Search

Background: Myocardial ischemia-reperfusion injury (MI/RI) significantly impacts the patients with acute myocardial infarction (AMI), with the NLRP3-mediated necrosis exacerbates the pathological progression of myocardial infarction. Exercise, recognized as a crucial approach for both disease prevention and treatment, is widely utilized in clinical practice worldwide and has demonstrated broad effectiveness in cardiovascular disease (CVD) prevention., Purpose: To explore the cardio protective effect of exercise preconditioning and the mechanism by which exercise modulation of NLRP3 improves myocardial ischemia and reperfusion injury., Methods and Results: In this study, C57BL/6 N mice were employed to establish an exercise preconditioning model and a MI/RI model. The exercise intervention involved moderate-intensity aerobic exercise on a treadmill (50-70% VO2max) for small animals. Our research findings indicate that moderate-intensity aerobic exercise intervention improved cardiac function, reduced myocardial injury and inflammatory response, decreased myocardial infarction area and degree of cell apoptosis in mice compared to those raised under conventional conditions. Additionally, the expression of NLRP3 in the myocardial tissue of mice with MI/RI was reduced after exercise intervention. Moreover, exercise inhibited the activation of apoptosis related proteins such as Caspase-1 and GSDMD, while reducing the levels of inflammatory factors such as IL-1β and IL-18., Conclusions: This study found that moderate-intensity aerobic exercise can reduce the inflammatory response, reduce the degree of cell pyroptosis, reduce myocardial ischemia and reperfusion injury, and achieve endogenous protective effects on the myocardium., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: To investigate the association of infant sleep and sleep trajectories through the first year of life with infant neurodevelopment., Methods: This study was conducted with 3251 infants in China. Sleep parameters were evaluated by the Brief Infant Sleep Questionnaire at 42days, 6months, and 1year of age. Neurodevelopment was evaluated at 1year of age using the Bayley Scales of Infant and Toddler Development, Third Edition. The latent variable growth curve model was used to evaluate the developmental trajectories of infant sleep, including total sleep duration trajectories, night awakening trajectories and sleep onset latency trajectories. Poisson regression was applied to assess the association between sleep parameters and sleep trajectories and infant neurodevelopment., Results: Infants with frequent night awakenings at 6months had a higher risk of nonoptimal gross motor development. Additionally, infants with prolonged sleep onset latency at 1year had an increased risk of nonoptimal fine and gross motor development. A consistent frequent night-awakening trajectory increased the risk of nonoptimal gross motor development (adjusted relative risk, 1.52; 95% confidence interval, 1.09 to 2.10). Furthermore, an increasing trajectory in sleep onset latency was associated with an increased risk of nonoptimal fine (adjusted relative risk, 2.70; 95% confidence interval, 1.12 to 6.51) and gross motor development (adjusted relative risk, 2.76; 95% confidence interval, 1.70 to 4.48). However, no significant association was observed between total sleep duration, or its trajectory, and infant neurodevelopment., Conclusions: Sleep problems or specific sleep trajectories during the initial year of life may increase risk of compromised neurodevelopment., Competing Interests: Declaration of conflicts of interest The authors declare that they have no competing interests., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Background: To create and develop a delivery approach for clinical inner ear gene therapy, we conducted a study of trans-round window membrane (RWM) microinjection using a pipetting microneedle via transcanal endoscopic ear surgery (TEES)., Methods: The implementation of the trans-RWM microinjection surgery involved seven cadaveric specimens, and the surgical procedures and the pipetting microneedle were developed and optimized. The TEES procedures included tympanic cavity visualization, RWM exposure, stapes footplate perforation, and trans-RWM microinjection. The feasibility of different pipetting microneedles was evaluated during microinjection., Results: Exposure of the RWM microinjection site could be easily achieved in TEES, and the soft-connected pipetting microneedle was most suitable for the trans-RWM microinjection. The fluid outflow from stapes perforation could be visibly observed during the microinjection, which indicated inner ear drug delivery was successful. This inner ear drug delivery approach was successfully applied in the clinical trial., Conclusion: The trans-RWM microinjection via the soft-connected pipetting microneedle in TEES was proved to be a feasible delivery approach of the inner ear gene therapy., Competing Interests: The authors have no conflicts of interest to declare. Funding and conflicts of interest: This project has received grants from the National Natural Science Foundation of China (82225014, 82171148, 82192864, 82201284), the National Key R&D Program of China (2020YFA0908201, 2021YFA1101302, 2023YFC2508400), Shanghai Municipal Health Commission (20224Z0003), Science and Technology Commission of Shanghai Municipality (21S11905100), Shanghai Municipal Education Commission (2023ZKZD12), the Shuguang Program (20SG08) supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation, and Fudan University (yg2022-23)., (Copyright © 2024, Otology & Neurotology, Inc.)

In an effort to identify novel antibacterial agents, we presented two series of aminoguanidine derivatives that were designed by incorporating 1,2,4-triazol moieties. All compounds exhibited strong in vitro antibacterial activity against a variety of testing strains. Compound 5f was identified as a potent antibacterial agent with a minimum inhibitory concentration (MIC) of 2-8 µg/mL against S. aureus, E. coli, S. epidermidis, B. subtilis, C. albicans, multi-drug resistant Staphylococcus aureus and multi-drug resistant Escherichia coli and low toxicity (Hela > 100 µM). Membrane permeability and transmission electron microscopy (TEM) image studies demonstrated that compound 5f permeabilized bacterial membranes, resulting in irregular cell morphology and the rapid death of bacteria. The results of the present study suggested that aminoguanidine derivatives with 1,2,4-triazol moieties were the intriguing scaffolds for the development of bactericidal agents., (© 2024. The Author(s).)

Goji berry (Lycium barbarum L.) is a nutrient-rich fruit and has received enormous interest for its health benefits. The beneficial effects of goji berry are linked to the absorption of bioactive compounds within the gastrointestinal digestion process and colon fermentation. Nonetheless, how certain bioactive compounds were released, and metabolism changed of the consumption of whole goji berries were still unclear. Therefore, the present study aimed to evaluate the digestion characteristics of key bioactive compounds in whole goji berries with an in vitro digestion model, and the effects of whole goji berries on the structure of gut microbiota were also investigated. Results showed that a significant release of carbohydrates during the digestion process, peaking within the first 15 min of the intestinal phase (421.4 ± 5.82 mg GE/g, dry weight, respectively), was observed, and the phenolic release reached the highest in the first 15 min of the gastric phase. Meanwhile, the bioaccessibilities of phenolic compounds and carbohydrates were determined to be 63.87% and 80.40%, respectively, after intestinal digestion. In addition, the undigested fractions of goji berries could be further fermented to produce short-chain fatty acids, which decreased the colon pH value (from 7.38 to 6.71) as well as the Firmicutes/Bacteroidetes ratio. Moreover, the goji berries regulated the composition of gut microbiota by promoting beneficial bacteria such as Bacteroides, Parabacteroides, and Paraclostridium, whereas inhibiting the proliferation of harmful bacteria (e.g., Fusobacterium). Our results indicated that the goji berry exhibited significant bioactivity during the digestion and fermentation stage and might provide some new insights into the utilization of goji berries in healthy food processing., (© 2024 Institute of Food Technologists.)

Oral aphthous ulcers are common mucosal lesions that cause pain and discomfort. There are diverse biomaterials and drug treatments for oral ulcers used in both research and clinical settings. However, the complex oral environment often results in low adhesion and short drug retention times, which lead to poor drug availability and treatment outcomes. In this study, a mussel-inspired adhesive hydrogel was developed by grafting catechol onto hyaluronic acid (C-HA), and dopamine was added for oxidative pre-polymerization to form modified hyaluronic acid (M-HA), which remarkably increased the adhesion of the hydrogels. Then, M-HA was interpenetrated into the gelatin methacryloyl (GelMA) network. Chlorhexidine gluconate (CHG) was then incorporated into the hydrogel to enhance its availability and therapeutic effect through its sustained-release capability. The GelMA/M-HA hydrogel demonstrated strong adhesion to wet tissues, antibacterial and anti-inflammatory properties, and good biocompatibility. In both rat oral ulcers and infected wounds, the adhesive hydrogel significantly accelerated the healing of the ulcers and infected wounds. These results indicated that this adhesive hydrogel offers a promising new strategy for the treatment of oral ulcers in clinical practice. STATEMENT OF SIGNIFICANCE: Oral ulcers are a common and high-incidence mucosal condition that seriously affect people's daily lives, often making it difficult for patients to chew and speak. However, a dynamic oral environment with various types of bacteria influences drug availability and treatment effects in clinical settings. To address this challenge, an adhesive, mussel-inspired, drug-loaded hydrogel was constructed using natural macromolecules (hyaluronic acid and gelatin) with good biocompatibility. Chlorhexidine gluconate (CHG), with its broad-spectrum antibacterial activity, has been incorporated to synergistically promote oral ulcer healing. The splendid adhesion, antibacterial, and therapeutic effects of this hydrogel demonstrated a new strategy for treating oral ulcers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Heart rate variability (HRV) is often reduced in patients with major depressive disorder (MDD) and is linked to symptoms. However, prior studies have mainly focused on short-term HRV, with limited exploration of the 24-h HRV circadian rhythm, despite its ability to comprehensively capture overall HRV distribution and dynamic fluctuations. In this study, we investigated the circadian rhythms of 24-h HRV indices in patients with MDD and their associations with symptom severity., Methods: We recorded 24-h electrocardiograms in 73 patients with MDD (53 in major depressive episode and 20 in remission period) and 31 healthy controls. An extended cosine model was used to model the circadian rhythm of six HRV indices by five parameters: the mesor, amplitude, duty cycle, curve smoothness, and acrophase. Symptom severity was evaluated using the Hamilton Depression Scale and Hamilton Anxiety Scale., Results: Compared with the control group, patients with MDD had a significantly smaller SampEn mesor, higher HF duty cycle, and lower heart rate (HR) duty cycle. They also had a significantly higher curve smoothness for HR, RMSSD, and HF. The mesor for SampEn, along with the curve smoothness for HR and ln RMSSD, were associated with certain symptoms in patients with MDD., Limitations: The cross-sectional design and psychiatric treatment of most patients with MDD limited our findings., Conclusion: Patients with MDD exhibit abnormal HRV circadian rhythms that are associated with symptoms. Moreover, 24-h ECG monitoring may potentially serve as an adjunct value to objectively evaluate clinical symptoms in these patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mercury is a well-known neurotoxicant for humans and wildlife. The epidemic of mercury poisoning in Japan has clearly demonstrated that chronic exposure to methylmercury (MeHg) results in serious neurological damage to the cerebral and cerebellar cortex, leading to the dysfunction of the central nervous system (CNS), especially in infants exposed to MeHg in utero. The occurrences of poisoning have caused a wide public concern regarding the health risk emanating from MeHg exposure; particularly those eating large amounts of fish may experience the low-level and long-term exposure. There is growing evidence that MeHg at environmentally relevant concentrations can affect the health of biota in the ecosystem. Although extensive in vivo and in vitro studies have demonstrated that the disruption of redox homeostasis and microtube assembly is mainly responsible for mercurial toxicity leading to adverse health outcomes, it is still unclear whether we could quantitively determine the occurrence of interaction between mercurial and thiols and/or selenols groups of proteins linked directly to outcomes, especially at very low levels of exposure. Furthermore, intracellular calcium homeostasis, cytoskeleton, mitochondrial function, oxidative stress, neurotransmitter release, and DNA methylation may be the targets of mercury compounds; however, the primary targets associated with the adverse outcomes remain to be elucidated. Considering these knowledge gaps, in this article, we conducted a comprehensive review of mercurial toxicity, focusing mainly on the mechanism, and genes/proteins expression. We speculated that comprehensive analyses of transcriptomics, proteomics, and metabolomics could enhance interpretation of "omics" profiles, which may reveal specific biomarkers obviously correlated with specific pathways that mediate selective neurotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In our investigation, we examined biochemical parameters and identified hydroxybutyrate dehydrogenase (HBDH) as a significant predictor for diffuse large B cell lymphoma (DLBCL) patients. A group of 100 patients was used to explore potential biomarkers related to progression-free survival (PFS). Subsequently, an independent cohort of 404 patients from a separate hospital was recruited to validate our findings. Our results revealed a strong association between elevated HBDH levels and poor PFS. Furthermore, although overexpression of LDHB, but not LDHA, was notably linked to poorer outcomes, HBDH expression emerged as a more robust predictor of clinical prognosis compared to LDH expression. Our investigations, which included metabolic and genetic pathway enrichment analyses, indicated that patients exhibiting heightened HBDH expression were characterized by distinct pathways related to energy metabolism and lymphoma progression. In conclusion, elevated HBDH levels were correlated with adverse survival and might serve as an independent parameter for evaluating patient outcomes., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

We report a rare case of thyroid diffuse large B-cell lymphoma with a BRAF V600E mutation, which mimics poorly differentiated thyroid cancer in fine needle aspiration cytology., Competing Interests: The authors declare that they have no competing interests in relation to this study., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Large amounts of azurophilic granules are considered to be a morphological feature of acute promyelocytic leukaemia (APL). However, a small percentage of acute myeloid leukaemia (AML) patients also have a large number of azurophilic granules. A large cohort of 3210 AML patients in our hospital was screened to identify AML patients who had a large number of azurophilic granules. The clinical parameters of these patients were collected and compared with typical AML patients (control Group 1) and APL patients (control Group 2). The incidence of AML with a large number of azurophilic granules was 1.26%. The fibrinogen and D-dimer levels of patients in the study group were more similar to those of patients in control Group 2, as was the incidence of bleeding events. Additionally, patients in the study group had higher FLT3-ITD and NPM1 mutation rates than patients in control Group 1. Finally, patients in the study group had a higher 30-day mortality rate than those in control Group 2 (24.2% vs. 9.09%) and showed a higher 30-day mortality trend than those in control Group 1. Therefore, we should pay more attention to the prevention of coagulation dysfunction and bleeding events for these patients., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Hydrothermal treatment (HTT) held promise for phosphorus (P) recovery from high-moisture biomass. However, traditional experimental studies of P hydrothermal conversion were time-consuming and labor-intensive. Thus, based on biomass characteristics and HTT parameters, Random Forest (RF) and Gradient Boosting Regression machine learning (ML) models were constructed to predict HTT P migration between total P in hydrochar (TP_HC) and process water (TP_PW) and hydrochar P transformation among inorganic P (IP_HC), organic P (OP_HC), non-apatite inorganic P (NAIP_HC), and apatite P (AP_HC). Results demonstrated that the RF models (test R 2  > 0.86) exhibited excellent performance in both single-target and multi-target predictions. Feature importance analysis identified TP_feed, O, C, and N as critical features influencing P distribution in hydrothermal products. TP_feed, NAIP_feed, temperature, and IP_feed were crucial factors affecting P form transformation in HC. This study provided valuable insights into understanding the migration and transformation of P and further guided experimental research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: In patients with acute promyelocytic leukemia (APL), additional chromosomal abnormalities (ACAs) are prognostic indicators. However, the clinical features of ACAs were not systematically reported in Chinese patients. Therefore, we enrolled a large cohort of APLs to demonstrate the clinical characteristics and prognostic value of ACAs., Methods: 268 patients with newly diagnosed APL with t(15;17)(q24;q21) were retrospectively enrolled, and their clinical characteristics and the predictive value of ACAs were assessed between patients with the presence and absence of ACAs., Results: APL patients with and without ACAs did not differ significantly in their clinical features or treatment response and clinical outcomes like overall survival (OS) and disease-free survival (DFS). It appeared to be substantially associated with worse OS in APL patients with trisomy 8, which was the most common ACA, although DFS was unaffected. Interestingly, the presence of ACAs or trisomy 8 affected OS and DFS in the subgroup of patients aged ≥60 years; by contrast, ACAs had no effect on OS or DFS in any treatment subgroup (ATRA + ATO/RIF or ATRA + ATO/RIF + CH or ATRA + CH), except for the ATRA + ATO/RIF + CH treatment subgroup, where their impact on DFS was less favorable., Conclusions: Our results suggested that OS and DFS were unaffected by ACAs. Nonetheless, in the subgroup of patients older than 60, the existence of ACAs or trisomy 8 appeared to impact OS and DFS negatively. Individuals with t(15;17) alone had a higher DFS and were more susceptible to ATRA + ATO/RIF + CH than individuals with t(15;17) ACAs.

While maternal exposure to high metal levels during pregnancy is an established risk factor for birth defects, the role of paternal exposure remains largely unknown. We aimed to assess the associations of prenatal paternal and maternal metal exposure and parental coexposure with birth defects in singletons. This study conducted within the Jiangsu Birth Cohort recruited couples in early pregnancy. We measured their urinary concentrations for 25 metals. A total of 1675 parent-offspring trios were included. The prevalence of any birth defects among infants by one year of age was 7.82%. Paternal-specific gravity-corrected urinary concentrations of titanium, vanadium, chromium, manganese, cobalt, nickel, copper, and selenium and maternal vanadium, chromium, nickel, copper, selenium, and antimony were associated with a 21-91% increased risk of birth defects after adjusting for covariates. These effects persisted after mutual adjustment for the spouse's exposure. Notably, when assessing the parental mixture effect by Bayesian kernel machine regression, paternal and maternal chromium exposure ranked the highest in relative importance. Parental coexposure to metal mixture showed a pronounced joint effect on the risk of overall birth defects, as well as for some specific subtypes. Our findings suggested a couple-based prevention strategy for metal exposure to reduce birth defects in offspring.

Purpose: A systematic review and meta-analysis were conducted to evaluate the diagnostic precision of radiomics in the differential diagnosis of parotid tumors, considering the increasing utilization of radiomics in tumor diagnosis. Although some researchers have attempted to apply radiomics in this context, there is ongoing debate regarding its accuracy., Methods: Databases of PubMed, Cochrane, EMBASE, and Web of Science up to May 29, 2024 were systematically searched. The quality of included primary studies was assessed using the Radiomics Quality Score (RQS) checklist. The meta-analysis was performed utilizing a bivariate mixed-effects model., Results: A total of 39 primary studies were incorporated. The machine learning model relying on MRI radiomics for diagnosis malignant tumors of the parotid gland, demonstrated a sensitivity of 0.80 [95% CI: 0.74, 0.86], SROC of 0.89 [95% CI: 0.27-0.99] in the validation set. The machine learning model based on MRI radiomics for diagnosis malignant tumors of the parotid gland, exhibited a sensitivity of 0.83[95% CI: 0.76, 0.88], SROC of 0.89 [95% CI: 0.17-1.00] in the validation set. The models also demonstrated high predictive accuracy for benign lesions., Conclusion: There is great potential for radiomics-based models to improve the accuracy of diagnosing benign and malignant tumors of the parotid gland. To further enhance this potential, future studies should consider implementing standardized radiomics-based features, adopting more robust feature selection methods, and utilizing advanced model development tools. These measures can significantly improve the diagnostic accuracy of artificial intelligence algorithms in distinguishing between benign and malignant tumors of the parotid gland., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023434931., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rao, Ma, Wang, Xiao, Wu, Shi, Guo and Fan.)

In response to the increasing number of agents and changing task scenarios in multi-agent collaborative systems, existing collaborative strategies struggle to effectively adapt to new task scenarios. To address this challenge, this paper proposes a knowledge distillation method combined with a domain separation network (DSN-KD). This method leverages the well-performing policy network from a source task as the teacher model, utilizes a domain-separated neural network structure to correct the teacher model's outputs as supervision, and guides the learning of agents in new tasks. The proposed method does not require the pre-design or training of complex state-action mappings, thereby reducing the cost of transfer. Experimental results in scenarios such as UAV surveillance and UAV cooperative target occupation, robot cooperative box pushing, UAV cooperative target strike, and multi-agent cooperative resource recovery in a particle simulation environment demonstrate that the DSN-KD transfer method effectively enhances the learning speed of new task policies and improves the proximity of the policy model to the theoretically optimal policy in practical tasks.

Beer fish is characterized by its distinctive spicy flavor and strong beer aroma. Currently, there is a lack of comprehensive research analyzing the changes in taste and volatile compounds that occur during the processing of beer fish. Thus, this study used HS-GC-IMS, electronic tongue, and electronic nose to investigate the changes in flavor components during various processing stages of beer fish. The obtained results were subsequently analyzed using multivariate statistical analysis. The results showed that the final beer fish product (SF) had the greatest amount of free amino acids (888.28 mg/100 g), with alanine, glutamic acid, and glycine contributing to the taste of SF. The inosine monophosphate (IMP) content of beer fish meat varied noticeably depending on processing stages, with deep-fried fish (FF) having the greatest IMP content (61.93 mg/100 g), followed by the final product (SF) and ultrasonic-cured fish (UF). A total of 67 volatiles were detected by GC-IMS, mainly consisting of aldehydes, ketones, and alcohols, of which aldehydes accounted for >37%, which had a great influence on the volatile flavor of beer fish. The flavor components' composition varied noticeably depending on the stage of processing. PLS-DA model screened 35 volatile flavor components (VIP > 1) as markers; the most significant differences were 1-propanethiol, isoamyl alcohol, ethanol, and eucalyptol. Ultrasonic processing, frying, and soaking sauce can significantly improve the formation of flavor compounds, resulting in a notable enhancement of the final beer fish's umami taste and overall flavor quality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 ., (© 2024. The Author(s).)

Background: Hepatocellular carcinoma (HCC) has high morbidity and mortality worldwide. Excision repair cross-complement 3 (ERCC3), a key functional gene in the nucleotide excision repair (NER) pathway, is commonly mutated or overexpressed in cancers and is thought to be a key gene contributing to the development of HCC. The characteristics of immune cell infiltration in the global tumor microenvironment (TME) mediated by ERCC3 and its related key genes in HCC are still unclear. The aim of this study was to integrate the role of ERCC3-related key genes in assessing the TME cell infiltration characteristics, immunotherapy efficacy, and prognosis of HCC patients. This study provides a theoretical basis for the study of immunological mechanisms and prognosis prediction in HCC., Methods: The HCC cohort from the TCGA database included 50 normal samples and 374 tumor samples to compare the differences in ERCC3-related gene expression and prognosis between liver tumor tissues and normal liver tissues and to analyze the extent to which different genes infiltrated TME cells by quantifying the relative abundance of 24 cells through single-sample genome enrichment analysis (ssGSEA). A risk score associated with the ERCC3 gene was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model., Results: The expression of 11 ERCC3-related genes was significantly upregulated in HCC tumor tissues compared to normal liver tissues, and high expression of these genes was significantly associated with poor prognosis in HCC patients. The key genes (11 ERCC3-related genes) were closely associated with the nucleic acid reduction signaling pathway in nucleic acid metabolism and the viral oncogenic pathway, suggesting that these key genes may play a role in tumor cell proliferation, migration, and invasion, as well as in the pathogenesis of virus-associated HCC. In addition, the infiltration characteristics of TME immune cells in normal and tumor tissues were different. Immune and mesenchymal activity was significantly lower in tumor tissues than in healthy liver tissues. This study revealed that key genes were significantly positively correlated with CTLA4 and enriched in central memory CD4 T cells, effector memory CD4 T cells, activated CD4 T cells, and type 2 T helper cells. The prognostic model constructed by regression analysis could better distinguish patients into high-risk and low-risk groups, and the survival analysis showed that the survival time of patients with high-risk score subtypes was significantly lower than that of patients with low-risk scores and that the high-risk group contained higher levels of immune-suppressive cells, which may be a mediator of immune escape. Moreover, multivariate analyses showed that the risk score profile is a reliable and unbiased biomarker for assessing the prognosis of HCC patients, and its value in predicting the outcome of immunotherapy was also confirmed., Conclusion: This study revealed a novel genetic signature that is significantly associated with TME cell infiltration and prognosis in HCC patients. It demonstrated that the combined action of multiple key genes associated with ERCC3 plays a crucial role in shaping the diversity and complexity of TME cell infiltrates. Evaluating the combined characteristics of multiple key genes associated with ERCC3 can help predict the outcome of immunotherapy in patients and provide new potential targets for immuno-individualized therapeutic studies on HCC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The role of rumination in depression remains controversial. We aimed to establish the ruminative tendency style theory (RTST), discuss the occurrence of depression in adolescents with rumination as the core, and explore the different associations between adolescent ruminative tendency, ruminative style, and depression., Methods: This study employed an online questionnaire survey of 1110 Chinese adolescents aged 12-17 years, assessing ruminative tendency, ruminative style, stressful life events, depressive state, depressive trait, the Big Five personality traits, and social support. Conditional process analysis was used to test the chain mediation effect with Ruminative Style as a moderator. After screening for the predictor variables, a logistic regression risk prediction model was established and validated internally., Results: The chain mediation effect of ruminative tendency and depressive trait between stressful life events and depressive state was significant, with the indirect effect accounting for 63.4%. Ruminative Style negatively moderated the relationship between Ruminative Tendency and Depressive Trait (β=-0.053，P＜0.001). The risk prediction model for depressive state showed good calibration and clinical utility. Area under the curve values for the validation and training sets were 0.926 and 0.927, respectively., Conclusion: Different associations may exist between adolescent ruminative tendency, ruminative style, and depression, and the proposal of ruminative style is of great significance for intervention in adolescent depression., Competing Interests: Declaration of Competing Interest There are no conflicts of interest in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9., Methods: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing., Findings: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 10 11 vector genomes [vg] and five received 1·5 × 10 12 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 10 11 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 10 12 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery., Interpretation: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9., Funding: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics., Competing Interests: Declaration of interests KG is a staff member at the Shanghai Refreshgene Therapeutics. ZC is a cofounder of Salubritas Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Microplastics (MPs) have been considered an emerging environmental pollutant which, when combined with toxic metals, enter the circulatory system of mammals and eventually cause damage. Therefore, it is important to study the toxicity of the mixture of MPs and heavy metals for evaluating risk assessment of mammals. In the present study, the toxicological effects of different concentrations of polystyrene (PS)-MPs alone or in combination with cadmium chloride (CdCl 2 ) during chronic exposure (8 weeks) were evaluated using intragastric administration in mice. Using comparative analysis, it was revealed that PS-MPs alone or in combination with Cd could destroy the normal structural morphology of liver tissue and increase the levels of two biochemical indicators of liver damage, thereby inducing changes in antioxidant and hyperoxide capacities. In addition, PS-MPs and/or Cd activated the antioxidant signaling pathway Nrf2-Keap1 and affected the endogenous apoptosis signaling pathway p53-Bcl-2/Bax, thus promoting apoptosis. These findings suggested that exposure to MPs alone or in combination with Cd led to adverse effects on the liver. Furthermore, it was revealed that co-exposure to MPs and Cd reduced Cd toxicity, thereby highlighting the possibility MPs may act as carriers of other toxic substances and coordinate with them. Therefore, evaluating the synergistic or anti-agonistic effects of MPs on the toxicity and bioavailability of xenobiotics is in the future critical in environmental toxicological studies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epstein-Barr virus (EBV)-positive nodal T-cell and NK-cell lymphoma is a rare neoplasm of cytotoxic T-cell or NK-cell lineage. Here, we report 26 cases affecting 14 men and 12 women with a median age of 52 years. All patients presented with disease involving multiple lymph nodes, and 20 of 22 (91%) fully staged patients had advanced Ann Arbor stage disease. Spleen, liver, and bone marrow were involved in 70%, 50%, and 52% of cases, respectively. These patients had a dismal prognosis with a median survival of 30 days. Histologically, lymph nodes were replaced by lymphoma in a diffuse pattern. Lymphoma cells were variable in size and large cell morphology was seen in 62% of cases. The neoplastic cells were CD4-/CD8- in 14 (54%) cases and CD4-/CD8+ in 12 (46%) cases. CD56 was positive in 14 (54%) cases. CD30 was positive in 20 (77%) cases; a strong and diffuse pattern was observed in 14 (54%) cases, mimicking, in part, anaplastic large cell lymphoma (ALCL). CD30 expression was associated with younger age and large cell morphology. In summary, EBV+ nodal T-cell and NK-cell lymphoma is an aggressive disease with a poor prognosis. These neoplasms are heterogeneous at the morphologic and immunophenotypic levels. Diffuse and strong expression of CD30 could potentially lead to a misdiagnosis of ALCL if EBV evaluation is not performed. Distinguishing between EBV+ nodal T-cell and NK-cell lymphoma from ALCL is important because treatment strategy and prognosis differ. CD30 expression offers a potential therapeutic target for patients with this aggressive disease., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung cancer., Competing Interests: Competing interests statement:The authors declare no competing interest.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Aquilegia is a model system for studying the evolution of adaptive radiation. However, very few studies have been conducted on the Aquilegia mitochondrial genome. Since mitochondria play a key role in plant adaptation to abiotic stress, analyzing the mitochondrial genome may provide a new perspective for understanding adaptive evolution., Results: The Aquilegia amurensis mitochondrial genome was characterized by a circular chromosome and two linear chromosomes, with a total length of 538,736 bp; the genes included 33 protein-coding genes, 24 transfer RNA (tRNA) genes and 3 ribosomal RNA (rRNA) genes. We subsequently conducted a phylogenetic analysis based on single nucleotide polymorphisms (SNPs) in the mitochondrial genomes of 18 Aquilegia species, which were roughly divided into two clades: the European-Asian clade and the North American clade. Moreover, the genes mttB and rpl5 were shown to be positively selected in European-Asian species, and they may help European and Asian species adapt to environmental changes., Conclusions: In this study, we assembled and annotated the first mitochondrial genome of the adaptive evolution model plant Aquilegia. The subsequent analysis provided us with a basis for further molecular studies on Aquilegia mitochondrial genomes and valuable information on adaptive evolution in Aquilegia., (© 2024. The Author(s).)

Introduction: Squamous cell carcinoma antigen (SCCA) is one of the auxiliary diagnostic indicators of lung squamous cell carcinoma, and an increase in serum SCCA can predict the occurrence of lung squamous cell carcinoma. However, whether SCCA is also elevated in pneumonia patients without malignancy is still not clear. Therefore, we studied influencing factors of elevated serum SCCA in patients with community-acquired pneumonia., Methods: We retrospectively enrolled 309 patients who were admitted to the Respiratory department with normal serum Carcinoembryonic antigen (CEA), Neuron specific enolase (NSE), and Cytokeratin 19 fragment (CYFRA21-1) level and were diagnosed with community-acquired pneumonia (CAP). The patients' serum SCCA level, body temperature, age, sex, white blood cell (WBC) count, hypersensitive C-reactive protein (Hs-CRP) level, and serum amyloid A (SAA) were recorded. Logistic regression models were used to analyze the risk factors of SCCA elevation. The dose-response relationship between temperature and risk of SCCA increase was analyzed using Restricted cubic splines (RCS)., Results: Of the 309 patients, 143(46.3%) showed elevated SCCA levels. The logistic regression analysis revealed a significant influence of age and body temperature on elevated SCCA (P <0.05) levels. For every one-year increase in age, the probability of elevated SCCA decreased by 3% [OR=0.97,95%CI:0.95,0.99].For every 1°C increase in body temperature, the risk of elevated SCCA increased by 2.75 times [OR=3.75,95%CI:2.55,5.49].The patients were sorted into quartiles based on body temperature. Compared with patients in the Q1 of body temperature group, patients in the Q3 group were at 7.92 times higher risk [OR=7.92, 95%CI:3.27,19.16].and the risk of elevated SCCA was increased by 22.85 times in the Q4 group [OR=23.85,95%CI:8.38,67.89] after adjusting for age, gender, Hs-CRP, SAA, and WBC. RCS analysis showed there was a linear relationship between temperature index and risk of elevated SCCA., Conclusion: In summary, for CAP patients with normal CEA,NSE and CYFRA21-1 level, age and body temperature are influencing factors of SCCA elevation. Higher body temperature has a strong association with the occurrence of SCCA elevation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Tang, Liu and Zhang.)

The COVID-19 outbreak caused by SARS-CoV-2 in late 2019 has spread rapidly across the world to form a global epidemic of respiratory infectious diseases. Increased investigations on diagnostic tools are currently implemented to assist rapid identification of the virus because mass and rapid diagnosis might be the best way to prevent the outbreak of the virus. This critical review discusses the detection principles, fabrication techniques, and applications on the rapid detection of SARS-CoV-2 with three categories: rapid nuclear acid augmentation test, rapid immunoassay test and biosensors. Special efforts were put on enhancement of nanomaterials on biosensors for rapid, sensitive, and low-cost diagnostics of SARS-CoV-2 virus. Future developments are suggested regarding potential candidates in hospitals, clinics and laboratories for control and prevention of large-scale epidemic., (© 2023. The Author(s).)

Introduction: Artificial intelligence (AI) technology has made rapid progress for disease diagnosis and triage. In the field of ophthalmic diseases, image-based diagnosis has achieved high accuracy but still encounters limitations due to the lack of medical history. The emergence of ChatGPT enables human-computer interaction, allowing for the development of a multimodal AI system that integrates interactive text and image information., Objective: To develop a multimodal AI system using ChatGPT and anterior segment images for diagnosing and triaging ophthalmic diseases. To assess the AI system's performance through a two-stage cross-sectional study, starting with silent evaluation and followed by early clinical evaluation in outpatient clinics., Methods and Analysis: Our study will be conducted across three distinct centers in Shanghai, Nanjing, and Suqian. The development of the smartphone-based multimodal AI system will take place in Shanghai with the goal of achieving ≥90% sensitivity and ≥95% specificity for diagnosing and triaging ophthalmic diseases. The first stage of the cross-sectional study will explore the system's performance in Shanghai's outpatient clinics. Medical histories will be collected without patient interaction, and anterior segment images will be captured using slit lamp equipment. This stage aims for ≥85% sensitivity and ≥95% specificity with a sample size of 100 patients. The second stage will take place at three locations, with Shanghai serving as the internal validation dataset, and Nanjing and Suqian as the external validation dataset. Medical history will be collected through patient interviews, and anterior segment images will be captured via smartphone devices. An expert panel will establish reference standards and assess AI accuracy for diagnosis and triage throughout all stages. A one-vs.-rest strategy will be used for data analysis, and a post-hoc power calculation will be performed to evaluate the impact of disease types on AI performance., Discussion: Our study may provide a user-friendly smartphone-based multimodal AI system for diagnosis and triage of ophthalmic diseases. This innovative system may support early detection of ocular abnormalities, facilitate establishment of a tiered healthcare system, and reduce the burdens on tertiary facilities., Trial Registration: The study was registered in ClinicalTrials.gov on June 25th, 2023 (NCT05930444)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peng, Ma, Zhang, Yan, Lu, Cheng, Liao, Zhang, Wang, Zhao, Zhu, Qin, Jiang, Shi, Qian, Chen and Zhao.)

Ferroptosis induction through the suppression of glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2) has proven to be an effective approach in eliminating chemotherapy-resistant cells of various types. However, a comprehensive understanding of the roles of GPX4 and AIFM2 in acute myeloid leukemia (AML) has not yet been achieved. Using cBioPortal, DepMap, GEPIA, Metascape, and ONCOMINE, we compared the transcriptional expression, survival data, gene mutation, methylation, and network analyses of GPX4- and AIFM2-associated signaling pathways in AML. The results revealed that high expression levels of GPX4 and AIFM2 are associated with an adverse prognosis for AML patients. Overexpression of AIFM2 correlated with elevated mutation frequencies in NPM1 and DNMT3A. GPX4 upregulation modulated the following pathways: GO:0045333, cellular respiration; R-HSA-5389840, mitochondrial translation elongation; GO:0009060, aerobic respiration; R-HSA-9609507, protein localization; and R-HSA-8953854, metabolism of RNA. On the other hand, the overexpression of AIFM2 influenced the following processes: GO:0048704, embryonic skeletal system morphogenesis; GO:0021546, rhombomere development; GO:0009954, proximal/distal pattern formation; and GO:0048732, gland development. This study identifies the high expression of GPX4 and AIFM2 as novel biomarkers predicting a poor prognosis for AML patients. Furthermore, ferroptosis induction may improve the stratified treatment of AML.

Pathogenic mutations in the OTOF gene cause autosomal recessive hearing loss (DFNB9), one of the most common forms of auditory neuropathy. There is no biological treatment for DFNB9. Here, we designed an OTOF gene therapy agent by dual-adeno-associated virus 1 (AAV1) carrying human OTOF coding sequences with the expression driven by the hair cell-specific promoter Myo15 , AAV1-hOTOF. To develop a clinical application of AAV1-hOTOF gene therapy, we evaluated its efficacy and safety in animal models using pharmacodynamics, behavior, and histopathology. AAV1-hOTOF inner ear delivery significantly improved hearing in Otof -/- mice without affecting normal hearing in wild-type mice. AAV1 was predominately distributed to the cochlea, although it was detected in other organs such as the CNS and the liver, and no obvious toxic effects of AAV1-hOTOF were observed in mice. To further evaluate the safety of Myo15 promoter-driven AAV1-transgene, AAV1-GFP was delivered into the inner ear of Macaca fascicularis via the round window membrane. AAV1-GFP transduced 60%-94% of the inner hair cells along the cochlear turns. AAV1-GFP was detected in isolated organs and no significant adverse effects were detected. These results suggest that AAV1-hOTOF is well tolerated and effective in animals, providing critical support for its clinical translation., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, therapy resistance, and poor prognosis in many cancers. Although both DUBs are involved in the regulation of similar genes and signaling pathways, such as histone H2B monoubiquitination (H2Bub1), c-Myc, FOXP3, and p53, the interdependence of USP22 and USP7 expression has never been described. In the study, we found that targeting USP7 via either siRNA-mediated knockdown or pharmaceutical inhibitors dramatically upregulates USP22 in cancer cells. Mechanistically, the elevated USP22 occurs through a transcriptional pathway, possibly due to desuppression of the transcriptional activity of SP1 via promoting its degradation upon USP7 inhibition. Importantly, increased USP22 expression leads to significant activation of downstream signal pathways including H2Bub1 and c-Myc, which may potentially enhance cancer malignancy and counteract the anticancer efficacy of USP7 inhibition. Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of p53 tumor suppressor signaling pathway. In addition, USP22-Ko cancer cells are more sensitive to a combination of cisplatin and USP7 inhibitor. USP7 inhibitor treatment further suppresses in vivo angiogenesis and tumor growth and induced more apoptosis in USP22-Ko cancer xenografts. Taken together, our findings demonstrate that USP7 inhibition can dramatically upregulate USP22 in cancer cells; and targeting USP7 and USP22 may represent a more effective approach for targeted cancer therapy, which warrants further study. Video Abstract., (© 2023. The Author(s).)

Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an accurate method for quantifying gene expression levels. Choosing appropriate reference genes to normalize the data is essential for reducing errors. Gelsemium elegans is a highly poisonous but important medicinal plant used for analgesic and anti-swelling purposes. Gelsenicine is one of the vital active ingredients, and its biosynthesis pathway remains to be determined. In this study, G. elegans leaf tissue with and without the application of one of four hormones (SA, MeJA, ETH, and ABA) known to affect gelsenicine synthesis, was analyzed using ten candidate reference genes. The gene stability was evaluated using GeNorm, NormFinder, BestKeeper, ∆CT, and RefFinder. The results showed that the optimal stable reference genes varied among the different treatments and that at least two reference genes were required for accurate quantification. The expression patterns of 15 genes related to the gelsenicine upstream biosynthesis pathway was determined by RT-qPCR using the relevant reference genes identified. Three genes 8-HGO , LAMT , and STR , were found to have a strong correlation with the amount of gelsenicine measured in the different samples. This research is the first study to examine the reference genes of G. elegans under different hormone treatments and will be useful for future molecular analyses of this medically important plant species.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer with major challenges in both prevention and therapy. Metformin, adenosine monophosphate-activated protein kinase (AMPK) activator, has been suggested to reduce the incidence of HCC when used for patients with diabetes in preclinical and clinical studies. However, the possible effects of metformin and their mechanisms of action in non-diabetic HCC have not been adequately investigated., Methods: Fah -/-  mice were used to construct a liver-injury-induced non-diabetic HCC model for exploring hepatocarcinogenesis and therapeutic potential of metformin. Changes in relevant tumour and biochemical indicators were measured. Bulk and single-cell RNA-sequencing analyses were performed to validate the crucial role of proinflammatory/pro-tumour CD8 + T cells. In vitro and in vivo experiments were performed to confirm Cyp26a1-related antitumour mechanisms of metformin., Results: RNA-sequencing analysis showed that chronic liver injury led to significant changes in AMPK-, glucose- and retinol metabolism-related pathways in Fah -/- mice. Metformin prevented the formation of non-diabetic HCC in Fah -/- mice with chronic liver injury. Cyp26a1 ddexpression in hepatocytes was significantly suppressed after metformin treatment. Moreover, downregulation of Cyp26a1 occurred in conjunction with increased levels of all-trans-retinoic acid (atRA), which is involved in the activation of metformin-suppressed hepatocarcinogenesis in Fah-/- mice. In contrast, both CD8 +  T-cell infiltration and proinflammatory/pro-tumour cytokines in the liver were significantly upregulated in Fah -/- mice during chronic liver injury, which was notably reversed by either metformin or atRA treatment. Regarding mechanisms, metformin regulated the decrease in Cyp26a1 enzyme expression and increased atRA expression via the AMPK/STAT3/Gadd45β/JNK/c-Jun pathway., Conclusions: Metformin inhibits non-diabetic HCC by upregulating atRA levels and downregulating CD8 + T cells. This is the first reporting that the traditional drug metformin regulates the metabolite atRA via the Cyp26a1-involved pathway. The present study provides a potential application of metformin and atRA in non-diabetic HCC., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Gastrointestinal nematodes (GINs) have seriously affected the production and earnings of animal husbandry in various countries, while some species of GINs infect humans. At present, little is known about the species and prevalence of GINs in Qinghai-Tibetan Plateau (QTP)., Methods: In this study, 528 fresh faecal samples were collected from typical areas in different altitudes with seven species of livestock in Qinghai, Tibet, Gansu and Yunnan Provinces. ITS-2 rRNA gene of nematodes was employed to detect by PCR and sequencing analysis. Phylogenetic analysis of related sequences was performed using MEGA 6.0 software., Results: The overall prevalence of GINs was 80.3% with 20 species of GINs detected, while Teladorsagia circumcincta was the dominant one, and four of which were zoonotic species such as Trichostrongylus colubriformis, Trichostrongylus axei, Trichostrongylus vitrinus and Oesophagostomum stephanostomum., Conclusion: The study provided panoptic information on the prevalence and species diversity of GINs in QTP area, which is useful and valuable for reference of measure formulation in livestock husbandry and public health concerns. The parasites of T. circumcincta, Cylicocyclus nassatus, Strongylus edentatus, Cylicostephanus longibursatus, Telephlebia brevicauda, Cyathostomum catinatum, Mecistocirrus digitatus, Cooperia punctata, Cylicodontophorus bicoronatus, Nematodirus oiratianus and Oesophagostomum asperum were firstly reported the presence in QTP area. The study also showed that horse could be infected by T. circumcincta, goat could be infected by C. nassatus, cattle could be infected by S. edentatus and C. bicoronatus,and O. stephanostomum could infect yak, cattle and Mongolian sheep in worldwide. Nevertheless, more investigations are needed, such as microscopic examination, to accurately determine the species in the region., (© 2021 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Kupffer cells, the liver tissue resident macrophages, are critical in the detection and clearance of cancer cells. However, the molecular mechanisms underlying their detection and phagocytosis of cancer cells are still unclear. Using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that the cell-surface transmembrane protein ERMAP expressed on various cancer cells signaled to activate phagocytosis in Kupffer cells and to control of liver metastasis. ERMAP interacted with β-galactoside binding lectin galectin-9 expressed on the surface of Kupffer cells in a manner dependent on glycosylation. Galectin-9 formed a bridging complex with ERMAP and the transmembrane receptor dectin-2, expressed on Kupffer cells, to induce the detection and phagocytosis of cancer cells by Kupffer cells. Patients with low expression of ERMAP on tumors had more liver metastases. Thus, our study identified the ERMAP-galectin-9-dectin-2 axis as an 'eat me' signal for Kupffer cells., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Circular RNAs (circRNAs), a type of endogenous noncoding RNA (ncRNA), exert vital roles in leukemia progression and are promising prognostic factors. Here, we report a novel circRNA, circSLC25A13 (hsa&#95;circ&#95;0081188), which was increased in acute myeloid leukemia (AML) patients with poor overall survival (OS) comparing to patients with good prognosis. Knockdown of circSLC25A13 in AML cells inhibited proliferation and increased cell apoptosis in vitro and in vivo. Enhanced circSLC25A13 expression promoted the survival of AML cells. Mechanistically, circSLC25A13 played as a microRNA sponge of miR-616-3p, which inhibited the expression of adenylate cyclase 2 (ADCY2). Downregulation of miR-616-3p and overexpression of ADCY2 partially rescued circSLC25A13 deficient induced cell growth arrest. In summary, through competitive absorption of miR-616-3p and thereby upregulating ADCY2 expression, circSLC25A13 promoted AML progression. Moreover, circSLC25A13 may represent a potential novel biomarker for the prognosis of AML and offer a potential therapeutic target for AML treatment., (© 2023 Wiley Periodicals LLC.)

Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by iron overload and ROS accumulation, ferroptosis is modulated by various cellular metabolic and signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, the DHODH-CoQH2 system and the sex hormones suppress ferroptosis. Mitochondrial iron metabolism regulates ferroptosis and mitochondria also undergo a morphological change during ferroptosis, these changes include increased membrane density and reduced mitochondrial cristae. Moreover, mitochondrial energy metabolism changes during ferroptosis, the increased oxidative phosphorylation and ATP production rates lead to a decrease in the glycolysis rate. In addition, excessive oxidative stress induces irreversible damage to mitochondria, diminishing organelle integrity. ROS production, mitochondrial membrane potential, mitochondrial fusion and fission, and mitophagy also function in ferroptosis. Notably, some ferroptosis inhibitors target mitochondria. Ferroptosis is a major mechanism for cell death associated with the progression of cancer. Metastasis-prone or metastatic cancer cells are more susceptible to ferroptosis. Inducing ferroptosis in tumor cells shows very promising potential for treating drug-resistant cancers. In this review, we present a brief retrospect of the discovery and the characteristics of ferroptosis, then we discuss the regulation of ferroptosis and highlight the unique role played by mitochondria in the ferroptosis of cancer cells. Furthermore, we explain how ferroptosis functions as a double-edged sword as well as novel therapies aimed at selectively manipulating cell death for cancer eradication., (© 2023. The Author(s).)

Glutamine metabolic reprogramming in acute myeloid leukaemia (AML) cells contributes to the decreased sensitivity to antileukemic drugs. Leukaemic cells, but not their myeloid counterparts, largely depend on glutamine. Glutamate dehydrogenase 1 (GDH1) is a regulation enzyme in glutaminolysis. However, its role in AML remains unknown. Here, we reported that GDH1 was highly expressed in AML: high GDH1 was one of the independent negative prognostic factors in AML cohort. The dependence of leukaemic cells on GDH1 was proved both in vitro and in vivo. High GDH1 promoted cell proliferation and reduced survival time of leukaemic mice. Targeting GDH1 eliminated the blast cells and delayed AML progression. Mechanistically, GDH1 knockdown inhibited glutamine uptake by downregulating SLC1A5. Moreover, GDH1 invalidation also inhibited SLC3A2 and abrogated the cystine-glutamate antiporter system Xc - . The reduced cystine and glutamine disrupted the synthesis of glutathione (GSH) and led to the dysfunction of glutathione peroxidase-4 (GPX4), which maintains the lipid peroxidation homeostasis by using GSH as a co-factor. Collectively, triggering ferroptosis in AML cells in a GSH depletion manner, GDH1 inhibition was synthetically lethal with the chemotherapy drug cytarabine. Ferroptosis induced by inhibiting GDH1 provides an actionable therapeutic opportunity and a unique target for synthetic lethality to facilitate the elimination of malignant AML cells., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML., (© 2022. Higher Education Press.)

Multifunctional nanoaggregates are widely used in cancer phototheranostics. However, it is challenging to construct their multifunctionality with a single component, and deliver them rapidly and efficiently without complex modifications. Herein, a NIR-absorbing small molecule named TBT-2(TP-DPA) is designed and certify its theranostic potentials. Then, their nanoaggregates, which are simply encapsulated by DSPE-PEG, demonstrate a photothermal efficiency of 51% while keeping a high photoluminescence quantum yield in the NIR region. Moreover, the nanoaggregates can be excited and delivered by an 808 nm pulse laser to solid tumors within only 40 min. The delivery efficiency and theranostic efficacy are better than that of the traditional enhanced permeability and retention (EPR) effect (generally longer than 24 hours). This platform is first termed as the photoinduced thermoacoustic (PTA) process, and confirm its application requires both NIR-responsive materials and pulse laser irradiation. This study not only inspires the design of multifunctional nanoaggregates, but also offers a feasible approach to their fast delivery. The platform reported here provides a promising prospect to boost the development of multifunctional theranostic drugs and maximize the efficacy of used medicines for their clinical applications., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtypes of lymphoma. Clinical biomarkers are still required for DLBCL patients to identify high-risk patients. Therefore, we developed and validated the platelet-to-albumin (PTA) ratio as a predictor for DLBCL patients., Methods: A group of 749 patients was randomly divided into a training set (600 patients) and an internal validation set (149 cases). The independent cohort of 110 patients was enrolled from the other hospital as an external validation set. Penalized smoothing spline (PS) Cox regression models were used to explore the non-linear relationship between the PTA ratio and overall survival (OS) as well as progression-free survival (PFS), respectively., Results: A U-shaped relation between the PTA ratio and PFS was identified in the training set. The PTA ratio less than 2.7 or greater than 8.6 was associated with the shorter PFS. Additionally, the PTA ratio had an additional prognostic value to the well-established predictors. What's more, the U-shaped pattern of the PTA ratio and PFS was respectively validated in the two validation sets., Discussion: A U-shaped association between the PTA ratio and PFS was found in patients with DLBCLs. The PTA ratio can be used as a biomarker, and may suggest abnormalities of both host nutritional aspect and systemic inflammation in DLBCL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Li, Yu, Zhang, Mao, Chen, Hu, Zhou, Xie, Tong and Jin.)

Introduction: Chronic subjective tinnitus has become an increasingly serious hazard that affects the health-related quality of life for millions of people. Due to the lack of curative treatment strategies, this study aims to introduce a novel acoustic therapy named the modified tinnitus relieving sound (MTRS) for tinnitus and to evaluate the efficacy of MTRS in comparison with unmodified music (UM) which served as a control., Methods and Analysis: A randomized, double-blinded, controlled, clinical trial will be carried out. Sixty-eight patients with subjective tinnitus will be recruited and randomly allocated into two groups in 1:1 ratio. The primary outcome is Tinnitus Handicapped Inventory (THI); the secondary outcomes are the Hospital Anxiety and Distress Scale (HADS; HADS subscales for Anxiety (HADS-A) and Depression (HADS-D)), Athens Insomnia Scale (AIS), the visual analog scale (VAS) for tinnitus, and tinnitus loudness matched by sensation level (SL). Assessment will be performed at baseline and at 1, 3, 9, and 12 months post-randomization. The sound stimulus will be persistent until 9 months after randomization, and be interdictory in the last three months. Data collected during the intervention process will be analyzed and compared to baseline., Ethics and Dissemination: This trial received ethical approval from the Institutional Review Board (IRB) of Eye & ENT Hospital of Fudan University (No. 2017048). The study results will be disseminated via academic journals and conferences., Funding: This study is supported by the Shanghai Shenkang Development Program (SHDC12019119), the Excellent Doctors-Excellent Clinical Researchers Program (SYB202008), the Shanghai Rising-Star Program (23QC1401200), the Shanghai Rising Stars of Medical Talent Youth Development Program (2021-99), the National Natural Science Foundation of China (81800912), and the National Natural Science Foundation of Shanghai (21ZR1411800)., Trial Registration: ClinicalTrials.gov NCT04026932. Registered on 18 July 2019., (© 2023. The Author(s).)

This study sought to explore relationships between video gaming time and cognitive functioning in children and adolescents to provide a scientific reference for a reasonable time range of game use. A total of 649 participants aged 6-18 years were recruited through an online survey using convenience sampling. We used a combination of multiple linear regression models, smoothing splines, piecewise linear regression models, and log-likelihood ratio tests to comprehensively analyze the linear and nonlinear relationships between video gaming time and cognitive functions. Neurocognitive functioning was assessed using the digit symbol test, spatial span back test, Stroop task, and Wisconsin card sorting test. Facial and voice emotion recognition tests were used to evaluate social cognitive functioning. Video gaming time had a saturation effect on improving correct answers to the digit symbol test, which means that performance did not increase with increasing video gaming time when the video gaming duration reached 20 h/week (adjusted β = -0.58; 95% CI: -1.22, 0.05). Furthermore, both the relationship between video gaming time and the Wisconsin Card Sorting Test and the facial emotion recognition score showed a threshold effect. The completed categories of the Wisconsin Card Sorting Test began to decline after 17 h/week of playtime, and a decline in facial emotion recognition occurred after playing video games for over 20 h/week. These results suggest that children and adolescents should restrict their video gaming time to within a certain range, which could help reduce the negative effects of video games and retain their positive effects., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, but there is a deficiency of early diagnosis biomarkers and therapeutic targets. Drug resistance accounts for most HCC-related deaths, yet the mechanisms underlying drug resistance remain poorly understood., Methods: Expression of Frizzled-10 (FZD10) in liver cancer stem cells (CSCs) was identified by means of RNA sequencing and validated by means of real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of FZD10 on liver CSC expansion and lenvatinib resistance. RNA sequencing, RNA binding protein immunoprecipitation, and luciferase report assays were applied to explore the mechanism underlying FZD10-mediated liver CSCs expansion and lenvatinib resistance., Results: Activation of FZD10 in liver CSCs was mediated by METTL3-dependent N6-methyladenosine methylation of FZD10 messenger RNA. Functional studies revealed that FZD10 promotes self-renewal, tumorigenicity, and metastasis of liver CSCs via activating β-catenin and YAP1. The FZD10-β-catenin/YAP1 axis is activated in liver CSCs and predicts poor prognosis. Moreover, FZD10-β-catenin/c-Jun axis transcriptionally activates METTL3 expression, forming a positive feedback loop. Importantly, the FZD10/β-catenin/c-Jun/MEK/ERK axis determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort, patient-derived tumor organoids, and patient-derived xenografts further suggest that FZD10 might predict lenvatinib clinical benefit in patients with HCC. Furthermore, treatment of lenvatinib-resistant HCC with adeno-associated virus targeting FZD10 or a β-catenin inhibitor restored lenvatinib response., Conclusions: Elevated FZD10 expression promotes expansion of liver CSCs and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Identifying therapeutic targets and prognostic biomarkers significantly contributes to individualized treatment of acute myeloid leukemia (AML). Dihydropyrimidinase-like 2 (DPYSL2) expression was decreased in homoharringtonine (HHT)-resistant AML cells, which were established by our group. DPYSL2 plays an important role in axon growth and has oncogene effect in glioblastoma. However, little research has been conducted to investigate the function of DPYSL2 in AML pathogenesis., Methods: Auto-docking was used to reveal the targeting relationship between HHT and DPYSL2. Overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were used to evaluate the prognostic impact of DPYSL2 for AML. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. In vivo growth and survival were assessed using a xenotransplantation mice model. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML and were confirmed by Western blot., Results: We found DPYSL2 was the target of HHT. Next, we found AML cell lines and patients had higher DPYSL2 expression levels than the normal samples. Further multivariate analysis demonstrated that high DPYSL2 expression was an independent poor prognostic factor for OS, EFS, and RFS in AML. Inhibition of DPYSL2 expression suppressed cell growth, induced apoptosis in AML cell lines, and prolonged the survival of AML xenograft NCG mice. Through RNA-seq analysis from TCGA and our data, the JAK2/STAT3/STAT5-PI3K P85/AKT/GSK3b axis was thought to be the critical pathway in regulating DPYSL2 in AML development., Conclusions: We first time confirmed that DPYSL2 was a target of HHT and played an oncogene role in AML by regulating JAK/STAT signaling pathway. Therefore, DPYSL2 could serve as a novel prognostic marker and therapeutic target for AML treatment., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)