Manipulating Radiation-Sensitive Z-DNA Conformation for Enhanced Radiotherapy.

DNA double-strand breaks (DSBs) yield highly determines radiotherapy efficacy. However, improving the inherent radiosensitivity of tumor DNA to promote radiation-induced DSBs remains a challenge. Using theoretical and experimental models, the underexplored impact of Z-DNA conformations on radiosensitivity, yielding higher DSBs than other DNA conformations, is discovered. Thereout, a radiosensitization strategy focused on inducing Z-DNA conformation, utilizing CBL@HfO2 nanocapsules loaded with a Z-DNA inducer CBL0137, is proposed. A hollow mesoporous HfO2 (HM-HfO2) acts as a delivery and an energy depositor to promote Z-DNA breakage. The nanocapsule permits the smart DSBs accelerator that triggers its radiosensitization with irradiation stimulation. Impressively, the CBL@HfO2 facilitates the B-Z DNA conformational transition, augmenting DSBs about threefold stronger than irradiation alone, generating significant tumor suppression with a 30% cure rate. The approach enables DSBs augmentation by improving the inherent radiosensitivity of DNA. As such, it opens up an era of Z-DNA conformation manipulation in radiotherapy.

Impact of Practical Online Lessons on Chinese Medical Students' Perception of Radiation Oncology.

Radiotherapy is an essential component of oncology treatment. It is imperative that clinicians and medical students have a fundamental understanding of radiotherapy. However, radiation oncology education is deficient worldwide. This study introduced an hour-long online Massive Open Online Course (MOOC) as a supplement to the basic curriculum for 8-year medical students at Peking Union Medical College and Tsinghua University in China. The students' personal opinions and comprehension of radiation oncology therapy were assessed through pre- and post-test questionnaires before and after the MOOC study. The results indicated that the percentage of students interested in radiotherapy increased, and their knowledge of radiotherapy significantly improved after the online MOOC study, suggesting that short-term MOOC study may stimulate students' interest in learning and improving their knowledge of radiation therapy. The study suggests that the combination of online and offline teaching may be a feasible way to develop radiation oncology education in the future.

Radiotherapy for postoperative vaginal recurrences of cervical squamous cell carcinoma: analysis of dosing and prognosis.

Squamous cell carcinoma (SCC) is the most common type of vaginal recurrence in cervical cancer patients, and the role of salvage radiotherapy on these patients remains unclear. This study aimed to investigate the efficacy of salvage radiotherapy for vaginal recurrence of SCC in patients who previously underwent surgery and to explore prognostic factors associated with survival. Ninety-seven patients with histologically proven SCC who were treated for vaginal recurrence at Peking Union Medical College Hospital were identified. All patients had previously undergone surgery and received salvage radiotherapy. Factors predictive of overall survival (OS), progression-free survival (PFS), and local control (LC) were investigated. The median follow-up time was 42.5 months. The estimated 5-year OS, PFS, and LC rates were 84%, 79%, and 91%. On multivariate analysis, inguinal lymph node metastasis was significantly associated with poor OS; a tumour size ≤4 cm was associated with longer PFS (p < 0.05); the recurrence pattern was an independent predictor of LC (p < 0.05). In the 45 patients with recurrences that were paravaginal or invasive of surrounding organs, biologically equivalent doses in 2 Gy fractions of ≥72.6 Gy were independently predictive of longer LC (p < 0.05). RT is an effective treatment for postoperative vaginal recurrence in patients with cervical SCC. For patients with extravaginal recurrence, a salvage dose of ≥72.6 Gy appears to be optimal.Impact statementWhat is already known on this subject? Radiotherapy plays a critical role in treating recurrent cervical cancer, but the effectiveness of RT for vaginal recurrence in patients who previously underwent surgery remains limited. Few studies have focussed on the effect of RT dose on patient survival.What do the results of this study add? This study investigated the efficacy of RT in patients with cervical squamous cell carcinoma who experienced postoperative recurrence. Lymph node metastasis, tumour size and recurrence pattern were significantly associated with survival. Moreover, an EQD2 ≥ 72.6 Gy was independently predictive of longer LC.What are the implications of these findings for clinical practice and/or further research? RT is an effective treatment for postoperative vaginal recurrence in patients with cervical squamous cell carcinoma. For patients with extravaginal recurrence, a salvage dose of ≥72.6 Gy appears to be optimal.

Radiotherapy for Vaginal Recurrences of Cervical Cancer in Patients After Prior Surgery: Analysis of Effect and Prognostic Factors.

OBJECTIVE: The role of salvage radiotherapy (RT) in the treatment for vaginal recurrence of cervical cancer in patients after prior surgery remains controversial. The aim of this study was to evaluate the efficacy and toxicity of salvage RT and explore prognostic factors associated with the survival after recurrence. METHODS: Patients with cervical cancer, treated for vaginal recurrences at Peking Union Medical College Hospital between July 2011 and November 2019, were identified. All the patients underwent prior surgery for primary tumor and received salvage RT including external beam radiotherapy (EBRT), brachytherapy (BT), or both. The irradiation field and dose depended on the conditions of patients. Recurrence patterns were classified into four categories according to the site of recurrence. Prognostic factors on the overall survival (OS), progression-free survival (PFS), and local control (LC) were analyzed, and late toxicity was evaluated. RESULTS: A total of 141 patients were included in the analysis, with a median follow-up time of 40.8 months. The estimated 5-year OS, PFS, and LC rates were 81%, 75%, and 87%, respectively. In multivariate analysis, endovaginal recurrence and no irradiation history were favorable prognostic factors associated with OS (all p < 0.05), PFS (all p < 0.05), and LC (all p < 0.05). The area under the receiver operating characteristic (ROC) curve (AUC) of the recurrence pattern is larger than the stage of primary tumor (0.734 vs. 0.670). CONCLUSIONS: RT was an effective treatment with tolerable toxicity for vaginal recurrences of cervical cancer in patients with prior surgery. Recurrence pattern and irradiation history were important prognostic factors.

Combining In Silico Tools with Multicriteria Analysis for Alternatives Assessment of Hazardous Chemicals: Accounting for the Transformation Products of decaBDE and Its Alternatives.

Transformation products ought to be an important consideration in chemical alternatives assessment. In this study, a recently established hazard ranking tool for alternatives assessment based on in silico data and multicriteria decision analysis (MCDA) methods was further developed to include chemical transformation products. Decabromodiphenyl ether (decaBDE) and five proposed alternatives were selected as case chemicals; biotic and abiotic transformation reactions were considered using five in silico tools. A workflow was developed to select transformation products with the highest occurrence potential. The most probable transformation products of the alternative chemicals were often similarly persistent but more mobile in aquatic environments, which implies an increasing exposure potential. When persistence (P), bioaccumulation (B), mobility in the aquatic environment (M), and toxicity (T) are considered (via PBT, PMT, or PBMT composite scoring), all six flame retardants have at least one transformation product that can be considered more hazardous, across diverse MCDA. Even when considering transformation products, the considered alternatives remain less hazardous than decaBDE, though the range of hazard of the five alternatives was reduced. The least hazardous of the considered alternatives were melamine and bis(2-ethylhexyl)-tetrabromophthalate. This developed tool could be integrated within holistic alternatives assessments considering use and life cycle impacts or additionally prioritizing transformation products within (bio)monitoring screening studies.

Evaluating oral and inhalation bioaccessibility of indoor dust-borne short- and median-chain chlorinated paraffins using in vitro Tenax-assisted physiologically based method.

Though ingestion and inhalation of dust have been suggested as important exposure routes contributing chlorinated paraffins (CPs) build-up in humans, the bioaccessibility of dust-borne CPs in the organ environment has not been well-studied, which may hinder an accurate estimation of exposure risks. In this study, the ingestion and inhalation bioaccessibility of dust-borne short- and median-chain CPs (SCCPs and MCCPs) was assessed using (colon-extended) physiologically based extraction test with the addition of Tenax. The ingestion bioaccessibility of SCCPs 51.5 %Cl, SCCPs 63 %Cl, MCCPs 42 %Cl, and MCCPs 57 %Cl was in ranges of 21.1-44.0 %, 11.7-45.8 %, 21.9-36.6 %, and 7.9-32.9 %, respectively. Multiple linear regression analysis demonstrated statistically significant associations of ingestion bioaccessibility with carbon chain length and chlorine substitution. The ingestion bioaccessibility of CPs also increased with co-existence of carbohydrate/protein. The inhalation bioaccessibility of SCCPs (16.7-38.7 % in artificial lysosomal fluid and 15.5-34.1 % in modified Gamble solution) was significantly higher than MCCPs (<5 %), and varied with dust particle size/total organic carbon content. Our study indicates that modest bioaccessible fractions of CPs in dust should be taken into account to refine the estimation of human exposure, and their bioaccessibility may be affected by CP molecular size, nutritional content and dust property.

Efficacy of adjuvant radiotherapy for treatment of adrenocortical carcinoma: a retrospective study and an updated meta-analysis.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. Surgical resection is the standard treatment for localized ACC, but the local recurrence remains high. Adjuvant radiation (ART) has been proposed as a means to reduce recurrence rates in ACC after surgery with conflicting results from nonrandomized studies. We performed a retrospective study and a meta-analysis to determine the impact of ART on survival outcomes. METHODS: A retrospective study of the adrenocortical cancer database in Peking Union Medical College was conducted. We selected postoperative ACC patients with or without ART. A meta-analysis is also performed to compare the outcomes between ART and only surgical resection in ACC patients. The obtained data were analyzed using SPSS 23.0 and Stata 15.0 statistical software. Differences between two groups were compared using the log-rank test for retrospective analysis and estimated by calculating the odds ratio (OR) and 95% confidence interval (CI) for meta-analysis. RESULTS: Of a total of 75 patients available in the database, 12 patients underwent postoperative ART and were matched one to one to patients with only surgical resection. There was no significant difference on overall survival between ART group and control group (log-rank P = 0.149). Locoregional recurrence was diagnosed in 2 of the ART group, and in 4 of the control group (P = 0.64). A total of 238 participants were selected for the meta-analysis, of which 111 and 127 patients underwent ART after surgical resection and only surgical resection, respectively. Overall survival is significantly higher in ART group, with an odds ratio (OR) of 2.41 (95% CI of 1.33, 4.38; P = 0.004). Besides, meta-analysis significantly favored ART for locoregional recurrence-free survival and disease-free survival, with an OR of 4.08 and 2.27, respectively. CONCLUSIONS: Our results show that compared to only surgical resection, ART is an effective postoperative treatment for ACC.

Studies of Emission Processes of Polymer Additives into Water Using Quartz Crystal Microbalance-A Case Study on Organophosphate Esters.

Plastic materials contain various additives, which can be released during the entire lifespan of plastics and pose a threat to the environment and human health. Despite our knowledge on leakage of additives from products, accurate and rapid approaches to study emission kinetics are largely lacking, in particular, methodologies that can provide in-depth understanding of polymer/additive interactions. Here, we report on a novel approach using quartz crystal microbalance (QCM) to measure emissions of additives to water from polymer films spin-coated on quartz crystals. The methodology, being accurate and reproducible with a standard error of ±2.4%, was applied to a range of organophosphate esters (OPEs) and polymers with varying physicochemical properties. The release of most OPEs reached an apparent steady-state within 10 h. The release curves for the studied OPEs could be fitted using a Weibull model, which shows that the release is a two-phase process with an initial fast phase driven by partitioning of OPEs readily available at or close to the polymer film surface, and a slower phase dominated by diffusion in the polymer. The kinetics of the first emission phase was mainly correlated with the hydrophobicity of the OPEs, whereas the diffusion phase was weakly correlated with molecular size. The developed QCM-based method for assessing and studying release of organic chemicals from a polymeric matrix is well suited for rapid screening of additives in efforts to identify more sustainable replacement polymer additives with lower emission potential.

Chlorinated Paraffins in Two Snake Species from the Yangtze River Delta: Tissue Distribution and Biomagnification.

Very-short, short-, medium-, and long-chain chlorinated paraffins (vSCCPs, SCCPs, MCCPs, and LCCPs, respectively) were analyzed in different tissues of the terrestrial short-tailed mamushi (Gloydius brevicaudus) and the semi-aquatic red-backed rat snake (Elaphe rufodorsata) from the Yangtze River Delta, China. The total CP concentrations in liver, muscle, and adipose tissues in the two snake species were in the range of 2500-24 000, 4900-48 000, and 12-630 ng/g lw, respectively. Tissue burdens indicated that vSCCPs (C6-9) and SCCPs (C10-13) preferentially distributed to snake liver, while adipose was an important storage site and sink of MCCPs (C14-17) and LCCPs (C>18). On a lipid weight basis, vSCCPs and SCCPs were found in highest concentrations in red-backed rat snake liver and MCCPs and LCCPs in muscle, whereas for short-tailed mamushi, all CP groups were predominant in muscle, probably reflecting ecosystem/food web differences. Moreover, vSCCPs, SCCPs, MCCPs, and LCCPs were found to be biomagnified from black-spotted frogs to red-backed rat snakes with mean (maximum) biomagnification factors of 2.2 (3.4), 1.9 (3.7), 1.8 (2.8), and 1.7 (4.5), respectively. This is the first field study of biomagnification potential involving vSCCPs and LCCPs and highlights the need to include all CPs in studies.

Combining in Silico Tools with Multicriteria Analysis for Alternatives Assessment of Hazardous Chemicals: A Case Study of Decabromodiphenyl Ether Alternatives.

Alternatives assessment is applied for minimizing the risk of unintentionally replacing a hazardous chemical with another hazardous chemical. Central challenges are the diversity of properties to consider and the lack of high-quality experimental data. To address this, a novel alternatives assessment procedure was developed based on in silico data and multicriteria decision analysis (MCDA) methods. As a case study, 16 alternatives to the flame retardant decabromodiphenyl ether were considered. The hazard properties included persistence (P), bioaccumulation potential (B), toxicities (T), and mobility in water (M). Databases were consulted and 2866 experimental data points were collected for the target chemicals; however, these were mostly replicate data points for some hazard criteria for a subset of alternatives. Therefore, in silico data and three MCDA strategies were tested including heat mapping, multiattribute utility theory (MAUT), and Elimination Et Choix Traduisant la REalité (ELECTRE III). The heat map clearly showed that none of the target chemicals are hazard-free, whereas MAUT and ELECTRE III agreed on ranking the "least worst" choices. This study identified several challenges and the complexity in the alternatives assessment processes motivating more case studies combining in silico and MCDA approaches.

Tissue-Specific Accumulation, Sexual Difference, and Maternal Transfer of Chlorinated Paraffins in Black-Spotted Frogs.

The restriction on usage of short-chain chlorinated paraffins (SCCPs) under Stockholm Convention may promote the production and application of medium chain chlorinated paraffins (MCCPs) and long chain chlorinated paraffins (LCCPs) as substitutes. This study focused on the tissue-specific exposure to SCCPs, MCCPs, and LCCPs in black-spotted frog, a prevalent amphibian species in the Yangtze River Delta, China. The total CP concentrations in frog liver, muscle, and egg samples ranged of 35-1200, 6.3-97, and 6.8-300 ng/g wet weight (ww), respectively. Livers and eggs contained primary SCCPs (on average 78%) while MCCPs (43%) together with SCCPs (41%) were dominant in muscles. A significantly negative correlation was observed between hepatosomatic index and CPs concentration in liver ( p < 0.01), indicating that CP exposure may lower survival rates of frogs by suppressing the energy storage in liver. Additionally, maternal transfer, an important uptake pathway for CPs, was evaluated for the first time by calculating the ratios of CP levels in eggs to those in their paired liver tissues. The ratio of egg to liver for CP congener groups raised with the increasing of log Kow values, indicating mother to egg transport of CPs was related to the lipophilicity of the chemicals.

Structure-Dependent Activity of Polybrominated Diphenyl Ethers and Their Hydroxylated Metabolites on Estrogen Related Receptor γ: in Vitro and in Silico Study.

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor having functional cross-talk with classical estrogen receptors. Here, we investigated whether ERRγ is a potential target of polybrominated diphenyl ethers (PBDEs) and their hydroxylated metabolites (OH-PBDEs). By using a fluorescence competitive binding method established in our laboratory, the binding potencies of 30 PBDEs/OH-PBDEs with ERRγ were determined for the first time. All of the tested OH-PBDEs and some PBDEs bound to ERRγ with Kd values ranging from 0.13-13.61 µM. The OH-PBDEs showed much higher binding potency than their parent PBDEs. A quantitative structure-activity relationship (QSAR) model was developed to analyze the chemical binding potencies in relation to their structural and chemical characteristics. The QSAR model indicated that the molecular size, relative ratios of aromatic atoms, and hydrogen bond donors and acceptors were crucial factors for PBDEs/OH-PBDEs binding. By using a reporter gene assay, we found that most of the low-brominated PBDEs/OH-PBDEs exerted agonistic activity toward ERRγ, while high-brominated PBDEs/OH-PBDEs had no effect on the basal ERRγ activity. The docking results showed that the low-brominated PBDEs/OH-PBDEs tended to take an agonistic binding mode while the high-brominated ones tended to take an antagonistic binding mode. Overall, our results suggest ERRγ to be a potential novel target for PBDEs/OH-PBDEs.

Spatial distribution and bioaccumulation of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in snails (Bellamya aeruginosa) and sediments from Taihu Lake area, China.

Taihu Lake area is one of the densest metropolitan areas in the world including diverse industrial activity. In the present study, the snail (Bellamya aeruginosa) and sediment were collected from the Taihu Lake area to investigate the contamination status, congener pattern, spatial distribution, and bioaccumulation effect of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). The samples underwent liquid extraction, lipid removal by sulfuric acid, and acidic silica gel column, and subsequently analyzed by gas chromatography-electron capture detector (GC-ECD) and gas chromatography-mass spectrometry (GC-MS). Concentration of ∑22PCBs ranged between 90 and 680 ng g-1 lipid weight in the snails and between 0.018 and 0.82 ng g-1 dry weight in the sediments. Concentration of ∑24PBDEs varied from 25 to 200 ng g-1 lipid weight in the snails and from 0.62 to 67 ng g-1 dry weight in the sediments. The levels of PCBs and PBDEs observed were in the medium to low range compared with other studies in the world. CB-153 was the predominant PCB congener in both snails and sediments whereas BDE-209 showed a low bioavailability in the snails, even if it contributed up to 70% of ∑24PBDEs in the sediments. The spatial distribution showed that the highest concentration of PCBs and PBDEs were detected in samples from Zhushan Lake. East Taihu Lake and Dianshan Lake showed lower concentration of PCBs and PBDEs than the other sampling sites. Biota-sediment accumulation was found between snails and sediments of most of PCB and PBDE congeners except for the highly brominated BDEs (i.e., BDE-209). Therefore, sediment is suggested to be an appropriate matrix to monitor BDE-209 while aquatic species such as the snail could be good for monitoring of PCBs and lower brominated BDE congeners. No significant correlation (Spearman correlation test, two-tailed) of CB-153 (r = 0.54, p = 0.27) or BDE-47 (r = 0.60, p = 0.21) was found between snails and sediments.