Deciphering the driving factors and probabilistic health risks of potentially toxic elements in arid surface water: Insights from the Tarim River Basin.

Potentially toxic elements (PTEs) in surface water in arid areas pose a serious threat to environmental safety and human health within a basin. It is important to determine the factors controlling PTEs and to assess the likelihood that they will pose a risk to human health in order to support the development of environmental protection and risk management strategies. In this study, a structural equation model and Bayesian method were combined to discuss the distribution and probabilistic health risks of PTEs in surface water in arid area, and the Tarim River Basin was taken as a case study. The results show that the average concentrations of As, Co, Cu, and Ni in the surface water in the Tarim River Basin ranged from 0.04 to 2.92 µg/L, which do not exceed the international standard values. However, the maximum value of As (19.20 µg/L) exceeded both the recommended drinking water standards and the Chinese irrigation water standards. Spatially, the high As concentrations were distributed in the upper reaches of the Kashgar River, and the high Co, Cu and Ni concentrations were distributed in reservoirs and lakes on the main stream of the Tarim River. The concentrations of the PTEs in the surface water in the basin were not only affected by random anthropogenic factors such as traffic discharge, agricultural activities and mining industry, but were also directly and indirectly influenced by climatic factors. The results of the probabilistic health risk assessment showed that the 95th percentile the total hazard index for infants exceeded the allowable value of 1, and the total carcinogenic risk of PTEs exposure in four age groups was at the notable level. In this study, we conducted a comprehensive analysis of the controlling factors and health risks associated with PTEs in surface water in the Tarim River Basin, and the findings are expected to provide a scientific basis for regional water environment management and safety control.

ZG16 enhances the maturation of dendritic cells via induction of CD40 and contributes to the antitumor immunity in pancreatic cancer.

Dendritic cells (DCs) are critical mediators of antigen priming and T-cell activation. Zymogen granule protein 16 (ZG16) is demonstrated as an anti-oncogene in T-cell mediated antitumor immunity, but its effect on DCs is largely unknown. Herein, we wonder whether ZG16 affects the activation of DCs in pancreatic cancer. Firstly, the increased ZG16 expression was observed during the maturation of DCs derived from mouse bone marrow or human peripheral blood. Then, overexpression of ZG16 or exogenous introduction of recombinant ZG16 protein induced the expression of MHC II, CD86, CD84, and CCR7 on the surface of DCs, thereby facilitating the secretion of proinflammatory mediators IL-1ß, IL-6, TNF-α, and IL-12/p70, supporting the promoting effect of ZG16 on DC maturation. By establishing the subcutaneous and orthotopic mouse models of pancreatic cancer, we confirmed that intraperitoneal injection of recombinant ZG16 protein (Re-mZG16) could induce tumor regression by stimulating DC maturation and enhancing antitumor responses of CD4 + , CD8 + , PD-1 + , and Ctla4+ cells. Besides, Re-mZG16 in combination with gemcitabine showed a synergistic effect in the treatment of pancreatic cancer. Mechanistically, we demonstrated that ZG16 inhibited the ubiquitination and degradation of CD40, which depended on the lectin domain of ZG16. In conclusion, this study provided a novel insight into the role of ZG16-CD40 axis in DC-based immunotherapy for pancreatic cancer.

Effects of Green Tea Extract Epigallocatechin-3-Gallate on Oral Diseases: A Narrative Review.

OBJECTIVES: Oral diseases are among the most prevalent diseases globally. Accumulating new evidence suggests considerable benefits of epigallocatechin-3-gallate (EGCG) for oral health. This review aims to explore the role and application of EGCG in main oral diseases. METHODS: This narrative review thoroughly examines and summarizes the most recent literature available in scientific databases (PubMed, Web of Science, Scopus, and Google Scholar) reporting advances in the role and application of EGCG within the dental field. The major keywords used included "EGCG", "green tea extract", "oral health", "caries", "pulpitis", "periapical disease", "periodontal disease", "oral mucosa", "salivary gland", and "oral cancer". CONCLUSIONS: EGCG prevents and manages various oral diseases through its antibacterial, anti-inflammatory, antioxidant, and antitumor properties. Compared to traditional treatments, EGCG generally exhibits lower tissue irritation and positive synergistic effects when combined with other therapies. Novel delivery systems or chemical modifications can significantly enhance EGCG's bioavailability, prolong its action, and reduce toxicity, which are current hotspots in developing new materials. CLINICAL SIGNIFICANCE: this review provides an exhaustive overview of the biological activities of EGCG to major oral diseases, alongside an exploration of applications and limitations, which serves as a reference for preventing and managing oral ailments.

Automated information extraction model enhancing traditional Chinese medicine RCT evidence extraction (Evi-BERT): algorithm development and validation.

Background: In the field of evidence-based medicine, randomized controlled trials (RCTs) are of critical importance for writing clinical guidelines and providing guidance to practicing physicians. Currently, RCTs rely heavily on manual extraction, but this method has data breadth limitations and is less efficient. Objectives: To expand the breadth of data and improve the efficiency of obtaining clinical evidence, here, we introduce an automated information extraction model for traditional Chinese medicine (TCM) RCT evidence extraction. Methods: We adopt the Evidence-Bidirectional Encoder Representation from Transformers (Evi-BERT) for automated information extraction, which is combined with rule extraction. Eleven disease types and 48,523 research articles from the China National Knowledge Infrastructure (CNKI), WanFang Data, and VIP databases were selected as the data source for extraction. We then constructed a manually annotated dataset of TCM clinical literature to train the model, including ten evidence elements and 24,244 datapoints. We chose two models, BERT-CRF and BiLSTM-CRF, as the baseline, and compared the training effects with Evi-BERT and Evi-BERT combined with rule expression (RE). Results: We found that Evi-BERT combined with RE achieved the best performance (precision score = 0.926, Recall = 0.952, F1 score = 0.938) and had the best robustness. We totally summarized 113 pieces of rule datasets in the regulation extraction procedure. Our model dramatically expands the amount of data that can be searched and greatly improves efficiency without losing accuracy. Conclusion: Our work provided an intelligent approach to extracting clinical evidence for TCM RCT data. Our model can help physicians reduce the time spent reading journals and rapidly speed up the screening of clinical trial evidence to help generate accurate clinical reference guidelines. Additionally, we hope the structured clinical evidence and structured knowledge extracted from this study will help other researchers build large language models in TCM.

Flavopereirine exerts anti-cancer activities in various human thyroid cancer cells.

Thyroid cancer (TC) stands out as the most prevalent endocrine malignancy globally, with a steadily increasing incidence. Its clinical manifestations include enlarged thyroid nodules, dysphagia, enophthalmos, and various other symptoms. While standard treatments such as thyroidectomy and radioiodine therapy effectively manage most cases of differentiated thyroid cancers (DTC), some recurrent cases of DTC or those involving poorly differentiated thyroid cancers (PDTC) require specialized interventions. However, existing drugs primarily address symptom management without offering a curative solution. Therefore, the development of a new therapeutic agent for these challenging cases is of utmost importance. Flavopereirine, derived from Geissospermum vellosii, has demonstrated promise as a potential anti-cancer agent across various human cancers. However, its specific anti-cancer effects on human thyroid cancer (TC) have remained unclear. Therefore, this study aims to investigate the anti-cancer activity of flavopereirine in human TC. The research findings revealed that flavopereirine effectively hinders the growth of human TC cells, induces cell cycle arrest, promotes apoptosis, and modulates autophagy. Moreover, the study delved into the underlying mechanisms by which flavopereirine influenced signaling pathways. To validate these anti-cancer effects, an in vivo zebrafish model was utilized, confirming the efficacy of flavopereirine against human TC cells. In summary, this study establishes that flavopereirine exhibits notable anti-human TC activities, positioning it as a promising therapeutic candidate for the treatment of human thyroid cancer.

Targeting RBM39 through indisulam induced mis-splicing of mRNA to exert anti-cancer effects in T-cell acute lymphoblastic leukemia.

BACKGROUND: Despite the use of targeted therapeutic approaches, T-cell acute lymphoblastic leukemia (T-ALL) is still associated with a high incidence of complications and a poor prognosis. Indisulam (also known as E7070), a newly identified molecular glue compound, has demonstrated increased therapeutic efficacy in several types of cancer through the rapid degradation of RBM39. This study aimed to evaluate the therapeutic potential of indisulam in T-ALL, elucidate its underlying mechanisms and explore the role of the RBM39 gene. METHODS: We verified the anticancer effects of indisulam in both in vivo and in vitro models. Additionally, the construction of RBM39-knockdown cell lines using shRNA confirmed that the malignant phenotype of T-ALL cells was dependent on RBM39. Through RNA sequencing, we identified indisulam-induced splicing anomalies, and proteomic analysis helped pinpoint protein changes caused by the drug. Comprehensive cross-analysis of these findings facilitated the identification of downstream effectors and subsequent validation of their functional roles. RESULTS: Indisulam has significant antineoplastic effects on T-ALL. It attenuates cell proliferation, promotes apoptosis and interferes with cell cycle progression in vitro while facilitating tumor remission in T-ALL in vivo models. This investigation provides evidence that the downregulation of RBM39 results in the restricted proliferation of T-ALL cells both in vitro and in vivo, suggesting that RBM39 is a potential target for T-ALL treatment. Indisulam's efficacy is attributed to its ability to induce RBM39 degradation, causing widespread aberrant splicing and abnormal translation of the critical downstream effector protein, THOC1, ultimately leading to protein depletion. Moreover, the presence of DCAF15 is regarded as critical for the effectiveness of indisulam, and its absence negates the ability of indisulam to induce the desired functional alterations. CONCLUSION: Our study revealed that indisulam, which targets RBM39 to induce tumor cell apoptosis, is an effective drug for treating T-ALL. Targeting RBM39 through indisulam leads to mis-splicing of pre-mRNAs, resulting in the loss of key effectors such as THOC1.

Geochemical behavior of rare earth elements in agricultural soils along the Syr Darya River within the Aral Sea Basin.

The widespread use of rare earth elements (REEs) across various industries makes them a new type of pollutant. Additionally, REEs are powerful indicators of geochemical processes. As one of the two main rivers in the Aral Sea, identifying the geochemical behavior of REEs in agricultural soils of the Syr Darya River is of great significance for subsequent indicative studies. In this study, the geochemical characteristics, influencing factors, and potential application significance of REEs in agricultural soils from three sampling areas along the Syr Darya River were analyzed using soil geography and elemental geochemical analyses. The results showed that the highest total concentration of REEs in the agricultural soil was in Area I, with a mean value of 142.49 µg/g, followed by Area III with a mean value of 124.56 µg/g, and the lowest concentration was in Area II with a mean value of 122.48 µg/g. The agricultural soils in the three regions were enriched in light rare earth elements (LREEs), with mean L/H values of 10.54, 10.13, and 10.24, respectively. The differentiation between light and heavy rare earth elements (HREEs) was also high. The concentration of REEs in agricultural soil along the Syr Darya River was primarily influenced by minerals such as monazite and zircon, rather than human activities (the pollution index of all REEs was less than 1.5). The relationship between Sm and Gd can differentiate soils impacted by agricultural activities from natural background soils. The results of this study can serve as a basis for indicative studies of REEs in Central Asia.

Which is the best TACE agent for patients with different NLR hepatocellular carcinomas? A systematic review and network meta-analysis.

Background: Transarterial chemoembolization (TACE) is a common treatment for hepatocellular carcinoma (HCC), but the best therapeutic agent for TACE treatment has not been determined. The neutrophil/lymphocyte ratio (NLR) is a systemic immune system marker; however, the ability of the NLR to predict the prognosis of patients with HCC is unknown, and no studies have been conducted to determine the most appropriate TACE regimen for HCC patients with different NLRs. Methods: The PubMed, Embase, Web of Science, and CNKI databases were searched through May 28, 2023. Comparisons of overall survival (OS) among cohort studies with different NLRs and different TACE treatment regimens were performed with a random effects model. Findings: Thirty-five studies involving 9210 patients were included in this meta-analysis. The results showed that Group 3-4 (NLR<2.5) patients had a significantly longer OS than Group 1-2 (NLR 2.5-5.0). Among the patients, Group 1-3 (NLR 2.0-5.0) patients had the best survival after treatment with adriamycin (lnHR (95 % CI = 0.48 [0.31, 0.75] and lnHR (95 % CI = 0.41 [0.19, 0.91]). Among the Group 4 patients (NLR<2.0), the best outcome was obtained with platinum + adriamycin (lnHR (95 % CI = 0.59 [0.45, 0.78]), followed by adriamycin. A subgroup analysis of TACE combined with other treatments showed that adriamycin combined with sorafenib was the most effective and superior to the other treatment agents. Interpretation: The NLR can be used to predict the prognosis of HCC patients treated with TACE; the higher the NLR is, the worse the prognosis. Adriamycin may be the best therapeutic agent for HCC patients treated with TACE.

Effects of general and spinal anesthesia on postoperative rehabilitation in older adults after lower limb surgery: a retrospective cohort study.

Objective: To investigate the effects of perioperative general anesthesia (GA) and spinal anesthesia (SA) on postoperative rehabilitation in elderly patients with lower limb surgery. Methods: This retrospective propensity score-matched cohort study included patients aged 65 years or older who underwent lower limb surgery between January 1, 2020, and May 31, 2023. The GA and SA were selected at the request of the orthopedic surgeon, patient, and their family members. The main outcomes included the incidence of the patient's inability to self-care at discharge, postoperative complications including pulmonary infection, thrombus of lower extremity veins, infection of incisional wound and delirium, length of hospital stay, and incidence of severe pain in the first 2 days postoperatively. Results: In total, 697 patients met the inclusion criteria, and 456 were included in the final analysis after propensity score matching. In the GA and SA groups, 27 (11.84%) and 26 (11.40%) patients, respectively, could not care for themselves at discharge. The incidence rates did not differ between the groups (p = 0.884). In contrast, the incidence of postoperative complications (GA: 10.53% and SA: 4.39%; p = 0.013) and the length of hospital stay (GA: 16.92 ± 10.65 days and SA: 12.75 ± 9.15 days; p < 0.001) significantly differed between the groups. Conclusion: The choice of anesthesia is independent of the loss of postoperative self-care ability in older patients (>65 years) and is not a key factor affecting postoperative rehabilitation after lower limb surgery. However, compared with GA, SA reduces the incidence of postoperative complications and a prolonged hospital stay. Thus, SA as the primary anesthetic method is a protective factor against a prolonged hospital stay.

Honokiol Suppresses Cell Proliferation and Tumor Migration through ROS in Human Anaplastic Thyroid Cancer Cells.

BACKGROUND: Honokiol is a natural polyphenolic compound extracted from Magnolia officinali, which is commonly used material in Chinese herbal medicine, has a variety of biological functions, including anti-tumor, anti-oxidant, anti-inflammation, anti-microbial and anti-allergy. Although honokiol has numerous beneficial effects on human diseases, the underlying mechanisms of tumor metastasis are still unclear. Previously, we reported that honokiol suppresses thyroid cancer cell proliferation with cytotoxicity through cell cycle arrest, apoptosis, and dysregulation of intracellular hemostasis. Herein, we hypothesized that the antioxidant effect of honokiol might play a critical role in thyroid cancer cell proliferation and migration. METHODS: The cell viability assays, cellular reactive oxygen species (ROS) activity, cell migration, and immunoblotting were performed after cells were treated with honokiol. RESULTS: Based on this hypothesis, we first demonstrated that honokiol suppresses cell proliferation in two human anaplastic thyroid carcinoma (ATC) cell lines, KMH-2 and ASH-3, within a dosage- and time-dependent manner by cell counting kit-8 (CCK-8) assay. Next, we examined that honokiol induced ROS activation and could be suppressed by pre-treated with an antioxidant agent, N-acetyl-l-cysteine (NAC). Furthermore, the honokiol suppressed cell proliferation can be rescued by pre-treated with NAC. Finally, we demonstrated that honokiol inhibited ATC cell migration by modulating epithelial-mesenchymal transition (EMT)-related markers by Western blotting. CONCLUSION: Taken together, we provided the potential mechanism for treating ATC cells with honokiol, which significantly suppresses tumor proliferation and inhibits tumor metastasis in vitro through reactive oxygen species (ROS) induction.

Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia.

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.

Germ line genetic NBN variation and predisposition to B-cell acute lymphoblastic leukemia in children.

ABSTRACT: Biallelic mutation in the DNA-damage repair gene NBN is the genetic cause of Nijmegen breakage syndrome, which is associated with predisposition to lymphoid malignancies. Heterozygous carriers of germ line NBN variants may also be at risk for leukemia development, although this is much less characterized. By sequencing 4325 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), we systematically examined the frequency of germ line NBN variants and identified 25 unique, putatively damaging NBN coding variants in 50 patients. Compared with the frequency of NBN variants in gnomAD noncancer controls (189 unique, putatively damaging NBN coding variants in 472 of 118 479 individuals), we found significant overrepresentation in pediatric B-ALL (P = .004; odds ratio, 1.8). Most B-ALL-risk variants were missense and cluster within the NBN N-terminal domains. Using 2 functional assays, we verified 14 of 25 variants with severe loss-of-function phenotypes and thus classified these as nonfunctional or partially functional. Finally, we found that germ line NBN variant carriers, all of whom were identified as heterozygous genotypes, showed similar survival outcomes relative to those with wild type status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, and the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy. These trials were registered at www.clinicaltrials.gov as #NCT01225874, NCT00075725, NCT00103285, NCI-T93-0101D, and NCT00137111.

Superbinder based phosphoproteomic landscape revealed PRKCD_pY313 mediates the activation of Src and p38 MAPK to promote TNBC progression.

Phosphorylation proteomics is the basis for the study of abnormally activated kinase signaling pathways in breast cancer, which facilitates the discovery of new oncogenic agents and drives the discovery of potential targets for early diagnosis and therapy of breast cancer. In this study, we have explored the aberrantly active kinases in breast cancer development and to elucidate the role of PRKCD_pY313 in triple negative breast cancer (TNBC) progression. We collected 47 pairs of breast cancer and paired far-cancer normal tissues and analyzed phosphorylated tyrosine (pY) peptides by Superbinder resin and further enriched the phosphorylated serine/threonine (pS/pT) peptides using TiO2 columns. We mapped the kinases activity of different subtypes of breast cancer and identified PRKCD_pY313 was upregulated in TNBC cell lines. Gain-of-function assay revealed that PRKCD_pY313 facilitated the proliferation, enhanced invasion, accelerated metastasis, increased the mitochondrial membrane potential and reduced ROS level of TNBC cell lines, while Y313F mutation and low PRKCD_pY313 reversed these effects. Furthermore, PRKCD_pY313 significantly upregulated Src_pY419 and p38_pT180/pY182, while low PRKCD_pY313 and PRKCD_Y313F had opposite effects. Dasatinib significantly inhibited the growth of PRKCD_pY313 overexpression cells, and this effect could be enhanced by Adezmapimod. In nude mice xenograft model, PRKCD_pY313 significantly promoted tumor progression, accompanied by increased levels of Ki-67, Bcl-xl and Vimentin, and decreased levels of Bad, cleaved caspase 3 and ZO1, which was opposite to the trend of Y313F group. Collectively, the heterogeneity of phosphorylation exists in different molecular subtypes of breast cancer. PRKCD_pY313 activates Src and accelerates TNBC progression, which could be inhibited by Dasatinib.

An Automated Heart Shunt Recognition Pipeline Using Deep Neural Networks.

Automated recognition of heart shunts using saline contrast transthoracic echocardiography (SC-TTE) has the potential to transform clinical practice, enabling non-experts to assess heart shunt lesions. This study aims to develop a fully automated and scalable analysis pipeline for distinguishing heart shunts, utilizing a deep neural network-based framework. The pipeline consists of three steps: (1) chamber segmentation, (2) ultrasound microbubble localization, and (3) disease classification model establishment. The study's normal control group included 91 patients with intracardiac shunts, 61 patients with extracardiac shunts, and 84 asymptomatic individuals. Participants' SC-TTE images were segmented using the U-Net model to obtain cardiac chambers. The segmentation results were combined with ultrasound microbubble localization to generate multivariate time series data on microbubble counts in each chamber. A classification model was then trained using this data to distinguish between intracardiac and extracardiac shunts. The proposed framework accurately segmented heart chambers (dice coefficient = 0.92 ± 0.1) and localized microbubbles. The disease classification model achieved high accuracy, sensitivity, specificity, F1 score, kappa value, and AUC value for both intracardiac and extracardiac shunts. For intracardiac shunts, accuracy was 0.875 ± 0.008, sensitivity was 0.891 ± 0.002, specificity was 0.865 ± 0.012, F1 score was 0.836 ± 0.011, kappa value was 0.735 ± 0.017, and AUC value was 0.942 ± 0.014. For extracardiac shunts, accuracy was 0.902 ± 0.007, sensitivity was 0.763 ± 0.014, specificity was 0.966 ± 0.008, F1 score was 0.830 ± 0.012, kappa value was 0.762 ± 0.017, and AUC value was 0.916 ± 0.006. The proposed framework utilizing deep neural networks offers a fast, convenient, and accurate method for identifying intracardiac and extracardiac shunts. It aids in shunt recognition and generates valuable quantitative indices, assisting clinicians in diagnosing these conditions.

The Prediction Effect of HbA1c on Nosocomial Infection in Diabetic Patients was Analyzed Based on Decision Curve and Dose Response.

Objective: To analyze the predictive efficacy of HbA1c on nosocomial infection in diabetic patients. Methods: 566 patients with diabetes who received treatment in our hospital from January 2021 to January 2023 were selected as the study objects. All patients received relevant treatment in the hospital. Patients with nosocomial infection during treatment were included in the occurrence group, and those without nosocomial infection were included in the non-occurrence group. The level of HbA1c and other laboratory indicators before admission were compared between the two groups of patients [gender, hypertension, age, body mass index (BMI), length of stay, primary caregiver, duration of disease, diabetes complications, antibiotic use, fasting blood glucose (FBG), invasive treatment, hemoglobin (HGB) and insulin resistance index (HO) MA-IR), to analyze the relationship between each index and the occurrence of hospital infection in diabetic patients, and to test the predictive value of HbA1c level in the occurrence of hospital infection in diabetic patients. Results: Among 566 patients with diabetes admitted to our hospital, 139 patients had nosocomial infection, accounting for 24.56%, and 427 patients did not have nosocomial infection, accounting for 75.44%. There were no differences in gender, hypertension, BMI, main caregiver, or HGB between the two groups (P > .05). Age, hospital stay, course of disease, FBG, HbA1c and HOMA-IR in the occurrence group were higher than those in the non-occurrence group, and the proportion of diabetes complications, antibiotic use and invasive treatment was significantly higher than that in the non-occurrence group, with statistical significance (P < .05). Logistics regression analysis showed that old age, long hospital stay, long course of disease, diabetes complications, antibiotic use, high level of FBG, high level of HbA1c, invasive treatment and high level of HOMA-IR were all risk factors for nosocomial infection in diabetic patients (OR > 1, P < .05). The ROC curve showed that the AUC of FBG and HbA1c in predicting the occurrence of hospital infection in diabetic patients was 0.764 and 0.875, respectively, and the predictive energy of HbA1c was higher than that of FBG. Conclusion: HbA1c level is correlated with the occurrence of hospital infection events in diabetic patients, and the correlation intensity with the occurrence of hospital infection events in diabetic patients presents a nonlinear dose-response relationship. Detection of HbA1c levels in diabetic patients is conducive to predicting the probability of hospital infection events, and strict control of HbA1c levels in diabetic patients is conducive to improving patient prognosis.

Transcription factor FOXM1 specifies chromatin DNA to extracellular vesicles.

Extracellular vesicle DNAs (evDNAs) hold significant diagnostic value for various diseases and facilitate transcellular transfer of genetic material. Our study identifies transcription factor FOXM1 as a mediator for directing chromatin genes or DNA fragments (termed FOXM1-chDNAs) to extracellular vesicles (EVs). FOXM1 binds to MAP1LC3/LC3 in the nucleus, and FOXM1-chDNAs, such as the DUX4 gene and telomere DNA, are designated by FOXM1 binding and translocated to the cytoplasm before being released to EVs through the secretory autophagy during lysosome inhibition (SALI) process involving LC3. Disrupting FOXM1 expression or the SALI process impairs FOXM1-chDNAs incorporation into EVs. FOXM1-chDNAs can be transmitted to recipient cells via EVs and expressed in recipient cells when they carry functional genes. This finding provides an example of how chromatin DNA fragments are specified to EVs by transcription factor FOXM1, revealing its contribution to the formation of evDNAs from nuclear chromatin. It provides a basis for further exploration of the roles of evDNAs in biological processes, such as horizontal gene transfer.

[Distribution Characteristics and Environmental Driving Factors of Cyanobacteria Community in Impounded Lakes and Reservoirs in Shandong on the East Route of South-to-North Water Diversion Project].

To investigate the distribution characteristics of the cyanobacteria community and the driving factors in impounded lakes and reservoirs in Shandong on the east route of the South-to-North Water Diversion Project, monthly samples of phytoplankton and the aquatic environment from Nansi Lake, Dongping Lake, Datun Reservoir, Donghu Reservoir, and Shuangwangcheng Reservoir were collected from May to November during 2010 to 2019. A total of 44 planktonic cyanobacteria taxa were identified with 23 filamentous cyanobacteria taxa. Pseudanabaena limnetica, Cylindrospermopsis raciborskii, Microcystis aeruginosa, and Microcystis wesenbergii were the dominant harmful cyanobacteria species, with a high detection frequency and abundance in all lakes and reservoirs. By analyzing the distribution characteristics of the cyanobacteria community in impounded lakes and reservoirs, we found that filamentous cyanobacteria had growth advantages in the water with large hydraulic disturbances, which should be the key points of cyanobacteria prevention and control in the future. Pearson correlation analysis and generalized linear fitting curve results showed that total nitrogen, total phosphorus, water temperature, and water depth played a key role in affecting the growth of P. limnetica, C. raciborskii, M. aeruginosa, and M. wesenbergii. The nitrogen and phosphorus nutrients could promote the growth of harmful cyanobacteria. Due to the good temperature adaptability, P. limnetica could still become the dominant species in early summer and late autumn, and C. raciborskii, M. aeruginosa, and M. wesenbergii had growth advantages when the water temperature was higher than 25℃. In addition, shallow water was more conducive to the growth of C. raciborskii. It was suggested that based on strengthening of the control of nitrogen and phosphorus nutrient input in lakes and reservoirs, the key monitoring of P. limnetica in lakes should be conducted in early summer and late autumn, and the growth of C. raciborskii in shallow water areas should be paid close attention in the high temperature period to ensure the safety of water quality.

Clerodendranthus spicatus inhibits epithelial-mesenchymal transition of renal tubular cells through the NF-κB/Snail signalling pathway in hyperuricaemia nephropathy.

CONTEXT: Clerodendranthus spicatus Thunb. (Labiatae) (CS), a perennial traditional Chinese medicinal herb that can reduce serum uric acid (sUA) levels and ameliorate renal function is widely used to treat hyperuricaemic nephropathy (HN). OBJECTIVE: To investigate the molecular mechanism of action of CS in HN treatment using in vivo and in vitro experiments. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into control, HN, CS and positive control allopurinol groups. The HN group was intraperitoneally injected with 750 mg/kg oxonic acid potassium (OA), whereas the CS group was injected with OA along with a gavage of CS (low dose 3.125 g/kg, high dose 6.25 g/kg) for five weeks. For in vitro studies, uric acid-treated HK2 cells were used to verify the therapeutic mechanism of CS in HN. RESULTS: HN rats exhibit pathological phenotypes of elevated sUA levels and renal injury. CS significantly improved these symptoms and sUA (p < 0.05) and blood urea nitrogen (p < 0.01) levels, and dramatically improved renal tubular injury in HN rats. The IC50 value of UA (uric acid) in HK2 cells was 826.32 ± 3.55 µg/mL; however, 120 ng/mL CS had no significant cytotoxicity on HK2 cells. In vivo and in vitro studies showed that CS inhibited NF-κB phosphorylation and inhibited α-smooth muscle actin (α-SMA) and vimentin expression while increasing E-cadherin expression, suggesting that CS inhibited the fibrotic process in renal cells, thus protecting renal function. DISCUSSION AND CONCLUSIONS: These findings provide a fundamental understanding of the application of CS in HN treatment to better guide clinical interventions.

68Ga-PSMA-11 PET/CT versus 68Ga-PSMA-11 PET/MRI for the detection of biochemically recurrent prostate cancer: a systematic review and meta-analysis.

Purpose: Our aim was to conduct a meta-analysis and systematic review in order to compare the diagnostic efficacy of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in patients with biochemically recurrent after radical prostatectomy and biochemically recurrent prostate cancers (BCR) after hybrid RT and RP. Methods: Up until February 2023, we searched PubMed, Embase, and Web of Science for pertinent papers. Studies examining the utility of 68Ga-PSMA-11 PET/CT or PET/MRI as a screening tool for biochemically recurrent prostate cancer were included. To measure heterogeneity, we employed the I2 statistic. In cases of substantial heterogeneity (I2 > 50%), we used the random effect model to produce a forest plot. In other cases, we utilized the fixed model. Furthermore, we assessed the quality of the studies included using the Quality Assessment of Diagnostic Performance Studies (QUADAS-2) method. Results: In total, 37 studies involving 8409 patients were examined. For 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI, the combined total detection rate was 0.70 (95% CI: 0.65-0.75) and 0.71 (95% CI:0.67-0.75), respectively. 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI did not substantially differ in terms of the overall detection rate for BCR (P = 0.58). The detection rate was unaffected by the PSA values (all P > 0.05). Conclusion: The diagnostic efficacy of 68Ga-PSMA-11 PET/CT appears to be equivalent to that of 68Ga-PSMA-11 PET/MRI in detecting biochemically recurrent prostate cancer. Nonetheless, it should be noted that not all studies have used pathological biopsies as the gold standard. Therefore, additional larger prospective studies are needed to address this issue. Systematic review registration: identifier CRD42023410039.

Germline Genetic NBN Variation and Predisposition to B-cell Acute Lymphoblastic Leukemia in Children.

Biallelic mutation in the DNA-damage repair gene NBN is the genetic cause of Nijmegen Breakage Syndrome, which is associated with predisposition to lymphoid malignancies. Heterozygous carriers of germline NBN variants may also be at risk for leukemia development, although this is much less characterized. We systematically examined the frequency of germline NBN variants in pediatric B-ALL and identified 25 putatively damaging NBN coding variants in 50 of 4,183 B-ALL patients. Compared with the frequency of NBN variants in 118,479 gnomAD non-cancer controls we found significant overrepresentation in pediatric B-ALL (p=0.004, OR=1.77). Most B-ALL-risk variants were missense and cluster within the NBN N-terminal domains. Using two functional assays, we verified 14 of 25 variants with severe loss-of-function phenotypes and thus classified these as pathogenic or likely pathogenic. Finally, we found that heterozygous germline NBN variant carriers showed similar survival outcomes relative to those with WT status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy.