Stimulatory Anticancer Effect of Resveratrol Mediated by G Protein-Coupled Estrogen Receptor in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most high-risk cancers; however, it has been suggested that estrogen signaling in CRC could have a protective effect. Therefore, we focused on the function of the G protein-coupled estrogen receptor (GPER) among the estrogen receptors in CRC. In this study, we investigated the therapeutic effect of resveratrol via GPER in CRC (RKO and WiDr) cells, CRC cell-derived xenograft models, and organoids (30T and 33T). Resveratrol significantly suppressed cell viability and proliferation in highly GPER-expressing RKO cells compared to that in low GPER-expressing WiDr cells. In xenograft models, resveratrol also delayed tumor growth and exhibited a high survival rate depending on GPER expression in RKO-derived tumors. Furthermore, resveratrol significantly inhibited the viability of organoids with high GPER expression. Additionally, the anticancer effect of resveratrol on CRC showed that resveratrol rapidly responded to GPER, while increasing the expression of p-ERK and Bax and cleaving PARP proteins.

Fisetin induces the upregulation of AKAP12 mRNA and anti-angiogenesis in a patient-derived organoid xenograft model.

Colorectal cancer (CRC) is associated with high incidence and mortality rates. Targeted therapies for CRC cause various adverse effects, necessitating the development of novel approaches to control CRC progression. In this milieu, we investigated the anti-CRC effects of fisetin, a natural plant flavonoid. Cytotoxicity was performed in CRC patient-derived organoids (30 T and 33 T). Fisetin-induced tumor growth was evaluated in a CRC patient-derived organoid xenograft (PDOX) model. RNA sequencing, immunohistochemistry, and western blotting were performed subsequently. Fisetin significantly decreased organoid viability in a dose-dependent manner. In the PDOX model, fisetin significantly delayed tumor growth, showing a decrease in Ki-67 expression and the induction of apoptosis. In tumor tissues, four genes were identified as differentially expressed between the control and fisetin-treated groups. Among these, A-kinase anchoring protein 12 (AKAP12) level was significantly increased by fisetin treatment (fold change > 2, p < 0.05). Notably, fisetin significantly inhibited vascular endothelial growth factor (VEGF) and epithelial cell adhesion molecule (EpCAM) via upregulation of AKAP12. Our results demonstrate the upregulation of AKAP12 mRNA and inhibition of angiogenesis by fisetin as a therapeutic strategy against CRC.

Identification and evaluation of beliefs about sport participation among South Korean university students.

Objective: To identify and evaluate salient beliefs about sport participation among South Korean university students. Participants: Total 234 undergraduate students were recruited in the main study from one university located in Seoul, South Korea. Methods: An elicitation study was conducted to identify salient beliefs about sport participation. Structural equation modeling was used to examine the effects of the elicited salient beliefs on intention to participate in sports and sport participation behavior. Results: Four of ten salient beliefs identified from the elicitation study (i.e., "builds social relationship," "makes me tired," "takes too much time," and "friends") indirectly affected sport participation behavior through intention. Conclusion: The four salient beliefs may play a critical role in developing effective interventions or policies for promoting sport participation.

Differences in salient beliefs associated with voluntary exercise training among South Korean firefighters before and after COVID-19.

BACKGROUND: Participating in voluntary exercise training is important to meet occupational requirements as well as firefighters' health and safety. The purpose of this study is to identify salient beliefs associated with voluntary exercise training among firefighters in the pandemic era by comparing outcomes with those from a previous elicitation study, which was carried out before the COVID-19 outbreak. METHODS: A total of 57 firefighters are recruited to participate in an elicitation study. Participants are requested to respond to six open-ended questions related to voluntary exercise training. Content analysis is used to create categories that combine similar factors in each belief. Beliefs mentioned by more than 30% of participants are used for comparison with the results of the previous research. RESULTS: "Improves my physical ability" (n = 44) and "cause injury" (n = 17) are identified as behavioral beliefs in the present study, whereas "makes me tired" and "takes too much time" were also elicited in Lee's study. Normative beliefs are "family members" (n = 45) and "colleagues" (n = 27) and these results are consistent with those in Lee's study. "Lack of time" (n = 28), "exercise facilities" (n = 19), and "COVID-19" (n = 19) are elicited as control beliefs in the present study, whereas "physical condition" (n = 21) and "exercise partners" (n = 14) were elicited as other control beliefs, and "COVID-19" was not mentioned in Lee's study. CONCLUSION: This study can contribute valuable information about salient beliefs associated with exercise training behavior among firefighters, particularly under pandemic conditions. Future researchers should develop tailored exercise training programs for firefighters based on current elicited beliefs.

Process and Outcome Evaluations of Interventions to Promote Voluntary Exercise Training Among South Korean Firefighters.

The main aim of the present study is to evaluate reach, dose, fidelity, and outcomes of the interventions for promoting voluntary exercise training among South Korean firefighters. Four interventions for promoting voluntary exercise training among firefighters (i.e., virtual reality exercise system intervention, poster intervention, monitor intervention, and wearable health device intervention) were performed in a fire station located in Seoul, South Korea. To evaluate reach and dose received related to each intervention, participants were asked to answer several simple questions. Three process evaluators completed a 20-item survey to share their impressions related to the quality of intervention delivery. Paired t test was used to examine mean changes in primary (i.e., mean minutes of exercise training per week) and secondary outcomes (i.e., beliefs and intention) between pre- and postinterventions. More than 60% of participants experienced monitor and wearable health device interventions. Process evaluators tend not to agree with a statement saying that the number of the virtual reality exercise equipment was appropriate. Among firefighters who participated in exercise training less than 150 min per week at 1-month follow-up, mean minutes of exercise training per week increased by 67.95 min after interventions. Future studies need to examine whether the monitor and wearable health device interventions effectively increase exercise training participation among firefighters in other fire stations located in Seoul, South Korea.

Advanced Xenograft Model with Cotransplantation of Patient-Derived Organoids and Endothelial Colony-Forming Cells for Precision Medicine.

Preclinical evaluation models have been developed for precision medicine, with patient-derived xenograft models (PDXs) and patient-derived organoids (PDOs) attracting increasing attention. However, each of these models has application limitations. In this study, an advanced xenograft model was established and used for drug screening. PDO and endothelial colony-forming cells (ECFCs) were cotransplanted in NRGA mice (PDOXwE) to prepare the model, which could also be subcultured in Balb/c nude mice. Our DNA sequencing analysis and immunohistochemistry results indicated that PDOXwE maintained patient genetic information and tumor heterogeneity. Moreover, the model enhanced tumor growth more than the PDO-bearing xenograft model (PDOX). The PDO, PDOXwE, and clinical data were also compared in the liver metastasis of a colorectal cancer patient, demonstrating that the chemosensitivity of PDO and PDOXwE coincided with the clinical data. These results suggest that PDOXwE is an improvement of PDOX and is suitable as an evaluation model for precision medicine.

A Patient-Derived Organoid-Based Radiosensitivity Model for the Prediction of Radiation Responses in Patients with Rectal Cancer.

Patient-derived tumor organoids closely resemble original patient tumors. We conducted this co-clinical trial with treatment-naive rectal cancer patients and matched patient-derived tumor organoids to determine whether a correlation exists between experimental results obtained after irradiation in patients and organoids. Between November 2017 and March 2020, we prospectively enrolled 33 patients who were diagnosed with mid-to-lower rectal adenocarcinoma based on endoscopic biopsy findings. We constructed a prediction model through a machine learning algorithm using clinical and experimental radioresponse data. Our data confirmed that patient-derived tumor organoids closely recapitulated original tumors, both pathophysiologically and genetically. Radiation responses in patients were positively correlated with those in patient-derived tumor organoids. Our machine learning-based prediction model showed excellent performance. In the prediction model for good responders trained using the random forest algorithm, the area under the curve, accuracy, and kappa value were 0.918, 81.5%, and 0.51, respectively. In the prediction model for poor responders, the area under the curve, accuracy, and kappa value were 0.971, 92.1%, and 0.75, respectively. Our patient-derived tumor organoid-based radiosensitivity model could lead to more advanced precision medicine for treating patients with rectal cancer.

Gene Expression Profiles Associated with Radio-Responsiveness in Locally Advanced Rectal Cancer.

LARC patients were sorted according to their radio-responsiveness and patient-derived organoids were established from the respective cancer tissues. Expression profiles for each group were obtained using RNA-seq. Biological and bioinformatic analysis approaches were used in deciphering genes and pathways that participate in the radio-resistance of LARC. Thirty candidate genes encoding proteins involved in radio-responsiveness-related pathways, including the immune system, DNA repair and cell-cycle control, were identified. Interestingly, one of the candidate genes, cathepsin E (CTSE), exhibited differential methylation at the promoter region that was inversely correlated with the radio-resistance of patient-derived organoids, suggesting that methylation status could contribute to radio-responsiveness. On the basis of these results, we plan to pursue development of a gene chip for diagnosing the radio-responsiveness of LARC patients, with the hope that our efforts will ultimately improve the prognosis of LARC patients.

The Role of Dopamine Receptor D2 in Bridging the Intention-Behavior Gap in Sport Participation.

Previous studies have identified that a behavior can occur through the strongest predictor intention, but there is a gap between intention and behavior. Dopamine receptor D2 (DRD2) is known to account for a variance in sporting behaviors in human and animal subjects. However, the relationship between DRD2 and sport participation has been poorly studied, and the limited available reports are inconsistent. The present study was performed to examine the impact of DRD2 on sport participation among Korean university students based on the integrated behavioral model (IBM). Data were collected from enrolled university students in Seoul (N = 45). Participants answered survey questions first, and then they gave investigators their hair to provide DNA information (i.e., the A1 allele of DRD2). DRD2 had a significant effect on sport participation, but only in male students. Male students who carried the A1 allele of DRD2 significantly participated in 105.10 min more sporting activities than male students who did not. Moreover, the effect of intention on sport participation was significantly decreased when considering DRD2. Despite the small sample size, the results of this study could be a preliminary case for a larger study and indicate the direction of future research. Our results suggest that DRD2 may have played an important role as the "actual skill" shown in the IBM.

Valproic acid protects intestinal organoids against radiation via NOTCH signaling.

Radiotherapy is a leading treatment for various types of cancer. However, exposure to high-dose ionizing radiation causes acute gastrointestinal injury and gastrointestinal syndrome. This has significant implications for human health, and therefore, radioprotection is a major area of research. Radiation induces the loss of intestinal stem cells; hence, the protection of stem cells expressing LGR5 (a marker of intestinal epithelial stem cells) is a key strategy for the prevention of radiation-induced injury. In this study, we identified valproic acid (VPA) as a potent radioprotector using an intestinal organoid culture system. VPA treatment increased the number of LGR5+ stem cells and organoid regeneration after irradiation. N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT, an inhibitor of NOTCH signaling) blocked the radioprotective effects of VPA, indicating that NOTCH signaling is a likely mechanism underlying the observed effects of VPA. In addition, VPA acted as a radiosensitizer via the inhibition of histone deacetylase (HDAC) in a colorectal cancer organoid. These results demonstrate that VPA exerts strong protective effects on LGR5+ stem cells via NOTCH signaling and that the inhibition of NOTCH signaling reduces these protective effects, providing a basis for the improved management of radiation injury.

Longitudinal analysis of Socioecological obesogenic factors in a National Sample of U.S. children.

BACKGROUND: Childhood obesity is a serious public health threat. Although many researchers conducted research on socioecological determinants of childhood obesity, their longitudinal effects remain inconclusive especially among young children. This study examined socioecological factors and associated transitions of children's body mass index (BMI) status throughout children's kindergarten to elementary school years, using data from a national longitudinal sample. METHODS: The baseline sample of this study included 1264 children (weighted N = 379,297) extracted from the Early Childhood Longitudinal Study (baseline mean age: 5.24 years). The socioecological framework guided selection of socioecological obesogenic variables (e.g., family activity and parental involvement). Longitudinal ordered logistic regressions were performed to determine the associations between socioecological obesogenic variables and unhealthy/healthy changes in BMI status that captured transitions between healthy and unhealthy weight status (i.e., overweight, obesity, and severe obesity). RESULTS: Children with Hispanic ethnicity and nonwhite, less socioeconomic and environmental support, and living in households with fewer family members were more likely than their counterparts to have unhealthy BMI status changes over time (all ps < 0.05). Over the study period, girls were less likely than boys to experience transitions to unhealthy BMI status (all ps < 0.05). CONCLUSION: As hypothesized a priori, the findings of the current affirmed multiple dimensions of how sociological obesogenic factors may influence children's BMI status changes in a longitudinal setting. In order to maintain children's long-term healthy weight, more attention should be paid to socioeconomic obesogenic factors surrounding children as well as individual determinants of obesity (e.g., being physically active and having well-balanced nutrition).

Butyrate enhances the efficacy of radiotherapy via FOXO3A in colorectal cancer patient­derived organoids.

Enhancing the radioresponsiveness of colorectal cancer (CRC) is essential for local control and prognosis. However, consequent damage to surrounding healthy cells can lead to treatment failure. We hypothesized that short­chain fatty acids (SCFAs) could act as radiosensitizers for cancer cells, allowing the administration of a lower and safer dose of radiation. To test this hypothesis, the responses of three­dimensional­cultured organoids, derived from CRC patients, to radiotherapy, as well as the effects of combined radiotherapy with the SCFAs butyrate, propionate and acetate as candidate radiosensitizers, were evaluated via reverse transcription­quantitative polymerase chain reaction, immunohistochemistry and organoid viability assay. Of the three SCFAs tested, only butyrate suppressed the proliferation of the organoids. Moreover, butyrate significantly enhanced radiation­induced cell death and enhanced treatment effects compared with administration of radiation alone. The radiation­butyrate combination reduced the proportion of Ki­67 (proliferation marker)­positive cells and decreased the number of S phase cells via FOXO3A. Meanwhile, 3/8 CRC organoids were found to be non­responsive to butyrate with lower expression levels of FOXO3A compared with the responsive cases. Notably, butyrate did not increase radiation­induced cell death and improved regeneration capacity after irradiation in normal organoids. These results suggest that butyrate could enhance the efficacy of radiotherapy while protecting the normal mucosa, thus highlighting a potential strategy for minimizing the associated toxicity of radiotherapy.

The Effects of Number of Fire Dispatches and Other Situational Factors on Voluntary Exercise Training Among Korean Firefighters: A Multilevel Logistic Regression Analysis.

According to previous research, participation in exercise training (ET) by South Korean firefighters varies with shift type, and the effect of shift type is greater in large cities than in small towns. However, shift types differ among regions, depending on the number of dispatches. Therefore, the present study examined the impact of the number of fire dispatches and other situational factors on ET. A series of multilevel logistic regression analysis was applied to analyze the data collected from South Korean firefighters (N = 5219) in 2017. According to the firefighters, participation in ET is higher among those who have someone to instruct their ET (Coefficient (Coef) = 0.057, SE = 0.017, p < 0.001) and who can do ET while on duty (Coef = 0.048, SE = 0.014, p < 0.001). The number of fire dispatches had a significant effect on participation in ET (Coef = -0.000, SE = 0.000, p < 0.01), meaning that the firefighters' participation in ET varies with the number of fire dispatches in each region. Our main findings indicate that the number of fire dispatches is a key factor affecting ET participation among firefighters, and the other situational factors also play a role. Therefore, ET programs that firefighters can participate in between calls should be established.

The effect of physically or non-physically forced sexual assault on trajectories of sport participation from adolescence through young adulthood.

BACKGROUND: Sexual assault is one of potential factors that may greatly affect an individual's sport participation. The purpose of this study is to investigate the effect of experiencing physically or non-physically forced sexual activity on trajectories of sport participation from adolescence to young adulthood. METHODS: This study used the National Longitudinal Study of Adolescent Health (Add Health) data. Group-based trajectory modeling was utilized to examine the effect of experiencing sexual assault on trajectories of sport participation from adolescence to young adulthood. RESULTS: A three-group trajectory model (high-stable group, high-decreasing group, and low-stable group) best fit sport participation among male participants and a two-group trajectory model (high-decreasing group and low-stable group) best fit sport participation among female participants. Both physically and non-physically forced sexual activity did not have significant effect on trajectories of sport participation among male participants. On the other hand, non-physically forced sexual assault significantly affected sport participation trajectory among female participants. CONCLUSIONS: Special care is required in developing sport promotion program for women victims of non-physically forced sexual activity. The results of this study also suggest that group-based trajectory modeling is a useful technique to examine distinct trajectories of sport participation from adolescence through young adulthood.

Predicting Voluntary Exercise Training among Korean Firefighters: Using Elicitation Study and the Theory of Planned Behavior.

Background: Firefighters are required to have high levels of aerobic and anaerobic power because they often perform physically demanding work in dangerous environments. Therefore, it is important to find out salient factors influencing voluntary exercise training among Korean firefighters based on well-validated theory. Methods: The present study conducted an elicitation study to elicit salient behavioral, normative, and control beliefs about exercise training among Korean firefighters and identified salient beliefs that have a significant indirect effect on behavior through intention using structural equation modeling. Results: Although ten modal salient beliefs obtained from our elicitation study are similar to those elicited from previous TPB belief-based research with a focus on exercise behavior, only three of these (i.e., "improves my physical ability" (coef. = 0.078, p = 0.006), "takes too much time" (coef. = 0.064, p = 0.023), and "colleagues" (coef. = 0.069, p = 0.016) indirectly influenced exercise training behavior through intention among Korean firefighters. Conclusions: Our results may contribute to the literature by providing important information suggesting that three modal salient beliefs are major cognitive determinants of exercise training behavior among Korean firefighters and they may play an essential role in developing effective programs or policies for promoting Korean firefighters' exercise training.

Relationship between Shift Type and Voluntary Exercise Training in South Korean Firefighters.

BACKGROUND: According to the National Fire Agency, 69% of South Korean firefighters prefer the three circuit system. Since the three circuit system involves working for 24 h consecutively, it could reduce work performance of firefighters and their participation in exercise training (ET) and fitness levels could be affected by shift type. The present study examined the impact of shift type on ET and identified the interaction effect between shift type and city size on ET among South Korean firefighters. METHODS: A series of logistic regression models were used to analyze the data collected from incumbent outside workers among Korean firefighters (N = 5196) in 2017. RESULTS: Firefighters under the 3 circuit system participated in ET less frequently than did those under the 21 circuit system, and the difference was greater in large cities than in small towns. This could be because of the greater opportunity to participate in leisure activities in large cities, or because participating in ET is easier for firefighters in small towns, who tend to be less busy than those in large cities. CONCLUSIONS: The three circuit system is not feasible in the present situation in South Korea. Therefore, an environment suitable for the three circuit system should be established.

5-Fluorouracil as a Tumor-Treating Field-Sensitizer in Colon Cancer Therapy.

Colorectal cancer (CRC) is a major cause of mortality that can be treated effectively with chemotherapy and radiotherapy, although resistance to these therapeutic modalities often occurs. Tumor-treating fields (TTFields) can block tumor growth by selectively impairing tumor cell division. In this study, we investigated the mechanism by which 5-fluorouracil (5-FU) sensitizes tumor cells to TTFields. Human HCT116 and SW480 CRC cells were treated with 5-FU and/or TTFields, and characterized in vitro in terms of cell viability, apoptosis through reactive oxygen species production, autophagy, and metastatic potentials. The biological effects of 5-FU and/or TTFields were studied via positron emission tomography and computed tomography on xenograft tumor growth and were confirmed with organoid models of patients. Our results revealed that combination treatment with 5-FU and TTFields increased the efficiency of TTFields therapy in colon cancer cells by downregulating signaling pathways associated with cell proliferation, survival, cell invasion, and migration while upregulating pathways mediating apoptosis and autophagic cell death. The novel mechanistic insights gleaned in this study suggest that combination therapy with TTFields and 5-FU may be effective in treating CRC, although safety and efficacy testing in patients with CRC will need to be performed before this strategy can be implemented clinically for TTF-sensitization.

Immuno-PET imaging based radioimmunotherapy in head and neck squamous cell carcinoma model.

The epidermal growth factor receptor (EGFR) is one of the most comprehensively studied molecular targets in head and neck squamous cell carcinoma (HNSCC). However, inherent and acquired resistance are serious problems and are responsible for limited clinical efficacy and tumor recurrence. In this study, we evaluated the feasibility of immuno-positron emission tomography (PET) imaging and radioimmunotherapy (RIT) with 64Cu-/177Lu-PCTA-cetuximab in cetuximab-resistant SNU-1066 HNSCC xenografted model. The cellular uptake of 64Cu/177Lu-3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA)-cetuximab showed good correlation with western blot and flow cytometry analysis in EGFR expression level of various HNSCC cells. 177Lu-PCTA-cetuximab selectively killed cetuximab-resistant SNU-1066 cells in vitro. 64Cu-/177Lu-PCTA-cetuximab specifically accumulated in SNU-1066 tumor and those uptakes were peaked at 48 h and 7 day, respectively in biodistribution, PET and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. RIT with single dose of 177Lu-PCTA-cetuximab exhibited significant tumor regression and markedly reduced 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake, compared to other groups. Proliferation index were dramatically decreased and apoptotic index increased in RIT group. These results suggest that a diagnostic and therapeutic convergence radiopharmaceutical, 64Cu-/177Lu-PCTA-cetuximab has the potential of target selection using immuno-PET imaging and targeted therapy by RIT in EGFR expressing cetuximab-resistant HNSCC tumors.

Promoter methylation of cysteine dioxygenase type 1: gene silencing and tumorigenesis in hepatocellular carcinoma.

BACKGROUNDS/AIMS: Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor and is silenced by promoter methylation in various malignancies. The relationship between the CDO1 methylation status and hepatocellular carcinoma (HCC) tumorigenesis was evaluated. METHODS: Using a HCC cell line (SNU423), an in vitro demethylation study was performed to confirm whether promoter methylation causes CDO1 down-regulation. The SNU423 cells transfected with the CDO1 cell function was compared to that of naïve cells. An in vivo study using immunohistochemical staining of HCC specimens that were collected from patients who underwent curative liver resection was also performed. RESULTS: CDO1 was activated after demethylation treatment in the HCC specimens. Moreover, tumor cell proliferation, colony-forming, migration, and invasion activities significantly decreased after CDO1 transfection (p<0.05). The percentage of tumors that were larger than 5 cm was higher in patients who had a lower expression of CDO1 (p=0.030). Vascular invasion and histological grade were independent prognostic factors for poor overall and recurrence-free survival. The degree of CDO1 expression was not an independent prognostic factor in this study's population. CONCLUSIONS: These results suggested that methylation down-regulated CDO1 expression in the HCC cells. CDO1 methylation may be a potentially valuable diagnostic biomarker for HCC.

MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin.

Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and recent studies have reported miRNA-mediated radiotherapy resistance. However, further research is necessary to reveal the regulation mechanisms, and treatment strategies using miRNA are yet to be established for ESCC. We compared the miRNA expression profiles of ESCC parental (TE-4) and acquired radioresistance (TE-4R) cell lines using a miRNA microarray and qRT-PCR. Our data showed that miR-338-5p, one of the target miRNA biomarkers, was significantly downregulated in TE-4R. Ectopic overexpression of miR-338-5p induced apoptosis and sensitivity to radiation treatment by interfering with survivin, which is a known inhibitor of apoptosis. Overexpression of survivin reversed miR-338-5p-induced apoptosis. Tumor xenograft experiments indicated that therapeutic delivery of the miR-338-5p mimics via direct injection into tumor mass increased sensitivity to radiation therapy. In conclusion, our findings suggest that miR-338-5p is a potential radiosensitizer and may be a therapeutic biomarker for radioresistant in ESCC.