Dessecting the Toxicological Profile of Polysorbate 80 (PS80): Comparative Analysis of Constituent Variability and Biological Impact Using a Zebrafish Model.

Polysorbate 80, commonly abbreviated as PS80, is a widely used pharmaceutical excipient renowned for its role as a solubilizer and stabilizer in drug formulations. Although PS80 is essential for various pharmaceutical applications, particularly in the formulation of injectable drugs, it has been implicated in a range of adverse reactions. However, due to the complexity of the composition of PS80, the differences in the types and contents of the constituents of PS80 from different manufacturers increase the probability or likelihood of their uneven quality. Addressing the complete spectrum of PS80's components is challenging; thus, most studies to date have examined PS80 as a singular entity. This approach, however, carries a degree of uncertainty, as it overlooks the unique composition and concentration of components within the PS80 used in experiments, which may not reflect the actual diversity in commercially available PS80 products. Recognizing the critical need to understand how PS80's composition influences biological effects and toxicity, our study aims to bridge this knowledge gap. By doing so, we can clarify how different PS80 compositions from various manufacturers might affect the quality of pharmaceutical formulations, and also guide excipient manufacturers toward producing higher-quality PS80. Such insights could further facilitate a more targeted application of PS80 in drug development. Building on our previous work, we isolated and prepared two key components of PS80-polyoxyethylene sorbitan monooleate (PSM) and polyoxyethylene isosorbide monooleate (PIM)-and conducted a systematic comparison. We evaluated the acute, hemolytic, and target organ toxicity of two different PS80 samples, as well as PSM and PIM, using a zebrafish model. Our research also delved into the potential mechanisms behind the observed toxicological effects, providing an in-depth understanding of PS80's impact on biological systems.The results show that PS80, PSM, and PIM resulted in developmental anomalies in larval zebrafish. The primary organs of acute toxicity in zebrafish exposed to PS80 and its typical components PSM and PIM include the cardiovascular system, kidneys, intestines, skin, and liver. Notably, PIM further induced severe pericardial edema and erythrocyte hemolysis, thereby affecting blood flow. The samples also instigated oxidative damage by disrupting the redox equilibrium in the larvae. Compared to PS80, both PSM and PIM induced greater oxidative damage, with PIM notably causing significantly higher lipid oxidation, suggesting that oxidative stress may play a crucial role in polysorbate80-induced toxicity. Furthermore, our study found that PS80 could induce alterations in DNA conformation. The findings underscore the necessity for excipient regulators to establish comprehensive quality standards for Polysorbate 80 (PS80). By implementing such standards, it is possible to minimize the clinical risks associated with the variability in PS80 composition, ensuring safer pharmaceutical products for patients.

Mechanistic Insight into the Mechanical Unfolding of the Integral Membrane Diacylglycerol Kinase.

The essential forces stabilizing membrane proteins and governing their folding and unfolding are difficult to decipher. Single-molecule atomic force spectroscopy mechanically unfolds individual membrane proteins and quantifies their dynamics and energetics. However, it remains challenging to structurally assign unfolding intermediates precisely and to deduce dominant interactions between specific residues that facilitate either the localized stabilization of these intermediates or the global assembly of membrane proteins. Here, we performed force spectroscopy experiments and multiscale molecular dynamics simulations to study the unfolding pathway of diacylglycerol kinase (DGK), a small trimeric multispan transmembrane enzyme. The remarkable agreement between experiments and simulations allowed precise structural assignment and interaction analysis of unfolding intermediates, bypassing existing limitations on structural mapping, and thus provided mechanistic explanations for the formation of these states. DGK unfolding was found to proceed with structural segments varying in size that do not correlate with its secondary structure. We identified intermolecular side-chain packing interactions as one of the major contributions to the stability of unfolding intermediates. Mutagenesis creating packing defects induced a dramatic decrease in the mechano-stability of corresponding intermediates and also in the thermo-stability of DGK trimer, in good agreement with predictions from simulations. Hence, the molecular determinants of the mechano- and thermo-stability of a membrane protein can be identified at residue resolution. The accurate structural assignment established and microscopic mechanism revealed in this work may substantially expand the scope of single-molecule studies of membrane proteins.

Functional modification of recombinant brain-derived neurotrophic factor and its protective effect against neurotoxicity.

Brain-derived neurotrophic factor (BDNF) is a neurotrophic protein that promotes neuronal survival, increases neurotransmitter synthesis, and has potential therapeutic effects in neurodegenerative and psychiatric diseases, but its drug development has been limited by the fact that recombinant proteins of BDNF are unstable and do not penetrate the blood-brain barrier (BBB). In this study, we fused a TAT membrane-penetrating peptide with BDNF to express a recombinant protein (TBDNF), which was then PEG-modified to P-TBDNF. Protein characterization showed that P-TBDNF significantly improved the stability of the recombinant protein and possessed the ability to penetrate the BBB, and in cellular experiments, P-TBDNF prevented MPTP-induced nerve cell oxidative stress damage, apoptosis and inflammatory response, and its mechanism of action was closely related to the activation of tyrosine kinase B (TrkB) receptor and inhibition of microglia activation. In animal experiments, P-TBDNF improved motor and cognitive deficits in MPTP mice and inhibited pathological changes in Parkinson's disease (PD). In conclusion, this paper is expected to reveal the mechanism of action of P-TBDNF in inhibiting neurotoxicity, provide a new way for treating PD, and lay the foundation for the future development of recombinant P-TBDNF.

Assessment of the Effect of Leonurine Hydrochloride in a Mouse Model of PCOS by Gene Expression Profiling.

Polycystic ovary syndrome (PCOS) is an endocrine disease commonly associated with metabolic disorders in females. Leonurine hydrochloride (Leo) plays an important role in regulating immunity, tumours, uterine smooth muscle, and ovarian function. However, the effect of Leo on PCOS has not been reported. Here, we used dehydroepiandrosterone to establish a mouse model of PCOS, and some mice were then treated with Leo by gavage. We found that Leo could improve the irregular oestros cycle of PCOS mice, reverse the significantly greater serum testosterone (T) and luteinising hormone (LH) levels, significantly reduce the follicle-stimulating hormone (FSH) level, and significantly increase the LH/FSH ratio of PCOS mice. Leo could also change the phenomenon of ovaries in PCOS mice presented with cystic follicular multiplication and a lacking corpus luteum. Transcriptome analysis identified 177 differentially expressed genes related to follicular development between the model and Leo groups. Notably, the cAMP signalling pathway, neuroactive ligand-receptor interactions, the calcium signalling pathway, the ovarian steroidogenesis pathway, and the Lhcgr, Star, Cyp11a, Hsd17b7, Camk2b, Calml4, and Phkg1 genes may be most related to improvements in hormone levels and the numbers of ovarian cystic follicles and corpora lutea in PCOS mice treated by Leo, which provides a reference for further study of the mechanism of Leo.

Application of sodium sulfobutylether-ß-cyclodextrin based on encapsulation.

Sodium Sulfobutylether-ß-cyclodextrin (SBE-ß-CD) is a derivative of ß-cyclodextrin, characterized by its stereo structure, which closely resembles a truncated cone with a hydrophobic internal cavity. The solubility of insoluble substances within the hydrophobic cavity is significantly enhanced, reducing contact between the guest and the environment. Consequently, SBE-ß-CD is frequently employed as a co-solvent and stabilizer. As the research progresses, it has been observed that the inclusion of SBE-ß-CD is reversible and competitive. Besides, some inclusion complexes undergo distinct physicochemical property alterations compared to the guests. Additionally, certain guests exhibit varying inclusions with SBE-ß-CD at different concentrations. These features have contributed to the expanding applications. SBE-ß-CD finds widespread application in pharmaceutics as a protective agent and pKa regulator, in pharmaceutical analysis as a chiral substance separator, and in biomedical engineering for encapsulating dyes and modifying sensors. The article will elaborate in detail on the physicochemical properties of SBE-ß-CD, encapsulation principles, and factors influencing the formation of inclusion complexes. Furthermore, the review focuses on the application of SBE-ß-CD through encapsulation in pharmaceutics, pharmaceutical analysis, and biomedical engineering. Finally, the prospects and potential applications of SBE-ß-CD are discussed.

Mitochondrial calcium uniporter promotes mitophagy by regulating the PINK1/Parkin pathway in caerulein­treated pancreatic ductal epithelial cells in vitro.

The mitochondrial calcium uniporter (MCU) is a major protein for the uptake of mitochondrial calcium to regulate intracellular energy metabolism, including processes such as mitophagy. The present study investigated the effect of the MCU on mitophagy in pancreatic ductal epithelial cells (PDECs) in acute pancreatitis (AP) in vitro. The normal human PDECs (HPDE6-C7) were treated with caerulein (CAE) to induce AP-like changes, with or without ruthenium red to inhibit the MCU. The mitochondrial membrane potentials (MMPs) and mitochondrial Ca2+ levels were analyzed by fluorescence. The expression levels of MCU, LC3, p62, and translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), putative kinase 1 (PINK1), and Parkin were measured by western blotting and immunofluorescence. Mitophagy was observed by confocal fluorescence microscopy and transmission electron microscopy. The results showed that CAE increased the MCU protein expression, mitochondrial Ca2+ levels, MMP depolarization and the protein expression of mitophagy markers including the LC3II/I ratio, PINK1, and Parkin. CAE decreased the protein expression of p62 and TOMM20, and promoted the formation of mitophagosomes in HPDE6-C7 cells. Notably, changes in these markers were reversed by inhibiting the MCU. In conclusion, an activated MCU may promote mitophagy by regulating the PINK1/Parkin pathway in PDECs in AP.

Five genes identified as prognostic markers for colorectal cancer through the integration of genome-wide association study and expression quantitative trait loci data.

Background: Colorectal cancer (CRC) is a prominent form of cancer globally, ranking second in terms of prevalence and serving as a leading cause of cancer-related deaths, but the underlying biological interpretation remains largely unknown. Methods: We used the summary data-based Mendelian randomization method to integrate CRC genome-wide association studies (ncase = 7062; ncontrol = 195,745) and expression quantitative trait loci summary data in peripheral whole blood (Consortium for Architecture of Gene Expression: n = 2765; Genotype-Tissue Expression [v8]: n = 755) and colon tissue (colon-transverse: n = 406; colon-sigmoid: n = 373) and identified related genes. Results: Genes ABTB1, CYP21A2, NLRP1, PHKG1 and PIP5K1C have emerged as significant prognostic markers for CRC patient survival. Functional analysis revealed their involvement in cancer cell migration and invasion mechanisms, providing valuable insights for the development of future anti-CRC drugs. Conclusion: We successfully identified five CRC risk genes, providing new insights and research directions for the effective mechanisms of CRC.

Immunotherapy-associated symptoms, distress, financial toxicity and unmet supportive care needs of patients with cancer.

PURPOSE: To examine the unmet care needs (i.e., overall needs and need subdomains [physical and daily living needs, psychological and emotional needs, care and support needs, and health-system and informational needs]) of patients with cancer undergoing immunotherapy alone or in combination with other anticancer therapies, as well as related influencing factors. METHODS: A cross-sectional design was adopted. Cancer patients who received immunotherapy completed consent and questionnaires. Unmet care needs were evaluated with the Chinese version of the Supportive Care Needs Survey Screening Tool, symptom severity with the Symptom Severity Scale, distress severity with the Distress Thermometer Scale, and financial toxicity using the Financial Toxicity - Functional Assessment of Chronic Illness Therapy Questionnaire. RESULTS: In total, 105 patients were surveyed. The most frequently reported unmet needs were psychological and emotional needs (56.2%) followed by health-system and informational needs (36.2%). The major factors associated with unmet care needs and their subdomains were years of education, symptoms, distress, and financial toxicity. Years of education predicted overall unmet care needs, psychological and emotional needs, and care and support needs; symptoms predicted overall unmet care needs and all four subdomains; distress predicted psychological and emotional needs and health-system and informational needs; and financial toxicity predicted overall needs and psychological and emotional needs. CONCLUSIONS: Patients with higher education, severe symptoms, distress, and financial toxicity reported more unmet care needs. The findings of this study could be incorporated into immunotherapy-related clinical practice guidelines and future interventions to improve the quality of cancer care.

PEG-modified nano liposomes co-deliver Apigenin and RAGE-siRNA to protect myocardial ischemia injury.

Ischemic heart disease (IHD) is a cardiac disorder in which myocardial damage occurs as a result of myocardial ischemia and hypoxia. Evidence suggests that oxidative stress and inflammatory responses are critical in the development of myocardial ischemia. Therefore, the combination of antioxidant and anti-inflammatory applications is an effective strategy to combat ischemic heart disease. In this paper, polyethylene glycol (PEG)-modified cationic liposomes were used as carriers to deliver apigenin (Apn) with small interfering RNA (siRNA) targeting the receptor for glycosylation end products (RAGE) (siRAGE) into cardiomyocytes to prevent myocardial ischemic injury through antioxidant and anti-inflammatory effects. Our results showed that we successfully prepared cationic PEG liposomes loaded with Apn and siRAGE (P-CLP-A/R) with normal appearance and morphology, particle size and Zeta potential, and good encapsulation rate, drug loading and in vitro release degree. In vitro, P-CLP-A/R was able to prevent oxidative stress injury in H9C2 cells, downregulate the expression of RAGE, reduce the secretion of cellular inflammatory factors and inhibit apoptosis through the RAGE/NF-κB pathway; In vivo, P-CLP-A/R was able to prevent arrhythmia and myocardial pathological injury, and reduce apoptosis and the area of necrotic myocardium in rats. In conclusion, P-CLP-A/R has a protective effect on myocardial ischemic injury and is expected to be a potential drug for the prevention of ischemic heart disease in the future.

Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-ß-Cyclodextrin.

Permeability has an important effect on drug absorption. In this study, the effect of different concentrations of sodium sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) on the absorption of ranitidine was investigated to examine the mechanism of permeability changes. The results of a parallel artificial membrane permeability assay (PAMPA) showed that increasing the concentration of sodium sulfobutyl ether-ß-cyclodextrin, 0, 0.12% (w/v), 0.36% (w/v) and 3.6% (w/v), respectively, caused the apparent permeability coefficient of ranitidine to decrease to 4.62 × 10-5, 4.5 × 10-5, 3.61 × 10-5 and 1.08 × 10-5 in Caco-2 cells, respectively. The same results were obtained from an oral pharmacokinetic study in rats. Further studies indicated that SBE-ß-CD significantly increased the zeta potential of ranitidine. SBE-ß-CD interacted with ranitidine charges to form a complex that reduced ranitidine permeability, and SBE-ß-CD should be chosen with caution for drugs with poor permeability.

Spatiotemporal single-cell transcriptomic profiling reveals inflammatory cell states in a mouse model of diffuse alveolar damage.

Diffuse alveolar damage (DAD) triggers neutrophilic inflammation in damaged tissues of the lung, but little is known about the distinct roles of tissue structural cells in modulating the recruitment of neutrophils to damaged areas. Here, by combining single-cell and spatial transcriptomics, and using quantitative assays, we systematically analyze inflammatory cell states in a mouse model of DAD-induced neutrophilic inflammation after aerosolized intratracheal inoculation with ricin toxin. We show that homeostatic resident fibroblasts switch to a hyper-inflammatory state, and the subsequent occurrence of a CXCL1-CXCR2 chemokine axis between activated fibroblasts (AFib) as the signal sender and neutrophils as the signal receiver triggers further neutrophil recruitment. We also identify an anatomically localized inflamed niche (characterized by a close-knit spatial intercellular contact between recruited neutrophils and AFib) in peribronchial regions that facilitate the pulmonary inflammation outbreak. Our findings identify an intricate interplay between hyper-inflammatory fibroblasts and neutrophils and provide an overarching profile of dynamically changing inflammatory microenvironments during DAD progression.

Anthropogenic contributions to antibiotic resistance gene pollution in household drinking water revealed by machine-learning-based source-tracking.

Although the presence of antibiotic resistance genes (ARGs) in drinking water and their potential horizontal gene transfer to pathogenic microbes are known to pose a threat to human health, their pollution levels and potential anthropogenic sources are poorly understood. In this study, broad-spectrum ARG profiling combined with machine-learning-based source classification SourceTracker was performed to investigate the pollution sources of ARGs in household drinking water collected from 95 households in 47 cities of eight countries/regions. In total, 451 ARG subtypes belonging to 19 ARG types were detected with total abundance in individual samples ranging from 1.4 × 10-4 to 1.5 × 10° copies per cell. Source tracking analysis revealed that many ARGs were highly contributed by anthropogenic sources (37.1%), mainly wastewater treatment plants. The regions with the highest detected ARG contribution from wastewater (∼84.3%) used recycled water as drinking water, indicating the need for better ARG control strategies to ensure safe water quality in these regions. Among ARG types, sulfonamide, rifamycin and tetracycline resistance genes were mostly anthropogenic in origin. The contributions of anthropogenic sources to the 20 core ARGs detected in all of the studied countries/regions varied from 36.6% to 84.1%. Moreover, the anthropogenic contribution of 17 potential mobile ARGs identified in drinking water was significantly higher than other ARGs, and metagenomic assembly revealed that these mobile ARGs were carried by diverse potential pathogens. These results indicate that human activities have exacerbated the constant input and transmission of ARGs in drinking water. Our further risk classification framework revealed three ARGs (sul1, sul2 and aadA) that pose the highest risk to public health given their high prevalence, anthropogenic sources and mobility, facilitating accurate monitoring and control of anthropogenic pollution in drinking water.

Bioinspired Young's Modulus-Hierarchical E-Skin with Decoupling Multimodality and Neuromorphic Encoding Outputs to Biosystems.

As key interfaces for the disabled, optimal prosthetics should elicit natural sensations of skin touch or proprioception, by unambiguously delivering the multimodal signals acquired by the prosthetics to the nervous system, which still remains challenging. Here, a bioinspired temperature-pressure electronic skin with decoupling capability (TPD e-skin), inspired by the high-low modulus hierarchical structure of human skin, is developed to restore such functionality. Due to the bionic dual-state amplifying microstructure and contact resistance modulation, the MXene TPD e-skin exhibits high sensitivity over a wide pressure range and excellent temperature insensitivity (91.2% reduction). Additionally, the high-low modulus structural configuration enables the pressure insensitivity of the thermistor. Furthermore, a neural model is proposed to neutrally code the temperature-pressure signals into three types of nerve-acceptable frequency signals, corresponding to thermoreceptors, slow-adapting receptors, and fast-adapting receptors. Four operational states in the time domain are also distinguished after the neural coding in the frequency domain. Besides, a brain-like machine learning-based fusion process for frequency signals is also constructed to analyze the frequency pattern and achieve object recognition with a high accuracy of 98.7%. The TPD neural system offers promising potential to enable advanced prosthetic devices with the capability of multimodality-decoupling sensing and deep neural integration.

The Effect of Walking Intervention on Cognitive Function Among Patients With Non-Central Nervous System Cancer: A Systematic Review.

BACKGROUND: Cognitive impairment is one of the most frequently reported symptoms in patients with non-central nervous system (non-CNS) cancer. Walking has positive effects on cognitive function. However, the effects of walking interventions on cognitive function outcomes in patients with non-CNS cancer are not well synthesized. OBJECTIVE: The aim of this study was to explore the characteristics of walking intervention and its effects on cognitive function in patients with non-CNS cancer. METHODS: Ten databases were searched to identify eligible randomized controlled trials from each database's inception to June 7, 2021. The Physiotherapy Evidence Database Scale was used to assess the quality of the included studies. RESULTS: Five randomized controlled trials involving 242 adults with non-CNS cancer were included. Two studies involving immediate treadmill walking interventions with moderate intensity at 40% to 60% maximal heart rate reported significantly improved objective cognitive domains of processing speed and spatial working memory with small to moderate effect sizes for cancer survivors. One study delivering home-based, moderate-intensity walking intervention had borderline significantly positive effects on perceived cognitive functioning for patients with non-CNS cancer during chemotherapy. CONCLUSION: Walking intervention with moderate intensity is a beneficial approach to improve objective cognitive domains of processing speed and spatial working memory and perceived cognitive function. IMPLICATIONS FOR PRACTICE: Nurses may provide moderate-intensity walking with 40% to 60% maximal heart rate monitoring to alleviate cognitive problems during the continuous process of cancer care. The modality and dosage of intervention should be adjusted depending on this population's tolerance to better maintain training.

Role of preoperative malnutrition and symptom severity in anorexia-cachexia-related quality of life in patients with operable pancreatic cancer.

PURPOSE: This study assessed the changes in malnutrition status, symptom severity, and anorexia-cachexia-related quality of life (QoL) before and after pancreatic surgery and identified significant factors associated with changes in anorexia-cachexia-related QoL in patients with operable pancreatic cancer. METHODS: In total, 76 patients with pancreatic cancer who were scheduled to undergo surgery were recruited from a medical center in northern Taiwan. The Mini Nutritional Assessment, Symptom Severity Scale, and Functional Assessment of Anorexia-Cachexia Therapy scale were used to assess the patients' nutritional status, symptom severity, and anorexia-cachexia-related QoL, respectively. Bioelectrical impedance analysis was performed using X-Scan Plus II to assess body composition. A generalized estimating equation approach was used to identify significant factors associated with anorexia-cachexia-related QoL. RESULTS: In total, 42.1% of the patients had malnutrition or were at risk of malnutrition before surgery. Preoperative malnutrition (ß = -3.857, p = .001) and higher early satiety (ß = -0.629, p = .005), insomnia (ß = -0.452, p = .025), and pain (ß = -0.779, p < .001) were associated with lower anorexia-cachexia-related QoL. CONCLUSION: Clinicians should actively assess the nutritional status of patients with pancreatic cancer before surgery and provide symptom cluster management interventions to improve nutrition, insomnia, and pain, which is crucial for enhancing patients' anorexia-cachexia-related QoL.

Temporal trends of breast cancer burden in the Western Pacific Region from 1990 to 2044: Implications from the Global Burden of Disease Study 2019.

INTRODUCTION: Breast cancer (BC) is a malignant disease that occurs worldwide and poses serious health burden. OBJECTIVES: To assess the prevalence of BC burden in the Western Pacific region (WPR) from 1990 to 2019, and to predict trends from 2020 to 2044. To analyze the driving factors and put forward the region-oriented improvement. METHODS: Based on the Global Burden of Disease Study 2019, BC cases, deaths, disability-adjusted life years (DALYs) cases, age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALYs rate in WPR from 1990 to 2019 was obtained and analysed. Age-period-cohort (APC) model was used to analyze age, period, and cohort effects in BC, and Bayesian APC (BAPC) was used to predict trends over the next 25 years. RESULTS: In conclusion, BC incidence and deaths in the WPR have increased rapidly over the past 30 years and are expected to continue to increase between 2020 and 2044. Among behavioral and metabolic factors, high body-mass index was the main risk factor for BC mortality in middle-income countries, whereas alcohol use was the main risk factor in Japan. Age is a key factor in the development of BC, with 40 years being the critical point. Incidence trends coincide with the course of economic development. CONCLUSIONS: The BC burden remains an essential public health issue in the WPR and will increase substantially in the future. More efforts should be made in middle-income countries to prompt the health behavior and minimize the burden of BC because these nations accounts for the majority of BC burden in the WPR.

A modified Ranson score to predict disease severity, organ failure, pancreatic necrosis, and pancreatic infection in patients with acute pancreatitis.

Background: Although there are several scoring systems currently used to predict the severity of acute pancreatitis, each of them has limitations. Determine the accuracy of a modified Ranson score in predicting disease severity and prognosis in patients with acute pancreatitis (AP). Methods: AP patients admitted or transferred to our institution were allocated to a modeling group (n = 304) or a validation group (n = 192). A modified Ranson score was determined by excluding the fluid sequestration parameter and including the modified computed tomography severity index (CTSI). The diagnostic performance of the modified Ranson score was compared with the Ranson score, modified CTSI, and bedside index of severity in acute pancreatitis (BISAP) score in predicting disease severity, organ failure, pancreatic necrosis and pancreatic infection. Results: The modified Ranson score had significantly better accuracy that the Ranson score in predicting all four outcome measures in the modeling group and in the validation group (all p < 0.05). For the modeling group the modified Ranson score had the best accuracy for predicting disease severity and organ failure, and second-best accuracy for predicting pancreatic necrosis and pancreatic infection. For the verification group, it had the best accuracy for predicting organ failure, second-best accuracy for predicting disease severity and pancreatic necrosis, and third-best accuracy for predicting pancreatic infection. Conclusion: The modified Ranson score provided better accuracy than the Ranson score in predicting disease severity, organ failure, pancreatic necrosis and pancreatic infection. Relative to the other scoring systems, the modified Ranson system was superior in predicting organ failure.

Inhibition of TRAF6 improves hyperlipidemic acute pancreatitis by alleviating pyroptosis in vitro and in vivo rat models.

OBJECTIVE: Hypertriglyceridemia (HTG) is one of the common causes of acute pancreatitis (AP). Hyperlipidemic acute pancreatitis (HTG-AP) is associated with higher mortality owing to its tendency for greater severity and rapid progression. The purpose of this study was to explore the mechanism of involvement of tumor necrosis factor receptor-related factor 6 (TRAF6) in pyroptosis during HTG-AP. METHODS: The HTG environment was simulated with palmitic acid treatment in vitro and a high-fat diet in vivo. Cerulein was used to establish the HTG-AP model, followed by genetic and pharmacological inhibition of TRAF6. Pyroptosis activation, inflammatory reaction, and the interaction between TRAF6 and pyroptosis in HTG-AP were assessed. RESULTS: HTG was found to aggravate the development of pancreatitis, accompanied by increased pyroptosis and enhanced inflammatory response in HTG-AP models. Mechanistically, TRAF6 downregulation decreased the activation of pyroptosis in cerulein-induced HTG-AP. CONCLUSION: Collectively, inhibition of TRAF6 improved HTG-AP and the associated inflammation by alleviating pyroptosis.

Cognitive Function in Patients at Different Stages of Treatment for Colorectal Cancer: A Comparative Cross-Sectional Study.

OBJECTIVES: To compare subjective and objective cognitive functions among patients at the following three stages of treatment for colorectal cancer (CRC): new diagnosis (Group A), ≤2 years since chemotherapy completion (Group B), and >2 years since chemotherapy completion (Group C). DATA SOURCES: A comparative cross-sectional approach was used in this study. The Functional Assessment of Cancer Therapy-Cognitive Function questionnaire and neuropsychological assessments were used to assess patients' subjective cognitive function, attention, memory, and executive functions. A total of 63 patients with stage I to III CRC were recruited from a medical center in northern Taiwan. We performed one-to-one-to-one propensity score matching to identify 36 individuals as eligible for this study. A generalized estimating equation was used to compare subjective and objective cognitive functions. CONCLUSION: We observed no significant between-group differences in subjective cognitive function and objective performance in overall cognition and memory. Group B had significantly longer reaction time in attention and processing speed than did Group A. Adjuvant chemotherapy had significantly deleterious effects on attention and processing speed in patients with CRC. These cognitive symptoms last for approximately 2 years after the completion of chemotherapy. IMPLICATIONS FOR NURSING PRACTICE: The early detection of cancer-related cognitive impairment is necessary for managing symptom distress. Future studies with a large sample size and longitudinal design may elucidate the trajectory of specific cognitive functions. Developing nursing interventions aimed at improving attention and executive function in patients with CRC are needed.

[Effects of Microplastic High-density Polyethylene on Cotton Growth, Occurrence of Fusarium wilt, and Rhizosphere Soil Bacterial Community].

Plastic mulch, especially polyethylene mulch, is widely used in agricultural production in China, but the microplastics formed by its degradation gradually have accumulated in soil, causing a series of environmental problems. At present, there have been many reports on the environmental biological effects of microplastics in farmland soil, but studies on the effects of microplastics on crop growth, disease occurrence, and rhizosphere soil bacterial communities are still lacking. In the previous study, it was found that 1% high-density polyethylene (HDPE, 500 mesh) could increase the incidence rate of cotton Fusarium wilt (33.3%) and inhibit growth, but this phenomenon was not found after soil sterilization. It was speculated that HDPE could affect the growth and occurrence of Fusarium wilt by regulating the soil microbial community. Therefore, high-throughput sequencing technology, combined with network and FAPROTAX function analysis, were used to investigate the effects of HDPE on the bacterial community structure, interaction network, and soil function in cotton rhizosphere in order to analyze the mechanism of HDPE. NovaSeq sequencing showed that the bacterial community of HDPE-treated cotton rhizosphere soil was composed of 54 phyla and 472 genera; the number of phyla and genera was higher than that in untreated soil. The α and ß diversity and ANOSIM/Adonis analyses showed that HDPE significantly reduced the richness of the bacterial community and changed the composition of the community structure. Based on a T-test species difference analysis, HDPE significantly reduced the relative abundance of bacteria with biological control, pollutant degradation, and antifungal drug synthesis (such as Kribbella, Massiliam, Hailiangium, and Ramlibacter).The change in the bacterial community will lead to the change in soil bacterial function. Further analysis of FAPROTAX function revealed that HDPE weakened some biochemical functions of bacteria in the cotton rhizosphere soil, such as aerobic chemoheterotrophy, fermentation, and nitrate reduction. The correlation network at the genus level showed that HDPE treatment weakened the interaction between rhizosphere bacteria, reduced the number of positive correlation connections, increased the number of negative correlation connections, simplified network structure, and changed the key flora. The above results showed that HDPE could reduce the cotton growth and the occurrence of Fusarium wilt by changing the bacterial community, interaction, and functional metabolism in rhizosphere soil, which can provide guidance for evaluating the ecological risk of polyethylene microplastics and the remediation of contaminated soil.