Investigation of morphology and structure of drug-loaded PLA-b-PEO-b-PLA polymeric micelle: A dissipative particle dynamics simulations study.

The dissipative particle dynamics (DPD) simulation was used to study the morphologies and structures of the paclitaxel-loaded PLA-b-PEO-b-PLA polymeric micelle. We focused on the influences of PLA block length, PLA-b-PEO-b-PLA copolymer concentration, paclitaxel drug content on morphologies and structures of the micelle. Our simulations show that: (i) with the PLA block length increase, the self-assemble structure of PLA-b-PEO-b-PLA copolymers with paclitaxel vary between onion-like structure (core-middle layer-shell) to spherical core-shell structure. The PEO shell thins and the size of the PLA core increases. The onionlike structures are comprised of the PEO hydrophilic core, the PLA hydrophobic middle layer, and the PEO hydrophilic shell, the distribution of the paclitaxel drug predominantly occurs within the hydrophobic intermediate layer; (ii) The system forms a spherical core-shell structure when a small amount of the drug is added, and within a certain range, the size of the spherical structure increases as the drug amount increases. When the drug contents (volume fraction) cdrug = 10%, it can be observed that the PLA4-b-PEO19-b-PLA4 spherical structures connect to form rod-shaped structures. With the length of PLA block NPLA = 8, as the paclitaxel drug concentrations cdrug = 4%, PEO has been insufficient to completely encapsulate the PLA and paclitaxel drug beads. To enhance drug loading capacity while maintaining stability of the system in aqueous solution, the optimal composition for loading paclitaxel is PLA4-b-PEO19-b-PLA4; the drug content is not higher than 4%; (iii) The paclitaxel-loaded PLA4-b-PEO19-b-PLA4 micelle undergo the transition from onionlike (core-middle layer-shell) to spherical (core-shell) to rod-shaped and lamellar structure as the PLA4-b-PEO19-b-PLA4 copolymer concentration increases from ccp = 10% to 40%.

The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies.

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.

Case report: A novel perspective on the treatment of primary tracheal small cell carcinoma: a patient's experience with immuno-combined EP therapy and literature review.

Tracheal small cell carcinoma (SCC) is a rare malignancy, for which the optimal treatment strategy has yet to be determined. Currently, treatment largely aligns with the therapeutic guidelines established for small cell lung cancer, although numerous unresolved issues remain. This paper details a case study of a patient with Stage IIIB primary tracheal SCC, who was treated with an immune-combined etoposide-platinum(EP) regimen. This treatment offers valuable insights into innovative approaches for managing such malignancies. Furthermore, the study includes a comprehensive literature review to better contextualize the findings. The patient, admitted on May 2, 2023, had been experiencing persistent symptoms of airway discomfort for 15 days. A bronchoscopy performed on May 4 revealed tracheal SCC, classified as T4N2M0, IIIB. Following the CAPSTONE-1 study's methodology, the patient underwent six cycles of PD-L1(adebrelimab) combined with EP therapy, leading to significant relief of symptoms and the eventual disappearance of the tracheal mass.

Grouped Multivariate Variational Mode Decomposition With Application to EEG Analysis.

OBJECTIVE: In this paper, a novel extended form of multivariate variational mode decomposition (MVMD) method to multigroup data named as grouped MVMD (GMVMD) is proposed. GMVMD is distinct from MVMD as it extracts common frequencies with strong correlations among regional channels. METHODS: Firstly, GMVMD utilizes a new clustering algorithm named as frequencies grouping algorithm to classify the nearest common frequencies among all channels to specified groups. Secondly, a generic variational optimization model which is extended from MVMD is formulated. Thirdly, alternating direction method of multipliers (ADMM) is utilized to obtain optimal solution of GMVMD model. RESULTS: The proposed method introduces an extra parameter to decide the number of clusterings which need to be specified by the user. The effectiveness and superiority of the algorithm are demonstrated on a series of experiments. The utility of GMVMD is verified by grouping real-world electroencephalogram (EEG) data having similar center frequencies successfully. CONCLUSION: GMVMD outperforms MVMD in mode-alignment, signal reduction error and et al. Significance: GMVMD can obtain more accurate center frequencies and less signal reduction error than MVMD.

Satellite-Type Sulfur Atom Distribution in Trithiocarbonate Bond-Bridged Dimeric Prodrug Nanoassemblies: Achieving Both Stability and Activatability.

Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo-drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self-assembly stability, and site-specific activation of prodrugs. The "in series" increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (─SC(S)S─), with a stable "satellite-type" distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. ─SC(S)S─ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self-assembly stability of homodimeric prodrugs while maintaining the on-demand bioactivation. Furthermore, ─SC(S)S─ bond inhibits antioxidant defense system, leading to up-regulation of the cellular ROS and apoptosis of tumor cells. These improvements of ─SC(S)S─ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. ─SC(S)S─ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.

Minor Changes in Response Modules Leading to a "U-Shaped" Conversion Rate of Docetaxel Prodrug Nanoassemblies.

The prodrug-based nanoassemblies offer an alternative to settle the deficiencies of traditional chemotherapy drugs. In this nanosystem, prodrugs typically comprise drug modules, modification modules, and response modules. The response modules are crucial for facilitating the accurate conversion of prodrugs at specific sites. In this work, we opted for differentiated disulfide bonds as response modules to construct docetaxel (DTX) prodrug nanoassemblies. Interestingly, a subtle change in response modules leads to a "U-shaped" conversion rate of DTX-prodrug nanoassemblies. Prodrug nanoassemblies with the least carbon numbers between the disulfide bond and ester bond (PDONα) offered the fastest conversion rate, resulting in powerful treatment outcomes with some unavoidable toxic effects. PDONß, with more carbon numbers, possessed a slow conversion rate and poor antitumor efficacy but good tolerance. With most carbon numbers in PDONγ, it demonstrated a moderate conversion rate and antitumor effect but induced a risk of lethality. Our study explored the function of response modules and highlighted their importance in prodrug development.

Effect of high-intensity ultrasound on the structural and functional properties of proteins in housefly larvae (Musca demestica).

Insect protein has gradually attracted wide attention from the international research community as a promising source of high-quality protein that can replace traditional protein sources. The larvae of the housefly, a prevalent and widespread species, contain high levels of protein with beneficial properties, namely, anti-fatigue, anti-radiation, and anti-aging functions, as well as liver protection and immunity enhancement. This work thoroughly examined the impact of high-intensity ultrasound (HIUS) on the structural and functional characteristics of housefly larval concentrate protein (HLCP). HLCP samples were sonicated for 20 min at a frequency of 20 kHz with varying energies (0, 100, 200, 300, 400, and 500 W). The findings demonstrated that sonication considerably altered the secondary and tertiary structures of HLCP but had no effect on molecular weight. With an increase in ultrasonic power, HLCP's particle size shrank, more hydrophobic groups were exposed, more free sulfhydryl groups were present, the solution's stability improved, and HLCP's solubility rose. In addition, HLCP's emulsification and foaming abilities were improved by HIUS treatment. It is anticipated that this study's findings will offer fresh insights into the implementation of HLCP in the food sector.

DHA and EPA inhibit porcine coronavirus replication by alleviating ER stress.

IMPORTANCE: Porcine epidemic diarrhea caused by porcine coronaviruses remains a major threat to the global swine industry. Fatty acids are extensively involved in the whole life of the virus. In this study, we found that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) significantly reduced the viral load of porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine delta coronavirus (PDCoV) and acted on the replication of the viruses rather than attachment and entry. We further confirmed that DHA and EPA inhibited PEDV replication by alleviating the endoplasmic reticulum stress. Meanwhile, DHA and EPA alleviate PEDV-induced inflammation and reactive oxygen species (ROS) levels and enhance the cellular antioxidant capacity. These data indicate that DHA and EPA have antiviral effects on porcine coronaviruses and provide a molecular basis for the development of new fatty acid-based therapies to control porcine coronavirus infection and transmission.

Grit in second language acquisition: a systematic review from 2017 to 2022.

Recent years have witnessed increasing attention to personality strength (grit) due to its merit in goal-seeking language learning processes. Two facets of grit, namely perseverance of effort (PE) and consistency of interest (CI), play a critical role in overcoming learning difficulties and strengthening willpower to pursue learning goals. The current review seeks to explore various issues related to grit, including its factor structure, the relationship between grit and frequently associated factors, as well as the utility of PE and CI in facilitating language learning. This exploration is based on the findings of 32 empirical articles published between 2017 and 2022 from three databases. The results indicate that although research which examines the role of grit has entered a fast growth phase since 2020, there is still a need for expansion and diversification in scopes, participants, research methods, and language contexts. Moreover, previous studies have not adequately addressed the critical issue of grit's conceptualization and factor structure. Finally, this study suggests that future researchers should impartially assess the factor structure and nature of PE and CI, to provide more robust evidence to clarify the relationship between grit and diverse emotions and positive institutions, in order to advance understanding of grit in second language learning.

[Retracted] MicroRNA­616 promotes the growth and metastasis of non­small cell lung cancer by targeting SOX7.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the cell formation assay data shown in Figs. 3D, 4D, 8D and 9D were strikingly similar to data that had already appeared in another article written by different authors at different research institutes [Wang Z, Jiang C, Chen W, Zhang G, Luo D, Cao Y Wu J, Ding Y and Liu B: Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma. Biomed Res Int: 732516, 2014]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 38: 2078­2086, 2017; DOI: 10.3892/or.2017.5854].

Becoming a Non-native Chinese Language Teacher: An Identity Triangle Model Analysis.

This study utilises the Identity Triangle Model (Dugas in Teach Dev 25(3):243-262, 2021, 10.1080/13664530.2021.1874500) to examine the experiences of one particular novice non-native Mandarin Chinese teacher at a university in New Zealand. A case study design was employed to track the identity negotiations of this European non-native Chinese speaker during 12 weeks of her first semester of teaching. Analysis of the data revealed nine subcategories within the psychological, behavioural, and relational domains according to the Identity Triangle Model. The findings suggest that this new non-native speaker teacher viewed her as an accidental teacher, exploring a teaching career without a strong instrumentalist aspiration or a clear career path in language teaching. Instead, she was more motivated by a desire for personal growth and the opportunity to reinvent themselves in a new cultural context. The results of this study offer theoretical implications for the adoption of a unified framework in future research on the identity of first-time language teachers, and practical implications for developing sustainable strategies aimed at recruiting and retaining non-native speaker teachers in foreign language education.

Erratum: Author correction to "DNA damage repair promotion in colonic epithelial cells by andrographolide downregulated cGAS‒STING pathway activation and contributed to the relief of CPT-11-induced intestinal mucositis" [Acta Pharmaceutica Sinica B 12 (2022) 262-273].

[This corrects the article DOI: 10.1016/j.apsb.2021.03.043.].

Cabazitaxel prodrug nanoassemblies with branched chain modifications: Narrowing the gap between efficacy and safety.

The clinical application of cabazitaxel (CTX) is restricted by severe dose-related toxicity, failing to considering therapeutic efficacy and safety together. Self-assembled prodrugs promote new drug delivery paradigms as they can self-deliver and self-formulate. However, the current studies mainly focused on the use of straight chains to construct self-assembled prodrugs, and the role of branched chains in prodrug nanoassemblies remains to be clarified. In this study, we systematically explored the structure-function relationship of prodrug nanoassemblies using four CTX prodrugs that contained branched chain aliphatic alcohols (BAs) with different alkyl lengths. Overall, CTX-SS-BA20 NPs with the proper alkyl length exhibited significant improvements in both antitumor efficacy and biosafety. Furthermore, compared with straight chain (SC) modified prodrug nanoassemblies (CTX-SS-SC20 NPs), CTX-SS-BA20 NPs still hold great therapeutic promise due to its good biosafety. These findings illustrated the significance of BAs as modified chains in designing prodrug nanoassemblies for narrowing the efficacy-to-safety gap of cancer therapy.

Rational Engineering Docetaxel Prodrug Nanoassemblies: Response Modules Guiding Efficacy Enhancement and Toxicity Reduction.

Prodrug-based nanoassemblies have been developed to solve the bottlenecks of chemotherapeutic drugs. The fabricated prodrugs usually consist of active drug modules, response modules, and modification modules. Among three modules, the response modules play a vital role in controlling the intelligent drug release at tumor sites. Herein, various locations of disulfide bond linkages were selected as response modules to construct three Docetaxel (DTX) prodrugs. Interestingly, the small structural difference caused by the length of response modules endowed corresponding prodrug nanoassemblies with unique characteristic. α-DTX-OD nanoparticles (NPs) possessed the advantages of high redox-responsiveness due to their shortest linkages. However, they were too sensitive to retain the intact structure in the blood circulation, leading to severe systematic toxicity. ß-DTX-OD NPs significantly improved the pharmacokinetics of DTX but may induce damage to the liver. In comparison, γ-DTX-OD NPs with the longest linkages greatly ameliorated the delivery efficiency of DTX as well as improved DTX's tolerance dose.

Integrating Transcriptomics and Metabolomics to Explore the Novel Pathway of Fusobacterium nucleatum Invading Colon Cancer Cells.

Colorectal cancer (CRC) is a malignancy with a very high incidence and mortality rate worldwide. Fusobacterium nucleatum bacteria and their metabolites play a role in inducing and promoting CRC; however, no studies on the exchange of information between Fusobacterium nucleatum extracellular vesicles (Fnevs) and CRC cells have been reported. Our research shows that Fusobacterium nucleatum ATCC25586 secretes extracellular vesicles carrying active substances from parental bacteria which are endocytosed by colon cancer cells. Moreover, Fnevs promote the proliferation, migration, and invasion of CRC cells and inhibit apoptosis; they also improve the ability of CRC cells to resist oxidative stress and SOD enzyme activity. The genes differentially expressed after transcriptome sequencing are mostly involved in the positive regulation of tumor cell proliferation. After detecting differential metabolites using liquid chromatography-tandem mass spectrometry, Fnevs were found to promote cell proliferation by regulating amino acid biosynthesis in CRC cells and metabolic pathways such as central carbon metabolism, protein digestion, and uptake in cancer. In summary, this study not only found new evidence of the synergistic effect of pathogenic bacteria and colon cancer tumor cells, but also provides a new direction for the early diagnosis and targeted treatment of colon cancer.

Neoadjuvant sintilimab and chemotherapy in patients with potentially resectable esophageal squamous cell carcinoma (KEEP-G 03): an open-label, single-arm, phase 2 trial.

BACKGROUND: The standard neoadjuvant treatments in patients with esophageal squamous cell carcinoma (ESCC) still have either poor safety or efficacy. Better therapies are needed in China. METHODS: This was an open-label, single-arm, phase 2 trial. Patients with potentially resectable ESCC (cT1b-3, Nany, M0 or T4a, N0-1, or M0) received preoperative intravenous sintilimab plus triplet chemotherapy (liposomal paclitaxel, cisplatin, and S-1) every 3 weeks for two cycles. The primary endpoints were safety and surgical feasibility; the secondary endpoint was major pathological response (MPR) rate. Genomic biomarkers (genetic mutations, tumor mutational burden (TMB), circulating tumor DNA status and immune microenvironment) in baseline tumor samples were investigated. RESULTS: All 30 patients completed two cycles of neoadjuvant treatment and underwent surgical resection. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 36.7% (11/30) of patients. The most frequent TRAEs were decreased white cell count (76.7%), anemia (76.7%), and decreased neutrophil count (73.3%). All TRAEs were hematological toxicities; none caused ≥30 days surgical delay. The MPR and pathological complete response (pCR) rates were 50.0% (15/30; 95% CI 33.2 to 66.9) and 20.0% (6/30; 95% CI 9.5 to 37.3), respectively. Patients with higher TMB and more clonal mutations were more likely to respond. ERBB2 alterations and ctDNA high-releaser status have a negative correlation with neoadjuvant ICI response. No significant difference was observed between therapeutic response and tumor immune microenvironment. CONCLUSIONS: Neoadjuvant sintilimab plus platinum-based triplet chemotherapy appeared safe and feasible, did not delay surgery and induced a pCR rate of 20.0% in patients with potentially resectable ESCC. TRIAL REGISTRATION NUMBER: NCT03946969.

Lactocaseibacillus rhamnosus zz-1 Supplementation Mitigates Depression-Like Symptoms in Chronic Stress-Induced Depressed Mice via the Microbiota-Gut-Brain Axis.

Accumulating evidence has revealed an association between depression and disordered intestinal microecology. The discovery of psychobiotics has provided a promising perspective for studying the treatment of psychiatric disorders. Here, we aimed to investigate the antidepressant abilities of Lactocaseibacillus rhamnosus zz-1 (LRzz-1) and elucidate the underlying mechanisms. The viable bacteria (2 × 109 CFU/day) were orally supplemented to depressed C57BL/6 mice induced by chronic unpredictable mild stress (CUMS), and the behavioral, neurophysiological, and intestinal microbial effects were assessed, with fluoxetine used as a positive control. The treatment with LRzz-1 effectively mitigated the depression-like behavioral disorders of depressed mice and reduced the expression of inflammatory cytokine mRNA (IL-1ß, IL-6, and TNF-α) in the hippocampus. In addition, LRzz-1 treatment also improved tryptophan metabolic disorder in the mouse hippocampus, as well as its peripheral circulation. These benefits are associated with the mediation of microbiome-gut-brain bidirectional communication. CUMS-induced depression impaired the intestinal barrier integrity and microbial homeostasis in mice, neither of which was restored by fluoxetine. LRzz-1 prevented intestinal leakage and significantly ameliorated epithelial barrier permeability by up-regulating tight-junction proteins (including ZO-1, occludin, and claudin-1). In particular, LRzz-1 improved the microecological balance by normalizing the threatened bacteria (e.g., Bacteroides and Desulfovibrio), exerting beneficial regulation (e.g., Ruminiclostridium 6 and Alispites), and modifying short-chain fatty acid metabolism. In summary, LRzz-1 showed considerable antidepressant-like effects and exhibited more comprehensive intestinal microecological regulation than other drugs, which offers novel insights that can facilitate the development of depression therapeutic strategies.

Precise engineering of disulfide bond-bridged prodrug nanoassemblies to balance antitumor efficacy and safety.

Prodrug-based nanoassemblies, which combine the merits of prodrug technology and nanocarriers, are regarded as promising platforms for cancer treatment. Notably, the chemical structure of prodrugs is closely associated with antitumor efficacy and safety, and the intrinsic relationships among them need further exploration. Herein, paclitaxel was conjugated with 2-octyldodecan-1-ol through different positions of disulfide bond to construct the prodrug nanoassemblies. Interestingly, the minor differences in chemical structure not only dominated the assembly performance and drug release of nanoassemblies, but also significantly impacted the pharmacokinetics, antitumor efficacy, and safety. It was worth noting that prodrug nanoassemblies with one carbon atom between disulfide bond and ester bond had faster drug release and better antitumor effect, while prodrug nanoassemblies with three carbon atoms between disulfide bond and ester bond possessed moderate antitumor effect and better safety. Our findings illustrated the structure-function relationships of self-assembled prodrugs and provided a promising paradigm for the precise engineering of advanced prodrug nanoplatforms. STATEMENT OF SIGNIFICANCE: 1. The major effects of minor differences in prodrug chemical structure on pharmacodynamics and safety were explored, which had important clinical reference significance and value. 2. The in-depth exploration of structure-function relationships to balance efficacy and safety had important guiding significance for the design of prodrug nanoassemblies.

Preventing falls: the use of machine learning for the prediction of future falls in individuals without history of fall.

Nowadays, it becomes of paramount societal importance to support many frail-prone groups in our society (elderly, patients with neurodegenerative diseases, etc.) to remain socially and physically active, maintain their quality of life, and avoid their loss of autonomy. Once older people enter the prefrail stage, they are already likely to experience falls whose consequences may accelerate the deterioration of their quality of life (injuries, fear of falling, reduction of physical activity). In that context, detecting frailty and high risk of fall at an early stage is the first line of defense against the detrimental consequences of fall. The second line of defense would be to develop original protocols to detect future fallers before any fall occur. This paper briefly summarizes the current advancements and perspectives that may arise from the combination of affordable and easy-to-use non-wearable systems (force platforms, 3D tracking motion systems), wearable systems (accelerometers, gyroscopes, inertial measurement units-IMUs) with appropriate machine learning analytics, as well as the efforts to address these challenges.

Heterogeneities of the perceptual-motor style during locomotion at height.

In a recent review, we summarized the characteristics of perceptual-motor style in humans. Style can vary from individual to individual, task to task and pathology to pathology, as sensorimotor transformations demonstrate considerable adaptability and plasticity. Although the behavioral evidence for individual styles is substantial, much remains to be done to understand the neural and mechanical substrates of inter-individual differences in sensorimotor performance. In this study, we aimed to investigate the modulation of perceptual-motor style during locomotion at height in 16 persons with no history of fear of heights or acrophobia. We used an inexpensive virtual reality (VR) video game. In this VR game, Richie's Plank, the person progresses on a narrow plank placed between two buildings at the height of the 30th floor. Our first finding was that the static markers (head, trunk and limb configurations relative to the gravitational vertical) and some dynamic markers (jerk, root mean square, sample entropy and two-thirds power law at head, trunk and limb level) we had previously identified to define perceptual motor style during locomotion could account for fear modulation during VR play. Our second surprising result was the heterogeneity of this modulation in the 16 young, healthy individuals exposed to moving at a height. Finally, 56% of participants showed a persistent change in at least one variable of their skeletal configuration and 61% in one variable of their dynamic control during ground locomotion after exposure to height.