GATA factor TRPS1, a new DNA repair protein, cooperates with reversible PARylation to promote chemoresistance in patients with breast cancer.

Resistance to DNA-damaging agents is a major unsolved challenge for breast cancer patients undergoing chemotherapy. Here, we show that elevated expression of transcriptional repressor GATA binding 1 (TRPS1) is associated with lower drug sensitivity, reduced response rate, and poor prognosis in chemotherapy-treated breast cancer patients. Mechanistically, elevated TRPS1 expression promotes hyperactivity of DNA damage repair (DDR) in breast cancer cells. We provide evidence that TRPS1 dynamically localizes to DNA breaks in a Ku70-and Ku80-dependent manner and that TRPS1 is a new member of the DDR protein family. We also discover that the dynamics of TRPS1 assembly at DNA breaks is regulated by its reversible PARylation in the DDR, and that mutations of the PARylation sites on TRPS1 lead to increased sensitivity to chemotherapeutic drugs. Taken together, our findings provide new mechanistic insights into the DDR and chemoresistance in breast cancer patients and identify TRPS1 as a critical DDR protein. TRPS1 may also be considered as a target to improve chemo-sensitization strategies and, consequently, clinical outcomes for breast cancer patients.

Human health risks of heavy metal(loid)s mediated through crop ingestion in a coal mining area in Eastern China.

The heavy metal(loid)s (HMs) in soils can be accumulated by crops grown, which is accompanied by crop ingestion into the human body and then causes harm to human health. Hence, the health risks posed by HMs in three crops for different populations were assessed using Health risk assessment (HRA) model coupled with Monte Carlo simulation. Results revealed that Zn had the highest concentration among three crops; while Ni was the main polluting element in maize and soybean, and As in rice. Non-carcinogenic risk for all populations through rice ingestion was at an "unacceptable" level, and teenagers suffered higher risk than adults and children. All populations through ingestion of three crops might suffer Carcinogenic risk, with the similar order of Total carcinogenic risk (TCR): TCRAdults > TCRTeenagers > TCRChildren. As and Ni were identified as priority control HMs in this study area due to their high contribution rates to health risks. According to the HRA results, the human health risk was associated with crop varieties, HM species, and age groups. Our findings suggest that only limiting the Maximum allowable intake rate is not sufficient to prevent health risks caused by crop HMs, thus more risk precautions are needed.

Improving prediction of soil heavy metal(loid) concentration by developing a combined Co-kriging and geographically and temporally weighted regression (GTWR) model.

The study of heavy metal(loid) (HM) contamination in soil using extensive data obtained from published literature is an economical and convenient method. However, the uneven distribution of these data in time and space limits their direct applicability. Therefore, based on the concentration data obtained from the published literature (2000-2020), we investigated the relationship between soil HM accumulation and various anthropogenic activities, developed a hybrid model to predict soil HM concentrations, and then evaluated their ecological risks. The results demonstrated that various anthropogenic activities were the main cause of soil HM accumulation using Geographically and temporally weighted regression (GTWR) model. The hybrid Co-kriging + GTWR model, which incorporates two of the most influential auxiliary variables, can improve the accuracy and reliability of predicting HM concentrations. The predicted concentrations of eight HMs all exceeded the background values for soil environment in China. The results of the ecological risk assessment revealed that five HMs accounted for more than 90% of the area at the "High risk" level (RQ ≥ 1), with the descending order of Ni (100%) = Cu (100%) > As (98.73%) > Zn (95.50%) > Pb (94.90%). This study provides a novel approach to environmental pollution research using the published data.

Impact of economic development on soil trace metal(loid)s pollution: A case study of China.

Recently, intensive anthropogenic activities, while promoting economic growth, have also exacerbated soil trace metal(loid) (TM) pollution. To explore the impact of economic development on soil TM pollution, a time-weighted method was introduced to calculate the average concentrations of eight TMs in Chinese topsoil from 2001 to 2020, and panel data on TMs and economic factors of 31 provinces were used for regression analysis. The results revealed that the average concentrations of soil TMs all exceeded their respective soil background values. Meanwhile, the spatial distribution of soil TMs was characterized by obvious regional heterogeneity, with economically developed areas being heavily polluted and having high ecological risks. In addition, the results derived from panel data models showed that the relationship between soil TM pollution and economic development in China presented a continuous growth curve, but with an N-shaped pattern in eastern China, a U-shaped pattern in central China, and a positive linearity in western China. Four control variables were also introduced to evaluate their impact on TM pollution, and the results indicated that the proportion of secondary industry and the road area per capita were the major influencing factors. Ultimately, the inflection point estimation results suggested that the soil TM pollution level will increase in eastern China, central China and western China with ongoing economic growth. Our findings contribute to the current understanding of the relationship between soil TM pollution and anthropogenic activities, and provide a scientific basis for adjusting and planning industrial development and layout according to the characteristics of soil TM pollution.

The role and application of vesicles in triple-negative breast cancer: Opportunities and challenges.

Extracellular vesicles (EVs) carry DNA, RNA, protein, and other substances involved in intercellular crosstalk and can be used for the targeted delivery of drugs. Triple-negative breast cancer (TNBC) is rich in recurrent and metastatic disease and lacks therapeutic targets. Studies have proved the role of EVs in the different stages of the genesis and development of TNBC. Cancer cells actively secrete various biomolecules, which play a significant part establishing the tumor microenvironment via EVs. In this article, we describe the roles of EVs in the tumor immune microenvironment, metabolic microenvironment, and vascular remodeling, and summarize the application of EVs for objective delivery of chemotherapeutic drugs, immune antigens, and cancer vaccine adjuvants. EVs-based therapy may represent the next-generation tool for targeted drug delivery for the cure of a variety of diseases lacking effective drug treatment.

Breaking the mold: Overcoming resistance to immune checkpoint inhibitors.

Immune checkpoint blockade-based therapies are effective against a sorts of cancers. However, drug resistance is a problem that cannot be ignored. This review intends to elucidate the mechanisms underlying drug tolerance induced by PD-1/PD-L1 inhibitors, as well as to outline proposed mechanism-based combination therapies and small molecule drugs that target intrinsic immunity and immune checkpoints. According to the differences of patients and types of cancer, the optimization of individualized combination therapy will help to enhance PD-1/PD-L1-mediated immunoregulation, reduce chemotherapy resistance, and provide new ideas for chemotherapy-resistant cancer.

Human activities contributing to the accumulation of high-risk trace metal(loid)s in soils of China's five major urban agglomerations.

Rapid urbanization has accelerated the accumulation of trace metal(loid)s (TMs) in soils, but the relationship between this accumulation and human activities remains largely unknown. Therefore, based on 775 published literatures (2001-2020), this study aimed to identify the influence of human activities on TM accumulation. Results showed that all soil TM concentrations were higher than their corresponding Chinese soil background values. The pollution risk assessment indicated that the soil TMs in the study area were at moderate levels, and the value of Pollution load index was 2.10. According to the assessment of health risks, the non-carcinogenic risks for adults were at the "Negligible risk" level; while the carcinogenic risk was not negligible for all populations, with children being more susceptible than adults. Meanwhile, six high-risk TMs were identified based on the grading of Contaminating factors (CF ≥ 3) and contribution to health risk (≥ 75%), including four high pollution risk TMs (Cd, Hg, Cu, and Pb) and two high health risk TMs (Cr and As) . In addition, in accordance with the results of the Random forest model, the accumulation of soil high-risk TMs was closely related to influencing factors associated with human activities. The accumulation of Hg and Cr among five major urban agglomerations had the same influencing factors (the number of industrial companies and the amount of industrial wastewater discharge for Hg; the amount of pesticide application and highway mileage for Cr). However, there were significant differences in the factors influencing the accumulation of the other four high-risk TMs (including Cd, As, Cu and Pb), due to the different characteristics of each urban agglomeration. Our results provide new insights into the relationship between human activities and soil TM accumulation.

New insights into health risk assessment on soil trace metal(loid)s: Model improvement and parameter optimization.

Trace metal(loid)s (TMs) in soils may pose potential health risks to humans. Due to model uncertainty and variability of exposure parameters, the traditional health risk assessment (HRA) model may lead to inaccurate risk assessment results. Therefore, this study developed an improved HRA model to assess health risks by combining two-dimensional Monte Carlo simulation (2-D MCS) with a Logistic Chaotic sequence based on published data from 2000 to 2021. The results showed children and adult females were the high-risks populations for Non-carcinogenic risk and Carcinogenic risk, respectively. Meanwhile, children's Ingestion rate (IngR < 160.233 mg/day) and adult females' Skin adherence factor (0.026 mg/(cm2•d) < AF < 0.263 mg/(cm2•d)) were used as recommended exposure to make the health risk within acceptable range. Additionally, when performing risk assessment using actual exposure parameters, priority control TMs were identified, with As being the priority control TM for Southwest China and Inner Mongolia, whereas Cr and Pb for Tibet and Yunnan, respectively. Compared to health risk assessment, improved models increased risk assessment accuracy and provided recommended exposure parameter for high-risk populations. This study will provide new insights for soil-related health risk assessment.

Source apportionment and human health risk of PAHs accumulated in edible marine organisms: A perspective of "source-organism-human".

Most PAHs produced by human activities can be absorbed and accumulated by edible organisms and pose a potential hazard to human health. However, the source apportionment and human health risk of PAHs accumulated in edible organisms remains largely unknown. Therefore, we conducted source analysis and health risk assessment based on the PAH concentrations in ten marine fish from coastal areas of Guangdong, China. Results showed that the pollution of PAHs in fish organisms was at "Minimally polluted" level, and that all marine fish had the ability to accumulate PAHs. Risk assessment indicated Carcinogenic risk of PAHs in four populations was at a "Cautionary risk" level, with urban children suffered the highest risk. Petroleum pollution, Coal and biomass combustion, and Marine transport emissions were identified as the main anthropogenic sources for PAHs in organisms, and Marine transport emissions accounted for the highest Carcinogenic risk. The Acceptable daily intake for all populations were far below their actual daily intake without causing "Cautionary risk". Our findings provide new insights into the source apportionment and health risk of PAHs from a "source-organism-human" perspective, and suggested that joint management of three anthropogenic sources would be an effective way to prevent the health risks of PAHs.

Mechanisms of drug resistance in breast cancer liver metastases: Dilemmas and opportunities.

Breast cancer is the leading cause of cancer-related deaths in females worldwide, and the liver is one of the most common sites of distant metastases in breast cancer patients. Patients with breast cancer liver metastases face limited treatment options, and drug resistance is highly prevalent, leading to a poor prognosis and a short survival. Liver metastases respond extremely poorly to immunotherapy and have shown resistance to treatments such as chemotherapy and targeted therapies. Therefore, to develop and to optimize treatment strategies as well as to explore potential therapeutic approaches, it is crucial to understand the mechanisms of drug resistance in breast cancer liver metastases patients. In this review, we summarize recent advances in the research of drug resistance mechanisms in breast cancer liver metastases and discuss their therapeutic potential for improving patient prognoses and outcomes.

Spatio-temporal characteristics of soil Cd pollution and its influencing factors: A Geographically and temporally weighted regression (GTWR) method.

Soil Cd pollution is the result of the combined influence of various human activities over a long period of time, and then quantifying the influence is essential for the prevention and control. Based on published literature data during 2000-2020, this study investigated the pollution characteristics and influencing factors of soil Cd in the Yangtze River Delta. The results were as follows: (1) The average Cd concentration was higher than the Chinese soil criteria value (0.30 mg/kg), and the proportion of Cd concentration exceeding its background value was 87.43%. (2) The assessment results using Contamination factor (CF) and Geo-accumulation index (Igeo) indicated that the soil Cd pollution risk could not negligible in the study area. (3) The pollution center shifted significantly owing to the combined effect of human activities. (4) The main influencing factors of Cd pollution obtained by Geographically and temporally weighted regression (GTWR) model were GDP per capita, Consumption of chemical fertilizer, Output value of primary industry, and Output value of secondary industry, but there were significant differences in the dominant factors for different provinces. Our findings contribute to the current understanding of the relationship between Cd pollution and human activities, and provide a scientific basis for pollution control.

The Chemical and Pharmacological Research Progress on a Kind of Chinese Herbal Medicine, Fructus Malvae.

Since the outbreak of the COVID-19 pandemic, traditional Chinese medicine has played an important role in the treatment process. Furthermore, the discovery of artemisinin in Artemisia annua has reduced the incidence of malaria all over the world. Therefore, it is becoming urgent and important to establish a novel method of conducting systematic research on Chinese herbal medicine, improving the medicinal utilization value of traditional Chinese medicine and bringing great benefits to human health all over the world. Fructus Malvae, a kind of Chinese herbal medicine which has been recorded in the "Chinese Pharmacopoeia" (2020 edition), refers to the dry, ripe fruits of Malva verticillata L. Recently, some studies have shown that Fructus Malvae exhibits some special pharmacological activities; for example, it has diuretic, anti-diabetes, antioxidant and anti-tumor properties, and it alleviates hair loss. Furthermore, according to the reports, the active ingredients separated and identified from Fructus Malvae contain some very novel compounds such as nortangeretin-8-O-ß-d-glucuronopyranoside and 1-O-(6-deoxy-6-sulfo)-glucopyranosyl-2-O-linolenoyl-3-O-palmitoyl glyceride, which could be screened as important candidate compounds for diabetes- or tumor-treatment drugs, respectively. Therefore, in this research, we take Fructus Malvae as an example and systematically summarize the chemical constituents and pharmacological activity research progress of it. This review will be helpful in promoting the development and application of Fructus Malvae and will also provide an example for other investigations of traditional Chinese medicine.

Risk assessment and driving factors of trace metal(loid)s in soils of China.

Recently, with the rapid development of China's economy, the pollution of trace metal(loid)s (TMs) in soils has become increasingly severe and attracted widespread attention. Based on 1,402 published papers from 2000 to 2021, this study aimed to analyze the pollution intensity, ecological risk and driving factors for eight TMs (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in Chinese soils. Results showed that the average concentrations of eight TMs in Chinese soils all exceeded background values, and the pollution of Cd and Hg was the most serious. Based on Principal component analysis of pollution intensity and ecological risk, the priority control TMs were identified for the heavily polluted provinces. The results of Geo-detector model suggested that Urban development factors contributed most to the TM accumulation in Chinese soils. Further, spatial analysis using bivariate Moran's I indicated that industrial activities contributed most to soil TM accumulation in the middle and lower reaches of the Yangtze River, while soil TM pollution in the southwest and northwest provinces was mainly caused by mining and metal smelting. This study investigated the relationship between soil TM pollution and anthropogenic activities, thus providing a scientific basis for controlling soil TM pollution at a large-scale level.

Seasonal Variation and Contamination Risk Assessment of Heavy Metals in Surface Sediment of an Estuary Alluvial Island in Eastern China.

The heavy metal pollution of estuary wetlands caused by industrial and agricultural production activities has aroused widespread concern. The Hakanson Pollution index, Geo-accumulation index (Igeo) and Redundancy analysis were used to explore the seasonal variation and contamination risk of heavy metals in surface sediments. Results showed that the heavy metal concentrations were ranked in descending order: Cd > Cu > Zn > Pb > Cr. The analysis result of HPI and Igeo showed that there was a low level of heavy metal contamination both in summer and winter. Redundancy analysis showed that the correlation between heavy metals and physicochemical properties of sediment was significantly different in winter and summer. Our findings provide scientific support for the prevention of heavy metal pollution in estuary wetlands.

Robot-assisted distal training improves upper limb dexterity and function after stroke: a systematic review and meta-regression.

INTRODUCTION: Stroke is one of the top 10 causes of death worldwide, and more than half of stroke patients face distal upper extremity dysfunction. Considering that robot-assisted training may be effective in improving distal upper extremity function, the review evaluated the effect of robot-assisted distal training on motor function, hand dexterity, and spasticity after stroke. METHODS: Eleven databases were systematically searched for randomised controlled trials (RCTs) from inception until Aug 28, 2021. Meta-analysis and meta-regression were performed to investigate the overall effect and source of heterogeneity, respectively. RESULTS: Twenty-two trials involving 758 participants were included in this systematic review. The overall effect of robot-assisted distal training on the motor function of the wrists and hands was significant improvement (MD = 3.92; 95% CI, 3.04-4.80; P < 0.001). The robot-assisted training had a significantly beneficial effect on other motor functions (MD = 2.84; 95% CI, 1.54-4.14; P < 0.001); dexterity (MD = 9.01; 95% CI, -12.07--5.95; P < 0.001), spasticity, upper extremity strength (SMD = 0.42; 95% CI, 0.07-0.78; P = 0.02) and activities of daily living (SMD = 0.70; 95% CI, 0.29-1.23; P < 0.001). A series of subgroup analyses showed preferable design and effective regime of training. Meta-regression indicated the statistically significant effect of the year of trial, country, and duration on the effectiveness of training. CONCLUSION: Robot-assisted distal training has a significant effect on motor function, dexterity and spasticity of the upper extremity, compared to conventional therapy.

3D-Printed Strong Dental Crown with Multi-Scale Ordered Architecture, High-Precision, and Bioactivity.

Mimicking the multi-scale highly ordered hydroxyapatite (HAp) nanocrystal structure of the natural tooth enamel remains a great challenge. Herein, a bottom-up step-by-step strategy is developed using extrusion-based 3D printing technology to achieve a high-precision dental crown with multi-scale highly ordered HAp structure. In this study, hybrid resin-based composites (RBCs) with "supergravity +" HAp nanorods can be printed smoothly via direct ink writing (DIW) 3D printing, induced by shear force through a custom-built nozzle with a gradually shrinking channel. The theoretical simulation results of finite element method are consistent with the experimental results. The HAp nanorods are first highly oriented along a programmable printing direction in a single printed fiber, then arranged in a layer by adjusting the printing path, and finally 3D printed into a highly ordered and complex crown structure. The printed samples with criss-crossed layers by interrupting crack propagation exhibit a flexural strength of 134.1 ± 3.9 MPa and a compressive strength of 361.6 ± 8.9 MPa, which are superior to the corresponding values of traditional molding counterparts. The HAp-monodispersed RBCs are successfully used to print strong and bioactive dental crowns with a printing accuracy of 95%. This new approach can help provide customized components for the clinical restoration of teeth.

Determination of priority control factors for the management of soil trace metal(loid)s based on source-oriented health risk assessment.

Trace metal(loid)s (TMs) in soils can seriously threaten the ecological environment and human health. With the limitation of resources and costs, determining priority control factor is critical for managing soil TM pollution. To explore the pollution characteristics, source apportionment, and human health risk of TMs, a total of 209 surface soil samples were collected from Anqing City, China. Results showed that all the average values of TM concentration, except for Cr, were higher than their corresponding background value. Using a Positive matrix factorization model coupled with Correlation analysis, four sources (including agricultural sources, atmospheric deposition sources, industrial sources, and natural sources) were identified as the determinants for the accumulation of soil TMs, with the contribution rates of 12.4%, 8.1%, 64.1%, and 15.4%, respectively. The assessment of probabilistic health risks revealed that Non- carcinogenic risks of all populations were acceptable (HI < 1), while Carcinogenic risks were all at a high level (TCR > 10E-04). Agricultural pollution and As were identified as priority control factors, according to the analysis results of the relationship among TMs, pollution sources and health risks. Our findings provide scientific support for decision-makers to formulate target control policies and reduce management costs of soil pollution.

High body mass index and sleep problems during pregnancy: A meta-analysis and meta-regression of observational studies.

Despite the well-established correlation of weight and sleeping problems, little is known about the nature of the association. The present study examined whether pregnant women with high body mass index have a risk of developing sleep problems, and identified any covariates that affect this relationship. We systematically searched electronic databases, specialized journals, various clinical trial registries, grey literature databases and the reference list of the identified studies. All observational studies were obtained from inception until 9 August 2020. The Newcastle-Ottawa Scale was adopted to assess the quality of studies. Stata software was used to conduct meta-analysis and meta-regression. Forty-six observational studies involving 2,240,804 participants across 16 countries were included. Quality assessment scores ranged from 4 to 10 (median = 6). Meta-analyses revealed that the risk of sleep apnea, habitual snoring, short sleep duration and poor sleep quality is increased in pregnant women with high body mass index, but not for daytime sleepiness, insomnia or restless legs syndrome. Subgroup differences were detected on body mass index between different regions, nature of population, year of publication, age group and study quality. Random-effects meta-regression analyses showed that year and quality of publication were covariates on the relationships between pre-pregnant body mass index and sleep apnea risk. Our review shows that sleep apnea, habitual snoring, short sleep duration and poor sleep quality are important concerns for pregnant women with high body mass index. Developing screening and targeted interventions is recommended to promote efficacious perinatal care.

Health risk assessment of heavy metal(loid)s in park soils of the largest megacity in China by using Monte Carlo simulation coupled with Positive matrix factorization model.

Urban Parks are important places for residents to engage in outdoor activities, and whether heavy metal(loid)s (HMs) in park soils are harmful to human health has aroused people's concern. A total of 204 topsoil samples containing nine HMs were collected from 78 urban parks of Shanghai in China, and used to assess the health risks caused by HMs in soils. The results revealed that the Hg, Cd and Pb were the main enriched pollutants and posed higher ecological risks than the other HMs. Four HM sources (including natural sources, agricultural activities, industrial production and traffic emissions) were identified by combining the Positive matrix factorization model and Correlation analysis, with the contribution rate of 48.24%, 7.03%, 13.04% and 31.69%, respectively. The assessment of Probabilistic health risks indicated that the Non-carcinogenic risks for all populations were negligible. However, the Total carcinogenic risk cannot be negligible and children were more susceptible than adults. The assessment results of source-oriented health risks showed that industrial production and traffic emissions were estimated to be the most important anthropogenic sources of health risks for all populations. Our results provide scientific support needed for the prevention and control of HM pollution in urban parks.

Game-based brain training for improving cognitive function in community-dwelling older adults: A systematic review and meta-regression.

BACKGROUND: Given that increasing aging is associated with a natural decline in cognitive function, identifying effective interventions that can help to prevent cognitive decline in older adults is a research priority. OBJECTIVE: To synthesize the best evidence to assess the effectiveness of game-based brain training in improving cognitive function and to evaluate the preferred design features of the intervention. METHODS: Twelve databases, trial registries, and gray literature resources were systematically searched for in randomized controlled trials. Meta-analysis and random-effects meta-regression were conducted using Comprehensive Meta-analysis Software 3.0. Overall effect was measured using Hedges's g and determined using Z-statistics. Cochran's Q test and I2 were used to investigate heterogeneity. The Grading of Recommendation, Assessment, Development, and Evaluation system was used to assess overall quality of evidence. RESULTS: Fifteen trials among 759 older adults were conducted. Meta-analysis revealed that game-based brain training significantly improved processing speed (g = 0.23), selective attention (g = 0.40), and short-term memory (g = 0.35) versus a control group. Our subgroup analyses emphasized that non-time pressure games, multiplayer, computer platform, provider support, sessions ≤ 3 times per week for ≤ 60 min. each comprised a preferable design. Meta-regression identified game design (ß = 0.211, p = 0.008) that had statistically significant effects on processing speed. Egger's regression asymmetry test (p = 0.293) suggested no publication bias. CONCLUSIONS: Game-based brain training can be considered a supplementary intervention for improving cognitive functions in community-dwelling older adults. Future trials should use well-designed trials with large sample sizes.