Ozone responses to reduced precursor emissions: A modeling analysis on how attainable goals can improve air quality in the Mexico City Metropolitan Area.

High tropospheric ozone (O3) concentrations prevent the improvement of the air quality in the Mexico City Metropolitan Area (MCMA). Although the problem has improved considerably since the 1990s, a rebound in O3 levels in recent years has raised concerns about the deteriorating air quality. The nonlinear relationship between O3 formation and the emissions of its main precursors, i.e., volatile organic compounds (VOCs) and nitrogen oxides (NOx), is a challenge when measures are enacted for effective mitigation of the O3 problem. This study evaluated the reduction in precursors, VOCs and NOx, using an up-to-date regional air quality model (HERMES-Mex-WRF-CMAQ). For evaluating realizable scenarios, the decline in VOC achieved in Japan after policy implementation was the targeted VOC reduction (40 % from area sources), and the NOx reduction observed in the MCMA during the COVID-19 pandemic was the targeted NOx reduction (40 % from mobile sources). The analysis evaluated the O3 responses to changes in a single precursor and a combination of both during a period of high O3 concentrations (April 2019). The results showed that 40 % reduction in VOC emissions would decrease the O3 8-h maximum concentrations by 16 %. However, 40 % reduction in NOx emissions would increase O3 by >15 %. The simultaneous reduction of both precursors did not significantly affect O3 levels. The diagnosis of ozone sensitivity using the H2O2/HNO3 ratios reinforced the simulation findings, indicating that VOC emissions limited ozone formation in most MCMA areas. As the simulated scenarios were based on factual case studies, our research offers insights into the realistic aims of MCMA policies to reduce O3 levels.

Impact of introducing net-zero carbon strategies on tropospheric ozone (O3) and fine particulate matter (PM2.5) concentrations in Japanese region in 2050.

In this study, we estimated the future emission inventory of primary air pollutants in Japan in 2050 after introducing low-carbon technology based on the results of the socio-economic model provided by the Japanese government. The results suggested that introducing net-zero carbon technology would contribute to a 50-60 % decrease in primary NOx, SO2, and CO emissions and a ~30 % decrease in primary emissions of volatile organic compounds (VOCs) and PM2.5. The estimated emission inventory and future meteorological conditions in 2050 were applied as inputs to a chemical transport model. A scenario involving the application of future reduction strategies with relatively moderate global warming (RCP4.5) was evaluated. The results showed that the concentration of tropospheric ozone (O3) was highly reduced compared with that in 2015 after applying net-zero carbon reduction strategies. On the other hand, the fine particulate matter (PM2.5) concentration under the 2050 scenario was expected to be equal or higher because of the growth in secondary aerosol formation caused by the increase in short-wave radiation. Finally, the premature mortality change from 2015 to 2050 was analyzed, and the change in air quality contributed by net-zero carbon technology will contribute to a ~4000 decrease in premature deaths in Japan.

Improvement of the Theoretical Model for Evaluating Evaporative Emissions in Parking and Refueling Events of Gasoline Fleets Based on Thermodynamics.

Evaporative emissions from gasoline vehicles are known as an emission source of volatile organic compounds that are the precursors of tropospheric ozone and secondary organic aerosols. We formulated new estimation models based on thermodynamics for two main evaporation processes, namely diurnal breathing loss (DBL) and refueling loss (RFL) from gasoline vehicles. The models enable us to evaluate real-world evaporative emissions using the fuel composition and environmental temperature as input parameters. The proposed models well replicated the experimental results of the canister breakthrough emission from DBL (DBLb) and RFL obtained in previous experimental studies. The evaporative DBLb and RFL emissions in Japan in 2015 were then estimated using the new models. The evaporative emission from DBLb was approximately 8800 t/y, and that from RFL was 73,300 t/y. In addition, we estimated the variation in fuel evaporative emissions due to the market penetration of zero-emission vehicles. Even if the sale of gasoline vehicles is banned from 2035, the evaporative emissions of DBLb and RFL from gasoline vehicles will only be halved after 2040. The two models proposed for estimating the DBLb and RFL in this study are expected to be applied in the evaluation of the emission inventories of volatile organic compounds in future work.

Carotenoderma due to lycopenemia: A case report and evaluation of lycopene deposition in the skin.

Carotenoderma is a yellow-orange coloration of the skin caused by high levels of serum carotenoids, mostly due to the excessive intake of carotenoid-rich foods. The yellowish coloration is typically observed on the palms, soles, and nasolabial folds. Although the physical appearance is prominent, the condition itself is benign and harmless. Diagnosing carotenoderma is not difficult because of its unique manifestations, but its pathophysiology remains unclear. We report a relatively rare case of carotenoderma due to lycopenemia caused by the excessive intake of lycopene-rich vegetables and fruits. Lycopene is a carotenoid component that is distinguished by the high absorption of light around 488 nm. Given these characteristics, we examined a hematoxylin-eosin-stained specimen from the patient and tape-stripped samples by fluorescent microscopy with 488 nm wavelength emission and compared them with normal skin samples. Notably, the patient's samples showed a weaker autofluorescence in the stratum corneum and sweat glands. Furthermore, we measured carotenoid concentrations in the patient's skin noninvasively with Vegecheck® and found a higher score than the average of 24 healthy volunteers. These results support the long-held hypothesis that carotenoids are secreted in sweat and are deposited in the stratum corneum. To the best of our knowledge, no previous reports have measured skin carotenoid levels nor detailed the pathological findings of carotenoderma patients. This case further highlights that the excessive intake of lycopene causes carotenoderma and demonstrates that carotenoid deposition is particularly pronounced in the stratum corneum of the skin.

Exhaust emissions from gasoline vehicles after parking events evaluated by chassis dynamometer experiment and chemical kinetic model of three-way catalytic converter.

Despite the worldwide trend of introducing of zero-fuel-based vehicles to the market, the emissions of air pollutants and greenhouse gases from passenger vehicles are likely to remain a concern for the coming 20 to 30 years. In this study, exhaust emissions of gasoline engines running after varying parking durations were measured using a chassis dynamometer. The experimental results showed that exhaust emissions of hydrocarbons, nitrogen oxides, and carbon monoxide from most vehicles increased dramatically following 60 to 120 min of parking, and were higher than cold-start (1040 + min parking) emissions, indicating the impact of parking duration on atmospheric pollutant emissions. The after-treatment capacity of the three-way catalytic converter was evaluated by chemical kinetic modeling of the chemical reactions on the catalyst coupled with a time-dependent energy conservation equation. The results of the model calculation indicated that both the initial temperature of the three-way catalytic converter and the inlet engine gas temperature are critical factors impacting exhaust pollutants after parking; therefore, proper management to reduce the emissions after middle-term parking durations should be developed to mitigate air pollution.

Unbiased Detection of Driver Mutations in Extramammary Paget Disease.

PURPOSE: Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and PIK3CA. In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing. EXPERIMENTAL DESIGN: First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several in silico analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. ERBB2 expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence in situ hybridization. RESULTS: A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations. Copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted, and ERBB2 as recurrently amplified. ERBB2, ERBB3, and FGFR1 amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence in situ analysis validated ERBB2 amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of ERBB2 amplification status was observed in some cases. CONCLUSIONS: Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.

Detailed Inventory of the Evaporative Emissions from Parked Gasoline Vehicles and an Evaluation of Their Atmospheric Impact in Japan.

A detailed inventory was taken of evaporative emissions from parked gasoline vehicles in the Kanto region of Japan, 2015, based on the theoretical model to evaluate the amount of evaporative emissions. The inventory showed that evaporative emissions were high in metropolitan and urban areas because of the large populations in these areas and the high vehicle parking frequency. Using the new inventory, the sensitivity of evaporative emissions to the concentration of tropospheric ozone and secondary organic aerosol was evaluated using the chemical transport modeling solver, the community multiscale air quality modeling system (CMAQ), coupled with the weather research and forecasting (WRF) model. The calculation results showed that the evaporative emissions from permeation through fuel related parts were more significant in the generation of the tropospheric ozone than those from fuel tank venting. This was because the permeation emissions included a high proportion of high maximum incremental reactivity value components, such as aromatics. Neither of the evaporative emission types were significant secondary organic aerosol generators. Whole reduction of the evaporative emissions contributed an approximate 3 ppb decrease in tropospheric ozone in urban areas during the daytime. This information will contribute to the volatile organic compound (VOC) management strategy employed by governments worldwide.

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.

BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

Author Correction: Impact of next-generation vehicles on tropospheric ozone estimated by chemical transport model in the Kanto region of Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Variable indoleamine 2,3-dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy.

Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti-programmed death ligand-1 (PD-L1) is a well-studied biomarker for response to anti-programmed death-1 PD-1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3-dioxygenase (IDO) is correlated to a response to anti-CTLA-4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti-PD-1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD-L1 expression with response to anti-PD-1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti-PD-1 antibody from the perspective of IDO and PD-L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression-free survival (HR = 0.33, 95% CI = 0.13-0.81, P = 0.016), whereas PD-L1 expression on tumors was not associated with progression-free survival. Significantly lower expression of IDO in tumors was found in non-responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti-PD-1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings.

Modeling evaporative emissions from parked gasoline cars based on vehicle carbon canister experiments.

A time-step model was constructed to estimate the amount of evaporative emissions from vehicular diurnal breathing loss (DBL) on the basis of fuel adsorption-desorption experiments for several carbon canisters attached to seven gasoline vehicles using a chassis dynamometer. Experimental results showed that the canister's total volatile organic compound (VOC) storage ability is proportional to the canister volume, and a canister's desorption ability strongly depends on the amount of VOC trapped in the canister and the air purge flow rate of each vehicle. These properties were formulated into equations by regression analysis and used with the material balance inside the canister to propose a model for estimating emissions after carbon canister breakthrough, which are a function of a vehicle's driving and parking frequency. The model was applied to DBL experimental results derived from our previous studies to confirm its validity. Better agreement between the model and the previous experimental results was obtained when appropriate parameters were set. The proposed model is expected to contribute to estimating the VOC emission inventory for gasoline vehicles.

Association of Baseline Serum Levels of CXCL5 With the Efficacy of Nivolumab in Advanced Melanoma.

Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

Impact of next-generation vehicles on tropospheric ozone estimated by chemical transport model in the Kanto region of Japan.

The plans to introduce next-generation hybrid and zero-emission vehicles in the market are now enacted by governments in many countries to manage both global warming and air pollution problems. There are only a few studies evaluating the effects of the next-generation vehicles on the changes in concentrations of ozone generated by the photochemical reactions between volatile organic compounds and nitrogen oxides (NOx). To evaluate these changes, we performed chemical transport modeling in the Kanto region, Japan in the summer of 2013. The results show that if the vehicles are substituted by hybrid vehicles, average ozone concentrations increase in urban areas and decrease in suburban areas due to NOx titration. Substitution with zero-emission passenger vehicles decreases the concentrations in both urban and suburban areas. Substitution with both hybrid and zero-emission passenger and heavy-duty vehicles highly increases the concentrations in urban areas. Using the model results, we also discuss the effect of ozone concentration changes on premature mortality of humans in summer. The results suggest that, in some cases the introduction of next-generation vehicles might exasperate ozone concentrations, even leading to 5 to 10 times higher premature mortality during the summer compared to that of influenza and heat stroke in Japan.