Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

Kinetic Heterogeneity Improves the Specificity of Dynamic Enhanced MRI in Differentiating Benign and Malignant Breast Tumours.

RATIONALE AND OBJECTIVES: To investigate whether kinetic heterogeneity in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) improves the specificity of breast cancer (BC) diagnosis. MATERIALS AND METHODS: The DCE-MRI data of patients with benign breast tumours and BC from June 2020 to July 2022 were retrospectively evaluated. MATLAB and SPM were used to determine six major kinetic parameters: peak, enhancement volume, heterogeneity, as well as persistent, plateau, and washout proportions. Continuous variables were compared using the Student's t-test or Mann-Whitney U tests, and categorical variables were compared using the chi-square or Fisher's exact tests. Receiver operating characteristic curves were plotted. The intraclass correlation coefficient (ICC) was used to evaluate agreement between the two observers. Multivariate logistic regression analysis was conducted to calculate the odds ratios (ORs) with 95% confidence intervals (CIs) for the association between benign and malignant breast tumours. RESULTS: In total, 147 patients (mean age, 47 years old) were included in the study, 76 of whom had BC. Data analysis by the two observers showed good consistency in the peak, enhancement volume, persistent proportion, plateau proportion, washout proportion, and heterogeneity, with ICCs of 0.865, 0.988, 0.906, 0.940, 0.740, and 0.867, respectively (p < 0.001). In the DCE kinetic analysis, differences in all the six kinetic parameters were statistically significant (p < 0.05). The area under the curve for heterogeneity was 0.92 (95% CI:0.88,0.97), and the sensitivity and specificity were 0.895 and 0.845, respectively. Multivariate logistic regression analysis showed that heterogeneity was an independent predictor of BC compared to benign breast tumours (OR=2.020; 95% CI:1.316, 3.100; p = 0.001). CONCLUSION: The kinetic heterogeneity of DCE-MRI can effectively distinguish between benign and malignant breast tumours and improve the specificity of BC diagnosis.

Nontarget Identification of Novel Per- and Polyfluoroalkyl Substances (PFAS) in Soils from an Oil Refinery in Southwestern China: A Combined Approach with TOP Assay.

Oil refinery activity can be an emission source of perfluoroalkyl and polyfluoroalkyl substances (PFAS) to the environment, while the contamination profiles in soils remain unknown. This study investigated 44 target PFAS in soil samples collected from an oil refinery in Southeastern China, identified novel PFAS, and characterized their behaviors by assessing their changes before and after employing advanced oxidation using a combination of nontarget analysis and a total oxidizable precursor (TOP) assay. Thirty-four target PFAS were detected in soil samples. Trifluoroacetic acid (TFA) and hexafluoropropylene oxide dimer acid (HFPO-DA) were the dominant PFAS. Twenty-three novel PFAS of 14 classes were identified, including 8 precursors, 11 products, and 4 stable PFAS characterized by the TOP assay. Particularly, three per-/polyfluorinated alcohols were identified for the first time, and hexafluoroisopropanol (HFIP) quantified up to 657 ng/g dw is a novel precursor for TFA. Bistriflimide (NTf2) potentially associated with an oil refinery was also reported for the first time in the soil samples. This study highlighted the advantage of embedding the TOP assay in nontarget analysis to reveal not only the presence of unknown PFAS but also their roles in environmental processes. Overall, this approach provides an efficient way to uncover contamination profiles of PFAS especially in source-impacted areas.

Distribution, bioaccumulation, and health risk assessment of organochlorines across the riverine ecosystem of Punjab Province, Pakistan.

This study was designed to assess the distribution of organochlorines (OCs) in fish species, their spatio-temporal variations, bioaccumulation potential, and associated human health risks via dietary intake. The levels of twenty-three organochlorine pesticides (OCPs) and thirty-five polychlorinated biphenyls (PCBs) were analyzed in six fish species collected from the riverine ecosystem of Punjab Province, Pakistan. The results indicated that the mean levels of Σ23OCPs were 74.1 ng/g ww and 184 ng/g ww, and for Σ35PCBs the levels were 38.8 ng/g ww and 74.8 ng/g ww in herbivorous and carnivorous fish species, respectively. The most abundant contaminants in all fish species were DDTs (65%) and HCHs (14%) among OCPs and heavier PCB congeners (62%) among PCBs. As for dioxin-like PCBs, the WHO toxic equivalency values (ng TEQ/g ww) were in the range of 0.21 (Cyprinus Carpio) to 2.38 (Rita Rita), exceeding the maximum allowable limit of 0.004 ng TEQ/g, ww by the European Commission. Spatio-temporal analysis indicated relatively higher OC levels in winter season with elevated concentrations in fish samples from industrial zone. The bioconcentration factor (L/kg) values ranged from 723 to 2773 for PCBs and 315 to 923 for OCPs in all fish species, with higher levels were reported in carnivorous species. The human health risk assessment at both 50th and 95th percentiles revealed the absence of any significant non-carcinogenic risk as calculated HR was less than 1. However, the critical carcinogenic risk was found to be associated for most of the contaminants, signifying the dietary exposure to OCPs and PCBs might pose the public health concern.

In situ self-sacrificial synthesis of polypyrrole/biochar composites for efficiently removing short- and long-chain perfluoroalkyl acid from contaminated water.

Efficient removal of perfluoroalkyl acids (PFAAs), especially short-chain ones, from contaminated water is of great challenge and is urgently called for so as to safeguard the ecosystem and human health. Herein, polypyrrole (PPy) functionalized biochar (BC) composites were innovatively synthesized by an in situ self-sacrificial approach to allow efficient capture of PFAAs with different chain lengths. Compared with conventional PPy-based composites synthesized by direct polymerization using FeCl3 as an oxidizing agent, PPy/BC composites were fabricated utilizing freshly generated Fe3+ as an oxidizing agent from self-sacrificial Fe3O4 for pyrrole monomers in situ polymerizing on BC. As a result, with the support of BC and gradual release of Fe3+, PPy overcame its tendency to aggregate and became uniformly dispersed on BC, and meanwhile, PPy could well tailor the surface chemistry of BC to endow its positively charged surface. Consequently, the composites exhibited strong sorption capacities of 3.89 and 1.53 mmol/g for short-chain perfluorobutanoic acid (PFBA) and perfluorobutane sulfonic acid (PFBS), 2.55 and 1.22 mmol/g for long-chain perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), respectively, which were superior to those of pristine BC, commercial activated carbon, and anion exchange resins reported. Additionally, they could effectively remove 17 different classes of per- and polyfluoroalkyl substances (PFAS) (removal >95%) from actual PFAS-contaminated water, and the spent sorbent could be well regenerated and reused at least 5 times. An integrated analysis indicated that such an outstanding PFAA sorption performance on PPy/BC composites could be mainly attributed to surface adsorption enhanced by electrostatic attractions (anion exchange interaction) with the traditional hydrophobic interaction and pore filling of less contribution, particularly for short-chain analogues. These results are expected to inform the design of BC with greater ability to remove PFAS from water and the new sorbent could help water facilities comply with PFAS regulations.

Integrated metabolomics, transcriptomics, and proteomics analyses reveal co-exposure effects of polycyclic aromatic hydrocarbons and cadmium on ryegrass (Lolium perenne L.).

Cadmium (Cd) and polycyclic aromatic hydrocarbons (PAHs) are prominent soil contaminants found in industrial sites, and their combined effects on plants are not yet fully understood. To investigate the mechanisms underlying the co-exposure of Cd and PAHs and identify key biomarkers for their co-effects, an integrated analysis of metabolomics, transcriptomics, and proteomics was conducted on ryegrass leaves cultivated in soil. In nontarget metabolomics analysis, nine differentially expressed metabolites that were specifically induced by the compound exposure were identified. When combined with the analysis of differentially expressed genes and proteins, it was determined that the major pathways involved in the response to the co-stress of Cd and PAHs were linoleic acid metabolism and phenylpropanoid biosynthesis. The upregulation of 12,13-dihydroxy-9Z-octadecenoic acid and the downregulation of sinapyl alcohol were identified as typical biomarkers, respectively. Compared to scenarios of single exposures, the compound exposure to Cd and PAHs disrupted the oxidation of linoleic acid, leading to alterations in the profiles of linoleate metabolites. Additionally, it intensified hydroxylation, carboxylation, and methylation processes, and interfered with reactions involving coenzyme A, thus inhibiting lignin production. As a result, oxidative stress was elevated, and the cell wall defense system in ryegrass was weakened. The findings of this study highlight the ecological risks associated with unique biological responses in plants co-exposed to Cd and PAHs in polluted soils.

Serum organophosphate flame retardants and plasticizers in Chinese females of childbearing age: Association with serum reproductive and thyroid hormones.

Organophosphate flame retardants (OPFRs) are extensively used as flame retardants and plasticizers, but their endocrine disrupting potentials have raised concerns. However, the impacts of OPFR exposures on reproductive and thyroid hormones in females remains unclear. In this study, serum concentrations of OPFRs were investigated, and levels of reproductive and thyroid hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, anti-Müllerian hormone, prolactin (PRL), testosterone (T), and thyroid stimulating hormone, were analyzed in childbearing-age females undergoing in-vitro fertilization treatment from Tianjin, a coastal city in China (n = 319). Tris (2-chloroethyl) phosphate (TCEP) was the predominant OPFR, with a median concentration of 0.33 ng/mL and a detection frequency of 96.6%. In the whole population, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and tris(2-chloroisopropyl) phosphate (TCIPP) were positively associated with T (p < 0.05), while triethyl phosphate (TEP) was negatively associated with LH (p < 0.05) and LH/FSH (p < 0.01). Particularly, TCIPP was negatively associated with PRL in the younger subgroup (age≤30, p < 0.05). Moreover, TCIPP was negatively associated with diagnostic antral follicle counting (AFC) in the mediation analysis by a dominating direct effect (p < 0.01). In conclusion, serum levels of OPFRs were significantly associated with reproductive and thyroid hormone levels and a risk of decreased ovarian reserve in childbearing-age females, with age and body mass index being significant influencing factors.

Deep learning-based low-dose CT for adaptive radiotherapy of abdominal and pelvic tumors.

The shape and position of abdominal and pelvic organs change greatly during radiotherapy, so image-guided radiation therapy (IGRT) is urgently needed. The world's first integrated CT-linac platform, equipped with fan beam CT (FBCT), can provide a diagnostic-quality FBCT for achieve adaptive radiotherapy (ART). However, CT scans will bring the risk of excessive scanning radiation dose. Reducing the tube current of the FBCT system can reduce the scanning dose, but it will lead to serious noise and artifacts in the reconstructed images. In this study, we proposed a deep learning method, Content-Noise Cycle-Consistent Generative Adversarial Network (CNCycle-GAN), to improve the image quality and CT value accuracy of low-dose FBCT images to meet the requirements of adaptive radiotherapy. We selected 76 patients with abdominal and pelvic tumors who received radiation therapy. The patients received one low-dose CT scan and one normal-dose CT scan in IGRT mode during different fractions of radiotherapy. The normal dose CT images (NDCT) and low dose CT images (LDCT) of 70 patients were used for network training, and the remaining 6 patients were used to validate the performance of the network. The quality of low-dose CT images after network restoration (RCT) were evaluated in three aspects: image quality, automatic delineation performance and dose calculation accuracy. Taking NDCT images as a reference, RCT images reduced MAE from 34.34 ± 5.91 to 20.25 ± 4.27, PSNR increased from 34.08 ± 1.49 to 37.23 ± 2.63, and SSIM increased from 0.92 ± 0.08 to 0.94 ± 0.07. The P value is less than 0.01 of the above performance indicators indicated that the difference were statistically significant. The Dice similarity coefficients (DCS) between the automatic delineation results of organs at risk such as bladder, femoral heads, and rectum on RCT and the results of manual delineation by doctors both reached 0.98. In terms of dose calculation accuracy, compared with the automatic planning based on LDCT, the difference in dose distribution between the automatic planning based on RCT and the automatic planning based on NDCT were smaller. Therefore, based on the integrated CT-linac platform, combined with deep learning technology, it provides clinical feasibility for the realization of low-dose FBCT adaptive radiotherapy for abdominal and pelvic tumors.

Residual Channel Attention Network for Brain Glioma Segmentation.

A glioma is a malignant brain tumor that seriously affects cognitive functions and lowers patients' life quality. Segmentation of brain glioma is challenging because of inter-class ambiguities in tumor regions. Recently, deep learning approaches have achieved outstanding performance in the automatic segmentation of brain glioma. However, existing al-gorithms fail to exploit channel-wise feature interdependence to select semantic attributes for glioma segmentation. In this study, we implement a novel deep neural network that integrates residual channel attention modules to calibrate intermediate features for glioma segmentation. The proposed channel at-tention mechanism adaptively weights feature channel-wise to optimize the latent representation of gliomas. We evaluate our method on the established dataset BraTS2017. Experimental results indicate the superiority of our method. Clinical relevance - While existing glioma segmentation approaches do not leverage channel-wise feature dependence for feature selection our method can generate segmentation masks with higher accuracies and provide more insights on graphic patterns in brain MRI images for further clinical reference.

Non-target discovery of emerging PFAS homologues in Dagang Oilfield: Multimedia distribution and profiles in crude oil.

Per- and polyfluoroalkyl substances (PFASs) are applied in oil exploitation activity. In this study, non-target and suspect target analyses with high-resolution mass spectrometry were used for identification of novel PFASs in the oilfield environment. A total of thirty-seven PFAS homologues belonging to eight classes were identified as level 4 or above, which partly explained the amount of potential unknown PFAS-precursors that were indicated by total oxidisable precursor assay in our previous study. Hydrogen-substituted and ether-substituted homologues were the main identified PFASs, and seven of them were newly reported homologues. C1-C3 perfluoroalkane sulphonic acids (PFSAs) were also for the first time identified in the oilfield. The sediment-water partitioning coefficients of most identified PFAS homologues positively correlate with their predicted octanol-water partitioning coefficients while those of C1-C3 PFSAs may have elevated sediment partitioning potential as also previously observed for ultra-short chain C2-C3 perfluoroalkyl carboxylic acids. The crude oil and sludge samples were further examined with the target and identified PFAS profiles. An annual flux of 10.4 kg/y via oil production was estimated in Dagang Oilfield with 16.6 % not from the target PFASs. This demonstrates that oil exploitation activities can be a significant underlying source of PFASs to the environment.

Occupational exposure to organophosphate esters in e-waste dismantling workers: Risk assessment and influencing factors screening.

Organophosphate esters (OPEs) are increasingly added in electronic products as alternative flame retardants, which may result in high occupational exposure of electronic waste recycling employees. This study investigated occupational exposure to OPEs in an e-waste recycling site in northern China, with intent to explore the impacts of occupational exposure and dismantling manipulation mode. Human urine samples from three sites with different distances from the core dismantling area, including employees from family workshops and plants with centralized management and residents from nearby areas, were collected and analyzed for OPEs' metabolites (mOPEs). The urinary ∑mOPEs' median concentrations (0.910 ng/mL) of all employees were significantly higher than those of residents in Ziya Town (0.526 ng/mL) and Jinghai downtown (0.600 ng/mL), suggesting the risk of occupational OPEs' exposure associated with e-waste dismantling. However, the spatial variation was insignificant for residents with different distances from the e-waste recycling site. Besides, OPEs' exposure levels were significantly affected by manipulation modes and the urinary ∑mOPEs' median concentrations in the employees of family workshops (1.05 ng/mL) were significantly higher than those in plants with centralized management (0.667 ng/mL). The result suggests that mechanical dismantling and active ventilating measures can reduce the OPEs' occupational exposure risk. Moreover, ∑mOPEs were higher in volunteers with age above 50 years old and in the underweight subgroup. Finally, different categories of mOPEs in human urine showed associations with corresponding OPEs in dust samples in the same area.

E-waste dismantling-related occupational and routine exposure to melamine and its derivatives: Estimating exposure via dust ingestion and hand-to-mouth contact.

Melamine (MEL) and its derivatives are increasingly applied as nitrogenous flame retardants in consumer products. Nevertheless, limited information is available on their environmental occurrence and subsequent human exposure via multiple exposure pathways. In this study, we analysed MEL and its derivatives in dust (indication of the dust ingestion route) and hand wipe samples (indication of the hand-to-mouth route) collected in various microenvironments. The levels of ∑MELs in both dust (median: 24,100 ng/g) and participant hand samples (803 ng/m2) collected in e-waste dismantling workshops were significantly higher than those in samples collected in homes (15,600 ng/g and 196 ng/m2, respectively), dormitories (13,100 ng/g and 227 ng/m2, respectively) and hotel rooms (11,800 ng/g and 154 ng/m2, respectively). Generally, MEL dominated in dust samples collected in e-waste dismantling workshops, whereas cyanuric acid dominated in hand wipe samples. This may occur partly because the latter is an ingredient in disinfection products, which are more frequently employed in daily lives during the COVID-19 pandemic. Exposure assessment suggests that dust ingestion is an important exposure pathway among dismantling workers and the general population, whereas hand-to-mouth contact could not be overlooked in certain populations, such as children and dismantling workers not wear gloves at work.

Azulene-Containing Squaraines for Photoacoustic Imaging and Photothermal Therapy.

Photoacoustic imaging (PAI) guided photothermal therapy (PTT) can realize real-time diagnosis and in situ treatment of cancer at the same time. Absorption in the near-infrared (NIR) region with large molar extinction coefficient (ε) and high value of photothermal conversion efficiency (PCE) are key prerequisites for photothermal agents (PTAs) to realize dual PAI and PTT treatments. Squaraines have stable quinoid structures with strong planarity and rigidity, in favor of the NIR absorption and high ε values. On the other hand, azulene derivatives mostly have very faint fluorescence emission, which is beneficial for photothermal transformation. Herein, two azulene-containing squaraines Az-SQ-1 and Az-SQ-2 are synthesized as high-performance PTAs. In comparison with Az-SQ-1, Az-SQ-2 possesses larger εmax of 3 × 105 M-1 cm-1 at 780 nm in organic solution and higher PCE of 53.2% in the form of nanoparticles under 808 nm laser irradiation. Accordingly, Az-SQ-2 NPs present stronger photoacoustic signals (about 15.1-times the background signal) and more efficient suppression of tumor growth. Our research indicates that the introduction of azulene unit to traditional NIR dyes is a simple but effective approach to obtain outstanding PTAs in the aspect of phototheranostics.

Strong but reversible sorption on polar microplastics enhanced earthworm bioaccumulation of associated organic compounds.

Sorption/desorption of two organic compounds (OCs), phenanthrene (PHE), and 1-nitronaphthalene (1-Nnap) on three polar and one nonpolar polypropylene (PP) microplastics (MPs) and earthworm bioaccumulation of MP associated PHE were systematically studied. Poly-butylene succinate (PBS) with the lowest glass transition temperature (Tg) showed the highest sorption toward PHE and 1-Nnap (Kd: 25,639 ± 276 and 1673 ± 28.8 L kg-1, respectively), while polylactic acid (PLA) with the highest Tg showed the least sorption (182 ± 5 and near 0), confirming that hydrophobic partition was the main driving force of sorption. However, polar interactions also contributed to the preferential sorption of 1-Nnap on polar poly-hydroxyalkanoates (PHA). Moreover, small particle size favored the sorption of MPs and simulated weathering enhanced sorption on MPs with medium/high Tg. As for desorption, slight hysteresis was observed in most cases with near-zero hysteresis index (HI), and PHE generally had higher HI than 1-Nnap. The simulated digestive solution could further promote the desorption of PHE. The PHE concentrations in earthworms with the presence of 5% PBS or PP MPs in soil were 1.50-2.35 or 1.59-1.75 times that of the control without MPs; and PBS MPs with the smallest particle size showed the greatest enhancement. The results of this study confirmed that polar MPs could strongly but reversibly sorb both polar and nonpolar OCs and hence promote the bioaccumulation of OCs to soil organisms.

Comparative Pharmacological Profiles of Various Bovine, Ovine, and Porcine Heparins.

Unfractionated heparin is the first anticoagulant drug and has been successfully used clinically for over 80 years. Heparin and its analogues are used during surgery and dialysis and are often used to coat indwelling catheters and other devices where the vascular system is exposed. Most of the heparins used clinically are derived from porcine intestinal mucosa. However, heparins have also been manufactured from tissues of other mammalian species such as cows and sheep. Recently there have been attempts to generate bioengineered heparin in order to overcome contamination and antigenicity problems. Currently there are some concerns about the shortage of the porcine heparins as they are widely used in the manufacturing of the low-molecular-weight heparins. Moreover, due to cultural and religious reasons in some countries, alternative sources of heparins are needed. The Food and Drug Administration and other regulatory agencies have considered alternative sourcing of heparin for potential substitution of porcine heparin and are currently reviewing this matter. Numerous studies are ongoing to understand the structure-activity relationships of these various heparins. In this article, heparins from different animal sources were studied to determine the extent of biosimilarity between them. For these investigations, 10 batches each of bovine mucosal heparin (BMH), ovine mucosal heparin (OMH), and porcine mucosal heparin (PMH) were studied. These studies have demonstrated that OMH and PMH have comparable anticoagulant and antiproteases activities. However, BMH exhibited somewhat a lower potency compared to OMH and PMH in functional assays.

Non-Anticoagulant Low Molecular Weight Heparins for Pharmaceutical Applications.

Heparin is a polypharmacological agent with anticoagulant activity. Periodate oxidation of the nonsulfated glucuronic acid residue results in non-anticoagulant heparin derivative (NACH) of reduced molecular weight. Similar treatment of a low molecular weight heparin, dalteparin, also removes its anticoagulant activity, affording a second heparin derivative (D-NACH). A full structural characterization of these two derivatives reveals their structural differences. SPR studies display their ability to bind to several important heparin-binding proteins, suggesting potential new therapeutic applications.