Cost-effectiveness of Pembrolizumab in Combination with Chemotherapy as Neoadjuvant Treatment and Continued as a Single Agent Adjuvant Treatment for High-Risk Early-Stage Triple-Negative Breast Cancer in Hong Kong.

INTRODUCTION: The phase III randomized KEYNOTE-522 trial demonstrated that pembrolizumab in combination with chemotherapy as neoadjuvant treatment followed by adjuvant pembrolizumab (pembrolizumab + chemotherapy) provided significant improvements in event-free survival (EFS) and overall survival (OS) for patients with high-risk early-stage triple-negative breast cancer (eTNBC). The objective was to assess the cost-effectiveness of pembrolizumab + chemotherapy compared to neoadjuvant chemotherapy alone (chemotherapy) in patients with high-risk eTNBC from a Hong Kong third-party payer perspective. METHODS: A multistate transition model with four health states (event-free), locoregional recurrence, distant metastases, and death) was developed to assess the lifetime medical costs and health outcomes (3% annual discount), along with incremental cost-effectiveness ratios (ICERs) using efficacy and safety data from the KEYNOTE-522 trial. The health state utilities were derived from KEYNOTE-522 Euro-QoL-five-dimension five-level questionnaire (EQ-5D-5L) data. Costs were expressed in 2022 Hong Kong dollars (HKD). Scenario and sensitivity analyses were performed to assess the robustness of results. RESULTS: Over a 32-year time horizon, base case results showed that pembrolizumab + chemotherapy was associated with a 3.42 year longer EFS and expected gains of 3.05 life years (LYs) and 2.45 quality-adjusted life years (QALYs) compared to chemotherapy. The resultant ICERs were HKD 135,200 per QALY gained and HKD 108,463 per LY gained, which were lower than the World Health Organization (WHO) cost-effectiveness threshold of three times gross domestic product (GDP) per capita for Hong Kong of HKD 1,171,308 per QALY. The one-way sensitivity analyses (OWSA) and probabilistic sensitivity analysis (PSA) showed the results were robust across various inputs and alternative scenarios. CONCLUSION: On the basis of the analysis conducted for a 56-year-old cohort with high-risk eTNBC and assumptions in the model, pembrolizumab + chemotherapy represents a cost-effective proposition (as the ICER is approximately 35% of the GDP per capita in Hong Kong) for patients with high-risk eTNBC in Hong Kong.

The manuscript outlines the methods and results of a health economic model to estimate the cost-effectiveness of pembrolizumab + chemotherapy compared to neoadjuvant chemotherapy alone (chemotherapy) in patients with high-risk early-stage triple-negative breast cancer in the Hong Kong setting. The results of the manuscript show that the combination of pembrolizumab and chemotherapy provides an additional 3.05 life years and 2.45 quality-adjusted life years. Despite the potential drawbacks of employing gross domestic product (GDP) as a proxy for cost-effectiveness thresholds, the incremental cost-effectiveness ratio was less than three times GDP per capita in Hong Kong. Therefore, the new intervention was cost-effective. However, like any similar study, the results rely substantially on extrapolation of trial outcomes and thus sensitivity analysis has also been performed to handle the uncertainty associated with results. The one-way sensitivity analyses and probabilistic sensitivity analysis showed the results were robust. The manuscript provides economic evidence of the new intervention and provides new clinical insights.

ATF3 is involved in rSjP40-mediated inhibition of HSCs activation in Schistosoma japonicum-infected mice.

Schistosomiasis is a parasitic disease characterized by liver fibrosis, a process driven by the activation of hepatic stellate cells (HSCs) and subsequent collagen production. Previous studies from our laboratory have demonstrated the ability of Schistosoma japonicum protein P40 (SjP40) to inhibit HSCs activation and exert an antifibrotic effect. In this study, we aimed to elucidate the molecular mechanism underlying the inhibitory effect of recombinant SjP40 (rSjP40) on HSCs activation. Using a cell model in which rSjP40 inhibited LX-2 cell activation, we performed RNA-seq analyses and identified ATF3 as the most significantly altered gene. Further investigation revealed that rSjP40 inhibited HSCs activation partly by suppressing ATF3 activation. Knockdown of ATF3 in mouse liver significantly alleviated S. japonicum-induced liver fibrosis. Moreover, our results indicate that ATF3 is a direct target of microRNA-494-3p, a microRNA associated with anti-liver fibrosis effects. rSjP40 was found to downregulate ATF3 expression by upregulating microRNA-494-3p in LX-2 cells. This downregulation led to the inhibition of the expression of liver fibrosis proteins α-SMA and COL1A1, ultimately alleviating liver fibrosis caused by S. japonicum.

The roles and potential mechanisms of plant polysaccharides in liver diseases: a review.

Plant polysaccharides (PP) demonstrate a diverse array of biological and pharmacological properties. This comprehensive review aims to compile and present the multifaceted roles and underlying mechanisms of plant polysaccharides in various liver diseases. These diseases include non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), fibrosis, drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). This study aims to elucidate the intricate mechanisms and therapeutic potential of plant polysaccharides, shedding light on their significance and potential applications in the management and potential prevention of these liver conditions. An exhaustive literature search was conducted for this study, utilizing prominent databases such as PubMed, Web of Science, and CNKI. The search criteria focused on the formula "(plant polysaccharides liver disease) NOT (review)" was employed to ensure the inclusion of original research articles up to the year 2023. Relevant literature was extracted and analyzed from these databases. Plant polysaccharides exhibit promising pharmacological properties, particularly in the regulation of glucose and lipid metabolism and their anti-inflammatory and immunomodulatory effects. The ongoing progress of studies on the molecular mechanisms associated with polysaccharides will offer novel therapeutic strategies for the treatment of chronic liver diseases (CLDs).

Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway.

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPARα. Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP-TEAD complex. Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

The YY1-CPT1C signaling axis modulates the proliferation and metabolism of pancreatic tumor cells under hypoxia.

Carnitine palmitoyltransferase 1C (CPT1C) is an enzyme that regulates tumor cell proliferation and metabolism by modulating mitochondrial function and lipid metabolism. Hypoxia, commonly observed in solid tumors, promotes the proliferation and progression of pancreatic cancer by regulating the metabolic reprogramming of tumor cells. So far, the metabolic regulation of hypoxic tumor cells by CPT1C and the upstream mechanisms of CPT1C remain poorly understood. Yin Yang 1 (YY1) is a crucial oncogene for pancreatic tumorigenesis and acts as a transcription factor that is involved in multiple metabolic processes. This study aimed to elucidate the relationship between YY1 and CPT1C under hypoxic conditions and explore their roles in hypoxia-induced proliferation and metabolic alterations of tumor cells. The results showed enhancements in the proliferation and metabolism of PANC-1 cells under hypoxia, as evidenced by increased cell growth, cellular ATP levels, up-regulation of mitochondrial membrane potential, and decreased lipid content. Interestingly, knockdown of YY1 or CPT1C inhibited hypoxia-induced rapid cell proliferation and vigorous cell metabolism. Importantly, for the first time, we reported that YY1 directly activated the transcription of CPT1C and clarified that CPT1C was a novel target gene of YY1. Moreover, the YY1 and CPT1C were found to synergistically regulate the proliferation and metabolism of hypoxic cells through transfection with YY1 siRNA to CRISPR/Cas9-CPT1C knockout PANC-1 cells. Taken together, these results indicated that the YY1-CPT1C axis could be a new target for the intervention of pancreatic cancer proliferation and metabolism.

Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes.

BACKGROUND: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. METHODS: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. RESULTS: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. CONCLUSIONS: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

Development and Validation of an Evidence-Based Home Pursed Lip Breathing Protocol for Improving Health Outcomes in Patients With Chronic Obstructive Pulmonary Disease.

AIM: To develop and validate an evidence-based home pursed lip breathing (PLB) intervention protocol for improving related health outcomes (e.g., dyspnea and exercise capability) in patients with chronic obstructive pulmonary disease (COPD) and to present a detailed intervention development process. METHODS: This home PLB intervention protocol employed phase one of the Medical Research Council (MRC) Framework for Developing and Evaluating Complex Interventions to guide the development process of the PLB intervention. We searched for research evidence on 5 July 2023 from several databases, including PubMed, Embase (via Ovid), Cochrane Library, Google Scholar and China Biology Medicine Disk (CBM). Using the content validity index, a panel of experts assessed the appropriateness of the PLB protocol. RESULTS: We developed the preliminary home PLB intervention protocol on the basis of several underlying rationales, which encompass the extension of expiration time, enhancement of respiratory muscle strength, augmentation of tidal volume and integration of the most reliable research evidence obtained from four systematic reviews, five RCTs, five clinical trials, and 10 recommendations. We structured the PLB intervention with a designated time ratio of inspiration to expiration, set at 1:2. Additionally, this study recommends that the training parameters of the PLB intervention were as follows: three sessions per day, each lasting for 10 min, over 8 weeks. Individualised PLB training intensity adjusted the inhalation component according to each participant's tolerance level while emphasising the exhalation phase to ensure the complete expulsion of air from the lungs. The home PLB intervention protocol established strong content validity through consensus, which was reached among all panel experts. The item-level and scale-level content validity indices (CVIs) reached a maximum score of 1.0, indicating a high level of agreement and credibility in the protocol's content as evaluated by the expert panel. CONCLUSION: An optimal evidence-based home PLB protocol has been adapted and developed to manage health-related outcomes of patients with COPD. The protocol is transparent and fully supported by relevant mechanisms, concrete evidence, recommendations and experts' consensus. IMPLICATIONS FOR PRACTICE: In this study, we consulted patients with COPD about the 'Prepared Conditions Before PLB Practice', to ensure appropriate measures to prevent patients with COPD from potential risks. In addition, patients with COPD also contributed to the PLB exercise frequency distribution.

Self-Healing and Recyclable Polyurethane/Nanocellulose Elastomer Based on the Diels-Alder Reaction.

With the background of the fossil fuel energy crisis, the development of self-healing and recyclable polymer materials has become a research hotspot. In this work, a kind of cross-linking agent with pendent furan groups was first prepared and then used to produce the Polyurethane elastomer based on Diels-Alder chemistry (EPU-DA). In addition, in order to further enhance the mechanical properties of the elastomer, cellulose nanofibers (CNFs) were added into the Polyurethane system to prepare a series of composites with various contents of CNF (wt% = 0.1~0.7). Herein, the FTIR and DSC were used to confirm structure and thermal reversible character. The tensile test also indicated that the addition of CNF increased the mechanical properties compared to the pure Polyurethane elastomer. Due to their reversible DA covalent bonds, the elastomer and composites were recycled under high-temperature conditions, which extends Polyurethane elastomers' practical applications. Moreover, damaged coating can also be repaired, endowing this Polyurethane material with good potential for application in the field of metal protection.

ß-catenin mediates endodermal commitment of human ES cells via distinct transactivation functions.

BACKGROUND: ß-catenin, acting as the core effector of canonical Wnt signaling pathway, plays a pivotal role in controlling lineage commitment and the formation of definitive endoderm (DE) during early embryonic development. Despite extensive studies using various animal and cell models, the ß-catenin-centered regulatory mechanisms underlying DE formation remain incompletely understood, partly due to the rapid and complex cell fate transitions during early differentiation. RESULTS: In this study, we generated new CTNNB1-/- human ES cells (hESCs) using CRISPR-based insertional gene disruption approach and systematically rescued the DE defect in these cells by introducing various truncated or mutant forms of ß-catenin. Our analysis showed that a truncated ß-catenin lacking both N- and C-terminal domains (ΔN148C) could robustly rescue the DE formation, whereas hyperactive ß-catenin mutants with S33Y mutation or N-terminal deletion (ΔN90) had limited ability to induce DE lineage. Notably, the ΔN148C mutant exhibited significant nuclear translocation that was positively correlated with successful DE rescue. Transcriptomic analysis further uncovered that two weak ß-catenin mutants lacking the C-terminal transactivation domain (CTD) activated primitive streak (PS) genes, whereas the hyperactive ß-catenin mutants activated mesoderm genes. CONCLUSION: Our study uncovered an unconventional regulatory function of ß-catenin through weak transactivation, indicating that the levels of ß-catenin activity determine the lineage bifurcation from mesendoderm into endoderm and mesoderm.

Progression of m6A in the tumor microenvironment: hypoxia, immune and metabolic reprogramming.

Recently, N6-methyladenosine (m6A) has aroused widespread discussion in the scientific community as a mode of RNA modification. m6A comprises writers, erasers, and readers, which regulates RNA production, nuclear export, and translation and is very important for human health. A large number of studies have found that the regulation of m6A is closely related to the occurrence and invasion of tumors, while the homeostasis and function of the tumor microenvironment (TME) determine the occurrence and development of tumors to some extent. TME is composed of a variety of immune cells (T cells, B cells, etc.) and nonimmune cells (tumor-associated mesenchymal stem cells (TA-MSCs), cancer-associated fibroblasts (CAFs), etc.). Current studies suggest that m6A is involved in regulating the function of various cells in the TME, thereby affecting tumor progression. In this manuscript, we present the composition of m6A and TME, the relationship between m6A methylation and characteristic changes in TME, the role of m6A methylation in TME, and potential therapeutic strategies to provide new perspectives for better treatment of tumors in clinical work.

Spatiotemporal evolution and decoupling effects of sustainable water resources utilization in the Yellow River Basin: Based on three-dimensional water ecological footprint.

Clarifying the spatiotemporal evolution of sustainable water resources utilization (SWU) and its decoupling effects from economic growth (EG) is essential for the effective management of water ecosystems and sustainable development of basins. However, the traditional Ecological Footprint model limits the ability to compare SWU within a basin, and existing studies need to pay more attention to the importance of water renewability in quantifying SWU. Based on the capital flow and capital stock perspectives, this study constructed an evaluation method for SWU and its decoupling effect from EG by combining the three-dimensional Water Ecological Footprint (WEF), sustainable reclassification, and the Tapio model, and explored different types of SWU enhancement strategies. The results indicate that: (1) From 2010 to 2022, the SWU of the Yellow River Basin (YRB) shows a decreasing and then increasing trend and is generally in water ecological deficit, with a lower SWU in the middle and lower reaches. Overall, the per capita WEFsize decreased by 0.73% per year, while the WEFdepth increased by 0.26% per year, the pressure and stress on the SWU of the YRB are still significant. (2) Agricultural freshwater use and domestic greywater discharge dominate the WEF of the basin, and the problem of inversion of the water use structure with the industrial structure is evident. (3) Spatial differentiation within the basin is apparent, and SWU shows a spatial distribution of western strength and eastern weakness, with significant consumption of water capital stock due to insufficient water capital flow as the main reason. (4) Topio decoupling analysis shows that WEF and EG are mainly strongly decoupled, with WEF lagging behind EG; the decoupling relationship between SWU and EG evolves from END-SD-WD, reduces the consumption of water capital stock and increasing water capital flow is a reasonable way to realise its stable strong decoupling. This study is essential for SWU studies of large river basins in arid and semi-arid regions. It provides insights into the sustainable management and rational allocation of water resources in the YRB and other similar basins worldwide.

Benefits of exercise on cognitive impairment in alcohol use disorder following alcohol withdrawal.

Although most cognitive impairments induced by prolonged alcohol consumption tend to improve within the initial months of abstinence, there is evidence suggesting certain cognitive deficits may persist. This study aimed to investigate the impact of aerobic exercise on learning and memory in alcohol use disorder (AUD) mice following a period of abstinence from alcohol. We also sought to assess the levels of monoamine neurotransmitters in the hippocampus. To this end, we established an AUD mouse model through a two-bottle choice (sucrose fading mode and normal mode) and chronic intermittent alcohol vapor (combined with intraperitoneal injection) and randomly allocated mice into exercise groups to undergo treadmill training. Learning and memory abilities were assessed through the Morris water maze test and spontaneous activity was evaluated using the open field test. The levels of dopamine, norepinephrine, serotonin, and brain-derived neurotrophic factor in the hippocampus were quantified using enzyme-linked immunoassay (ELISA) kits. The findings reveal that after cessation of alcohol consumption, learning and memory abilities in AUD mice did not completely return to normal levels. The observed enhancement of cognitive functions in AUD mice through aerobic exercise may be attributed to restoring levels of monoamine neurotransmitters in the hippocampus, boosting brain-derived neurotrophic factor (BDNF) concentrations, and facilitating an increase in hippocampal mass. These results offer empirical evidence to support aerobic exercise as a viable therapeutic strategy to alleviate cognitive deficits associated with AUD.

Incidence, clinical classification and risk factors of cyclosporin A-induced liver injury in allogeneic haematopoietic stem cell transplant recipients.

AIMS: There is limited real-world data on cyclosporin A (CsA)-induced liver injury (CILI). This study aims to investigate the incidence, clinical classification and risk factors of CILI, thereby providing evidence to inform the treatment of CILI. METHODS: Inpatients receiving haematopoietic stem cell transplantation (HSCT) and treated with CsA were included. Patient information was collected to assess suspicious CILI by the Roussel Uclaf causality assessment method (RUCAM) scale. We evaluated the pattern and severity of CILI. The independent risk factors of CILI were identified by multivariable logistic regression. RESULTS: A total of 216 allogeneic HSCT (allo-HSCT) recipients were included in this study. The incidence of CILI was 15.3% (95% confidence interval [CI]: 10.4%-20.1%). Among these cases, 84.8% displayed a hepatocellular pattern, and 90.9% of CILI was of mild severity. Baseline alanine aminotransferase (ALT) level (OR = 1.030, 95% CI: 1.008-1.053, P = .008) and trough concentration level of CsA (OR = 1.007, 95% CI: 1.002-1.012, P = .009) were identified as independent risk factors for CILI. CONCLUSIONS: The incidence of CILI in allo-HSCT recipients is notably high. Recipients with elevated baseline ALT levels and higher exposure to CsA are more susceptible to developing CILI.

Clinical Characteristics and Risk Factors for Infection and Death in Critically Ill Patients with Pulmonary Infection with Elizabethkingia Spp.

Purpose: Elizabethkingia spp. infections have recently increased, and they are difficult to treat because of intrinsic antimicrobial resistance. This study aimed to investigate the clinical characteristics of patients with pulmonary infection with Elizabethkingia spp. and reveal the risk factors for infection and death. Patients and Methods: In this retrospective case-control study, patients were divided into infection and control groups based on the bacterial identification results. Patients in the infection group were further divided into survival and death groups according to their hospital outcomes. Clinical characteristics between different groups were compared. We further analyzed antimicrobial susceptibility testing results of the isolated strains. Results: A total of the 316 patients were divided into infection (n = 79), 23 of whom died, and control (n = 237) groups. Multivariate logistic regression analysis showed that glucocorticoid consumption (OR: 2.35; 95% CI: 1.14-4.81; P = 0.02), endotracheal intubation (OR: 3.74; 95% CI: 1.62-8.64; P = 0.002), and colistin exposure (OR: 2.50; 95% CI: 1.01-6.29; P = 0.046) were significantly associated with pulmonary infection with Elizabethkingia spp. Advanced age (OR: 1.07, 95% CI: 1.00-1.15; P = 0.046), high acute physiology and chronic health evaluation (APACHE) II score (OR: 1.21; 95% CI: 1.01-1.45; P = 0.037), and low albumin level (OR: 0.73, 95% CI: 0.56-0.96; P = 0.025) were significantly associated with in-hospital mortality of infected patients. Elizabethkingia spp. was highly resistant to cephalosporins, carbapenems, macrolides, and aminoglycoside, and was sensitive to fluoroquinolones, minocycline, and co-trimoxazole in vitro. Conclusion: Glucocorticoid consumption, tracheal intubation, and colistin exposure were associated with pulmonary infection with Elizabethkingia spp. for critically ill patients. Patients with advanced age, high APACHE II score, and low albumin level had higher risk of death from infection.

AgriGAN: unpaired image dehazing via a cycle-consistent generative adversarial network for the agricultural plant phenotype.

Artificially extracted agricultural phenotype information exhibits high subjectivity and low accuracy, while the utilization of image extraction information is susceptible to interference from haze. Furthermore, the effectiveness of the agricultural image dehazing method used for extracting such information is limited due to unclear texture details and color representation in the images. To address these limitations, we propose AgriGAN (unpaired image dehazing via a cycle-consistent generative adversarial network) for enhancing the dehazing performance in agricultural plant phenotyping. The algorithm incorporates an atmospheric scattering model to improve the discriminator model and employs a whole-detail consistent discrimination approach to enhance discriminator efficiency, thereby accelerating convergence towards Nash equilibrium state within the adversarial network. Finally, by training with network adversarial loss + cycle consistent loss, clear images are obtained after dehazing process. Experimental evaluations and comparative analysis were conducted to assess this algorithm's performance, demonstrating improved accuracy in dehazing agricultural images while preserving detailed texture information and mitigating color deviation issues.

Rehmanniae Radix Preparata ameliorates behavioral deficits and hippocampal neurodevelopmental abnormalities in ADHD rat model.

Objectives: Abnormal hippocampal neurodevelopment, particularly in the dentate gyrus region, may be a key mechanism of attention-deficit/hyperactivity disorder (ADHD). In this study, we investigate the effect of the most commonly used Chinese herb for the treatment of ADHD, Rehmanniae Radix Preparata (RRP), on behavior and hippocampal neurodevelopment in spontaneously hypertensive rats (SHR). Methods: Behavior tests, including Morris water maze (MWM) test, open field test (OFT) and elevated plus maze (EPM) test were performed to assess the effect of RRP on hyperactive and impulsive behavior. Hippocampal neurodevelopment was characterized by transmission electron microscopy, immunofluorescence, Golgi staining and Nissl staining approaches. Regulatory proteins such as Trkb, CDK5, FGF2/FGFR1 were examined by Western blot analysis. Results: The results showed that RRP could effectively control the impulsive and spontaneous behavior and improve the spatial learning and memory ability. RRP significantly reduced neuronal loss and increased the number of hippocampal stem cells, and promoted synaptic plasticity. In addition, FGF/FGFR signaling was upregulated after RRP treatment. Conclusion: RRP can effectively reduce impulsive and spontaneous behavior and ameliorate hippocampal neurodevelopmental abnormalities in ADHD rat model.

Combining metabolomics and transcriptomics to analyze key response metabolites and molecular mechanisms of Aspergillus fumigatus under cadmium stress.

The co-cultivation of fungi with microalgae facilitates microalgae harvesting and enhances heavy metal adsorption. However, the mechanisms of fungal tolerance to cadmium (Cd) have not yet been studied in detail. In this study, functional groups of fungi were analyzed under Cd stress using Fourier transform infrared spectrometer (FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), and transmission electron microscope (TEM) to explore their morphology. Confocal laser scanning microscope (CLSM) was used to characterize the changes in the content of extracellular polysaccharides and proteins, and a decrease in the ratio of glutathione (GSH) to oxidized glutathione (GSSG) was monitored. The GSH and GSSG contents in mycelium were 7.4 and 7.9 times higher than that in the control, respectively. After 72 h of Cd treatment, the fungal extracellular polysaccharide and extracellular protein contents increased by 16 and 11.4 mg/g, respectively, compared to the control. This provided several functional groups for the complexation of Cd ions to enhance fungal Cd tolerance. The metabolomic and transcriptomic results revealed a total of 358 differential metabolites after 20, 48, and 72 h in the positive and negative ion modes, and the number of differential metabolites specific to each group was 104, 14, and 89, respectively. There were 927, 1167, and 1287 up-regulated genes, and 1301, 1480, and 1683 down-regulated genes at 20, 48, and 72 h, respectively. Energy metabolism, amino acid metabolism, and the ABC transport system are the key metabolic pathways for tolerance enhancement and heavy metal detoxification in fungi. The expression of S-cysteinosuccinic acid was significantly up-regulated after Cd stress and associated with enhanced fungal tolerance and resistance to Cd.

Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC.