Global health impacts of ambient fine particulate pollution associated with climate variability.

Air pollution is a key global environmental problem raising human health concern. It is essential to comprehensively assess the long-term characteristics of air pollution and the resultant health impacts. We first assessed the global trends of fine particulate matter (PM2.5) during 1980-2020 using a monthly global PM2.5 reanalysis dataset, and evaluated their association with three types of climate variability including El Niño-Southern Oscillation, Indian Ocean Dipole and North Atlantic Oscillation. We then estimated PM2.5-attributable premature deaths using integrated exposure-response functions. Results show a significant increasing trend of ambient PM2.5 during 1980-2020 due to increases in anthropogenic emissions. Ambient PM2.5 caused a total of âˆ¼ 135 million premature deaths globally during the four decades. Occurrence of air pollution episodes was strongly associated with climate variability, which were associated with up to 14 % increase in annual global PM2.5-attributable premature deaths.

Long-term monitoring of clodronate in equine hair using liquid chromatography-tandem mass spectrometry.

Given the potential for long-term inhibition of bone remodeling/healing and detrimental effects to horses in training, bisphosphonates are tightly regulated in horseracing. Hair has proven to be an effective matrix for detection of drug administration to horses and has been particularly effective in detecting drugs for a long period of time post administration. Thus, hair may prove to be a useful matrix for detection of administration of this class of drugs. The objective of the current study was to develop an assay and assess the usefulness of hair as a matrix for long-term detection of clodronate to horses. Seven horses received a single intramuscular administration of 1.8 mg/kg clodronate. Hair samples were collected prior to and up to 6 months post administration. A liquid chromatography-tandem mass spectrometry method was developed and concentrations of clodronate measured in hair samples. The drug was first detected on day 7 in 4/7 horses, and on days 14, 28 and 35 in the remaining three horses. In 4/7 horses, clodronate was still detectable 6 months post administration. Results of this study demonstrate that, although there was significant inter-individual variability in detection times (63 to 180 days) and several intermediate times where the drug could not be detected but was subsequently detected in later timepoints, clodronate administration was detectable in hair for a prolonged period in most of the horses (4/7) studied.

Influences of approaching tropical cyclones on water vapor and aerosols in the atmospheric boundary layer of Guangdong-Hong Kong-Macau Greater Bay Area of China.

The outer circulation of tropical cyclones (TCs) on the western North Pacific has been reported to substantially influence the atmospheric environment over the Guangdong-Hong Kong-Macau Greater Bay Area (GBA) of China, whereas dynamic evolution and redistribution of water vapor and aerosol in the atmospheric boundary layer (ABL) responding to moving TCs have yet to be understood. This study aims to answer three key research questions related to the influences of the approaching TCs: (1) how do water vapor and aerosol particles over the GBA change during the TC approaching stage? (2) how does the ABL in terms of vertical wind structure respond to the approaching TCs? and (3) how does turbulence influence the vertical profile of aerosol during the approaching stage? Based on an intensive analysis of three-year reanalysis and Doppler LiDAR data, this study identified a dry-polluted time over the GBA when a TC was located at ~1000 km away on South China Sea. Before that, horizontal wind has consistently come from the northeast, creating a favorable condition for weak transboundary air pollution to the GBA. During the dry-polluted time, the highest surface PM2.5 concentration was resulted from the enhanced downdraft and early-stage wind shear, i.e., stronger wind started occurring at upper-level ABL, while the further turbulent mixing induced by wind shear enhancement and updrafts recovery pumped surface pollution upward to the upper level when TCs became closer. Our findings are expected to improve both weather and PM2.5 forecasts under the impacts of approaching TCs.

The effects of particle-induced oxidative damage from exposure to airborne fine particulate matter components in the vicinity of landfill sites on Hong Kong.

The physical, chemical and bioreactivity characteristics of fine particulate matter (PM2.5) collected near (<1 km) two landfill sites and downwind urban sites were investigated. The PM2.5 concentrations were significantly higher in winter than summer. Diurnal variations of PM2.5 were recorded at both landfill sites. Soot aggregate particles were identified near the landfill sites, which indicated that combustion pollution due to landfill activities was a significant source. High correlation coefficients (r) implied several inorganic elements and water-soluble inorganic ions (vanadium (V), copper (Cu), chloride (Cl-), nitrate (NO3-), sodium (Na) and potassium (K)) were positively associated with wind flow from the landfill sites. Nevertheless, no significant correlations were also identified between these components against DNA damage. Significant associations were observed between DNA damage and some heavy metals such as cadmium (Cd) and lead (Pb), and total Polycyclic Aromatic Hydrocarbons (PAHs) during the summer. The insignificant associations of DNA damage under increased wind frequency from landfills suggested that the PM2.5 loading from sources such as regional sources was possibly an important contributing factor for DNA damage. This outcome warrants the further development of effective and source-specific landfill management regulations for particulate matter production control to the city.

Note: Double-layered polyimide film heater with low magnetic field generation.

We designed a double-layered polyimide film heater where the direction of the injection current of each layer is opposite to that of the other layer to reduce the magnetic field. The width of the heater is 0.125 mm and the resistance is 21.2 Ω. This specially designed heater successfully demonstrated temperature controllability within 10 mK for an atomic cell in an atom spin gyroscope while minimizing the generation of the magnetic field to within 1 nT.

Chemical characterization and sources of personal exposure to fine particulate matter (PM2.5) in the megacity of Guangzhou, China.

Concurrent ambient and personal measurements of fine particulate matter (PM2.5) were conducted in eight districts of Guangzhou during the winter of 2011. Personal-to-ambient (P-C) relationships of PM2.5 chemical components were determined and sources of personal PM2.5 exposures were evaluated using principal component analysis and a mixed-effects model. Water-soluble inorganic ions (e.g., SO42-, NO3-, NH4+, C2O42-) and anhydrosugars (e.g., levoglucosan, mannosan) exhibited median personal-to-ambient (P/C) ratios < 1 accompanied by strong P-C correlations, indicating that these constituents in personal PM2.5 were significantly affected by ambient sources. Conversely, elemental carbon (EC) and calcium (Ca2+) showed median P/C ratios greater than unity, illustrating significant impact of local traffic, indoor sources, and/or personal activities on individual's exposure. SO42- displayed very low coefficient of divergence (COD) values coupled with strong P-C correlations, implying a uniform distribution of SO42- in the urban area of Guangzhou. EC, Ca2+, and levoglucosan were otherwise heterogeneously distributed across individuals in different districts. Regional air pollution (50.4 ± 0.9%), traffic-related particles (8.6 ± 0.7%), dust-related particles (5.8 ± 0.7%), and biomass burning emissions (2.0 ± 0.2%) were moderate to high positive sources of personal PM2.5 exposure in Guangzhou. The observed positive and significant contribution of Ca2+ to personal PM2.5 exposure, highlighting indoor sources and/or personal activities, were driving factors determining personal exposure to dust-related particles. Considerable discrepancies (COD values ranging from 0.42 to 0.50) were shown between ambient concentrations and personal exposures, indicating caution should be taken when using ambient concentrations as proxies for personal exposures in epidemiological studies.

A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR.

Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.

Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders.

Inherited muscular disorders (IMDs) are clinically and genetically heterogeneous genetic disorders. We investigated the mutational spectrum and genotype-phenotype correlations in Korean patients with IMD. We developed a targeted panel of 69 known IMD genes and recruited a total of 209 Korean patients with IMD. Targeted capture sequencing identified 994 different variants. Among them, 98 variants were classified as pathogenic/likely pathogenic variants; 38 were novel variations. A total of 39 patients had the pathogenic/likely pathogenic variants. Among them, 75 (36%) patients were genetically confirmed, and 18 (9%) patients had one heterozygous variant of recessive myopathy. However, two genetically confirmed patients had an additional heterozygous variant of another recessive myopathy. Four patients with one heterozygous variant of a recessive myopathy showed different phenotypes, compared with the known phenotype of the identified gene. The major causative genes of Korean patients with IMDs were DMD (19 patients), COL6A1 (9), DYSF (9), GNE (7), LMNA (7), CAPN3 (6), and RYR1 (5). This study showed the mutational and clinical spectra in Korean patients with IMD and confirmed the usefulness of strategies utilizing targeted sequencing.

The air quality and health impacts of domestic trans-boundary pollution in various regions of China.

Air pollution is one of the most pressing environmental problems in China. Literature has reported that outdoor air pollution leads to adverse health problems every year in China. Recent measurement studies found the important regional nature of particulates in China. Trans-boundary air pollution within China has yet to be fully understood. This study aimed to comprehensively understand the processes of domestic trans-boundary air pollution in China and to apportion the impacts of emissions in different regions on air quality and public health. We applied a state-of-the-art air quality model to simulate air quality in China and then adapted a form of integrated concentration-response function for China to estimate the resultant amount of premature mortality due to exposures to PM2.5. Our findings show that domestic trans-boundary impacts (TBI), on average, account for 27% of the total PM2.5 in China. We estimated that outdoor air pollution caused ~870,000 (95% CI: 130,000-1500,000) premature mortalities in China in 2010, of which on average 18% are attributed to TBI. Among all the regions, North China is the largest contributor to TBI due to 41% of the health impacts of its emissions occurring in other regions. Taiwan (TW) is the smallest contributor to TBI occurring in China, contributing 2% of the national TBI, while TBI causes 22% of the premature mortalities due to outdoor air pollution in TW. Our findings pinpoint the significant impacts of TBI on public health in China, indicating the need for cross-region cooperation to mitigate the air quality impacts and the nation's resultant health problems.

Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations.

Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.

Highly durable fuel cell electrodes based on ionomers dispersed in glycerol.

A major, unprecedented improvement in the durability of polymer electrolyte membrane fuel cells is obtained by tuning the properties of the interface between the catalyst and the ionomer by choosing the appropriate dispersing medium. While a fuel cell cathode prepared from aqueous dispersion showed 90 mV loss at 0.8 A cm(-2) after 30,000 potential cycles (0.6-1.0 V), a fuel cell cathode prepared from glycerol dispersion exhibited only 20 mV loss after 70,000 cycles. This minimum performance loss occurs even though there was an over 80% reduction of electrochemical surface area of the Pt catalyst. These findings indicate that a proper understanding and control of the catalyst-water-ionomer (three-phase) interfaces is even more important for maintaining fuel cell durability in typical electrodes than catalyst agglomeration, and this opens up a novel path for tailoring the functional properties of electrified interfaces.

Hysterectomy for recurrent postmenopausal bleeding revisited: missed sclerosing stromal ovarian tumour.

Sclerosing stromal tumour of the ovary is rare. Patients present with menstrual irregularities, pelvic pain, abdominal distension, and presence of a large pelvic mass during their twenties or thirties. We report a rare case of an ovarian sclerosing stromal tumour with an atypical presentation, in that it gave rise to recurrent postmenopausal bleeding.

Regulatory aspects of new medicines targeted at treatment of autoimmune diseases.

Autoimmune diseases comprise a diverse group of clinical dis orders that result from the body's adaptive immune system reacting against its own tissues.(1) Conversely, autoinflammatory disorders encompass a more limited group of diseases distinguished by recurrent episodes of inflammation but in the absence of high-titer autoantibodies and antigen-specific T cells.(2) The past 15 years have seen a tremendous growth in the development of highly effective treatments for these diseases.

Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1.

MicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3'-untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression- and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.

CHD5 Downregulation Associated with Poor Prognosis in Epithelial Ovarian Cancer.

BACKGROUND: The CHD5 gene located on 1p36 encodes a protein-chromodomain helicase DNA-binding protein 5. CHD5 has been shown to be a tumor suppressor gene candidate. This study investigated the involvement of CHD5 in ovarian cancer and its clinicopathological significance. METHODS: CHD5 expression in ovarian cancer and its counterpart were determined by quantitative RT-PCR. The correlation of CHD5 expression to clinicopathological features of the tumor was analyzed. RESULTS: CHD5 expression was downregulated by at least twofold in 32 of 72 (41%) invasive epithelial ovarian carcinomas when compared to 12 controls in Hong Kong Chinese women. CHD5 downregulation was correlated to clinical status (p < 0.05), but not to patient age, tumor type and grade, recurrence and clinical stage (p > 0.05). Survival analysis showed that patients with CHD5 downregulation in their tumors were associated with shorter disease-free and total survival times compared to those without CHD5 downregulation (p < 0.05). Cox proportional-hazards regression analysis indicated that downregulation of CHD5 is an independent adverse prognostic factor in ovarian cancer. CONCLUSION: This study shows that CHD5 is downregulated in a certain number of ovarian cancers and appears to be an adverse predictor candidate of ovarian cancer disease-free and total survival.

"Once Bitten, Twice Shy": participant perspectives in the aftermath of an early HIV vaccine trial termination.

The Step Study phase IIb HIV-1 vaccine trial was terminated early due to futility; subsequent analyses revealed increased susceptibility to HIV infection among a subset of test vaccine recipients. We conducted a mixed methods investigation, including a brief, self-administered baseline questionnaire and in-depth, semi-structured, 1-h interviews after unblinding, to explore experiences and perspectives among trial participants and key informants. Interviews were digitally recorded, transcribed, and analyzed using NVivo and thematic techniques. Forty-eight trial participants (46 gay/bisexual men) completed baseline surveys; 15 (14 gay/bisexual men) engaged in post-trial interviews. Participants indicated surprise and disappointment about the early trial termination and unexpected risks. Some articulated understanding the uncertainties of clinical trials, steadfast support and willingness to participate in the future; others reported greater risks than they deemed acceptable and unlikelihood of volunteering again. A few indicated mistrust of trial sponsors and ethics. Participants' most profound criticism was not about unexpected results, but perceived delays in unblinding and gaps in post-trial dissemination of information. Future HIV vaccine trials may benefit from increased emphasis on: (1) communication mechanisms among participants, investigators and trial sponsors, and (2) post-trial dissemination of information and psychosocial support.

Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib.

The use of selective inhibitors targeting Bcr-Abl kinase is now established as a standard protocol in the treatment of chronic myelogenous leukemia; however, the acquisition of drug resistance is a major obstacle limiting the treatment efficacy. To elucidate the molecular mechanism of drug resistance, we established K562 cell line models resistant to nilotinib and imatinib. Microarray-based transcriptome profiling of resistant cells revealed that nilotinib- and imatinib-resistant cells showed the upregulation of kinase-encoding genes (AURKC, FYN, SYK, BTK and YES1). Among them, the upregulation of AURKC and FYN was observed both in nilotinib- and imatinib-resistant cells irrespective of exposure doses, while SYK, BTK and YES1 showed dose-dependent upregulation of expression. Upregulation of EGF and JAG1 oncogenes as well as genes encoding ATP-dependent drug efflux pump proteins such as ABCB1 was also observed in the resistant cells, which may confer alternative survival benefits. Functional gene set analysis revealed that molecular categories of 'ATPase activity', 'cell adhesion' or 'tyrosine kinase activity' were commonly activated in the resistant clones. Taken together, the transcriptome analysis of tyrosine kinase inhibitors (TKI)-resistant clones provides the insights into the mechanism of drug resistance, which can facilitate the development of an effective screening method as well as therapeutic intervention to deal with TKI resistance.

Glutathione S-transferase M1 (GSTM1) polymorphism is associated with atopic dermatitis susceptibility in a Korean population.

Atopic dermatitis (AD) is a chronic pruritic skin condition affecting as much as 15% of children in industrialized countries. While the underlying pathophysiology of AD is not entirely understood, several studies have suggested that AD may mediated by oxidative stress. Glutathione S-transferases (GSTs) are a class of polymorphic enzymes that function to protect against oxidative stress. To identify any possible associations between GSTs polymorphisms and AD susceptibility, the prevalence of two specific polymorphisms -GSTM1 and GSTT1 (homozygous deletion vs. undeleted) - were quantified by multiplex PCR in 145 patients with AD and 267 healthy controls. In individuals with AD, GSTM1/GSTT1 polymorphisms were compared with family history of AD, age of disease onset, disease severity [per SCORing Atopic Dermatitis (SCORAD)], serum IgE level and presence of other allergic diseases. While the GSTM1-null genotype was found to be significantly associated with AD (P = 0.033, OR = 1.579, 95% CI = 1.037-2.403), the correlation between the GSTT1-null genotype and AD did not reach statistical significance (P = 0.577, OR = 1.125, 95% CI = 0.744-1.702). The GSTM1-null genotype was also found to be significantly associated with a childhood onset of AD, the absence of other allergic diseases, and a family history of AD. In combination, these results suggest that GSTM1 is associated with AD susceptibility in Korean subjects.

Transforming growth factor beta receptor II (TGFBR2) polymorphisms and the association with nonsegmental vitiligo in the Korean population.

The precise cause of vitiligo is unknown. However, autoimmunity is considered the most likely aetiology, especially in nonsegmental vitiligo (NSV). In this study we determined whether or not the transforming growth factor beta receptor II (TGFBR2) gene contributes to susceptibility for NSV in the Korean population. Blood samples were collected from 415 controls and 233 cases. We selected three single nucleotide polymorphisms (SNPs) in the TGFBR2 gene. The genotypes of the SNPs were determined using direct sequencing. All of the SNPs were significantly different between the vitiligo patients and controls (rs2005061, co-dominant, dominant, recessive, P < 0.05; rs3773645, co-dominant, dominant, recessive, P < 0.05; rs3773649, co-dominant, recessive, P < 0.05). In addition, haplotype 1 (CG) and haplotype 2 (GA) of the linkage disequilibrium (LD) block were also associated with a risk of NSV. The present study suggests that TGFBR2 might be related to NSV.