PURPOSE: Metabolic cooperation via gap junctional intercellular communication (GJIC) is an important mechanism of the bystander effect in gene therapy using the Herpes Simplex Virus thymidine kinase/ganciclovir (HSVtk/GCV) "prodrug" system. Since retinoids have been reported to increase GJIC by induction of connexin expression, we hypothesized that these compound could be used to augment the HSVtk/GCV bystander effect. MATERIALS AND METHODS: We transferred HSVtk gene to AB12 cell line that express connexin43 as a component of gap junction. We examined the effects of retinoic acid (RA) on GJIC utilizing a functional double-dye transfer study. To evaluate the bystander effect in vivo, a murine subcutaneous tumor model was established. Before proceeding with comparisons of HSVtk/GCV mediated bystander cell killing, we evaluated the effects of RA on flank tumor growth in order to rule out a potential antitumor effect of RA alone. Then we determined the effects of retinoic acid on bystander-mediated cell killing in an animal model. RESULTS: Addition of all-trans retinoic acid increased GJIC in AB12 cell line and was associated with more efficient GCV induced bystander killing in animal model. HSVtk transduced tumors in mice treated with the combination of GCV and retinoids were significantly smaller than those treated with GCV or retinoids alone. CONCLUSION: These results provide evidence that retinoids can augment the efficiency of cell killing with the HSVtk/GCV system by enhancing bystander effects and may thus be a promising new approach to improve response in gene therapy utilizing the HSVtk/GCV system to treat tumors.
Animals ; Bystander Effect ; Cell Line ; Connexin 43 ; Gap Junctions ; Genetic Therapy* ; Herpes Simplex* ; Homicide ; Mice ; Models, Animal ; Phosphotransferases* ; Retinoids ; Simplexvirus* ; Thymidine ; Tretinoin*

BACKGROUND: Metabolic cooperation via gap junctional intercellular communication (GJIC) is an important mechanism of the bystander effect in gene therapy using the Herpes Simplex Virus thymidine kinase/ganciclovir (HSVtk) 'prodrug' system. Since retinoids have been reported to increase GJIC by induction of connexin 43 expression, we hypothesized that treatment of tumor cells with retinoic acid could augment the bystander erect of the HSVtk/GCV system and result in improved tumor cell killing by enhancing GJIC. METHODS: We transferred HSVtk gene to SKHep-J cell line that does not express connexin43, and also transferred the gone to human and murine mesothelioma cell lines that express connexin43. We verified that retinoic acid enhanced GJIC utilizing a functional double-dye transfer study and evaluated the effects of retinoic acid on the growth rate of honor cells. We then tested the effects of retinoic acid on bystander-mediated cell killing. RESULTS: Addition of all-trans retinoic acid (RA) increased GJIC in cell lines expressing connexin43 and was associated with more efficient in vitro bystander killing in cells transduced with HSVtk via adenoviral and retroviral vectors. In contrast, there was no increase in the efficiency of the bystander effect after exposure to RA in a cell line which had no detectable connexin 43. CONCLUSION: These results provide evidence that retinoids can augment the efficiency of cell killing with the HSVtk/GCV system by enhancing bystander effect and may thus be a promising new approach to improve responses in gene therapy utilizing the HSVtk system to treat tumors.
Bystander Effect* ; Cell Line ; Connexin 43 ; Genetic Therapy* ; Herpes Simplex* ; Homicide ; Humans ; Mesothelioma ; Phosphotransferases* ; Retinoids ; Simplexvirus* ; Thymidine ; Tretinoin* ; Zidovudine

Selenium is an antioxidant trace element linked to cardiovascular disease and cancer. Although diet is a major source, relatively little else is known about independent determinants of selenium levels in free-living humans. In this study, we aimed to investigate the independent demographic, lifestyle, and dietary determinants of selenium levels in 1,997 men and 1,905 women in two large prospective U.S. cohorts. Toenail selenium levels were quantified using neutron activation analysis. Diet, geographic residence, demographic, and environmental factors were assessed by validated self-administered questionnaires. Multivariate generalized linear models were conducted to assess the independent relations of these factors with toenail selenium levels, correcting for measurement error in the diet. In multivariable-adjusted analyses, independent predictors of higher selenium were male gender (6.3% higher levels); living in West and Northern-Midwest U.S. regions (8.9% and 7.4% higher than Southern-Midwest regions, respectively); consumption of beef and bread products (between 0.7 - 2.5% higher per daily serving); and selenium supplement use (6.9% higher than non-users); whereas cigarette smoking (5-10% lower than never smokers) , older age (0.6% lower per 5 years), and consumption of eggs, white rice, dairy products, coffee, and alcohol (between 0.1 to 2.0% lower per daily serving) were associated with lower selenium. Multiple dietary and non-dietary factors independently predicted selenium levels, suggesting that both consumption and non-dietary processes (e.g., related to oxidant status) may affect levels. Significant geographic variation in selenium levels exists in the US.
Bread ; Cardiovascular Diseases ; Coffee ; Cohort Studies ; Dairy Products ; Diet ; Eggs ; Female ; Humans ; Life Style ; Linear Models ; Male ; Nails ; Neutron Activation Analysis ; Ovum ; Prospective Studies ; Surveys and Questionnaires ; Selenium ; Smoking

In completely edentulous patients, reference points for determining the occlusal plane and vertical dimension are lacking. Therefore, accurately recording the jaw relation is essential for the fabrication of dentures or implant prostheses. Traditional methods using occlusal rims for bite registration require time for fabrication and intraoral adjustments, leading to patient discomfort with multiple visits. Recently, several methods have been developed to address these limitations by simultaneously obtaining impressions and jaw relation records. The JB Fork (PNUADD Co., Ltd., Busan, Korea) is a one-step jaw-relation recording system that can be integrated with digital protocols for fabrication of dental prostheses. It allows for simultaneous impression-making, verification of the maxillary anterior tooth arrangement, and recording of vertical and horizontal jaw relations, thereby facilitating the transfer of the occlusal plane. This case report aims to present a method for acquiring jaw-relation records using a JB fork and digital scan data.

In completely edentulous patients, reference points for determining the occlusal plane and vertical dimension are lacking. Therefore, accurately recording the jaw relation is essential for the fabrication of dentures or implant prostheses. Traditional methods using occlusal rims for bite registration require time for fabrication and intraoral adjustments, leading to patient discomfort with multiple visits. Recently, several methods have been developed to address these limitations by simultaneously obtaining impressions and jaw relation records. The JB Fork (PNUADD Co., Ltd., Busan, Korea) is a one-step jaw-relation recording system that can be integrated with digital protocols for fabrication of dental prostheses. It allows for simultaneous impression-making, verification of the maxillary anterior tooth arrangement, and recording of vertical and horizontal jaw relations, thereby facilitating the transfer of the occlusal plane. This case report aims to present a method for acquiring jaw-relation records using a JB fork and digital scan data.

In completely edentulous patients, reference points for determining the occlusal plane and vertical dimension are lacking. Therefore, accurately recording the jaw relation is essential for the fabrication of dentures or implant prostheses. Traditional methods using occlusal rims for bite registration require time for fabrication and intraoral adjustments, leading to patient discomfort with multiple visits. Recently, several methods have been developed to address these limitations by simultaneously obtaining impressions and jaw relation records. The JB Fork (PNUADD Co., Ltd., Busan, Korea) is a one-step jaw-relation recording system that can be integrated with digital protocols for fabrication of dental prostheses. It allows for simultaneous impression-making, verification of the maxillary anterior tooth arrangement, and recording of vertical and horizontal jaw relations, thereby facilitating the transfer of the occlusal plane. This case report aims to present a method for acquiring jaw-relation records using a JB fork and digital scan data.

Background/Aims: The efficacy and safety of mepolizumab in patients with severe eosinophilic asthma has been evaluated in a global clinical trial programme. This post hoc analysis assesses the efficacy and safety of mepolizumab in Korean patients. Methods: Data from Korean patients in the Phase III, placebo-controlled, randomised DREAM (MEA112997/NCT01000506) and MENSA (MEA115588/ NCT01691521) studies were included. Patients ≥ 12 years old with severe eosinophilic asthma received mepolizumab (DREAM: 75, 250 or 750 mg intravenously [IV]; MENSA: 75 mg IV or 100 mg subcutaneously [SC]), or placebo every 4 weeks for 52 weeks (DREAM) or 32 weeks (MENSA). The primary outcome was the rate of clinically significant asthma exacerbations. Secondary outcomes included forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire (ACQ) and St George’s Respiratory Questionnaire (SGRQ) scores (MENSA only). Blood eosinophil counts (BEC) and safety were assessed throughout. Results: Reductions in the rate of clinically significant asthma exacerbations were observed with the approved (100 mg SC) and bioequivalent (75 mg IV) doses of mepolizumab in Korean patients who participated in DREAM and MENSA. In MENSA, trends for improvements from baseline at week 32 in pre-bronchodilator FEV1 (75 mg IV group), ACQ-5 and SGRQ scores (in both treatment groups) were seen versus placebo in Korean patients. Incidence of on-treatment adverse events was similar in Korean patients versus non-Korean patients as were observed reductions from baseline in BEC. Conclusions Mepolizumab treatment provided clinical benefits for Korean patients with severe eosinophilic asthma; the safety profile is consistent with the overall population.

Background: Inhibitory effects of denosumab on bone remodeling are reversible and disappear once treatment is discontinued. Herein, we examined whether and to what extent delayed denosumab administration is also associated with fracture risk using nation-wide data. Methods: The study cohort included women aged 45 to 89 years who were started on denosumab for osteoporosis between October 2017 and December 2019 using data from the Korean Health Insurance Review and Assessment service. Participants were stratified according to the time of their subsequent denosumab administration from the last denosumab administration, including those with within 30 days early dosing (ED30), within the planned time of 180–210 days (referent), within 30–90 days of delayed dosing (DD90), within 90–180 days of delayed dosing (DD180), and longer than 181 days of delayed dosing (DD181+). The primary outcome was the incidence of all clinical fractures. Results: A total of 149,199 participants included and 2,323 all clinical fractures (including 1,223 vertebral fractures) occurred. The incidence of all fractures was significantly higher in the DD90 compared to reference group (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.4). The risk of all fracture was even higher in the longer delayed DD180 group (HR, 1.9; 95% CI, 1.6 to 2.3) and DD181+ group (HR, 1.8; 95% CI, 1.5 to 2.2). Increased risks of fractures with delayed dosing were consistently observed for vertebral fractures. Conclusion Delayed denosumab dosing, even by 1 to 3 months, was significantly associated with increased fracture risk. Maintaining the correct dosing schedule should be emphasized when starting denosumab.

Background: Inhibitory effects of denosumab on bone remodeling are reversible and disappear once treatment is discontinued. Herein, we examined whether and to what extent delayed denosumab administration is also associated with fracture risk using nation-wide data. Methods: The study cohort included women aged 45 to 89 years who were started on denosumab for osteoporosis between October 2017 and December 2019 using data from the Korean Health Insurance Review and Assessment service. Participants were stratified according to the time of their subsequent denosumab administration from the last denosumab administration, including those with within 30 days early dosing (ED30), within the planned time of 180–210 days (referent), within 30–90 days of delayed dosing (DD90), within 90–180 days of delayed dosing (DD180), and longer than 181 days of delayed dosing (DD181+). The primary outcome was the incidence of all clinical fractures. Results: A total of 149,199 participants included and 2,323 all clinical fractures (including 1,223 vertebral fractures) occurred. The incidence of all fractures was significantly higher in the DD90 compared to reference group (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.4). The risk of all fracture was even higher in the longer delayed DD180 group (HR, 1.9; 95% CI, 1.6 to 2.3) and DD181+ group (HR, 1.8; 95% CI, 1.5 to 2.2). Increased risks of fractures with delayed dosing were consistently observed for vertebral fractures. Conclusion Delayed denosumab dosing, even by 1 to 3 months, was significantly associated with increased fracture risk. Maintaining the correct dosing schedule should be emphasized when starting denosumab.

Background: Inhibitory effects of denosumab on bone remodeling are reversible and disappear once treatment is discontinued. Herein, we examined whether and to what extent delayed denosumab administration is also associated with fracture risk using nation-wide data. Methods: The study cohort included women aged 45 to 89 years who were started on denosumab for osteoporosis between October 2017 and December 2019 using data from the Korean Health Insurance Review and Assessment service. Participants were stratified according to the time of their subsequent denosumab administration from the last denosumab administration, including those with within 30 days early dosing (ED30), within the planned time of 180–210 days (referent), within 30–90 days of delayed dosing (DD90), within 90–180 days of delayed dosing (DD180), and longer than 181 days of delayed dosing (DD181+). The primary outcome was the incidence of all clinical fractures. Results: A total of 149,199 participants included and 2,323 all clinical fractures (including 1,223 vertebral fractures) occurred. The incidence of all fractures was significantly higher in the DD90 compared to reference group (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.4). The risk of all fracture was even higher in the longer delayed DD180 group (HR, 1.9; 95% CI, 1.6 to 2.3) and DD181+ group (HR, 1.8; 95% CI, 1.5 to 2.2). Increased risks of fractures with delayed dosing were consistently observed for vertebral fractures. Conclusion Delayed denosumab dosing, even by 1 to 3 months, was significantly associated with increased fracture risk. Maintaining the correct dosing schedule should be emphasized when starting denosumab.