DNA-dependent protein kinase regulates cytosolic double-stranded DNA secretion from irradiated macrophages to increase radiosensitivity of tumors.

BACKGROUND AND PURPOSE: To investigate the molecular mechanism by which irradiated macrophages secrete cytosolic double-stranded DNA (c-dsDNA) to increase radiosensitivity of tumors. MATERIALS AND METHODS: Irradiated bone marrow-derived macrophages (BMDM) were co-incubated with irradiated EO771 or MC38 cancer cells to determine clonogenic survival. c-dsDNA were measured by agarose gel or enzyme-linked immunosorbent assay. BMDM or cancer cells were analyzed with immunostaining or western blot. Subcutaneously implanted MC38 cells in myeloid-specific Prkdc knockout (KO) mice or littermate control mice were irradiated with 8 Gy to determine radiosensitivity of tumors. RESULTS: We observed that irradiated BMDM significantly increased radiosensitivity of cancer cells. By performing immunostaining, we found that there was a dose-dependent increase in the formation of c-dsDNA and phosphorylation in DNA-dependent protein kinase (DNA-PK) in irradiated BMDM. Importantly, c-dsDNA in irradiated BMDM could be secreted to the extracellular milieu and this process required DNA-PK, which phosphorylated myosin light chain to regulate the secretion. The secreted c-dsDNA from irradiated BMDM then activated toll-like receptor-9 and subsequent nuclear factor kappa-light-chain-enhancer of activated B cells signaling in the adjacent cancer cells inhibiting radiation-induced DNA double strand break repair. Lastly, we observed that irradiated tumors in vivo had a significantly increased number of tumor-associated macrophages (TAM) with phosphorylated DNA-PK expression in the cytosol. Furthermore, tumors grown in myeloid-specific Prkdc KO mice, in which TAM lacked phosphorylated DNA-PK expression were significantly more radioresistant than those of the wild-type control mice. CONCLUSIONS: Irradiated macrophages can increase antitumor efficacy of radiotherapy through secretion of c-dsDNA under the regulation of DNA-PK.

FLASH Radiotherapy: A FLASHing Idea to Preserve Neurocognitive Function.

FLASH radiotherapy (FLASH RT) is a technique to deliver ultra-high dose rate in a fraction of a second. Evidence from experimental animal models suggest that FLASH RT spares various normal tissues including the lung, gastrointestinal track, and brain from radiation-induced toxicity (a phenomenon known as FLASH effect), which is otherwise commonly observed with conventional dose rate RT. However, it is not simply the ultra-high dose rate alone that brings the FLASH effect. Multiple parameters such as instantaneous dose rate, pulse size, pulse repetition frequency, and the total duration of exposure all need to be carefully optimized simultaneously. Furthermore it is critical to validate FLASH effects in an in vivo experimental model system. The exact molecular mechanism responsible for this FLASH effect is not yet understood although a number of hypotheses have been proposed including oxygen depletion and less reactive oxygen species (ROS) production by FLASH RT, and enhanced ability of normal tissues to handle ROS and labile iron pool compared to tumors. In this review, we briefly overview the process of ionization event and history of radiotherapy and fractionation of ionizing radiation. We also highlight some of the latest FLASH RT reviews and results with a special interest to neurocognitive protection in rodent model with whole brain irradiation. Lastly we discuss some of the issues remain to be answered with FLASH RT including undefined molecular mechanism, lack of standardized parameters, low penetration depth for electron beam, and tumor hypoxia still being a major hurdle for local control. Nevertheless, researchers are close to having all answers to the issues that we have raised, hence we believe that advancement of FLASH RT will be made more quickly than one can anticipate.

Sensing the oxygen and temperature in the adipose tissues - who's sensing what?

Adipose tissues, composed of various cell types, including adipocytes, endothelial cells, neurons, and immune cells, are organs that are exposed to dynamic environmental challenges. During diet-induced obesity, white adipose tissues experience hypoxia due to adipocyte hypertrophy and dysfunctional vasculature. Under these conditions, cells in white adipose tissues activate hypoxia-inducible factor (HIF), a transcription factor that activates signaling pathways involved in metabolism, angiogenesis, and survival/apoptosis to adapt to such an environment. Exposure to cold or activation of the ß-adrenergic receptor (through catecholamines or chemicals) leads to heat generation, mainly in brown adipose tissues through activating uncoupling protein 1 (UCP1), a proton uncoupler in the inner membrane of the mitochondria. White adipose tissues can undergo a similar process under this condition, a phenomenon known as 'browning' of white adipose tissues or 'beige adipocytes'. While UCP1 expression has largely been confined to adipocytes, HIF can be expressed in many types of cells. To dissect the role of HIF in specific types of cells during diet-induced obesity, researchers have generated tissue-specific knockout (KO) mice targeting HIF pathways, and many studies have commonly revealed that intact HIF-1 signaling in adipocytes and adipose tissue macrophages exacerbates tissue inflammation and insulin resistance. In this review, we highlight some of the key findings obtained from these transgenic mice, including Ucp1 KO mice and other models targeting the HIF pathway in adipocytes, macrophages, or endothelial cells, to decipher their roles in diet-induced obesity.

DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs): Beyond the DNA Double-Strand Break Repair.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a member of the phosphatidylinositol 3-kinase related kinase family is a well-known player in repairing DNA double strand break through non-homologous end joining pathway. This mechanism has allowed us to understand its critical role in T and B cell development through V(D)J recombination and class switch recombination, respectively. We have also learned that the defects in these mechanisms lead to severely combined immunodeficiency (SCID). Here we highlight some of the latest evidence where DNA-PKcs has been shown to localize not only in the nucleus but also in the cytoplasm, phosphorylating various proteins involved in cellular metabolism and cytokine production. While it is an exciting time to unveil novel functions of DNA-PKcs, one should carefully choose experimental models to study DNA-PKcs as the experimental evidence has been shown to differ between cells of defective DNA-PKcs and those of DNA-PKcs knockout. Moreover, while there are several DNA-PK inhibitors currently being evaluated in the clinical trials in attempt to increase the efficacy of radiotherapy or chemotherapy, multiple functions and subcellular localization of DNA-PKcs in various types of cells may further complicate the effects at the cellular and organismal level.

Racial Discrimination as a Cumulative Risk Factor Affecting Parental Stress on the Psychological Distress of Korean Americans (Both US- and Foreign-Born) amid COVID-19: Structural Equation Modeling.

This study examined the relationships of parental stress and racial discrimination to the psychological distress of Korean Americans (both US- and foreign-born) during the COVID-19 pandemic. It also explored whether racial discrimination moderated the effect of parental stress on psychological distress. Using primary data collected between May 24, 2020, and June 14, 2020, via an online questionnaire, confirmatory factor analysis and structural equation models were conducted on 339 Korean American parents. Results indicated that parental stress and racial discrimination were associated with parental psychological distress. However, when the sample was divided by parental sex, racial discrimination played as a moderator, the interaction of discrimination, and parenting stress was associated with more psychological distress only for mothers. Based on the study results, we recommended that policymakers should consider policies and programs that can reduce racism to make up for the public health crisis associated with COVID-19; clinical practitioners also need to provide appropriate virtual mental/physical health services and interventions that can decrease parental stress and psychological distress amid COVID-19.

Associations between accessibility to health care service, social support, and Korean Americans' mental health status amid the COVID-19 pandemic.

BACKGROUND: While previous studies have examined the relationships between social support and health care accessibility among ethnic minority populations, studies on Korean Americans remain scarce. Therefore, this study aims to assess the relationship between Korean Americans' mental health, accessibility to health care, and how they perceive the level of social support during the COVID-19 pandemic. METHOD/RESULT: We distributed online surveys to Korean Americans from May 24, 2020, to June 14, 2020, generating 790 responses from participants residing in 42 states. Binary Logistic and Ordinary Least Square regression analyses revealed that poor mental health was associated with language barriers inhibiting Korean Americans' access to COVID-19-related information. Their perceived social support from family members and close friends was positively associated with mental health. CONCLUSION: Our findings recommend that equipping community health care services with translators or interpreters is necessary. Additionally, health practitioners and staff should be trained to utilize telehealth tools to effectively treat individuals with mental health problems. American policymakers and health care professionals need to understand and address the unique hardships Korean Americans experience amid COVID-19.

Effects of Toxic Metal Contamination in the Tri-State Mining District on the Ecological Community and Human Health: A Systematic Review.

Although extensive research exists on toxic environments in the Tri-State Mining District (TSMD), there has been a lack of research on how harmful effects in TSMD could affect residents living in those areas. However, quite recently, such research regarding relationships between the health conditions of residents and toxic elements in the TSMD began to grow. The increase of empirical studies means greater complexity of the findings that require a more intricate understanding. To meet the goals of this study, an extensive, systematic review of the literature using PRISMA was conducted. This method resulted in 19 articles that define the harmful effects of the TSMD on the ecology and the physical health of residents. This research found that toxic metals not only negatively impact natural processes in the TSMD environments (fish species reduction, kidney and liver problems, and toxic diet) but also continuously affect the health of residents (high blood Pb and mortality).This study makes a vital contribution building upon the existing outcomes of the correlations between toxic elements in the TSMD areas and the health of residents. Furthermore, conclusions of this study provide updated information to policymakers and health-related professionals by providing adequate and innovative remediations and health-related services in the TSMD.

Predicting Psychological Distress Amid the COVID-19 Pandemic by Machine Learning: Discrimination and Coping Mechanisms of Korean Immigrants in the U.S.

The current study examined the predictive ability of discrimination-related variables, coping mechanisms, and sociodemographic factors on the psychological distress level of Korean immigrants in the U.S. amid the COVID-19 pandemic. Korean immigrants (both foreign-born and U.S.-born) in the U.S. above the age of 18 were invited to participate in an online survey through purposive sampling. In order to verify the variables predicting the level of psychological distress on the final sample from 42 states (n = 790), the Artificial Neural Network (ANN) analysis, which is able to examine complex non-linear interactions among variables, was conducted. The most critical predicting variables in the neural network were a person's resilience, experiences of everyday discrimination, and perception that racial discrimination toward Asians has increased in the U.S. since the beginning of the COVID-19 pandemic.

The effect of short-term creatine intake on blood lactic acid and muscle fatigue measured by accelerometer-based tremor response to acute resistance exercise.

PURPOSE: The purpose of this study was to investigate the effects of short-term creatine intake on muscle fatigue induced by resistance exercise in healthy adolescent men, i.e., lactic acid concentration and wrist and head tremor measured by an accelerometer. METHODS: Twelve healthy adolescent men who had no experience with creatine intake were included. The subjects were randomly assigned to the creatine group and the placebo group, followed by 5 days of creatine and placebo intake, and 5 times of 5 sets of leg press, leg extension, bench press, and arm curl exercises at 70% repetition maximum (RM). The lactic acid concentration before and after exercising, rate of perceived exertion (RPE), and accelerometer-based wrist tremor and head tremor during exercise were measured. Subsequently, after 7 days to allow for creatine washout, the same exercise treatment and measurement were performed in each group after switching drug and placebo between the groups. RESULTS: The level of lactic acid before and after the acute resistance exercise trial was significantly lower in the creatine group than in the placebo group (P <0.05). The mean RPE during the resistance exercise was significantly lower in the creatine group than in the placebo group (P <0.05). There was no difference between the two groups in the mean wrist tremor during resistance exercise, but the mean head tremor values were significantly lower in the creatine group than in the placebo group in the arm curl, the last event of the exercise trials (P <0.05). CONCLUSION: Short-term creatine intake reduces the blood fatigue factor increased by resistance exercise, and is thought to suppress fatigue, especially in the latter half of resistance exercise. Therefore, these findings indicate that short-term creatine intake can have an improved effect on anaerobic exercise performance.

The association of locomotive and non-locomotive physical activity measured by an accelerometer with functional fitness in healthy elderly men: a pilot study.

PURPOSE: The purpose of this study was to investigate the relationship of various aspects of daily physical activity, such as the number of steps, time spent in moderate to vigorous intensity physical activity (MVPA), and locomotive and non-locomotive MVPA measured by a triaxial accelerometer, with the functional fitness in healthy elderly men. METHODS: The subjects of this study were 22 healthy elderly men aged over 65 years. The participants wore a triaxial accelerometer for two weeks to estimate their daily physical activities. The level of functional fitness was measured based on "National Fitness Award 100 in Korea" immediately after the measurement of two weeks of daily physical activities. RESULTS: The results showed that active healthy elderly men with more than 6,500 walking steps per day and more than 60 min per day spent in MVPA showed a significantly higher 2-min marching in place and index of cardiorespiratory endurance compared to less physically active participants. Particularly, locomotive MVPA was significantly associated with cardiorespiratory endurance levels (r = 0.50), whereas non-locomotive MVPA was not associated with other measurements of functional fitness. CONCLUSION: Increased MVPA time, especially the locomotive MVPA, can effectively suppress the decrease in cardiorespiratory endurance level in elderly men. However, no association was observed between non-locomotive MVPA, such as household activities, and functional fitness in healthy elderly men.

Disulfiram deregulates HIF-α subunits and blunts tumor adaptation to hypoxia in hepatoma cells.

AIM: Disulfiram is an aldehyde dehydrogenase inhibitor that was used to treat alcoholism and showed anticancer activity, but its anticancer mechanism remains unclear. The aim of this study was to investigate the effects of disulfiram on the hypoxia-inducible factor (HIF)-driven tumor adaptation to hypoxia in vitro. METHODS: Hep3B, Huh7 and HepG2 hepatoma cells were incubated under normoxic (20% O2) or hypoxic (1% O2) conditions for 16 h. The expression and activity of HIF-1α and HIF-2α proteins were evaluated using immunoblotting and luciferase reporter assay, respectively. Semi-quantitative RT-PCR was used to analyze HIF-mediated gene expression. Endothelial tubule formation assay was used to evaluate the anti-angiogenic effect. RESULTS: Hypoxia caused marked expression of HIF-1α and HIF-1α in the 3 hepatoma cell lines, dramatically increased HIF activity and induced the expression of HIF downstream genes (EPO, CA9, VEGF-A and PDK1) in Hep3B cells. HIF-2α expression was positively correlated with the induction of hypoxic genes (CA9, VEGF-A and PDK1). Moreover, hypoxia markedly increased VEGF production and angiogenic potential of Hep3B cells. Disulfiram (0.3 to 2 µmol/L) inhibited hypoxia-induced gene expression and HIF activity in a dose-dependent manner. Disulfiram more effectively suppressed the viability of Hep3B cells under hypoxia, but it did not affect the cell cycle. Overexpression of HIF-2α in Hep3B cells reversed the inhibitory effects of disulfiram on hypoxia-induced gene expression and cell survival under hypoxia. CONCLUSION: Disulfiram deregulates the HIF-mediated hypoxic signaling pathway in hepatoma cells, which may contribute to its anticancer effect. Thus, disulfiram could be used to treat solid tumors that grow in a HIF-dependent manner.