritoneal cytology in patients with early-stage endometrial cancer (Stage 1 or 2) is controversial and perhaps depends on the presence of other factors. The ...relationship of other prognostic factors with positive peritoneal cytology remains unclear. This study aimed to investigate the association between positive peritoneal cytology and prognostic factors and the influence of positive peritoneal cytology on survival in patients with early-stage endometrial cancer.
We identified 351 articles on the PubMed, Cochrane and Embase databases using a combination of the following search terms: endometrial cancer, endometrial carcinoma, positive peritoneal cytology and positive peritoneal washing. When filtered for studies comparing positive peritoneal cytology with negative peritoneal cytology in early-stage endometrial cancer, 11 retrospective studies met the selection criteria. Meta-analyses were performed using Review Manager 5.3 software.
In patients with surgical stage 1 or 2 early-stage endometrial cancer, the incidence of Grade 3 was higher and 5-year overall survival was worse in patients with positive peritoneal cytology compared with negative peritoneal cytology. However, the incidence of Grade 1 was lower in those with positive peritoneal cytology compared with negative peritoneal cytology. In patients with surgical stage 1 early-stage endometrial cancer, the incidence of myometrial invasion ≥1/2 tended to be higher and 5-year progression-free survival was worse in the positive peritoneal cytology group than the negative peritoneal cytology group. However, the incidence of myometrial invasion <1/2 was lower in the positive peritoneal cytology group than the negative peritoneal cytology group.
This study demonstrates that positive peritoneal cytology in patients with early-stage endometrial cancer is significantly associated with other prognostic factors and survival, suggesting its potential as a prognostic factor.
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