Clinical signatures of genetic epilepsies precede diagnosis in electronic medical records of 32,000 individuals.

PURPOSE: An early genetic diagnosis can guide the time-sensitive treatment of individuals with genetic epilepsies. However, most genetic diagnoses occur long after disease onset. We aimed to identify early clinical features suggestive of genetic diagnoses in individuals with epilepsy through large-scale analysis of full-text electronic medical records (EMR). METHODS: We extracted 89 million time-stamped standardized clinical annotations using Natural Language Processing from 4,572,783 clinical notes from 32,112 individuals with childhood epilepsy, including 1,925 individuals with known or presumed genetic epilepsies. We applied these features to train random forest models to predict SCN1A-related disorders and any genetic diagnosis. RESULTS: We identified 47,774 age-dependent associations of clinical features with genetic etiologies a median of 3.6 years prior to molecular diagnosis. Across all 710 genetic etiologies identified in our cohort, neurodevelopmental differences between 6-9 months increased the likelihood of a later molecular diagnosis fivefold (P<0.0001, 95% CI=3.55-7.42). A later diagnosis of SCN1A-related disorders (AUC=0.91) or an overall positive genetic diagnosis (AUC=0.82) could be reliably predicted using random forest models. CONCLUSION: Clinical features predictive of genetic epilepsies precede molecular diagnoses by up to several years in conditions with known precision treatments. An earlier diagnosis facilitated by automated EMR analysis has the potential for earlier targeted therapeutic strategies in the genetic epilepsies.

Association between alcohol use disorder and risk of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a common sleep disorder characterised by recurrent upper airway collapse during sleep. Alcohol consumption has been linked to an increased risk of OSA due to its effects on the upper airway and body mass index (BMI). We aimed to investigate the correlation between alcohol use disorders and OSA. We used 11,859 participants data from Korean National Health and Nutrition Examination Surveys. The variable of interest was alcohol use disorder, measured using the Alcohol Use Disorders Identification Test, and the dependent variable was the risk of OSA, measured using the Snoring, Tiredness, Observed apnea, high blood Pressure, BMI, age, neck circumference, and male gender questionnaires. Multiple logistic regression was used to assess the association between alcohol use disorder and OSA risk after adjusted analysis. A significant association was found between alcohol use disorder and OSA (adjusted odds ratio [aOR] 2.14, 95% confidence interval [CI] 1.93-2.37). In the unemployed group, those with alcohol use disorder had the highest odds of being at risk of OSA compared with those who did not have this disorder (aOR 2.45, 95% CI 2.04-2.95). The OSA risk increased as the snoring frequency, amount of alcohol consumed, and frequency of binge drinking increased. This study suggests an association between alcohol use disorders and the risk of OSA. The frequency of alcohol consumption, quantity of alcohol consumed, and snoring frequency were associated with the risk of OSA. Therefore, ceasing alcohol consumption is recommended as an effective approach to enhancing sleep quality.

Association between watching eating shows and unhealthy food consumption in Korean adolescents.

BACKGROUND: Eating habits formed during adolescence greatly influence the maintenance of health in adulthood. With the recent development of social media and easy access to the Internet, adolescents watch plenty of food videos, particularly Mukbang and Cookbnag(eating show)content. This media genre's impact on food choices has been covered in several studies; however, studies on unhealthy eating habits directly related to adolescents' exposure to eating shows are insufficient. METHODS: For this study, we used data from the 18th Korea Youth Risk Behavior Survey conducted in 2022 and finalized 50,451 participants. The extent of exposure to eating show media over the course of a week, as well as the consumption of fast food, sugar-sweetened beverages (SSBs), and high caffeinated beverages within that week were measured through self-reporting questionnaires. We classified the participants into two groups based on their frequency of watching eating shows. A multiple logistic regression analysis was performed to investigate the association between eating show and unhealthy food consumption. RESULTS: For both males and females, eating show exposure was strongly associated with the consumption of fast food (male: OR:1.37, 95% CI:1.26-1.49; female: OR:1.46, 95% CI:1.36-1.57), SSB (male: OR:1.42, 95% CI:1.26-1.60; female: OR:1.51, 95% CI:1.35-1.70), and high caffeinated beverage (male: OR:1.30, 95% CI:1.23-1.37; female: OR:1.24, 95% CI:1.18-1.31). It was observed that both sexes were more likely to frequently eat unhealthy food than students who did not watch eating shows. CONCLUSION: Among Korean adolescents, students exposed to eating shows, which primarily aim to entertain, were more likely to consume fast food, SSBs, and high caffeinated beverages. Therefore, this study's findings suggest that eating show could influence adolescents' food choices, highlighting the need for interest in emerging cultures and corresponding health policies.

From integers to fractions: The role of analogy in transfer and long-term learning.

Fractions are the gatekeepers to advanced mathematics but are difficult to learn. One powerful learning mechanism is analogy, which builds fraction understanding on a pre-existing foundation of integer knowledge. Indeed, a short intervention that aligned fractions and integers on number lines improved children's estimates of fractions (Yu et al., 2022). The breadth and durability of such gains, however, are unknown, and analogies to other sources (such as percentages) may be equally powerful. To investigate this issue, we randomly assigned 109 fourth and fifth graders to one of three experimental conditions with different analogical sources (integers, percentages, or fractions) or a control condition. During training, children in the experimental conditions solved pairs of aligned fraction number line problems and proportionally-equivalent problems expressed in integers, percentages, or fractions (e.g., 3/8 on a 0-1 number line aligned with 3 on a 0-8 number line). Children in the control group solved fraction number-line problems sequentially. At pretest and a two-week delayed posttest, children completed a broad fraction knowledge battery, including estimation, comparison, categorization, ordering, and arithmetic. Results showed that aligning integers and fractions on number lines facilitated better estimation of fractional magnitudes, and the training effect transferred to novel fraction problems after two weeks. Similar gains were not observed for analogies using percentages. These findings highlight the importance of building new mathematical knowledge through analogies to familiar, similar sources.

Development and efficacy assessment of hand sanitizers and polylactic acid films incorporating caffeic acid and vanillin for enhanced antiviral properties against HCoV-229E.

BACKGROUND: Although three years after the outbreak of SARS-CoV-2, the virus is still having a significant impact on human health and the global economy. Infection through respiratory droplets is the main transmission route, but the transmission of the virus by surface contact cannot be ignored. Hand sanitizers and antiviral films can be applied to control SARS-CoV-2, but sanitizers and films show drawbacks such as resistance of the virus against ethanol and environmental problems including the overuse of plastics. Therefore, this study suggested applying natural substrates to hand sanitizers and antiviral films made of biodegradable plastic (PLA). This approach is expected to provide advantages for the easy control of SARS-CoV-2 through the application of natural substances. METHODS: Antiviral disinfectants and films were manufactured by adding caffeic acid and vanillin to ethanol, isopropyl alcohol, benzalkonium chloride, and PLA. Antiviral efficacies were evaluated with slightly modified international standard testing methods EN 14,476 and ISO 21,702. RESULTS: In suspension, all the hand sanitizers evaluated in this study showed a reduction of more than 4 log within 2 min against HCoV-229E. After natural substances were added to the hand sanitizers, the time needed to reach the detection limit of the viral titer was shortened both in suspension and porcine skin. However, no difference in the time needed to reach the detection limit of the viral titer was observed in benzalkonium chloride. In the case of antiviral films, those made using both PLA and natural substances showed a 1 log reduction of HCoV-229E compared to the neat PLA film for all treatment groups. Furthermore, the influence of the organic load was evaluated according to the number of contacts of the antiviral products with porcine skin. Ten rubs on the skin resulted in slightly higher antiviral activity than 50 rubs. CONCLUSION: This study revealed that caffeic acid and vanillin can be effectively used to control HCoV-229E for hand sanitizers and antiviral films. In addition, it is recommended to remove organic matter from the skin for maintaining the antiviral activity of hand sanitizer and antiviral film as the antiviral activity decreased as the organic load increased in this study.

Multi-Targeting Neuroprotective Effects of Syzygium aromaticum Bud Extracts and Their Key Phytocompounds against Neurodegenerative Diseases.

Alzheimer's disease (AD) is a neurodegenerative disease that causes a gradual loss of normal motor and cognitive function. The complex AD pathophysiology involves various factors such as oxidative stress, neuroinflammation, amyloid-beta (Aß) aggregation, disturbed neurotransmission, and apoptosis. The available drugs suffer from a range of side effects and are not able to cover different aspects of the disease. Therefore, finding a safer therapeutic approach that can affect multiple targets at a time is highly desirable. In the present study, the underlying neuroprotective mechanism of an important culinary spice, Syzygium aromaticum (Clove) extract, and major bioactive compounds were studied in hydrogen peroxide-induced oxidative stress in human neuroblastoma SH-SY5Y cell lines as a model. The extracts were subjected to GC-MS to identify important bioactive components. The extracts and key bio-actives reduced reactive oxygen species (ROS), restored mitochondrial membrane potential (MMP), and provided neuroprotection from H2O2-induced oxidative stress in cell-based assays due to the antioxidant action. They also reduced lipid peroxidation significantly and restored GSH content. Clove extracts have also displayed anti-acetylcholinesterase (AChE) activity, anti-glycation potential, and Aß aggregation/fibrilization inhibition. The multitarget neuroprotective approach displayed by Clove makes it a potential candidate for AD drug development.

Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system for augmented renal clearance prediction in a trauma subgroup of a mixed ICU population.

WHAT IS KNOWN AND OBJECTIVE: Augmented renal clearance is prevalent in trauma patients and leads to subtherapeutic levels of renally eliminated medications with potentially unfavourable clinical outcomes. The Augmented Renal Clearance of Trauma in Intensive Care (ARCTIC) score has been developed to predict augmented renal clearance in critically ill trauma patients. Our primary objective was to validate this score among the trauma subgroup of a mixed intensive care patient cohort. METHODS: This single-centre, retrospective, observational cohort study assessed augmented renal clearance using a timed 24-h urine collection performed weekly. ARC was defined as a measured creatinine clearance of ≥130 ml/min/1.73 m2 . ARCTIC score performance was evaluated through a receiver operator characteristic curves and analysis of sensitivities and specificities for the trauma subgroup, the medical/surgical subgroup and the pooled cohort. RESULTS AND DISCUSSION: Augmented renal clearance was observed in 33.9% (n = 58) of trauma patients (n = 171) and 15.7% (n = 24) of medical/surgical patients (n = 153). Examination of different cutoffs for the ARCTIC score in our trauma population confirmed that the optimal cutoff score was ≥6. Comparison between ROC curves for ARCTIC score and for regression model based upon our data in trauma patients indicated validation of the score in this subgroup. Comparison of sensitivities and specificities for ARCTIC score between trauma (93.1% and 41.6%, respectively) and medical/surgical subjects (87.5% and 49.6%, respectively) showed no clinical nor statistical difference, suggesting validation for the medical/surgical subgroup as well. WHAT IS NEW AND CONCLUSION: In our mixed ICU population, the ARCTIC score was validated in the trauma subgroup. We also found that the score performed well in the medical/surgical population. Future studies should assess the performance of the ARCTIC score prospectively.

Prion Mutations in Republic of Republic of Korea, China, and Japan.

Prion gene (PRNP) mutations are associated with diverse disease phenotypes, including familiar Creutzfeldt-Jakob Disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI). Interestingly, PRNP mutations have been reported in patients diagnosed with Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and frontotemporal dementia. In this review, we describe prion mutations in Asian countries, including Republic of Republic of Korea, China, and Japan. Clinical phenotypes and imaging data related to these mutations have also been introduced in detail. Several prion mutations are specific to Asians and have rarely been reported in countries outside Asia. For example, PRNP V180I and M232R, which are rare in other countries, are frequently detected in Republic of Korea and Japan. PRNP T188K is common in China, and E200K is significantly more common among Libyan Jews in Israel. The A117V mutation has not been detected in any Asian population, although it is commonly reported among European GSS patients. In addition, V210I or octapeptide insertion is common among European CJD patients, but relatively rare among Asian patients. The reason for these differences may be geographical or ethical isolation. In terms of clinical phenotypes, V180I, P102L, and E200K present diverse clinical symptoms with disease duration, which could be due to other genetic and environmental influences. For example, rs189305274 in the ACO1 gene may be associated with neuroprotective effects in cases of V180I mutation, leading to longer disease survival. Additional neuroprotective variants may be possible in cases featuring the E200K mutation, such as KLKB1, KARS, NRXN2, LAMA3, or CYP4X1. E219K has been suggested to modify the disease course in cases featuring the P102L mutation, as it may result in the absence of prion protein-positive plaques in tissue stained with Congo red. However, these studies analyzed only a few patients and may be too preliminary. The findings need to be verified in studies with larger sample sizes or in other populations. It would be interesting to probe additional genetic factors that cause disease progression or act as neuroprotective factors. Further studies are needed on genetic modifiers working with prions and alterations from mutations.

Region of freshwater influence (ROFI) and its impact on sediment transport in the lower Mekong Delta coastal zone of Vietnam.

The delta of the Mekong River is one of the largest in the world, with the Mekong River carrying a large amount of sediments in its Region of Freshwater Influence (ROFI). This study investigates the flow structure and movement of both suspended and bedload sediments in the ROFI of the Lower Mekong Delta (LMD) in order to identify areas prone to sediment accretion and erosion. This is accomplished by applying the three-dimensional Coastal and Regional Ocean COmmunity (CROCO) model and then calculating the sediment budget of different stretches of the coastline. The model outputs, depicting areas experiencing sediment accretion and erosion along the coastline of the LMD, are then compared against observations obtained during the period 1990-2015 and demonstrate the ability of the model to identify areas particularly prone to erosion and where preventive actions against coastal erosion should focus.

Human CD36hi monocytes induce Foxp3+ CD25+ T cells with regulatory functions from CD4 and CD8 subsets.

The fetal and neonatal immune systems are uniquely poised to generate tolerance to self, maternal and environmental antigens encountered in the womb and shortly after birth. However, the tolerogenic nature of fetal and neonatal immunity can be detrimental in the context of pathogens, leading to overwhelming bacterial infections or chronic viral infections. A variety of mechanisms contribute to fetal and neonatal tolerance, including a propensity to generate Foxp3+ regulatory T cells (Treg cells). However, the mechanism(s) of fetal Foxp3+ T-cell differentiation, the specific antigen-presenting cells required and factors that inhibit Treg generation after the neonatal period are poorly understood. Here, we demonstrate that a subset of CD14+ monocytes expressing the scavenger molecule, CD36, can generate CD4+ and CD8+ T cells that coexpress Foxp3 and T-bet from both umbilical cord blood. These Foxp3+ T-bet+ T cells potently suppress T-cell proliferation and ameliorate xenogeneic graft-versus-host disease. CD14+  CD36+ monocytes provide known Treg-inducing signals: membrane-bound transforming growth factor-beta and retinoic acid. Unexpectedly, adult peripheral blood monocytes are also capable of inducing Foxp3+ T cells from both cord blood and adult peripheral naïve T cells. The induction of Foxp3+ T cells in umbilical cord blood by monocytes was inhibited by the lymphoid fraction of adult peripheral blood cells. These studies highlight a novel immunoregulatory role of monocytes and suggest that antigen presentation by CD36hi monocytes may contribute to the peripheral development of Foxp3+ T-bet+ T cells with regulatory functions in both neonates and adults.

The role of a suburban forest in controlling vertical trace gas and OH reactivity distributions - a case study for the Seoul metropolitan area.

We present trace gas vertical profiles observed by instruments on the NASA DC-8 and at a ground site during the Korea-US air quality study (KORUS) field campaign in May to June 2016. We focus on the region near the Seoul metropolitan area and its surroundings where both anthropogenic and natural emission sources play an important role in local photochemistry. Integrating ground and airborne observations is the major research goal of many atmospheric chemistry field campaigns. Although airborne platforms typically aim to sample from near surface to the free troposphere, it is difficult to fly very close to the surface especially in environments with complex terrain or a populated area. A detailed analysis integrating ground and airborne observations associated with specific concentration footprints indicates that reactive trace gases are quickly oxidized below an altitude of 700 m. The total OH reactivity profile has a rapid decay in the lower part of troposphere from surface to the lowest altitude (700 m) sampled by the NASA DC-8. The decay rate is close to that of very reactive biogenic volatile organic compounds such as monoterpenes. Therefore, we argue that photochemical processes in the bottom of the boundary layer, below the typical altitude of aircraft sampling, should be thoroughly investigated to properly assess ozone and secondary aerosol formation.

Comparison of sampling methods in assessing the microbiome from patients with ulcerative colitis.

BACKGROUND: Dysbiosis of ulcerative colitis (UC) has been frequently investigated using readily accessible stool samples. However, stool samples might insufficiently represent the mucosa-associated microbiome status. We hypothesized that luminal contents including loosely adherent luminal bacteria after bowel preparation may be suitable for diagnosing the dysbiosis of UC. METHODS: This study included 16 patients with UC (9 men and 7 women, mean age: 52.13 ± 14.09 years) and 15 sex- and age-matched healthy individuals (8 men and 7 women, mean age: 50.93 ± 14.11 years). They donated stool samples before colonoscopy and underwent luminal content aspiration and endoscopic biopsy during the colonoscopy. Then, the composition of each microbiome sample was analyzed by 16S rRNA-based next-generation sequencing. RESULTS: The microbiome between stool, luminal contents, and biopsy was significantly different in alpha and beta diversities. However, a correlation existed between stool and luminal contents in the Procrustes test (p = 0.001) and Mantel test (p = 0.0001). The stool microbiome was different between patients with UC and the healthy controls. Conversely, no difference was found in the microbiome of luminal content and biopsy samples between the two subject groups. The microbiome of stool and lavage predicted UC, with AUC values of 0.85 and 0.81, respectively. CONCLUSION: The microbiome of stool, luminal contents, and biopsy was significantly different. However, the microbiome of luminal contents during colonoscopy can predict UC, with AUC values of 0.81. Colonoscopic luminal content aspiration analysis could determine microbiome differences between patients with UC and the healthy control, thereby beneficial in screening dysbiosis via endoscopy. TRIAL REGISTRATION: This trial was registered at http://cris.nih.go.kr . Registration No.: KCT0003352), Date: 2018-11-13.

Optimization and validation for quantification for allulose of jelly candies using response surface methodology.

A simple, rapid and reliable extraction method for allulose content in jelly were optimized using response surface methodology. The extraction method was selected based on preliminary experiments, with a three-factor, three-level central complex design including 20 experimental runs to optimize the extraction parameters. The optimum extraction factors predicted were temperature of 66 °C, solvent of 74% (v/v) ethanol, and extraction time of 24 min under shaking water bath extraction. The measured parameters were in accordance with the predicted values. The developed analytical method was validated with regard to linearity, accuracy and precision presenting recovery level from 90.79 to 95.18% and detection limits varying from 0.53 to 1.62 mg/mL. Finally, the method will be potentially applicable to a commercial jelly food using optimum extraction.

How should we understand the digital economy in Asia? Critical assessment and research agenda.

By Asian digital economy, we refer to high-tech developments, business and social transformations, and information-driven changes in the region's growth. We discuss its background and foundations, significance in Asia and contribution to removal of historical barriers in traditional business. We assess how new value chains are transforming country-level involvement in worldwide manufacturing and note "smiling curve theory" predictions about the global value chain in Asia for high-tech firms and their economies. The takeaway is that the digital economy in Asian nations involves revamping business processes through technology innovation, government policies for growth, and digital entrepreneurship. We analyze the "digital economy and society index", and attributes of nations, societies and economies, as a basis for framing our ideas. We consider research directions prompted by data analytics and AI, the platform economy, digital trade, fintech innovation, and societal and economic sustainability. We further highlight new issues in light of the COVID-19 pandemic.

Dynamics and development in number-to-space mapping.

Young children's estimates of numerical magnitude increase approximately logarithmically with actual magnitude. The conventional interpretation of this finding is that children's estimates reflect an innate logarithmic encoding of number. A recent set of findings, however, suggests that logarithmic number-line estimates emerge via a dynamic encoding mechanism that is sensitive to previously encountered stimuli. Here we examine trial-to-trial changes in logarithmicity of numerosity estimates to test an alternative dynamic model (D-MLLM) with both a strong logarithmic component and a weak response to previous stimuli. In support of D-MLLM, first-trial numerosity estimates in both adults (Study 1, 2, 3, and 4) and children (Study 4) were strongly logarithmic, despite zero previous stimuli. Additionally, although numerosity of a previous trial affected adults' estimates, the influence of previous numbers always accompanied the logarithmic-to-linear shift predicted by D-MLLM. We conclude that a dynamic encoding mechanism is not necessary for compressive mapping, but sequential effects on response scaling are a possible source of linearity in adults' numerosity estimation.

Tuning the photoreactivity of Z-hexatriene photoswitches by substituents - a non-adiabatic molecular dynamics study.

To understand how substituents can be used to increase the quantum yield of photochemical electrocyclic ring-closing of the Z-hexa-1,3,5-triene (HT) photoswitch forming cyclohexadiene (CHD), we investigate the S1 photo dynamics of HT and its derivatives 2,5-dimethyl-HT (DMHT), 2-isopropyl-5-methyl-HT (2,5-IMHT), 1-isopropyl-4-methyl-HT (1,4-IMHT), and 2,5-diisopropyl-HT (DIHT) using time-dependent density functional theory surface hopping dynamics. We report detailed photoproduct distributions, formation mechanisms, branching ratios, and wavelength-dependent product quantum yields. Most products have been confirmed experimentally and include all-trans HT derivatives, cyclopropanes, cyclobutenes, cyclopentene, cyclohexadienes, and bicyclic compounds. Regarding CHD formation, we find that for the 2,5-substituted derivatives DMHT, 2,5-IMHT, and DIHT, the branching ratios increase with increasing size of the substituents. In contrast the branching ratios of the E/Z-isomerization decrease with increasing size of the substituents. Due to steric interactions, increasing the size of the substituents increases the amount of gZg rotamers in the ground state, which are prone to CHD formation and have lower E/Z-isomerization probability. Furthermore, we find [1,4], [1,5], and [1,6]-sigmatropic hydrogen shift reactions occurring at large percentages (5% to 15%); for sterical reasons these reactions stem from tZg conformers. DIHT shows the lowest percentage of side product formation among the 2,5-substituted molecules and highest CHD branching ratio; its CHD quantum yield can be increased up to more than 64%, by excitation of DIHT on the red tail of its absorption spectrum, whereas the Z/E-isomerization is reduced below 5% and side reactions practically vanish. This makes DIHT the best candidate for applications in molecular switches.

Inhibition of STAT3 enhances the radiosensitizing effect of temozolomide in glioblastoma cells in vitro and in vivo.

Even with aggressive treatment involving radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential for targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome in glioblastoma. We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188, combined with temozolomide and radiation using in vitro assays with two established glioblastoma cell lines (U251 and U87) and two patient-derived glioblastoma cell lines (GBL12 and GBL28) as well as in vivo studies with nude mice bearing intracranial U251 xenografts. Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cells, which have high p-STAT3 expression levels. The enhanced radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and reversion of the epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 in GBL28 cells, which were originated from a patient with a high level of STAT3 expression and unmethylated MGMT. Targeting STAT3 using Cpd188 could be a viable therapeutic approach for improving the outcome of current standard therapy in glioblastoma patients with high p-STAT3 expression.

OH reactivity in urban and suburban regions in Seoul, South Korea - an East Asian megacity in a rapid transition.

South Korea has recently achieved developed country status with the second largest megacity in the world, the Seoul Metropolitan Area (SMA). This study provides insights into future changes in air quality for rapidly emerging megacities in the East Asian region. We present total OH reactivity observations in the SMA conducted at an urban Seoul site (May-June, 2015) and a suburban forest site (Sep, 2015). The total OH reactivity in an urban site during the daytime was observed at similar levels (∼15 s(-1)) to those previously reported from other East Asian megacity studies. Trace gas observations indicate that OH reactivity is largely accounted for by NOX (∼50%) followed by volatile organic compounds (VOCs) (∼35%). Isoprene accounts for a substantial fraction of OH reactivity among the comprehensive VOC observational dataset (25-47%). In general, observed total OH reactivity can be accounted for by the observed trace gas dataset. However, observed total OH reactivity in the suburban forest area cannot be largely accounted for (∼70%) by the trace gas measurements. The importance of biogenic VOC (BVOCs) emissions and oxidations used to evaluate the impacts of East Asian megacity outflows for the regional air quality and climate contexts are highlighted in this study.

Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) shows aggressive clinical behavior, but the treatment options are limited due to lack of a specific target. TNBC shares many clinical and pathological similarities with BRCA-deficient breast cancer, for which poly(ADP-ribose) polymerase (PARP) inhibitor is effective, but PARP inhibitor alone failed to show clinical effects in patients with sporadic TNBC. Radiation induces DNA double-strand breaks, and the phosphoinositide 3-kinase (PI3K) signaling pathway has been known to regulate steady-state levels of homologous recombination. A recent preclinical study showed that PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient TNBC to PARP inhibition. Therefore, we assessed the radiosensitizing effect, and the underlying mechanism of combination treatment with PARP inhibitor olaparib and PI3K inhibitor PI-103 in BRCA-proficient TNBC cells. METHODS: MDA-MB-435S cells were divided into four treatment groups, irradiation (IR) alone, olaparib plus IR, PI-103 plus IR, and olaparib plus PI-103 plus IR. Cells were exposed to the drugs for 2 hours prior to irradiation, and the cell survival curve was obtained using a clonogenic assay. Western blotting and immunofluorescent detection of γH2AX foci were performed. Xenograft and bioluminescence imaging were carried out to assess in vivo radiosensitivity. RESULTS: Combined use of olaparib and PI-103 enhanced radiation-induced death of MDA-MB-435S (sensitizer enhancement ratio[SER]0.05,1.7) and MDA-MB-231-BR (SER0.05,2.1) cells and significantly reduced tumor volume in a xenograft models (P < 0.001). Treatment with PI-103 showed persistent γH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1. CONCLUSIONS: Combined use of olaparib and PI-103 enhanced radiation-induced cell death in BRCA-proficient MDA-MB-435S and MDA-MB-231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC.

Acute and subchronic (28 days) oral toxicity studies of Codonopsis lanceolata extract in Sprague-Dawley rats.

Codonopsis lanceolata is a perennial plant that has been used as a food and in traditional medicine for the treatment of cough, bronchitis, and inflammation in East Asia including Korea, Japan, and China. However, information regarding its toxicity is limited. Therefore, we performed a safety evaluation of aqueous C. lanceolata root extract (CLE) in Sprague-Dawley rats. Assessment of acute toxicity revealed that CLE did not influence mortality, clinical appearance, body weight gain, or necropsy findings at a dose of 5000 mg/kg body weight. In the subchronic oral toxicity, data revealed that several significant alteration in food consumption, water consumption, protein excretion, WBCs levels, TGs, BUN levels, and the absolute and relative weights in the liver, spleen and lungs. However, these changes were transient and were not considered treatment related because they showed no apparent dose dependent. These results suggest that CLE (1250, 2500, and 5000 mg/kg body weight/day) administered orally does not cause acute or subchronic toxicity to male or female rats. The 50% lethal dose (LD50) of CLE was determined to be greater than 5000 mg/kg.