Clinical research progress of telomerase targeted cancer immunotherapy: a literature review.

Background and Objective: Telomerase is activated or overexpressed in 85-90% of tumors, which maintains the length of telomere and has become an important anti-cancer target. Increasing clinical and preclinical data suggest that telomerase-targeted cancer immunotherapy could achieve effective killing of tumor cells in vivo. This article reviews the research progress of telomerase targeted cancer immunotherapy in clinical and pre-clinical trials, aiming to provide a reference for further clinical research and treatment of cancers. Methods: We investigated the research progress of telomerase immunotherapy in the last 20 years from four electronic databases. Key Content and Findings: Telomerase-targeted immunotherapies have been developed with the arising of a new era in immuno-oncology, including peptide vaccines, DNA vaccines, dendritic cells (DCs), adoptive cell transfer (ACT) therapies, antibodies, etc. Some of them have been approved for undergoing clinical trials by the Food and Drug Administration (FDA) for the treatment of various cancers, such as pancreatic cancer, non-small cell lung cancer, melanoma, leukaemia. Of all the treatment modalities, vaccines are the primary treatment methods, some of which have been even entered into phase III clinical trials. The main clinical application direction of telomerase vaccine is the combination with other drugs and treatment modalities, including combination with other vaccines targeting human telomerase reverse transcriptase (hTERT), traditional chemotherapy drugs and immunosuppressors. We also summarized the recent findings of immunotherapy targeting hTERT, focusing on various vaccines and the current status of associated clinical trials. We further discussed the advantages, disadvantages and potential developmental directions of various telomerase-targeted immunotherapies. Conclusions: Telomerase-targeted cancer immunotherapy has promising prospects in improving patient survival expectancy. This review may provide data support and design ideas for all researchers and pharmaceutical enterprises in this field.

The Impact of Improved Compliance With Enhanced Recovery After Surgery on Frail Patients Undergoing Multi-Level Posterior Lumbar Fusion Surgery for Degenerative Lumbar Diseases.

Background: Patients with frailty are more prone to have perioperative adverse events, and enhanced recovery after surgery (ERAS) has been widely adopted to improve perioperative outcomes. The purpose of this study was to assess the impact of improved compliance with ERAS on perioperative outcomes in frail patients. Methods: Geriatric patients (over 65 years) who underwent multi-level lumbar fusion surgery between June 2017 and June 2022 were included. The patients were divided into two groups according to their degree of compliance with the ERAS. Stepwise nearest-neighbor propensity score matching 1:1 cohorts for age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) classfication and Charlson Comorbidity Index (CCI) was performed between groups, namely frail-compliant (FC), frail-noncompliant (FN). Further length of stay (LOS), complications and clinical efficacy were compared between groups. Results: There were 83 pairs of well-balanced patients with comparable clinical baseline data. It was worth noting that patients in FC group has significant lower overall complications (20.5% in the FC group vs 39.8% in the FN group, P = 0.007), major complications (7.2% in the FC group vs 19.3% in the FN group, P = 0.022) and shorter LOS (11.18 ± 5.32 in the FC group vs 14.45 ± 4.68 in the FN group, P < 0.001) than patients in FN group. In addition, the initial occurrence of ambulation (2.14 ± 1.21 in FC group vs 3.18 ± 1.73 in FN group, P = 0.012) and bowel movement (3.68 ± 1.24 in FC group vs 4.17 ± 1.32 in FN group, P = 0.031) were earlier for patients in FC group than patients in FN group. With regard to clinical efficacy, there were no significant difference between FC and FN group in terms of patients who meet minimal clinical important difference (MCID) for Oswestry Disability Index (ODI) at postoperative day (POD) 30, Visual Analog Scale (VAS) for back at POD 30-90 and VAS for legs at POD 30, 90, and 180 follow-up intervals. However, there were significant more patients meeting MCID for ODI at POD 90 and180, and VAS for back at POD 180 between FC and FN group. Conclusions: In this retrospective cohort study, we found that frail patients with higher ERAS adherence group had a lower incidence of overall complication, mjor complications, and a shorter LOS than their lower ERAS adherence counterparts. In addition, frail patients with higher ERAS adherence had earlier ambulatioin and bowel movement. More importantly, we found there were significant more patients meeting MCID for ODI at POD 90 and180, and VAS for back at POD 180 in higher ERAS adherence than their lower counterparts.

An autoantibody profile identified by human genome-wide protein arrays in rheumatoid arthritis.

Precise diagnostic biomarkers of anticitrullination protein antibody (ACPA)-negative and early-stage RA are still to be improved. We aimed to screen autoantibodies in ACPA-negative patients and evaluated their diagnostic performance. The human genome-wide protein arrays (HuProt arrays) were used to define specific autoantibodies from the sera of 182 RA patients and 261 disease and healthy controls. Statistical analysis was performed with SPSS 17.0. In Phase I study, 51 out of 19,275 recombinant proteins covering the whole human genome were selected. In Phase II validation study, anti-ANAPC15 (anaphase promoting complex subunit 15) exhibited 41.8% sensitivity and 91.5% specificity among total RA patients. There were five autoantibodies increased in ACPA-negative RA, including anti-ANAPC15, anti-LSP1, anti-APBB1, anti-parathymosin, and anti-UBL7. Anti-parathymosin showed the highest prevalence of 46.2% (p = 0.016) in ACPA-negative early stage (<2 years) RA. To further improve the diagnostic efficacy, a prediction model was constructed with 44 autoantibodies. With increased threshold for RA calling, the specificity of the model is 90.8%, while the sensitivity is 66.1% (87.8% in ACPA-positive RA and 23.8% in ACPA-negative RA) in independent testing patients. Therefore, HuProt arrays identified RA-associated autoantibodies that might become possible diagnostic markers, especially in early stage ACPA-negative RA.

A validated UPLC-MS/MS method for the quantification of immunosuppressive drugs in peripheral blood mononuclear cells using liquid-liquid extraction with low temperature purification without complex pretreatment steps.

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0-128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2-20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.

Effects of spray drying on the content of crystal proteins of Bacillus thuringiensis and the protection by organic and inorganic auxiliaries.

Spray drying is an important industrial method for the preparation of B. thuringiensis powder from fermentation liquor. The effect of spray drying on the crystal proteins, however, has not been reported in the literature so far. The present study systematically investigated the effect of inlet air temperature, outlet air temperature, atomizing air pressure and additives (including organic and inorganic auxiliaries) on the thermal destruction of crystal proteins of B. thuringiensis. The results indicated that the content of crystal proteins of B. thuringiensis powder decreased with increased inlet air temperature, outlet air temperature and atomising air pressure. The pseudo-z values for inlet air temperature, outlet air temperature and atomizing air pressure were 826.4 â„ƒ, 204.0 â„ƒ and 4.74 MPa, respectively. Among them, the outlet air temperature was a major parameter influencing the thermal destruction of crystal proteins, therefore, the decrease of the outlet air temperature was beneficial to increase the protein content in powder. Although the spray drying had an adverse effect on crystal proteins, the crystal protein content in spray-dried powder approached that in freeze-dried powder when the inlet air temperature of 165 â„ƒ, outlet air temperature of 70 â„ƒ and atomizing air pressure of 0.15 MPa were employed. The addition of some organic and inorganic auxiliaries to fermentation liquor can protect the crystal proteins from heat damage.

Enhancing Pseudomonas syringae pv. Actinidiae sensitivity in kiwifruit by repressing the NBS-LRR genes through miRNA-215-3p and miRNA-29-3p identification.

Kiwifruit bacterial canker, caused by Pseudomonas syringae pv. actinidiae (PSA), poses a grave threat to the global kiwifruit industry. In this study, we examined the role of microRNAs (miRNAs) in kiwifruit's response to PSA. Kiwifruit seedlings subjected to PSA treatment showed significant changes in both miRNA and gene expression compared to the control group. We identified 364 differentially expressed miRNAs (DEMs) and 7170 differentially expressed genes (DEGs). Further analysis revealed 180 miRNAs negatively regulating 641 mRNAs. Notably, two miRNAs from the miRNA482 family, miRNA-215-3p and miRNA-29-3p, were found to increase kiwifruit's sensitivity to PSA when overexpressed. These miRNAs were linked to the regulation of NBS-LRR target genes, shedding light on their role in kiwifruit's defence against PSA. This study offers insights into the miRNA482-NBS-LRR network as a crucial component in enhancing kiwifruit bioresistance to PSA infestation and provides promising candidate genes for further research.

Highly Stretchable and Oriented Wafer-Scale Semiconductor Films for Organic Phototransistor Arrays.

Stretchable organic phototransistor arrays have potential applications in artificial visual systems due to their capacity to perceive ultraweak light across a broad spectrum. Ensuring uniform mechanical and electrical performance of individual devices within these arrays requires semiconductor films with large-area scale, well-defined orientation, and stretchability. However, the progress of stretchable phototransistors is primarily impeded by their limited electrical properties and photodetection capabilities. Herein, wafer-scale and well-oriented semiconductor films were successfully prepared using a solution shearing process. The electrical properties and photodetection capabilities were optimized by improving the polymer chain alignment. Furthermore, a stretchable 10 × 10 transistor array with high device uniformity was fabricated, demonstrating excellent mechanical robustness and photosensitive imaging ability. These arrays based on highly stretchable and well-oriented wafer-scale semiconductor films have great application potential in the field of electronic eye and artificial visual systems.

Corrigendum: CD8 T cell response and its released cytokine IFN-γ are necessary for lung alveolar epithelial repair during bacterial pneumonia.

[This corrects the article DOI: 10.3389/fimmu.2023.1268078.].

Augmented reality navigation method based on image segmentation and sensor tracking registration technology.

With the rapid development of modern science and technology, navigation technology provides great convenience for people's life, but the problem of inaccurate localization in complex environments has always been a challenge that navigation technology needs to be solved urgently. To address this challenge, this paper proposes an augmented reality navigation method that combines image segmentation and multi-sensor fusion tracking registration. The method optimizes the image processing process through the GA-OTSU-Canny algorithm and combines high-precision multi-sensor information in order to achieve accurate tracking of positioning and guidance in complex environments. Experimental results show that the GA-OTSU-Canny algorithm has a faster image edge segmentation rate, and the fastest start speed is only 1.8 s, and the fastest intersection selection time is 1.2 s. The navigation system combining the image segmentation and sensor tracking and registration techniques has a highly efficient performance in real-world navigation, and its building recognition rates are all above 99%. The augmented reality navigation system not only improves the navigation accuracy in high-rise and urban canyon environments, but also significantly outperforms traditional navigation solutions in terms of navigation startup time and target building recognition accuracy. In summary, this research not only provides a new framework for the theoretical integration of image processing and multi-sensor data, but also brings innovative technical solutions for the development and application of practical navigation systems.

Simulation of the nutritional requirements and energy balance of adult cows in a northern temperate grassland.

The forage-livestock balance is an important component of natural grassland management, and realizing a balance between the nutrient energy demand of domestic animals and the energy supply of grasslands is the core challenge in forage-livestock management. This study was performed at the Xieertala Ranch in Hulunbuir City, Inner Mongolia. Using the GRAZPLAN and GrazFeed models, we examined the forage-livestock energy balance during different grazing periods and physiological stages of livestock growth under natural grazing conditions. Data on pasture conditions, climatic factors, supplemental feeding, and livestock characteristics, were used to analyze the metabolizable energy (ME), metabolizable energy for maintenance (MEm), and total metabolizable energy intake (MEItotal) of grazing livestock. The results showed that the energy balance between forage and animals differed for adult cows at different physiological stages. In the early lactation period, although the MEItotal was greater than MEm, it did not meet the requirement for ME. MEItotal was greater than ME during mid-lactation, but there was still an energy imbalance in the early and late lactation periods. In the late lactation period, MEItotal could meet ME requirements from April-September. Adult gestational lactating cows with or without calves were unable to meet their ME requirement, especially in the dry period, even though MEItotal was greater than MEm. Adult cows at different physiological stages exhibited differences in daily forage intake and rumen microbial crude protein (MCP) metabolism, and the forage intake by nonpregnant cows decreased as follows: early lactation > mid-lactation > late lactation, pregnant cows' lactation > dry period. For the degradation, digestion and synthesis of rumen MCP, early-lactation cows were similar to those in the mid-lactation group, but both were higher than those in the late-lactation group, while pregnant cows had greater degradation, digestion, and synthesis of MCP in the lactation period relative to the dry period. For lactating cows, especially those with calves, grazing energy requirements, methane emission metabolism and heat production were highest in August, with increased energy expenditure in winter. Overall, grazing energy, methane emissions and heat production by dry cows were low. In the context of global climate change and grassland degradation, managers must adopt different strategies according to the physiological stages of livestock to ensure a forage-livestock balance and the sustainable utilization and development of grasslands.

Triptonide induces apoptosis and inhibits the proliferation of ovarian cancer cells by activating the p38/p53 pathway and autophagy.

Ovarian cancer is a common malignant tumor in women, and 70 % of ovarian cancer patients are diagnosed at an advanced stage. Drug chemotherapy is an important method for treating ovarian cancer, but recurrence and chemotherapy resistance often lead to treatment failure. In this study, we screened 10 extracts of Tripterygium wilfordii, a traditional Chinese herb, and found that triptonide had potent anti-ovarian cancer activity and an IC50 of only 3.803 nM against A2780 cell lines. In addition, we determined that triptonide had a better antitumor effect on A2780 cell lines than platinum chemotherapeutic agents in vitro and that triptonide had no significant side effects in vivo. We found that triptonide induced apoptosis in ovarian cancer cells through activation of the p38/p53 pathway and it also induced cell cycle arrest at the S phase. In addition, we demonstrated that triptonide could activate lethal autophagy, which led to growth inhibition and cell death in ovarian cancer cells, resulting in an anti-ovarian cancer effect. Triptonide exerts its anti-ovarian cancer effect through activation of the p38/p53 pathway and induction of autophagy to promote apoptosis, which provides a new candidate drug and strategy for the treatment of ovarian cancer.

Differential polyvalent passive immune protection of egg yolk antibodies (IgY) against live and inactivated Vibrio fluvialis in fish.

Egg yolk antibodies (IgY) can be prepared in large quantities and economically, and have potential value as polyvalent passive vaccines (against multiple bacteria) in aquaculture. This study prepared live and inactivated Vibrio fluvialis IgY and immunized Carassius auratus prior to infection with V. fluvialis and Aeromonas hydrophila. The results showed that the two IgY antibodies hold effective passive protective rates against V. fluvialis and A. hydrophila in C. auratus. Further, the serum of C. auratus recognized the two bacteria in vitro, with a decrease in the bacteria content of the kidney. The phagocytic activity of C. auratus plasma was enhanced, with a decrease in the expression of inflammatory and antioxidant factors. Pathological sections showed that the kidney, spleen, and intestinal tissue structures were intact, and apoptosis and DNA damage decreased in kidney cells. Moreover, the immunoprotection conferred by the live V. fluvialis IgY was higher than that of the inactivated IgY. Addition, live V. fluvialis immunity induced IgY antibodies against outer membrane proteins of V. fluvialis were more than inactivated V. fluvialis immunity. Furthermore, heterologous immune bacteria will not cause infection, so V. fluvialis can be used to immunize chickens to obtain a large amount of IgY antibody. These findings suggest that the passive immunization effect of live bacterial IgY antibody on fish is significantly better than that of inactivated bacterial antibody, and the live V. fluvialis IgY hold potential value as polyvalent passive vaccines in aquaculture.

Differential responses of soil bacteria, fungi and protists to root exudates and temperature.

The impact of climate warming on soil microbes has been well documented, with studies revealing its effects on diversity, community structure and network dynamics. However, the consistency of soil microbial community assembly, particularly in response to diverse plant root exudates under varying temperature conditions, remains an unresolved issue. To address this issue, we employed a growth chamber to integrate temperature and root exudates in a controlled experiment to examine the response of soil bacteria, fungi, and protists. Our findings revealed that temperature independently regulated microbial diversity, with distinct patterns observed among bacteria, fungi, and protists. Both root exudates and temperature significantly influenced microbial community composition, yet interpretations of these factors varied among prokaryotes and eukaryotes. In addition to phototrophic bacteria and protists, as well as protistan consumers, root exudates determined to varying degrees the enrichment of other microbial functional guilds at specific temperatures. The effects of temperature and root exudates on microbial co-occurrence patterns were interdependent; root exudates primarily simplified the network at low and high temperatures, while responses to temperature varied between single and mixed exudate treatments. Moreover, temperature altered the composition of keystone species within the microbial network, while root exudates led to a decrease in their number. These results emphasize the substantial impact of plant root exudates on soil microbial community responses to temperature, underscoring the necessity for future climate change research to incorporate additional environmental variables.

Differences and implications of strontium distribution coefficient on various granite compositional materials.

The distribution coefficient (Kd) of radionuclides is a crucial parameter in assessing the safety of high-level radioactive waste (HLW) geological repository. It is determined in the laboratory through batch and column experiments. However, differences in obtained Kd values from distinct experiments have not been thoroughly assessed and compared. This study evaluated strontium (Sr) sorption on different granite materials using static batch and dynamic experiments (column and core-flooding experiments). The results from batch sorption experiments showed higher Sr sorption on granite under acidic and strongly alkaline conditions, low solid-liquid ratios, and low ionic strength. In column experiments, a two-site sorption model was used to simulate Sr transport in crushed granite and mixed pure minerals. The sorption of Sr on crushed granite exhibited a higher affinity than that of mixed pure minerals. The dual-porosity transport model was employed to investigate Sr transport behavior in fractured granite in the core-flooding experiment. Kd obtained from batch sorption experiments are four to twenty times higher than those from column experiments, and two to three orders of magnitude higher than that from a core-flooding experiment. The results of this study provide valuable insights into safety assessment for the HLW geological repository.

Objective sleep enhancement in Parkinson's disease: A sham-controlled trial of low-frequency repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex.

INTRODUCTION: Parkinson's disease (PD) is often accompanied by sleep disturbances, impacting patients' quality of life. While repetitive transcranial magnetic stimulation (rTMS) shows promise in improving self-reported sleep quality, its effects on objective sleep architecture in PD remain understudied. Sleep disturbances, including rapid eye movement (REM) and slow-wave sleep disturbances, correlate with cognitive decline and motor symptoms. This study investigated the effect of low-frequency rTMS targeting the right dorsolateral prefrontal cortex (DLPFC) modifying objective sleep architecture and explored symptom improvement mechanisms in PD patients. METHODS: In this randomized, double-blind, sham-controlled trial, 67 PD patients received 10 consecutive days of 1-Hz rTMS over the right DLPFC. Polysomnography assessed sleep microstructure, while electroencephalogram recordings evaluated power spectral density and sleep spindle activity. Clinical scales measured sleep quality, motor symptoms, and cognition at baseline, post-treatment, and 3 months post-rTMS. RESULTS: The rTMS group exhibited improvements in sleep quality, motor symptoms, and cognition post-treatment, persisting at the 3-month follow-up. There was a notable increase in the REM sleep proportion post-rTMS. The rTMS group exhibited elevated low-frequency (0.5-2 Hz) slow-wave electroencephalogram spectral density during non-REM sleep. Cognitive enhancement correlated with increased lower delta power, while motor symptom progression correlated with spindle frequency and slow-wave sleep percentage changes. CONCLUSION: Low-frequency rTMS targeting the right DLPFC holds promise for improving clinical symptoms and modulating sleep architecture in PD. These findings suggest a link between symptom improvement and sleep structure enhancement, highlighting the need for further investigation into the therapeutic potential of rTMS in PD management.

Discharge teaching quality positively predicts quality of life in colorectal cancer patients with temporary enterostomy: The mediating role of readiness for hospital discharge and stoma self-efficacy.

OBJECTIVES: This study aimed to examine the mediating role of readiness for hospital discharge (RHD) and stoma self-efficacy (SSE) in the relationship between quality of discharge teaching (QDT) and health-related quality of life (HRQOL) in colorectal cancer patients with temporary enterostomy, and the gender difference of mediating effect. BACKGROUND: It is not clear how RHD, QDT, SSE and HRQOL interact in colorectal cancer patients with temporary enterostomy. METHODS: This was a prospective follow-up survey. 221 colorectal cancer patients with temporary enterostomy were conveniently recruited from a general hospital in Southeast China. The Quality of Discharge Teaching Scale, Readiness for Hospital Discharge Scale, Stoma Self-Efficacy Scale, and Stoma Quality of Life Scale were used to collect data. Pearson's correlation and structural equation models were used to analyze the data. SPSS 26.0 and Amos 28.0 software were used for analysis the collected data. RESULTS: Regarding the relationship of QDT and HRQOL, only QDT-T had a direct effect among colorectal cancer patients with stomas (b = 0.233, P<0.001, percentile 95% CI = [0.145, 0.314]). However, both QDT-T and QDT-R can predict HRQOL indirectly through three paths: (1) the mediating role of SSE (b = 0.050, P = 0.009, percentile 95% CI = [0.013, 0.098]; b = 0.077, P = 0.008, percentile 95% CI = [0.021, 0.164]), (2) the mediating role of RHD (b = 0.044, P = 0.004, percentile 95% CI = [0.014, 0.085]; b = 0.044, P = 0.005, percentile 95% CI = [0.010, 0.102]), and (3) the chain mediating role of SSE and RHD (b = 0.030, P = 0.003, percentile 95% CI = [0.011, 0.059]; b = 0.047, P = 0.003, percentile 95% CI = [0.015, 0.103]). The similar chain mediating effect in male stoma patients was also found (b = 0.041, P = 0.002, percentile 95% CI = [0.016, 0.080]; b = 0.046, P = 0.004, percentile 95% CI = [0.011, 0.114]). CONCLUSIONS: Stoma self-efficacy and readiness for hospital discharge played important intermediary roles in the relationship between quality of discharge teaching and health-related quality of life in colorectal cancer patients with stomas. Health care providers can design SSE-enhancing and RHD-enhancing discharge planning for colorectal cancer patients with temporary enterostomies.

Correction: A robust and porous titanium metal-organic framework for gas adsorption, CO2 capture and conversion.

Correction for 'A robust and porous titanium metal-organic framework for gas adsorption, CO2 capture and conversion' by Xuze Pan, et al., Dalton Trans., 2023, 52, 3896-3906, https://doi.org/10.1039/D2DT03158B.

PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy.

BACKGROUND: PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. RESULTS: We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. CONCLUSIONS: In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors.

Insulin attenuates LPS-induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus.

AIMS: Neuroinflammation is a recognized contributor to cognitive disorders like Alzheimer's disease, with ferroptosis emerging as a novel mechanism underlying cognitive dysfunction associated with neuroinflammation. Insulin, pivotal in the central nervous system, holds promise for cognitive function enhancement. This study aimed to establish a cognitive impairment model through intracerebroventricular injection of lipopolysaccharide (LPS) and explore the impact of intracerebroventricular insulin injection on cognitive function in mice. METHODS: We employed diverse experimental techniques, including animal behavior testing, molecular assays, targeted metabolomics, nuclear medicine, and electron microscopy, to assess neurodegenerative changes, brain insulin resistance (IR), glucose uptake and metabolism, and ferroptosis. The model of cognitive impairment was induced via intracerebroventricular injection of LPS, followed by intracerebroventricular administration of insulin to evaluate its effects. RESULTS: Insulin treatment effectively mitigated LPS-induced cognitive decline and safeguarded against neuronal degeneration. Furthermore, insulin alleviated LPS-induced insulin resistance, enhanced glucose uptake in the hippocampus, and promoted the Pentose Phosphate Pathway (PPP) and nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, insulin activated the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway, reducing lipid peroxidation, and mitochondrial damage characteristic of LPS-induced ferroptosis in the hippocampus. CONCLUSION: Our findings underscore the therapeutic potential of insulin in alleviating LPS-induced cognitive impairment and ferroptosis by modulating glucose metabolism. This study offers a promising avenue for future interventions targeting cognitive decline.

Neurologic music therapy for non-fluent aphasia: a systematic review and meta-analysis of randomized controlled trials.

Introduction: The efficacy of neurologic music therapy (NMT) techniques for the treatment of non-fluent aphasia has been widely accepted by the rehabilitation medical community. However, consensus on which dimensions of speech function can be improved by NMT techniques and standardized intervention dosage remains elusive. This study aimed to provide evidence regarding the efficacy of NMT in improving speech function and explore the optimal intervention dose. A systematic review and meta-analysis were conducted to search for randomized clinical trials and open-label trials that evaluated speech functions after NMT. Methods: We searched all papers and reviews published from database inception to July 2023, including PubMed, Cochrane Library, Web of Science, Embase, and CNKI. Statistical analyses were mainly carried out on RevManV5.4.1 and pooled using a random-effects model. The primary outcome was the standardized mean difference (SMD) in speech functions, determined by calculating the change in speech functions score from baseline to the primary endpoint in the NMT group versus the control arm. Results: A total of 11 studies with 329 patients were included. NMT had a positive effect on repetition ability (SMD = 0.37, 95%CI [0.12, 0.62], p < 0.05), but did not lead to significant differences in naming, comprehension, spontaneous speech, or communication. When the intervention time was >20 h, NMT exhibited a significant advantage at improving repetition ability (SMD = 0.43, 95%CI [0.06, 0.79], p < 0.05). Discussion: This study provides evidence supporting the NMT enhancement of repetition ability in patients with non-fluent aphasia. Future large-sample studies are required to determine the optimal intervention dose of music therapy for different subtypes of non-fluent aphasia. Systematic review registration: PROSPERO, identifier CRD42023470313.