The Different Strategies for the Radiolabeling of [211At]-Astatinated Radiopharmaceuticals.

Astatine-211 (211At) has emerged as a promising radionuclide for targeted alpha therapy of cancer by virtue of its favorable nuclear properties. However, the limited in vivo stability of 211At-labeled radiopharmaceuticals remains a major challenge. This review provides a comprehensive overview of the current strategies for 211At radiolabeling, including nucleophilic and electrophilic substitution reactions, as well as the recent advances in the development of novel bifunctional coupling agents and labeling approaches to enhance the stability of 211At-labeled compounds. The preclinical and clinical applications of 211At-labeled radiopharmaceuticals, including small molecules, peptides, and antibodies, are also discussed. Looking forward, the identification of new molecular targets, the optimization of 211At production and quality control methods, and the continued evaluation of 211At-labeled radiopharmaceuticals in preclinical and clinical settings will be the key to realizing the full potential of 211At-based targeted alpha therapy. With the growing interest and investment in this field, 211At-labeled radiopharmaceuticals are poised to play an increasingly important role in future cancer treatment.

Mitigating radiation-induced brain injury via NLRP3/NLRC4/Caspase-1 pyroptosis pathway: Efficacy of memantine and hydrogen-rich water.

Radiation-induced brain injury (RIBI) is a significant challenge in radiotherapy for head and neck tumors, impacting patients' quality of life. In exploring potential treatments, this study focuses on memantine hydrochloride and hydrogen-rich water, hypothesized to mitigate RIBI through inhibiting the NLRP3/NLRC4/Caspase-1 pathway. In a controlled study involving 40 Sprague-Dawley rats, divided into five groups including a control and various treatment groups, we assessed the effects of these treatments on RIBI. Post-irradiation, all irradiated groups displayed symptoms like weight loss and salivation, with notable variations among different treatment approaches. Particularly, hydrogen-rich water showed a promising reduction in these symptoms. Histopathological analysis indicated substantial hippocampal damage in the radiation-only group, while the groups receiving memantine and/or hydrogen-rich water exhibited significant mitigation of such damage. Molecular studies, revealed a decrease in oxidative stress markers and an attenuated inflammatory response in the treatment groups. Immunohistochemistry further confirmed these molecular changes, suggesting the effectiveness of these agents. Echoing recent scientific inquiries into the protective roles of specific compounds against radiation-induced damages, our study adds to the growing body of evidence on the potential of memantine and hydrogen-rich water as novel therapeutic strategies for RIBI.

Based on the prognosis model of immunogenes, the prognosis model was constructed to predict the invasion of immune genes and immune cells related to primary liver cancer and its experimental validation.

Background: Primary liver cancer (PLC) is a prevalent malignancy of the digestive system characterized by insidious symptom onset and a generally poor prognosis. Recent studies have highlighted a significant correlation between the initiation and prognosis of liver cancer and the immune function of PLC patients. Purpose: Revealing the expression of PLC-related immune genes and the characteristics of immune cell infiltration provides assistance for the analysis of clinical pathological parameters and prognosis of PLC patients. Methods: PLC-related differentially expressed genes (DEGs) with a median absolute deviation (MAD > 0.5) were identified from TCGA and GEO databases. These DEGs were intersected with immune-related genes (IRGs) from the ImmPort database to obtain PLC-related IRGs. The method of constructing a prognostic model through immune-related gene pairs (IRGPs) is used to obtain IRGPs and conduct the selection of central immune genes. The central immune genes obtained from the selection of IRGPs are validated in PLC. Subsequently, the relative proportions of 22 types of immune cells in different immune risk groups are evaluated, and the differential characteristics of PLC-related immune cells are verified through animal experiments. Results: Through database screening and the construction of an IRGP prognosis model, 84 pairs of IRGPs (P < 0.001) were ultimately obtained. Analysis of these 84 IRGPs revealed 11 central immune genes related to PLC, showing differential expression in liver cancer tissues compared to normal liver tissues. Results from the CiberSort platform indicate differential expression of immune cells such as naive B cells, macrophages, and neutrophils in different immune risk groups. Animal experiments demonstrated altered immune cell proportions in H22 tumor-bearing mice, validating findings from peripheral blood and spleen homogenate analyses. Conclusion: Our study successfully predicted and validated PLC-related IRGs and immune cells, suggesting their potential as prognostic indicators and therapeutic targets for PLC.

Single-cell analysis reveals insights into epithelial abnormalities in ovarian endometriosis.

Ovarian endometriosis is characterized by the growth of endometrial tissue within the ovary, causing infertility and chronic pain. However, its pathophysiology remains unclear. Utilizing high-precision single-cell RNA sequencing, we profile the normal, eutopic, and ectopic endometrium from 34 individuals across proliferative and secretory phases. We observe an increased proportion of ciliated cells in both eutopic and ectopic endometrium, characterized by a diminished expression of estrogen sulfotransferase, which likely confers apoptosis resistance. After translocating to ectopic lesions, endometrial epithelium upregulates nicotinamide N-methyltransferase expression that inhibits apoptosis by promoting deacetylation and subsequent nuclear exclusion of transcription factor forkhead box protein O1, thereby leading to the downregulation of the apoptotic gene BIM. Moreover, epithelial cells in ectopic lesions elevate HLA class II complex expression, which stimulates CD4+ T cells and consequently contributes to chronic inflammation. Altogether, our study provides a comprehensive atlas of ovarian endometriosis and highlights potential therapeutic targets for modulating apoptosis and inflammation.

Effect Predictor of Driver Synonymous Mutations Based on Multi-Feature Fusion and Iterative Feature Representation Learning.

Accurate identification of driver mutations is crucial in genetic studies of human cancers. While numerous cancer driver missense mutations have been identified, research into potential cancer drivers for synonymous mutations has shown limited success to date. Here, we developed a novel machine learning framework, epSMic, for predicting cancer driver synonymous mutations. epSMic employs an iterative feature representation scheme that facilitates the learning of discriminative features from various sequential models in a supervised iterative mode. We constructed the benchmark datasets and encoded the embedding sequence, physicochemical property, and basic information such as conservation and splicing feature. The evaluation results on benchmark test datasets demonstrate that epSMic outperforms existing methods, making it a valuable tool for researchers in identifying functional synonymous mutations in cancer. We hope epSMic can enable researchers to concentrate on synonymous mutations that have a functional impact on cancer.

Low-molecular-weight organic acids-mediated transport of neonicotinoid pesticides through saturated soil porous media: Combined effects of the molecular structures of organic acids and the chemical properties of contaminants.

Empirical information about the transport properties of neonicotinoid pesticides through the soil as affected by the ubiquitous low molecular weight organic acids (LMWOAs) is lacking. Herein, the impacts of three LMWOAs with different molecular structures, including citric acid, acetic acid, and malic acid, on the mobility characteristics of two typical neonicotinoid pesticides (Dinotefuran (DTF) and Nitenpyram (NTP)) were explored. Interestingly, under acidic conditions, different mechanisms were involved in transporting DTF and NTP by adding exogenous LMWOAs. Concretely, acetic acid and malic acid inhibited DTF transport, ascribed to the enhanced electrostatic attraction between DTF and porous media and the additional binding sites provided by the deposited LMWOAs. However, citric acid slightly enhanced DTF mobility due to the fact that the inhibitory effect was weakened by the steric hindrance effect induced by the deposited citric acid with a large molecular size. In comparison, all three LMWOAs promoted NTP transport at pH 5.0. Because the interaction between NTP with soil organic matter (e.g., via π-π stacking interaction) was masked by the LMWOAs coating on soil surfaces. Nevertheless, LMWOAs could promote the mobility of both neonicotinoid pesticides at pH 7.0 due to the steric hindrance effect caused by the deposited organic acids and the competitive retention between LMWOAs and pesticides for effective surface deposition sites of soil particles. Furthermore, the extent of the promotion effects of LMWOAs generally followed the order of citric acid > malic acid > acetic acid. This pattern was highly related to their molecular structures (e.g., number and type of functional groups and molecular size). Additionally, when the background solutions contained Ca2+, the bridging effect of cations also contributed to the transport-enhancement effects of LMWOAs. The findings provide valuable information about the mobility behaviors of neonicotinoid pesticides co-existing with LMWOAs in soil-water systems.

Comprehensive brain tissue metabolomics and biological network technology to decipher the mechanism of hydrogen-rich water on Radiation-induced cognitive impairment in rats.

BACKGROUND: Hydrogen-rich water (HRW) has been shown to prevent cognitive impairment caused by ionizing radiation. This study aimed to investigate the pharmacological effects and mechanisms of HRW on ionizing radiation by coupling the brain metabolomics and biological target network methods. METHODS AND RESULTS: HRW significantly improves the cognitive impairment in rats exposed to ionizing radiation. Based on metabolomics and biological network results, we identified 54 differential metabolites and 93 target genes. The KEGG pathway indicates that glutathione metabolism, ascorbic acid and aldehyde acid metabolism, pentose and glucuronic acid interconversion, and glycerophospholipid metabolism play important roles in ionizing radiation therapy. CONCLUSION: Our study has systematically elucidated the molecular mechanism of HRW against ionizing radiation, which can be mediated by modulating targets, pathways and metabolite levels. This provides a new perspective for identifying the underlying pharmacological mechanism of HRW.

ACT001 Ameliorates ionizing radiation-induced lung injury by inhibiting NLRP3 inflammasome pathway.

Radiotherapy is a prevalent treatment modality for thoracic tumors; however, it can lead to radiation-induced lung injury (RILI), which currently lacks effective interventions. ACT001, a prodrug of micheliolide, has demonstrated promising clinical application potential, yet its impact on RILI requires further validation. This study aims to investigate the radioprotective effects of ACT001 on RILI and elucidate its underlying mechanism. Sprague-Dawley rats were utilized to induce RILI following 20 Gy X-ray chest irradiation, and lung tissue inflammation and fibrosis were assessed using hematoxylin and eosin (H&E) and Masson staining. Lung injury, inflammation, and oxidative stress markers were evaluated employing commercial kits. Pyroptosis-related differentially expressed genes (DEGs) were analyzed using a microarray dataset from the Gene Expression Omnibus (GEO) database, and their functions and hub genes were identified through protein-protein interaction networks. Pyroptosis-related genes were detected via RT-qPCR, western blotting, immunofluorescence, and immunohistochemistry. The results demonstrated that ACT001 ameliorated RILI, diminished pro-inflammatory cytokine release and fibrosis, and mitigated the activation of the NLRP3 inflammasome while inhibiting pyroptosis in lung tissue. In conclusion, our study reveals that ACT001 can suppress NLRP3 inflammasome-mediated pyroptosis and improve RILI, suggesting its potential as a novel protective agent for RILI.

Primary Kaposi's Sarcoma of the Nasal Cavity: Clinical Experience and Review of the Literature.

Kaposi's sarcoma (KS) is a vascular sarcoma derived from vascular endothelial cells and presents with multiple lesions. It mainly appears on the skin and oral mucosa, usually in the face, oral mucosa, and genitals. Very few cases of primary lesions in the nasal cavity have been reported. It is often difficult to diagnose only by imaging examination. Here, we describe a case of KS in a patient who was human immunodeficiency virus (HIV)-negative, in which the primary sites were the nasal mucosa and nasal septum. A diagnosis was made according to the patient's clinical presentation, physical examination, laboratory examination, imaging examination, and histopathological results. We used surgical resection combined with chemotherapy, with 6 months' postoperative follow-up without recurrence. We reviewed the relevant literature to identify similar cases and summarize the findings reported on this rare manifestation of KS. We recommend that, where possible, antiviral therapy such as interferon, and regular review should continue, to improve the survival rate and patients' quality of life.

[Analysis of clinical characteristics and surgical efficiency of severe laryngomalacia in children].

Objective:To analyze the clinical characteristics and factors affecting surgical efficiency in children with severe laryngomalacia. Methods:Retrospectively collect medical records of children with severe laryngomalacia who underwent supraglottoplasty in Children's Hospital of Chongqing Medical University between January 1, 2015 and May 1, 2019. And analyze the clinical characteristics, the improvement of main symptoms at different time points, and the influence factors on the surgical efficiency. Results:According to the anatomical classification of severe laryngomalacia, type Ⅳ accounted for the highest proportion（66.1%）, and type Ⅰ was the lowest（3.6%）. All children had stridor and dyspnea, 82.1% cases presented feeding difficulties, and 67.9% cases presented failure to thrive. The proportion of children with medical comorbidities was 62.5%, of which congenital heart disease had the highest incidence（39.3%） The surgical efficiency of severe laryngomalacia without comorbidities was 100.0%, with one type of comorbidity was 96.0%, with multiple comorbidities was 30.0%（P<0.01）. Stridor, dyspnea, feeding difficulties were significantly improved at one month after surgery in most cases. In the group of surgical age less than 3 months, the surgical efficiency were 61.5%, 61.5% and 69.2% at 1, 3, 6 months after surgery, respectively; the surgical efficiency of children without comorbidities were 100.0%（P>0.05） at 1, 3 ,6 months after surgery. In the group of surgical age older than 3 months, the surgical efficiency of children were 100.0% at 1, 3, 6 months after surgery regardless with or without comorbidities. The surgical failure rate and reoperation rate in children without comorbidities was 0, but in the children with comorbidities were 22.9%（P<0.05） and 20.0%（P<0.05）, respectively. The surgical failure rate and reoperation rate in children with multiple comorbidities was significantly higher than children with only one comorbidity（70.0% vs. 4.0%; 60.0% vs. 4.0%, P<0.01）. The overall operation success rate was 85.7% in severe laryngomalacia children in our hospital. Conclusion:Most children with severe laryngomalacia are associated with multiple medical comorbidities, and with more complex anatomical types. Supraglottoplasty can effectively improve the symptoms in most children with severe laryngomalacia. The existence of multiple comorbidities is the main cause of surgical failure.

Cigarette smoke extract amplifies NADPH oxidase-dependent ROS production to inactivate PTEN by oxidation in BEAS-2B cells.

Chronic obstructive pulmonary disease (COPD) is widely recognized as a global public health problem and the third leading cause of mortality worldwide by 2020. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual-specificity protein and lipid phosphatase that plays an important role in COPD. However, the redox regulation of PTEN in the development of COPD was poorly studied. Our results showed that cigarette smoke extract (CSE) could oxidize PTEN in a time-dependent manner in BEAS-2B cells, whereas PTEN oxidation exposed to CSE was delayed compared to that of H2O2. Additionally, we found that ROS derived from DUOX1 and 2 of NADPH oxidases were mainly responsible for oxidative inactivation PTEN, also simultaneously led to Trx-1 inactivation by dimerization. Oxidative mechanism of PTEN exposed to CSE was mediated by forming a disulfide bond between Cys71and Cys124, similar to H2O2. Inactivation of PTEN resulted in the increased phosphorylation of Akt. In conclusion, CSE exposure could elevate the intracellular ROS mainly from DUOX1 and 2 to oxidize PTEN and Trx-1 resulting in Akt activation, eventually cause the occurrence of COPD, suggesting that PTEN is a potential target for new therapies in COPD.

Prediction of circRNA-disease associations based on inductive matrix completion.

BACKGROUND: Currently, numerous studies indicate that circular RNA (circRNA) is associated with various human complex diseases. While identifying disease-related circRNAs in vivo is time- and labor-consuming, a feasible and effective computational method to predict circRNA-disease associations is worthy of more studies. RESULTS: Here, we present a new method called SIMCCDA (Speedup Inductive Matrix Completion for CircRNA-Disease Associations prediction) to predict circRNA-disease associations. Based on known circRNA-disease associations, circRNA sequence similarity, disease semantic similarity, and the computed Gaussian interaction profile kernel similarity, we used speedup inductive matrix completion to construct the model. The proposed SIMCCDA method obtains an area under ROC curve (AUC) of 0.8465 with leave-one-out cross validation in the dataset, which is obtained by the combination of the three databases (circRNA disease, circ2Disease and circR2Disease). Our method surpasses other state-of-art models in predicting circRNA-disease associations. Furthermore, we conducted case studies in breast cancer, stomach cancer and colorectal cancer for further performance evaluation. CONCLUSION: All the results show reliable prediction ability of SIMCCDA. We anticipate that SIMCCDA could be utilized to facilitate further developments in the field and follow-up investigations by biomedical researchers.

Effect of Hydrogen-Rich Water on Radiation-Induced Cognitive Dysfunction in Rats.

The goal of this work was to determine whether hydrogen-rich water (HRW) could attenuate radiation-induced cognitive dysfunction in rats and to explore the underlying mechanisms. Rats received 30 Gy whole-brain irradiation using a 6-MeV electron beam. Either purified water or HRW (0.8-0.9 ppm) was administrated at 10 min prior to irradiation, as well as a daily HRW treatment after irradiation for 30 consecutive days. The Morris water maze was used to test spatial memory in the rats. The concentration of glutathione (GSH), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG) and the super-oxidedismutase (SOD) activity in cerebral cortex, as well as brain-derived neurotrophic factor (BDNF) level in serum, were measured. Immunofluorescence staining was adopted to detect proliferating cells. The expression of BDNF-TrkB pathway-related genes and proteins were detected using qRT-PCR and Western blot. Models of cognitive dysfunction were successfully established using a 30 Gy dose of ionizing radiation. Compared to the radiation treated group, the radiation-HRW treated group showed significantly decreased escape latency (P < 0.05), but increased retention time, swimming distance of original platform quadrant (P < 0.05) and number of platform crossings (P < 0.05). Furthermore, the SOD, GSH (P < 0.05) and BDNF (P < 0.05) levels in the radiation-HRW treated group were higher compared to the radiation treated group. The MDA and 8-OHdG levels (P < 0.05) were decreased in the radiation-HRW treated group when compared to the radiation treated group. Additionally, treatment with HRW increased the number of BrdU+NeuN+ cells in the radiation treated group. The mRNA and protein levels of BDNF and TrkB (P < 0.05) in radiation-HRW treated group was higher than that in the radiation treated group. Collectively, our study indicates that HRW has a protective effect on radiation-induced cognitive dysfunction, and that the possible mechanisms mainly involve anti-oxidative and anti-inflammatory reactions, and its protection of newborn neurons by regulating the BDNF-TrkB signaling pathway.

BCL6 mediates the effects of Gastrodin on promoting M2-like macrophage polarization and protecting against oxidative stress-induced apoptosis and cell death in macrophages.

Cerebral palsy (CP) is the most common childhood disability worldwide, yet biomarkers for predicting CP are lacking. By subjecting peripheral blood samples from 62 CP patients and 30 healthy controls to Affymetrix GeneChip® PrimeView™ HumanGene Expression Microarray analysis, we identified the novel biomarker B-cell lymphoma 6 (BCL6) as the most upregulated gene in the CP samples. Gastrodin is a traditional Chinese medicine and bioactive compound that promotes adductor angle release, as well as gross and fine motor performance by increasing Gross Motor Function Measure-66 and Fine Motor Function Measure-45 scores. Gastrodin upregulates the mRNA expression of Mgl2 and Mrc1, M2 macrophage markers, and arginase activity, an M2 polarization indicator, in murine RAW264.7 macrophages. Moreover, these effects were blocked by BCL6 siRNA, which also abrogated the protective effects of Gastrodin against hydrogen peroxide-induced apoptosis and death in RAW264.7 cells. Our work identified BCL6 as a novel biomarker for early prediction of CP. Moreover, we demonstrated that Gastrodin not only stimulated polarization toward M2-like macrophages, which promote tissue repair, but also rescued macrophages from oxidative stress, apoptosis and death by inducing BCL6 expression. BCL6-targeted therapeutic strategies have promise for improving motor performance in CP patients.

Genetic complementation of hepatitis C virus nonstructural protein functions associated with replication exhibits requirements that differ from those for virion assembly.

UNLABELLED: Within the polyprotein encoded by hepatitis C virus (HCV), the minimum components required for viral RNA replication lie in the NS3-5B region, while virion assembly requires expression of all virus components. Here, we have employed complementation systems to examine the role that HCV polyprotein precursors play in RNA replication and virion assembly. In a trans-complementation assay, an HCV NS3-5A polyprotein precursor was required to facilitate efficient complementation of a replication-defective mutation in NS5A. However, this requirement for precursor expression was partially alleviated when a second functional copy of NS5A was expressed from an additional upstream cistron within the RNA to be rescued. In contrast, rescue of a virion assembly mutation in NS5A was more limited but exhibited little or no requirement for expression of functional NS5A as a precursor, even when produced in the context of a second replicating helper RNA. Furthermore, expression of NS5A alone from an additional cistron within a replicon construct gave greater rescue of virion assembly in cis than in trans. Combined with the findings of confocal microscope analysis examining the extent to which the two copies of NS5A from the various expression systems colocalize, the results point to NS3-5A playing a role in facilitating the integration of nonstructural (NS) proteins into viral membrane-associated foci, with this representing an early stage in the steps leading to replication complex formation. The data further imply that HCV employs a minor virion assembly pathway that is independent of replication. IMPORTANCE: In hepatitis C virus-infected cells, replication is generally considered an absolute prerequisite for virus particle formation. Here we investigated the role that the viral protein NS5A has in both replication and particle assembly using complementation assays and microscopy. We found that efficient rescue of replication required NS5A to be expressed as part of a larger polyprotein, and this correlated with detection of NS5A at sites where replication occurred. In contrast, rescue of particle assembly did not require expression of NS5A within the context of a polyprotein. Interestingly, although only partial restoration of particle assembly was possible by complementation, that proportion that could be rescued benefitted from expressing NS5A from the same RNA being packaged. Collectively, these findings provide new insight into aspects of polyprotein function. They also support the existence of a minor virion assembly pathway that bypasses replication.

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94.

Peptide selectivity is a feature of inhibitory receptors for MHC class I expressed by natural killer (NK) cells. CD94-NKG2A operates in tandem with the polymorphic killer cell Ig-like receptors (KIR) and Ly49 systems to inhibit NK cells. However, the benefits of having two distinct inhibitory receptor-ligand systems are not clear. We show that noninhibitory peptides presented by HLA-E can augment the inhibition of NKG2A(+) NK cells mediated by MHC class I signal peptides through the engagement of CD94 without a signaling partner. Thus, CD94 is a peptide-selective NK cell receptor, and NK cells can be regulated by nonsignaling interactions. We also show that KIR(+) and NKG2A(+) NK cells respond with differing stoichiometries to MHC class I down-regulation. MHC-I-bound peptide functions as a molecular rheostat controlling NK cell function. Selected peptides which in isolation do not inhibit NK cells can have different effects on KIR and NKG2A receptors. Thus, these two inhibitory systems may complement each other by having distinct responses to bound peptide and surface levels of MHC class I.