A novel strategy for spinal cord reconstruction via vascularized allogeneic spinal cord transplantation combine spinal cord fusion.

AIMS: Spinal cord injuries (SCI) pose persistent challenges in clinical practice due to the secondary injury. Drawing from our experience in spinal cord fusion (SCF), we propose vascularized allogeneic spinal cord transplantation (vASCT) as a novel approach for SCI, much like organ transplantation has revolutionized organ failure treatment and vascularized composite-tissue allotransplantation has addressed limb defects. MATERIALS AND METHODS: In this study, 24 dogs were paired and underwent vASCT, with donor spinal cord grafts and polyethylene glycol (PEG) application for SCF. The experimental group (n = 8) received tacrolimus and methylprednisolone, while the control group (n = 4) received only methylprednisolone. Safety and efficacy of vASCT were evaluated through electrophysiology, imaging, and 6-month follow-up. RESULTS: The experimental group showed substantial recovery in hind limb motor function. Imaging revealed robust survival of spinal cord grafts and restoration of spinal cord continuity. In contrast, the control group maintained hind limb paralysis, with imaging confirming spinal cord graft necrosis and extensive defects. Electrophysiologically, the experimental group exhibited restored motor evoked potential signal conduction postoperatively, unlike the control group. Notably, PEG application during vASCT led to signal conduction recovery in intraoperative spinal cord evoked potential examinations for all dogs. CONCLUSION: In the vASCT surgical model, the combination of PEG with tacrolimus has demonstrated the ability to reconstruct spinal cord continuity and restore hind limb motor function in beagles. Notably, a low dose of tacrolimus has also exhibited an excellent anti-immune rejection effect. These findings highlight vASCT's potential promise as a therapeutic strategy for addressing irreversible SCI.

Measurable imaging-based changes in enhancement of intrahepatic cholangiocarcinoma after radiotherapy reflect physical mechanisms of response.

Background: Although escalated doses of radiation therapy (RT) for intrahepatic cholangiocarcinoma (iCCA) are associated with durable local control (LC) and prolonged survival, uncertainties persist regarding personalized RT based on biological factors. Compounding this knowledge gap, the assessment of RT response using traditional size-based criteria via computed tomography (CT) imaging correlates poorly with outcomes. We hypothesized that quantitative measures of enhancement would more accurately predict clinical outcomes than size-based assessment alone and developed a model to optimize RT. Methods: Pre-RT and post-RT CT scans of 154 patients with iCCA were analyzed retrospectively for measurements of tumor dimensions (for RECIST) and viable tumor volume using quantitative European Association for Study of Liver (qEASL) measurements. Binary classification and survival analyses were performed to evaluate the ability of qEASL to predict treatment outcomes, and mathematical modeling was performed to identify the mechanistic determinants of treatment outcomes and to predict optimal RT protocols. Results: Multivariable analysis accounting for traditional prognostic covariates revealed that percentage change in viable volume following RT was significantly associated with OS, outperforming stratification by RECIST. Binary classification identified ≥33% decrease in viable volume to optimally correspond to response to RT. The model-derived, patient-specific tumor enhancement growth rate emerged as the dominant mechanistic determinant of treatment outcome and yielded high accuracy of patient stratification (80.5%), strongly correlating with the qEASL-based classifier. Conclusion: Following RT for iCCA, changes in viable volume outperformed radiographic size-based assessment using RECIST for OS prediction. CT-derived tumor-specific mathematical parameters may help optimize RT for resistant tumors.

Impacts of Elevated CO2 and a Nitrogen Supply on the Growth of Faba Beans (Vicia faba L.) and the Nitrogen-Related Soil Bacterial Community.

Ecosystems that experience elevated CO2 (eCO2) are crucial interfaces where intricate interactions between plants and microbes occur. This study addressed the impact of eCO2 and a N supply on faba bean (Vicia faba L.) growth and the soil microbial community in auto-controlled growth chambers. In doing so, two ambient CO2 concentrations (aCO2, daytime/nighttime = 410/460 ppm; eCO2, 550/610 ppm) and two N supplement levels (without a N supply-N0-and 100 mg N as urea per kg of soil-N100) were applied. The results indicated that eCO2 mitigated the inhibitory effects of a N deficiency on legume photosynthesis and affected the CO2 assimilation efficiency, in addition to causing reduced nodulation. While the N addition counteracted the reductions in the N concentrations across the faba beans' aboveground and belowground plant tissues under eCO2, the CO2 concentrations did not significantly alter the soil NH4+-N or NO3--N responses to a N supply. Notably, under both aCO2 and eCO2, a N supply significantly increased the relative abundance of Nitrososphaeraceae and Nitrosomonadaceae, while eCO2 specifically reduced the Rhizobiaceae abundance with no significant changes under aCO2. A redundancy analysis (RDA) highlighted that the soil pH (p < 0.01) had the most important influence on the soil microbial community. Co-occurrence networks indicated that the eCO2 conditions mitigated the impact of a N supply on the reduced structural complexity of the soil microbial communities. These findings suggest that a combination of eCO2 and a N supply to crops can provide potential benefits for managing future climate change impacts on crop production.

Effects of Carbon Fiber Content on the Crystallization and Rheological Properties of Carbon Fiber-Reinforced Polyamide 6.

Carbon fiber (CF)-reinforced polyamide 6 (PA6) composites have an excellent performance, attributed to properties such as light quality, high strength, and vibration reduction, and they are widely used in fields such as aerospace and transportation. Four kinds of carbon fiber-reinforced polyamide 6 (CF/PA6) composite pellets with carbon fiber contents of 20, 30, 40, and 50 wt.% were prepared using twin screw extrusion. The results were characterized using a simultaneous thermal analyzer, capillary rheometer, electronic universal material testing machine, and scanning electron microscope (SEM); their crystallization, rheological behavior, mechanical properties, surface structure, etc., were studied. DSC results indicate that an increase in carbon fiber content enhances the thermal stability of CF/PA6 and narrows the crystallization window but has a minor effect on the molecular chain diffusion time. The crystallinity reaches its maximum at a carbon fiber content of 40 wt.%, reaching 55.16%. The steady-state rheological behavior reveals that CF/PA6 behaves as a pseudoplastic fluid, exhibiting shear-thinning behavior. When the carbon fiber content is 40 wt.%, the power law exponent (n) reaches its maximum, and the consistency coefficient (K) decreases by 300 Pa⋅sn compared to the 30 wt.% content. With increasing temperature, n increases while K decreases. SEM observations reveal that samples with carbon fiber contents of 20 wt.% and 40 wt.% exhibit better fiber dispersion and orientation. However, the interfacial bonding strength is superior in the 40 wt.% sample. When the carbon fiber content reaches 50 wt.%, significant injection molding defects occur at the clamping end, leading to extensive matrix tearing during tension testing.

Development of a nomogram for postoperative surgical site infections in patients undergoing bowel resection for Crohn's disease.

BACKGROUND: Surgical site infection (SSI) is a significant concern due to its potential to cause delayed wound healing and prolonged hospital stays. This study aims to develop a predictive model in patients with Crohn's disease. METHODS: We conducted single-factor and multi-factor logistic regression analyses to identify risk factors, resulting in the development of a logistic regression model and the creation of a nomogram. The model's effect was validated by employing enhanced bootstrap resampling techniques, calibration curves, and DCA curves. Finally, we investigated the risk factors for wall and intra-abdominal infections separately. RESULTS: 90 of 675 patients (13.3 %) developed SSI. Several independent risk factors for SSI were identified, including higher postoperative day one neutrophil count (p = 0.033), higher relative blood loss (p = 0.018), female gender (p = 0.021), preoperative corticosteroid use (p = 0.007), Montreal classification A1 and L2 (p < 0.05), previous intestinal resection (p = 0.017), and remaining lesions (p = 0.015). Additionally, undergoing strictureplasty (p = 0.041) is a protective factor against SSI. These nine variables were used to develop an SSI prediction model presented as a nomogram. The model demonstrated strong discrimination (adjusted C-statistic=0.709, 95 % CI: 0.659∼0.757) and precise calibration. The decision curve showed that the nomogram was clinically effective within a probability threshold range of 3 % to 54 %. Further subgroup analysis revealed distinct risk factors for wall infections and intra-abdominal infections. CONCLUSION: We established a new predictive model, which can guide the prevention and postoperative care of SSI after Crohn's disease bowel resection surgery to minimize its occurrence rate.

Reduction of intracortical inhibition (ICI) correlates with cognitive performance and psychopathology symptoms in schizophrenia.

Cognitive impairment is a core symptom of schizophrenia (SZ), with GABAergic dysfunction in the brain potentially serving as a critical pathological mechanism underlying this condition. Intracortical inhibition (ICI), which includes short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), can be used to assess the inhibitory function of cortical GABAergic neurons. The aim of this study was to investigate the relationship between ICI and cognitive function, as well as psychopathological symptoms, in SZ patients. We recruited 130 SZ patients and 105 healthy controls (HCs). All subjects underwent paired-pulse transcranial magnetic stimulation (ppTMS) measurements, which included resting motor threshold (RMT), SICI and LICI. The cognitive function of all subjects was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). The psychopathological symptoms of the SZ group were assessed using the Positive and Negative Syndrome Scale (PANSS). We examined group differences in MCCB scores, RMT, SICI, and LICI. Within the SZ group, we assessed the relationship between ICI and cognitive function, as well as psychopathological symptoms. Two-way ANOVA, Mann-Whitney U test, Receiver operating characteristic (ROC) curves, and partial Spearman correlation analysis were performed. The SZ group showed a worse cognitive score in all 6 cognitive dimensions of the MCCB compared to the HC group (all p < 0.05). The SZ group had lower degree of SICI and LICI compared to the HC group (both p < 0.05). ROC curves analysis showed that SICI and LICI all displayed good performance in differentiating SZ patients and HCs (both p < 0.05), and SICI exhibited a better performance, yielding an area under the curve (AUC) of 0.856 (95% CI 0.807-0.904). Furthermore, in the SZ group, SICI demonstrated a significant negative correlation with PANSS positive score, negative score, general psychopathology score, and total score (all pBonferroni < 0.05), and LICI demonstrated a significant negative correlation with PANSS positive score, general psychopathology score and total score (all pBonferroni < 0.05). Additionally, in the SZ group, SICI demonstrated a significant positive correlation with speed of processing score, working memory score, verbal learning score, visual learning score, and reasoning and problem-solving score of the MCCB (all pBonferroni < 0.05), while LICI was only weakly positive correlated with speed of processing score of the MCCB (r = 0.247, p = 0.005, pBonferroni = 0.03). Our results demonstrate that the reduction of ICI could serve as a trait-dependent in-vivo biomarker of GABAergic deficits for SZ and related cognitive impairments.

Subcellular localization and function analysis of PINK1 mitron in PD progression: mitron modulates mitochondrial morphology to regulate neuronal death.

Parkinson's disease (PD) is a multi-factorial neurodegenerative disorder. Loss or degeneration of the dopaminergic neurons in the substantia nigra and development of Lewy Bodies in dopaminergic neurons were the defining pathologic changes. MiRNAs fine-tune the protein levels by post-transcriptional gene regulation. MiR-7019-3p is encoded within the 5th intron of PD associated protein PINK1. In present study, we firstly demonstrated miR-7019-3p expression is significantly up regulated in PD mice model and neuron cell models, miR-7019-3p mainly existed in mitochondria, miR-7019-3p could regulate the structure and function of mitochondria in neuronal cells. We predicted and verified that mitochondria associated protein OPA1 and 12s rRNA, 16s rRNA and polycistronic RNA are target genes of miR-7019-3p. Finally, we proved that SP1 protein could independently regulate the expression of miR-7019-3p at the upstream. The evidences in the study suggest the role miR-7019-3p in the regulation of mitochondrial structure and function, and this kind of regulation could be implemented or promoted through the pathway of SP1-miR-7019-3p-OPA1/12s rRNA, 16s rRNA and polycistronic RNA. Our results have suggested a promising and potential therapeutic target for reversing mitochondria dysregulation in neuronal cells during Parkinson's disease process.

High-Capacity Zinc Anode Enabled by a Recyclable Biomass Bamboo Membrane Separator.

Aqueous zinc ion batteries have gained attention as viable energy storage systems, yet the occurrence of detrimental side reactions and Zn dendrite formation undermines the efficiency of Zn anodes. Controlling water activity have proven to be an effective strategy in mitigating these challenges. However, strategies such as electrolyte design and electrode protection layer show weakness to varying degrees. Here, a new oxygen-functionalized biomass bamboo membrane separator (denoted as BM) is proposed to restrain the activity of water molecules. This BM separator features a unique, multi-tiered 2D interlayer that facilitates rapid ion diffusion. Additionally, the oxygen functional groups of the BM separator can form hydrogen bonds with water molecules, effectively transforming water molecules from a free state to a bound state. Consequently, the Zn/Zn asymmetric coin cell using BM can work at the ultrahigh rate and capacity of 30 mA cm-2 and 30 mAh cm-2 for more than 80 h while its counterparts using glass fiber can barely work. Moreover, full cells using BM separator exhibited a capacity retention of 89.7% after 1000 cycles at 10 A g-1. This study reveals the important influence of water-limited activity on Zn anode protection and provides an avenue for the design of novel separator.

Electrochemically chalcogenative annulation enabled construction of functionalized saturated N-heterocycles.

An efficient chalcogenative annulation strategy for constructing functionalized saturated N-heterocycles from unactivated alkenes with dichalcogenides under electrochemical conditions has been presented. This protocol is applicable to mono-, di- or tri-substituted alkenes, providing a straightforward pathway to aziridines, azetidines, pyrrolidines, and piperidines with high regioselectivity. Moreover, the strategy is qualified to realize the oxychalcogenation of alkenes as well.

Impact of manganese mining on potentially toxic elements pollution and bioaccumulation in Spirogyra varians and Hydrilla verticillata in the Xiaojiang River.

Potentially toxic elements (PTEs) pose a significant threat to aquatic ecosystems. This study investigated the content and potential sources of PTEs (Cr, Mn, Ni, Cu, Zn, Cd, Pb) in water, sediment, and dominant aquatic plants (Hydrilla verticillata and Spirogyra varians) in the Xiaojiang River, located near the Zhaiying manganese mine in Guizhou Province, China. Correlation analysis, principal component analysis (PCA), and cluster analysis were employed to assess PTE distribution and potential sources. Water PTE concentrations complied with the Class II standard (GB3838-2002), indicating no water pollution. However, sediment PTE levels exceeded background values, particularly Mn, which exhibited moderate to strong contamination. Cd also showed moderate contamination, posing a considerable ecological risk. Cd was the main potential pollutant with the highest contribution rate. Mn and Cd were therefore identified as priority pollutants requiring targeted abatement strategies. Mining activities likely represent the primary source, but combined pollution from vehicle traffic and agriculture might also contribute. Hydrilla verticillata demonstrated a higher capacity for PTE enrichment from sediment compared to Spirogyra varians, suggesting its potential for sediment remediation (except for Cu). A significant correlation existed between both plant species and sediment PTE content. PCA supported the association between S. varians and sediment PTEs. Linear regression analyses revealed better correlations between S. varians and sediment Mn, Ni, Cu, and Zn (0.77, 0.68, 0.82, and 0.79, respectively). Taken together, these findings suggest that S. varians serves as an effective bioindicator for monitoring sediment contamination with PTEs.

Mitigating citrus fruit cracking: the efficacy of chelated calcium or silicon foliar fertilizers in 'Okitsu no. 58' citrus fruit.

The 'Okitsu No. 58' citrus variety is highly prone to fruit cracking, which jeopardizes yield and results in economic losses. In this study, we investigated the impacts of spraying 5 distinct concentrations (0.1, 0.2, 0.3, 0.4, and 0.5 g/L) of chelated calcium (Ca) or silicon (Si) fertilizers at the young fruit stage (60-90 days after flowering, DAF) on fruit cracking and quality in the citrus variety 'Okitsu No. 58'. The results showed either Ca or Si fertilizer treatments reduced fruit cracking. We found that all Ca and partial Si treatments (0.4 and 0.5 g/L) significantly promoted the accumulation of Ca content in the peel. Notably, Ca or Si treatments significantly reduced polygalacturonase (PG) activity and inhibited the production of water-soluble pectin (WSP) in the peel. Additionally, Ca or Si treatments elevated the superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) content of the peels. Changes in these parameters likely contributed to strengthening the durability of peel cell wall constituents, thus enhancing the fruit's resistance to fruit cracking. Overall, except for the C3 (0.3 g/L of Ca), Ca or Si fertilizers contributed to fruit conventional quality, mainly in terms of higher soluble sugars (SS) and SS/TA (titratable acid). Therefore, our findings will provide a reference for the prevention and control of citrus fruit cracking and the development of new fertilizers.

Hybridizing mechanistic modeling and deep learning for personalized survival prediction after immune checkpoint inhibitor immunotherapy.

We present a study where predictive mechanistic modeling is combined with deep learning methods to predict individual patient survival probabilities under immune checkpoint inhibitor (ICI) immunotherapy. This hybrid approach enables prediction based on both measures that are calculable from mechanistic models of key mechanisms underlying ICI therapy that may not be directly measurable in the clinic and easily measurable quantities or patient characteristics that are not always readily incorporated into predictive mechanistic models. A deep learning time-to-event predictive model trained on a hybrid mechanistic + clinical data set from 93 patients achieved higher per-patient predictive accuracy based on event-time concordance, Brier score, and negative binomial log-likelihood-based criteria than when trained on only mechanistic model-derived values or only clinical data. Feature importance analysis revealed that both clinical and model-derived parameters play prominent roles in increasing prediction accuracy, further supporting the advantage of our hybrid approach.

Identification of histopathological classification and establishment of prognostic indicators of gastric adenocarcinoma based on deep learning algorithm.

The aim of this study is to establish a deep learning (DL) model to predict the pathological type of gastric adenocarcinoma cancer based on whole-slide images(WSIs). We downloaded 356 histopathological images of gastric adenocarcinoma (STAD) patients from The Cancer Genome Atlas database and randomly divided them into the training set, validation set and test set (8:1:1). Additionally, 80 H&E-stained WSIs of STAD were collected for external validation. The CLAM tool was used to cut the WSIs and further construct the model by DL algorithm, achieving an accuracy of over 90% in identifying and predicting histopathological subtypes. External validation results demonstrated the model had a certain generalization ability. Moreover, DL features were extracted from the model to further investigate the differences in immune infiltration and patient prognosis between the two subtypes. The DL model can accurately predict the pathological classification of STAD patients, and provide certain reference value for clinical diagnosis. The nomogram combining DL-signature, gene-signature and clinical features can be used as a prognostic classifier for clinical decision-making and treatment.

Comparison of multiplex PCR capillary electrophoresis assay and PCR-reverse dot blot assay for human papillomavirus DNA genotyping detection in cervical cancer tissue specimens.

Background: The study aimed to evaluate the positivity rates and genotype distribution of the multiplex PCR capillary electrophoresis (MPCE) and PCR-Reverse Dot Blot (PCR-RDB) assays for human papillomavirus (HPV) detection in cervical cancer tissue specimens, and to explore their detection principles and applications in large-scale population screening. Methods: The MPCE and PCR-RDB assays were performed separately on 425 diagnosed cervical cancer tissue specimens. Subsequently, the results of both assays were compared based on the HPV infection positivity rates and genotype distribution. Results: The overall positive rates of HPV genotypes for the MPCE and PCR-RDB assays were 97.9% and 92.9%, respectively. A p-value < 0.001 indicated a statistically significance difference in consistency between the two assays. The kappa value was 0.390, indicating that the consistency between both assays was fair. HPV16 was the most common single-genotype infection type, with infection rates detected via MPCE and PCR-RDB assays being 75.7% and 68.3%, respectively. In the age group >50 years, the HPV multiple-type infection rate detected via MPCE assay was significantly higher than that detected by the PCR-RDB assay, with a statistically significant difference (p = 0.002). Conclusion: To reduce the false-negative rate and improve screening efficiency, the MPCE assay, which targets the oncogenic gene E6/E7 segments, can be extended to the general female population for the early detection, diagnosis, and treatment of cervical cancer.

Responses in species diversity in the Hulunbuir grassland to phosphorus addition under nitrogen-limiting and non-limiting conditions.

The phenomenon of nitrogen deposition resulting in species loss in terrestrial ecosystems has been demonstrated in several experiments. Nitrogen (N) and phosphorus (P), as major nutrients required for plant growth, exhibit ecological stoichiometric coupling in many ecosystems. The increased availability of nitrogen can exacerbate the ecological effects of phosphorus. To reveal the ecological effects of phosphorus under nitrogen-limiting and non-limiting conditions, we conducted a controlled N-P interaction experiment over 5 years in the Hulunbuir meadow steppe, where two nitrogen addition levels were implemented: 0 g N·m-2·a-1 (nitrogen-limiting condition) and 10 g N·m-2·a-1 (nitrogen-non-limiting condition), together with six levels of phosphorus addition (0, 2, 4, 6, 8, and 10 g P·m-2·a-1). The results showed that nitrogen addition (under nitrogen-non-limiting conditions) significantly decreased species diversity in the steppe community, which was exacerbated under phosphorus addition. Under nitrogen-limiting conditions, phosphorus addition had no marked impact on species diversity compared to the control; however, there were substantial differences between different levels of phosphorus addition, exhibiting a unimodal change. Under both experimental nitrogen conditions, the addition of 6 g P·m-2·a-1 was the threshold for affecting the community species diversity. Nitrogen addition reduced the relative biomass of legumes, bunch grasses, and forbs, but substantially increased the relative biomass of rhizomatous grasses. In contrast, phosphorus addition only markedly affected the relative biomass of forbs and rhizomatous grasses, with the former showing a unimodal pattern of first increasing and then decreasing with increasing phosphorus addition level, and the latter exhibiting the opposite pattern. The different responses of rhizomatous grasses and other functional groups to nitrogen and phosphorus addition were observed to have a regulatory effect on the changes in grassland community structure. Phosphorus addition may increase the risk of nitrogen deposition-induced species loss. Both nitrogen and phosphorus addition lead to soil acidification and an increase in the dominance of the already-dominant species, and the consequent species loss in the forb functional group represents the main mechanism for the reduction in community species diversity.

Evaluation of the Reliability of the CCM-300 Chlorophyll Content Meter in Measuring Chlorophyll Content for Various Plant Functional Types.

Chlorophyll fluorescence is a well-established method to estimate chlorophyll content in leaves. A popular fluorescence-based meter, the Opti-Sciences CCM-300 Chlorophyll Content Meter (CCM-300), utilizes the fluorescence ratio F735/F700 and equations derived from experiments using broadleaf species to provide a direct, rapid estimate of chlorophyll content used for many applications. We sought to quantify the performance of the CCM-300 relative to more intensive methods, both across plant functional types and years of use. We linked CCM-300 measurements of broadleaf, conifer, and graminoid samples in 2018 and 2019 to high-performance liquid chromatography (HPLC) and/or spectrophotometric (Spec) analysis of the same leaves. We observed a significant difference between the CCM-300 and HPLC/Spec, but not between HPLC and Spec. In comparison to HPLC, the CCM-300 performed better for broadleaves (r = 0.55, RMSE = 154.76) than conifers (r = 0.52, RMSE = 171.16) and graminoids (r = 0.32, RMSE = 127.12). We observed a slight deterioration in meter performance between years, potentially due to meter calibration. Our results show that the CCM-300 is reliable to demonstrate coarse variations in chlorophyll but may be limited for cross-plant functional type studies and comparisons across years.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

ROS-Responsive Ferrocenyl Amphiphilic PAMAM Dendrimers for On-Demand Delivery of siRNA Therapeutics to Cancer Cells.

Small interfering RNA (siRNA) therapeutics, characterized by high specificity, potency, and durability, hold great promise in the treatment of cancer and other diseases. However, the clinic implementation of siRNA therapeutics critically depends on the safe and on-demand delivery of siRNA to the target cells. Here, we reported a family of ferrocenyl amphiphilic dendrimers (Fc-AmDs) for on-demand delivery of siRNA in response to the high ROS content in cancer cells. These dendrimers bear ROS-sensitive ferrocene moieties in the hydrophobic components and positively chargeable poly(amidoamine) dendrons as the hydrophilic entities, possessing favorable safety profiles and ROS responsive properties. One of these ferrocenyl amphiphilic dendrimers, Fc-C8-AmD 8A, outperforms in siRNA delivery, benefiting from its optimal balance of hydrophobicity and hydrophilicity. Its ROS feature facilitates specific and efficient disassembly of its complex with siRNA in ROS-rich cancer cells for effective siRNA delivery and gene silencing. Moreover, Fc-C8-AmD 8A also integrates the features and beneficial properties of both lipid and dendrimer vectors. Therefore, it represents a novel on-demand delivery system for cancer cell-specific siRNA delivery. This work opens new perspectives for designing self-assembly nanosystems for on-demand drug delivery.

Microscopic and submicroscopic exploration of diplolepideae peristome structures in hygroscopic movement.

BACKGROUND: The Diplolepideae are the larger group within the Arthrodontae mosses, characterized by peristomes formed from residual cell walls. It is now understood that these peristomes exhibit diverse hygroscopic movements, playing a crucial role in spore release. However, the exact mechanism behind this movement remains unclear, lacking direct evidence. This study investigated the microscopic and submicroscopic structures of the peristomes in three Diplolepideae species: Hypopterygium fauriei (Besch.), Pylaisia levieri (Müll. Hal.) Arikawa and Regmatodon declinatus (Hook.) Brid. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to reveal the differences in their hygroscopic movement mechanisms. RESULTS: The three species exhibited distinct responses upon wetting: H. fauriei's exostome closed inwards, P. levieri' opened outwards, and R. declinatus' elongated significantly. These differences are attributed to the varying microfibril deposition in the exostome layers. Uniform deposition in the inner layer and minimal deposition in the outer layer enabled exostome opening upon wetting and closing when dry. Our findings suggest that the diastole and contraction of fine microfibrils in the exostome plates and ridges are the key drivers of hygroscopic movement. CONCLUSIONS: This study provides further evidence at both the structural and submicroscopic levels, contributing to the unraveling of the hygroscopic movement mechanism in Diplolepideae peristomes. This enhanced understanding sheds light on the relationship between peristome structure and function.