Baicalein sensitizes triple negative breast cancer MDA-MB-231 cells to doxorubicin via autophagy-mediated down-regulation of CDK1.

Triple negative breast cancer (TNBC) is a kind of refractory cancer with poor response to conventional chemotherapy. Recently, the combination of baicalein and doxorubicin was reported to exert a synergistic antitumor effect on breast cancer. However, the underlying mechanism how baicalein sensitizes breast cancer cells to doxorubicin remains to be elucidated. Here, it was found that 20 µM baicalein increased the autophagy markers including the ratio of LC3B II/I, GFP-LC3 punctate aggregates and down-regulation of p62 expression, and up-regulated mitophagy marker PINK1 and Parkin in TNBC MDA-MB-231 cells as well. In contrast, doxorubicin decreased the levels of autophagy markers, and significantly up-regulated CDK1 in MDA-MB-231 cells. Pretreatment with baicalein markedly inhibited the doxorubicin-induced decrease in autophagy markers and up-regulation of CDK1, which was reversed by the autophagy inhibitor 3-Methyladenine. Moreover, baicalein alleviated the doxorubicin-induced expression and phosphorylation (at Ser616) of mitochondrial fission protein Drp1. Intriguingly, the autophagy inhibitor 3-Methyladenine also significantly weakened the effect of baicalein on doxorubicin-induced viability decrease and apoptosis in MDA-MB-231 cells. Taken together, our data indicate that baicalein improves the chemosensitivity of TNBC cells to doxorubicin through promoting the autophagy-mediated down-regulation of CDK1, also suggest a novel strategy for prevention of TNBC in the future.

Understanding current and projected emergency department presentations and associated healthcare costs in a changing thermal climate in Adelaide, South Australia.

BACKGROUND: Exposure to extreme temperatures is associated with increased emergency department (ED) presentations. The resulting burden on health service costs and the potential impact of climate change is largely unknown. This study examines the temperature-EDs/cost relationships in Adelaide, South Australia and how this may be impacted by increasing temperatures. METHODS: A time series analysis using a distributed lag nonlinear model was used to explore the exposure-response relationships. The net-attributable, cold-attributable and heat-attributable ED presentations for temperature-related diseases and costs were calculated for the baseline (2014-2017) and future periods (2034-2037 and 2054-2057) under three climate representative concentration pathways (RCPs). RESULTS: The baseline heat-attributable ED presentations were estimated to be 3600 (95% empirical CI (eCI) 700 to 6500) with associated cost of $A4.7 million (95% eCI 1.8 to 7.5). Heat-attributable ED presentations and costs were projected to increase during 2030s and 2050s with no change in the cold-attributable burden. Under RCP8.5 and population growth, the increase in heat-attributable burden would be 1.9% (95% eCI 0.8% to 3.0%) for ED presentations and 2.5% (95% eCI 1.3% to 3.7%) for ED costs during 2030s. Under the same conditions, the heat effect is expected to increase by 3.7% (95% eCI 1.7% to 5.6%) for ED presentations and 5.0% (95% eCI 2.6% to 7.1%) for ED costs during 2050s. CONCLUSIONS: Projected climate change is likely to increase heat-attributable emergency presentations and the associated costs in Adelaide. Planning health service resources to meet these changes will be necessary as part of broader risk mitigation strategies and public health adaptation actions.

Comparison of obesity-related indicators for identifying metabolic syndrome among normal-weight adults in rural Xinjiang, China.

BACKGROUND: This study aimed to compare the ability of certain obesity-related indicators to identify metabolic syndrome (MetS) among normal-weight adults in rural Xinjiang. METHODS: A total of 4315 subjects were recruited in rural Xinjiang. The questionnaire, biochemical and anthropometric data were collected from them. Binary logistic regression was used to analyze the association between the z-score of each index and MetS. The area under the receiver-operating characteristic (ROC) curves were used to compare the diagnostic ability of each index. According to the cut-off value of each index, nomogram models were established and their diagnostic ability were evaluated. RESULTS: After adjusting for confounding factors, each indicator in different genders was correlated with MetS. Triglyceride-glucose index (TyG index) showed the strongest association with MetS in both males (OR = 3.749, 95%CI: 3.173-4.429) and females (OR = 3.521,95%CI: 2.990-4.148). Lipid accumulation product (LAP) showed the strongest diagnostic ability in both males (AUC = 0.831, 95%CI: 0.806-0.856) and females (AUC = 0.842, 95%CI: 0.820-0.864), and its optimal cut-off values were 39.700 and 35.065, respectively. The identification ability of the TyG index in different genders (males AUC: 0.817, females AUC: 0.817) was slightly weaker than LAP. Waist-to-height ratio (WHtR) had the similar AUC (males: 0.717, females: 0.747) to conicity index (CI) (males: 0.734, females: 0.749), whereas the identification ability of a body shape index (ABSI) (males AUC: 0.700, females AUC: 0.717) was relatively weak. Compared with the diagnostic ability of a single indicator, the AUC of the male nomogram model was 0.876 (95%CI: 0.856-0.895) and the AUC of the female model was 0.877 (95%CI: 0.856-0.896). The identification ability had been significantly improved. CONCLUSION: LAP and TyG index are effective indicators for identifying MetS among normal-weight adults in rural Xinjiang. Nomogram models including age, CI, LAP, and TyG index can significantly improve diagnostic ability.

Diagnostic value of an enhanced MRI combined with serum CEA, CA19-9, CA125 and CA72-4 in the liver metastasis of colorectal cancer.

OBJECTIVE: This paper aims to explore the diagnostic value of enhanced magnetic resonance imaging (MRI) combined with a carcinoembryonic antigen (CEA) and carbohydrate antigen in terms of the liver metastasis of colorectal cancer. METHODS: A total of 167 colorectal cancer patients with liver metastasis and 167 colorectal cancer patients without liver metastasis were selected as the subjects. An automatic electrochemiluminescence analyser was then used to detect the tumour markers CEA, CA19-9, CA125 and CA72-4. The consistency between the MRI examination and clinical pathological examination was also analysed, and the sensitivity, specificity and positive and negative predictive values of various combined detection methods were compared. RESULTS: The abnormal rates of CEA, CA19-9, CA125 and CA72-4 in the two groups were statistically significant (P < 0.05), while the results of the enhanced MRI and clinicopathological examination for liver metastasis in patients with colon cancer were largely consistent (Kappa coefficient = 0.788, P < 0.000). However, the two methods were inconsistent. The false positive rate of the enhanced MRI examination was 15.3%, while the false negative rate was 6.0%. The specificity (94.61%), positive predictive value (92.68%) and positive likelihood ratio (12.67%) were the highest for the MRI combined with serial CEA, while the sensitivity (98.80%) and negative predictive value (97.22%) were the highest with the MRI combined with parallel CEA, and this combination returned the lowest negative likelihood ratio (0.03). CONCLUSION: The combination of MRI and CEA excludes non-metastatic patients and identifies colorectal liver metastasis cancer patients. Overall, it has a higher diagnostic value.

Atomic-Scale Visualization of Stepwise Growth Mechanism of Metal-Alkynyl Networks on Surfaces.

One of the most appealing topics in the study of metal-organic networks is the growth mechanism. However, its study is still considered a significant challenge. Herein, using scanning tunneling microscopy, the growth mechanisms of metal-alkynyl networks on Ag(111) and Au(111) surfaces were investigated at the atomic scale. During the reaction of 1,3,5-tris(chloroethynyl)benzene on Ag(111), honeycomb Ag-alkynyl networks formed at 393 K, and only short chain intermediates were observed. By contrast, the same precursor formed honeycomb Au-alkynyl networks on Au(111) at 503 K. Progression annealing led to a stepwise evolution process, in which the sequential activation of three Cl-alkynyl bonds led to the formation of dimers, zigzag chains, and novel chiral networks as the intermediates. Moreover, density functional theory calculations indicate that chlorine atoms are crucial in assisting the breakage of metal-alkynyl bonds to form Cl-metal-alkynyl, which guarantees the reversibility of the break/formation equilibration as the key to forming regular large-scale organometallic networks.

Alternative complement pathway is activated in the brains of scrapie-infected rodents.

Activation of complement system in central nervous system (CNS) of the patients suffering from prion diseases or animal models infected with prion agents experimentally is reported repeatedly, but which pathways are involved in the complement system during prion infection is not well documented. Here, we evaluated the level of complement factor B (CFB), which is the key factor that triggers alterative pathway (AP) of complement in the brain tissues of scrapie-infected mice with various methodologies. We found that the levels of mRNA and protein of CFB significantly increased in the brain tissues of scrapie-infected mice. Morphologically, the increased CFB-specific signal overlapped with the elevated C3 signal in brain sections of scrapie-infected mice, meanwhile overlapped with damaged neurons and activated microglia, but not with the proliferative astrocytes. Additionally, the level of complement factor P (CFP), the key positive regulator of AP, also increased remarkably in the brain tissues of infected mice. The transcriptional levels of CD55 and CD46, two negative regulators of AP, decreased without significance in brain tissues of scrapie-infected mice at the terminal stage. However, the mRNA and protein levels of CFH, another negative regulator of AP, increased. Through the dynamic analyses of the expressions of CFB, CFP, and CFH in brain sections of 139A-infected mice, which were collected at different time-points during incubation period, illustrated time-dependent increase levels of each factor during the incubation period of scrapie infection. Taken together, our data here demonstrate that the AP of complement cascade is activated in the CNS microenvironment during prion infection.

On-surface synthesis of 2D COFs on Cu(111) via the formation of thermodynamically stable organometallic networks as the template.

Template-directed polymerization is an effective approach used to afford regular 2D covalent organic frameworks (COFs), thus the regularity of the template is crucial for the quality of the resulting 2D COFs. For the Ullmann reactions on Cu(111), aryl iodides and bromides are activated at low temperature to form organometallic C-Cu-C structures, which lead to kinetic trapping and irregular organometallic networks. Therefore, the subsequent annealing step can only afford irregular 2D COFs. In this manuscript, the molecule 4,4''-dibromo-5'-(4-chlorophenyl)-1,1':3',1''-terphenyl incorporated two Br terminals and one Cl terminal has been used to demonstrate different reactivities of a C-Cl bond and a C-Br bond via the hierarchical activation of the C-Br bond and the C-Cl bond on Cu(111). At room temperature, zigzag, armchair, and ring-like organometallic chains formed due to the activation of the C-Br bond to generate a C-Cu-C structure while C-Cl remained intact, illustrating that the C-Cl bond is more stable than C-Br. Further annealing at 433 K activated the C-Cl bond to produce regular organometallic networks as the thermodynamic product. Using the simpler molecule 1,3,5-tris(4-chlorophenyl)benzene as the precursor, the self-assembly of the intact molecules was observed on Cu(111) at 300 K without activation of the C-Cl bond. After annealing at 433 K, similar thermodynamically stable organometallic networks formed directly, which were used as a template to generate regular 2D COFs upon further annealing at 510 K.

Joint effect of heatwaves and air quality on emergency department attendances for vulnerable population in Perth, Western Australia, 2006 to 2015.

BACKGROUND: As global warming and the frequency and intensity of heatwaves increases, health service utilization, including emergency department attendances (EDA) have correspondingly increased across the world. The impact of air quality on health adds to the complexity of the effects. Potential joint effects between heatwaves and air quality on EDA have been rarely reported in the literature, prompting this study. OBJECTIVES: To investigate the potential joint effect of heatwaves and air quality on the EDA for vulnerable populations in the Perth metropolitan area, Western Australia. METHODS: A time series design was used. Daily data on EDA, heatwaves (excess heat factor>0) and air pollutants (CO, SO2, NO2, O3, PM10 and PM2.5) were collected for Perth, Western Australia from 2006 to 2015. Poisson regression modelling was used to assess the associations between heatwaves, air quality, and EDA. Risk assessments on age, gender, Aboriginality, socio-economic status (SES), and joint effect between heatwaves and air quality on EDA were conducted. RESULTS: The EDA rate was higher in heatwave days (77.86/100,000/day) compared with non-heatwave days (73.90/100,000/day) with rate ratio of 1.053 (95% confidence interval 1.048, 1.058). The EDA rate was higher in males, people older than 60 years or younger than 15 years, Aboriginal people, and people with low SES. Exposure to CO, SO2, O3 and PM2.5 increased risk on EDA and exposure to PM2.5 showed joint effect with heatwave and increased risk of EDA by 6.6% after adjustment of all other risk factors. CONCLUSIONS: EDA is an important indicator to evaluate heatwave related morbidity for emergency medical service as EDA rate increased during heatwaves with relative high concentrations of air pollutants. As all air pollutants measured in the study were lower than the Australian National Standards, the joint effect of heatwaves and air quality needs to be further examined when it exceeds the standards.

Rapidly progressive cognitive impairment caused by intracranial dural arteriovenous fistulas (DAVFs): a case report.

Intracranial dural arteriovenous fistulas (DAVFs), constituting approximately 10 to15% of intracranial vascular malformations, are anomalous direct connections between dural arteries and venous sinuses, meningeal veins, or cortical veins; the arterial feeders are various, usually fed by branches of internal carotid, external carotid, or vertebral artery (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al. JN 124(6):1752-65, 2016; Terada T et al. JN 80(5):884-9, 1994). Spectrums of clinical presentations are widespread, arranging from pulsatile tinnitus to intracranial hemorrhage. Such DAVFs with rapidly progressive dementia as primary presentation, which has been reported in several literature, are still extremely scarce (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al JN 124(6):1752-65, 2016). Up to 2015, similar reports are less than 20 cases (Holoekamp et al. JN 124(6):1752-65, 2016). Herein, we report a patient who was misdiagnosed with encephalitis, presented thalamic dementia, and was ultimately diagnosed of DAVFs.

Atorvastatin Pretreatment Attenuates Ischemic Brain Edema by Suppressing Aquaporin 4.

BACKGROUND: Cerebral edema, a serious complication of acute cerebral infarction, has a crucial impact on morbidity and mortality in the early stage of cerebral infarction. And aquaporin 4 (AQP4), a bidirectional water transporting protein, plays a pivotal role in edema formation. At experimental model, it has proven that atorvastatin could exert pleiotropic neuroprotection on acute cerebral infarction independent of its cholesterol-lowering action. It was a common protective manifestation that atorvastatin can reduce the infarct volume and cerebral edema. However, little is known about atorvastatin improving ischemic brain edema by regulating AQP4 expression. This study intended to investigate the neuroprotection effects of atorvastatin pretreatment in rats with cerebral ischemia and further explore the potential relationship between atorvastatin and AQP4 expression. METHODS: Fifty-one adult male Sprague Dawley rats were randomly divided into 3 groups: sham, middle cerebral artery occlusion (MCAO), and atorvastatin pretreatment (Ator) group. For Ator group, 20 mg/kg of atorvastatin injectable suspension was administered once for 7days by gavage before operation, whereas the others were administered the same volume of saline matching. Except for sham group, MCAO and Ator groups were subjected to permanent MCAO by modified intraluminal suture method. Infarct volume, neurological deficit, brain water content (BWC), immunohistochemistry, western blot, and polymerase chain reaction (PCR) were measured at 24 hours after MCAO. RESULTS: Compared with sham group, the mNSS, infarct volume, and BWC of ischemic hemisphere were significantly increased (P < 0.001) in MCAO group. Positive cells and protein levels of p-p38MAPK and AQP4 in peri-infarction were significantly increased (P < 0.01). The mRNA levels of p38MAPK and AQP4 were also prominently upregulated (P < 0.01). Interestingly, preadministration of atorvastatin dramatically decreased infarct volume and the BWC of ischemic hemisphere compared with MCAO group (P < 0.05). The overexpressions of p-p38MAPK and AQP4 in peri-infarction were significantly decreased (P < 0.05) and their mRNA levels were downregulated by atorvastatin pretreatment (P < 0.05). Neurological deficits were also dramatically improved (P < 0.001). CONCLUSION: To the best of our knowledge, this is the first study that demonstrates an effect of atorvastatin on expression of AQP4, and we propose that decreased AQP4 expression through a p38MAPK-suppression pathway may be the mechanism of atorvastatin alleviating ischemic cerebral edema.

A serum metabolomic analysis for diagnosis and biomarker discovery of primary biliary cirrhosis and autoimmune hepatitis.

BACKGROUND: Because of the diversity of the clinical and laboratory manifestations, the diagnosis of autoimmune liver disease (AILD) remains a challenge in clinical practice. The value of metabolomics has been studied in the diagnosis of many diseases. The present study aimed to determine whether the metabolic profiles, based on ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), differed between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), to identify specific metabolomic markers, and to establish a model for the diagnosis of AIH and PBC. METHODS: Serum samples were collected from 20 patients with PBC, 19 patients with AIH, and 25 healthy individuals. UPLC-MS data of the samples were analyzed using principal component analysis, partial least squares discrimination analysis and orthogonal partial least squares discrimination analysis. RESULTS: The partial least squares discrimination analysis model (R2Y=0.991, Q2=0.943) was established between the AIH and PBC groups and exhibited both sensitivity and specificity of 100%. Five groups of biomarkers were identified, including bile acids, free fatty acids, phosphatidylcholines, lysolecithins and sphingomyelin. Bile acids significantly increased in the AIH and PBC groups compared with the healthy control group. The other biomarkers decreased in the AIH and PBC groups compared with those in the healthy control group. In addition, the biomarkers were downregulated in the AIH group compared with the PBC group. CONCLUSIONS: The biomarkers identified revealed the pathophysiological changes in AILD and helped to discriminate between AIH and PBC. The predictability of this method suggests its potential application in the diagnosis of AILD.

Enhanced Aluminum-Ion Storage Properties of N-Doped Titanium Dioxide Electrode in Aqueous Aluminum-Ion Batteries.

Aqueous aluminum-ion batteries (AIBs) have great potential as devices for future large-scale energy storage systems due to the cost efficiency, environmentally friendly nature, and impressive theoretical energy density of Al. However, currently, available materials used as anodes for aqueous AIBs are scarce. In this study, a novel sol-gel method was used to synthesize nitrogen-doped titanium dioxide (N-TiO2) as a potential anode material for AIBs in water. The annealed N-TiO2 showed a high discharge capacity of 43.2 mAh g-1 at a current density of 3 A g-1. Analysis of the electrode kinetics revealed that the N-TiO2 anodes exhibited rapid diffusion of aluminum ions, low resistance to charge transfer, and high electronic conductivity, enabling good rate performance. The successful implementation of a nitrogen-doping strategy provides a promising approach to enhance the electrochemical characteristics of electrode materials for aqueous AIBs.

Impact of elevated fine particulate matter (PM 2.5 ) during landscape fire events on cardiorespiratory hospital admissions in Perth, Western Australia.

BACKGROUND: Australia has experienced extreme fire weather in recent years. Information on the impact of fine particulate matter (PM 2.5 ) from landscape fires (LFs) on cardiorespiratory hospital admissions is limited. METHODS: We conducted a population-based time series study to assess associations between modelled daily elevated PM 2.5 at a 1.5×1.5 km resolution using a modified empirical PM 2.5 exposure model during LFs and hospital admissions for all-cause and cause-specific respiratory and cardiovascular diseases for the study period (2015-2017) in Perth, Western Australia. Multivariate Poisson regressions were used to estimate cumulative risk ratios (RR) with lag effects of 0-3 days, adjusted for sociodemographic factors, weather and time. RESULTS: All-cause hospital admissions and overall cardiovascular admissions increased significantly across each elevated PM 2.5 concentration on most lag days, with the strongest associations of 3% and 7%, respectively, at the high level of ≥12.60 µg/m3 on lag 1 day. For asthma hospitalisation, there was an excess relative risk of up to 16% (RR 1.16, 95% CI 1.00 to 1.35) with same-day exposure for all people, up to 93% on a lag of 1 day in children and up to 52% on a lag of 3 days in low sociodemographic groups. We also observed an increase of up to 12% (RR 1.12, 95% CI 1.02 to 1.24) for arrhythmias on the same exposure day and with over 154% extra risks for angina and 12% for heart failure in disadvantaged groups. CONCLUSIONS: Exposure to elevated PM 2.5 concentrations during LFs was associated with increased risks of all-cause hospital admissions, total cardiovascular conditions, asthma and arrhythmias.

Multi-medium residues and ecological risk of herbicides in a typical agricultural watershed of the Mollisols region, Northeast China.

The widespread use of herbicides impacts non-target organisms, promotes weed resistance, posing a serious threat to the global goal of green production in agriculture. Although the herbicide residues have been widely reported in individual environmental medium, their presence across different media has received scant attention, particularly in Mollisols regions with intensive agricultural application of herbicides. A systematic investigation was conducted in this study to clarify the occurrence of herbicide residues in soil, surface water, sediments, and grains from a typical agricultural watershed in the Mollisols region of Northeast China. Concentrations of studied herbicides ranged from 0.30 to 463.49 µg/kg in soil, 0.31-29.73 µg/kg in sediments, 0.006-1.157 µg/L in water, and 0.32-2.83 µg/kg in grains. Among these, Clomazone was the most priority herbicide detected in soil, sediments, and water, and Pendimethalin in grains. Crop types significantly affected the residue levels of herbicides in grains. Clomazone posed high ecological risks in soil and water, with 86.4 % of water samples showing high risks from herbicide mixtures (RQ > 1). These findings aid in enhancing our comprehension of the pervasive occurrence and potential ecological risks of herbicides in different media within typical agricultural watersheds, providing detailed data to inform the development of targeted mitigation strategies.

HGF ameliorates cardiomyocyte apoptosis and inflammatory response in sepsis via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway.

OBJECTIVE: This study aimed to analyze the impact of HGF on cardiomyocyte injury, apoptosis, and inflammatory response induced by lipopolysaccharide (LPS). METHODS: Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify the levels of HGF, interleukin (IL)-6, IL-10, creatine phosphokinase-isoenzyme-MB (CK-MB), and cardiac troponin I (cTnI) in the samples. qPCR and Western blotting (WB) were employed to assess the mRNA and protein expressions of HGF, IL-10, IL-6, PI3K, AKT, p-PI3K, and p-AKT. RESULTS: The outcomes of the in vivo experiment revealed that serum levels of IL-6, IL-10, HGF and SOFA scores in the SC group were elevated in contrast to the non-SC group. The correlation analysis indicated a substantial and positive association among serum HGF, IL-6, and IL-10 levels and SOFA scores. Relative to IL-6, IL-10 levels, and SOFA scores, serum HGF demonstrated the highest diagnostic value for SC. Following LPS administration to stimulate H9c2 cells across various periods (0, 12, 24, 48, and 72 h), the levels of myocardial injury markers (CK-MB and cTnI) in the cell supernatants, intracellular inflammatory factors (mRNA and protein levels of IL-10 and IL-6), apoptosis and ROS levels, exhibited a gradual increase followed by a subsequent decline. Following the overexpression of HGF, there was an increase in cell viability, and a decrease in apoptosis, inflammation, oxidative stress injuries, and the protein phosphorylation expressions of PI3K and AKT. After knockdown of HGF expression, the activity of LPS-induced H9c2 cells was further reduced, leading to increased cell injury, apoptosis, inflammation, oxidative stress,and the expression levels of PI3K and Akt protein phosphorylation were further elevated. CONCLUSION: HGF was associated with decreased LPS-induced H9c2 apoptosis and inflammation in H9c2 cells, alongside an improvement in cell viability, indicating potential cytoprotective effects. The mechanism underlying these impacts may be ascribed to the suppression of the PI3K/AKT signaling pathway.

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China.

AIM: To evaluate retrospectively the association of cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) gene polymorphisms with the pharmacokinetics of cyclosporine A (CsA) in Chinese renal transplant patients. METHODS: One hundred and twenty-six renal transplant patients were recruited. Blood samples were collected, and corresponding clinical indices were recorded on the seventh day after the procedure. The patients were genotyped for CYP3A4*1G, CYP3A5*3C, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T polymorphisms. Whole blood trough concentrations of CsA at time zero (C(0)) were measured before the drug administration. A multiple regression model was developed to analyze the effects of genetic factors on the CsA dose-adjusted C(0) (C(0)/dose) based on several clinical indices. RESULTS: The CYP3A5*3C polymorphism influenced the C(0) and C(0)/dose of CsA, which were significantly higher in patients with the GG genotype than in patients with the AA or GA genotypes. No significant differences were detected for other SNPs (CYP3A4*1G, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T). In a univariate analysis using Pearson's correlation test, age, hemoglobin, blood urea nitrogen and blood creatinine levels were significantly correlated with the log-transformed CsA C(0)/dose. In the multiple regression model, CYP3A5*3C, age, hemoglobin and blood creatinine level were associated with the log-transformed CsA C(0)/dose. CONCLUSION: CYP3A5*3C correlates with the C(0)/dose of CsA on the seventh day after renal transplantation. The allele is a putative indicator for the optimal CsA dosage in the early phase of renal transplantation in the Chinese population.

An investigation of oxidative DNA damage in pharmacy technicians exposed to antineoplastic drugs in two Chinese hospitals using the urinary 8-OHdG assay.

OBJECTIVE: To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS (Pharmacy Intravenous Admixture Service) in two Chinese hospitals. METHODS: Urinary 8-OHdG served as a biomarker. 5-Fluorouracil (5-FU) concentrations in air, masks and gloves were determined. The spill exposure of each PIVAS technician to antineoplastic drugs was investigated. Eighty subjects were divided into exposed group I, II, and control group I, II. RESULTS: 5-FU concentration ratios for gloves and masks in exposed group I were significantly higher than those in exposed group II (P<0.05 or P<0.01). The average urinary 8-OHdG concentrations in exposed group I, control group I, exposed group II, and control group II were 14.69±0.93, 10.68±1.07, 10.57±0.55, and 11.96±0.73 ng/mg Cr, respectively. Urinary 8-OHdG concentration in exposed group I was significantly higher than that in control group I or that in exposed group II (P<0.01). There was a significant correlation between urinary 8-OHdG concentrations and spill frequencies per technician (P<0.01). CONCLUSION: There was detectable oxidative DNA damage in PIVAS technicians exposed to antineoplastic drugs. This oxidative DNA damage may be associated with their spill exposure experience and contamination of their personal protective equipment.

Ultrasonic Features and Molecular Subtype Predict Somatic Mutations in TP53 and PIK3CA Genes in Breast Cancer.

RATIONALE AND OBJECTIVES: To predict mutations in TP53 and PIK3CA genes in breast cancer using ultrasound (US) signatures and clinicopathology. MATERIALS AND METHODS: In this study, we developed and trained a model in 386 breast cancer patients to predict TP53 and PIK3CA mutations. The clinicopathological and US characteristics (including two-dimensional and color Doppler US) were investigated. Statistically significant variables were used to build predictive models, then a combined model was developed using the multivariate logistic regression analysis. RESULTS: Univariate and multivariate analyses revealed that calcifications on US was an independent predictor of TP53 mutation (p < 0.05), whereas diameter on US and US type were independent predictors of PIK3CA mutation in breast cancer (all p < 0.05). Meanwhile, Luminal B/Human epidermal growth factor receptor two-positive (HER2+), HER2+/estrogen receptor-negative (ER-), and triple-negative breast cancer (TNBC) subtypes were strong predictors of TP53 mutation (odds ratio [OR] = 3.13, 3.18, 3.44, respectively, all p < 0.05). HER2+/ER- and TNBC subtypes were negative predictors of PIK3CA mutation (OR = 0.223, 0.241, respectively, all p < 0.05). The areas under curves (AUCs) for PIK3CA mutation in the training set increased from 0.553-0.610 to 0.741 in the multivariate model that combined US features and molecular subtype, with a sensitivity and specificity of 80.6% and 58.7%, respectively. The application of the multivariate model in the validation set achieved acceptable discrimination (AUC = 0.715). For TP53 mutation, the AUC was 0.653. CONCLUSION: US is a non-invasive modality to recognize the presence of TP53 and PIK3CA mutation. The models combined with US features and molecular subtype have implications for the practical application of predicting gene mutation for individual decision-making regarding treatment planning.

Exposure to fine particulate matter (PM2.5) during landscape fire events and the risk of cardiorespiratory emergency department attendances: a time-series study in Perth, Western Australia.

BACKGROUND: Landscape fires (LFs) are the main source of elevated particulate matter (PM2.5) in Australian cities and towns. This study examined the associations between daily exposure to fine PM2.5 during LF events and daily emergency department attendances (EDA) for all causes, respiratory and cardiovascular outcomes. METHODS: Daily PM2.5 was estimated using a model that included PM2.5 measurements on the previous day, remotely sensed aerosols and fires, hand-drawn tracing of smoke plumes from satellite images, fire danger ratings and the atmosphere venting index. Daily PM2.5 was then categorised as high (≥99th percentile), medium (96th-98th percentile) and low (≤95th percentile). Daily EDA for all-cause and cardiorespiratory conditions were obtained from the Western Australian Emergency Department Data Collection. We used population-based cohort time-series multivariate regressions with 95% CIs to assess modelled daily PM2.5 and EDA associations from 2015 to 2017. We estimated the lag-specific associations and cumulative risk ratios (RR) at lags of 0-3 days, adjusted for sociodemographic factors, weather and time. RESULTS: All-cause EDA and overall cardiovascular presentations increased on all lagged days and up to 5% (RR 1.05, 95% CI 1.03 to 1.06) and 7% (RR 1.07, 95% CI 1.01 to 1.12), respectively, at the high level. High-level exposure was also associated with increased acute lower respiratory tract infections at 1 (RR 1.19, 95% CI 1.10 to 1.29) and 3 (RR 1.17, 95% CI 1.10 to 1.23) days lags and transient ischaemic attacks at 1 day (RR 1.25, 95% CI 1.02 to 1.53) and 2 (RR 1.20, 95% CI 1.01 to 1.42) days lag. CONCLUSIONS: Exposure to PM2.5 concentrations during LFs was associated with an increased risk of all-cause EDA, overall EDA cardiovascular diseases, acute respiratory tract infections and transient ischaemic attacks.