Analysis of fungal diversity in the gut feces of wild takin (Budorcas taxicolor).

Introduction: The composition of the intestinal microbiome correlates significantly with an animal's health status. Hence, this indicator is highly important and sensitive for protecting endangered animals. However, data regarding the fungal diversity of the wild Budorcas taxicolor (takin) gut remain scarce. Therefore, this study analyzes the fungal diversity, community structure, and pathogen composition in the feces of wild B. taxicolor. Methods: To ensure comprehensive data analyses, we collected 82 fecal samples from five geographical sites. Amplicon sequencing of the internal transcribed spacer (ITS) rRNA was used to assess fecal core microbiota and potential pathogens to determine whether the microflora composition is related to geographical location or diet. We further validated the ITS rRNA sequencing results via amplicon metagenomic sequencing and culturing of fecal fungi. Results and discussion: The fungal diversity in the feces of wild Budorcas taxicolor primarily comprised three phyla (99.69%): Ascomycota (82.19%), Fungi_unclassified (10.37%), and Basidiomycota (7.13%). At the genus level, the predominant fungi included Thelebolus (30.93%), Functional_unclassified (15.35%), and Ascomycota_unclassified (10.37%). Within these genera, certain strains exhibit pathogenic properties, such as Thelebolus, Cryptococcus, Trichosporon, Candida, Zopfiella, and Podospora. Collectively, this study offers valuable information for evaluating the health status of B. taxicolor and formulating protective strategies.

Untargeted metabolomics reveals that declined PE and PC in obesity may be associated with prostate hyperplasia.

BACKGROUND: Recent studies have shown that obesity may contribute to the pathogenesis of benign prostatic hyperplasia (BPH). However, the mechanism of this pathogenesis is not fully understood. METHODS: A prospective case-control study was conducted with 30 obese and 30 nonobese patients with BPH. Prostate tissues were collected and analyzed using ultra performance liquid chromatography ion mobility coupled with quadrupole time-of-flight mass spectrometry (UPLC-IMS-Q-TOF). RESULTS: A total of 17 differential metabolites (3 upregulated and 14 downregulated) were identified between the obese and nonobese patients with BPH. Topological pathway analysis indicated that glycerophospholipid (GP) metabolism was the most important metabolic pathway involved in BPH pathogenesis. Seven metabolites were enriched in the GP metabolic pathway. lysoPC (P16:0/0:0), PE (20:0/20:0), PE (24:1(15Z)/18:0), PC (24:1(15Z)/14:0), PC (15:0/24:0), PE (24:0/18:0), and PC (16:0/18:3(9Z,12Z,15Z)) were all significantly downregulated in the obesity group, and the area under the curve (AUC) of LysoPC (P-16:0/0/0:0) was 0.9922. The inclusion of the seven differential metabolites in a joint prediction model had an AUC of 0.9956. Thus, both LysoPC (P-16:0/0/0:0) alone and the joint prediction model demonstrated good predictive ability for obesity-induced BPH mechanisms. CONCLUSIONS: In conclusion, obese patients with BPH had a unique metabolic profile, and alterations in PE and PC in these patients be associated with the development and progression of BPH.

Silicon Hybridization for the Preparation of Room-Temperature Curing and High-Temperature-Resistant Epoxy Resin.

Specialized epoxy resin, capable of achieving room-temperature profound curing and sustaining prolonged exposure to high-temperature environments, stands as a pivotal material in modern high-end manufacturing sectors including aerospace, marine equipment fabrication, machinery production, and the electronics industry. Herein, a silicon-hybridized epoxy resin, amenable to room-temperature curing and designed for high-temperature applications, was synthesized using a sol-gel methodology with silicate esters and silane coupling agents serving as silicon sources. Resin characterization indicates a uniform distribution of silicon elements in the obtained silicon hybrid epoxy resin. In comparison to the non-hybridized epoxy resin, notable improvements are observed in room-temperature curing performance, heat resistance, and mechanical strength.

Gegen Qinlian Decoction Modulates Atherosclerosis and Lipid Metabolism Through Cellular Interplay and Signaling Pathways.

OBJECTIVE: The objective of this study is to investigate Gegen Qinlian decoction (GQD) effects on lipid metabolism and explore its mechanism for preventing and treating atherosclerosis. METHODS: An atherosclerotic rat model was established;, and after an 8-week high-fat diet, atherosclerosis and non-alcoholic fatty liver disease were assessed. Subsequently, GQD was administered at low and high doses. Histopathological aortic wall changes, hepatic lipid deposition, and blood lipid changes were evaluated. ELISA indicated the influence of TNF-α and IL-13, and Western blotting revealed MerTK, ABCA1, and LXR-α expression. A foam macrophage model was established, and Cell activity was detected by the MTT method. ELISA indicated the influence of PPAR-γ. The expression of ABCA1, ABCA7, ABCG1, GAS6, MerTK, SCARB1, LXR- α and LXR-ß mRNA were detected by qPCR， and Western blotting revealed MerTK and LXR-α expression. The impact of drug-containing serum of GQD on efferocytosis-related factors was studied. RESULTS: GQD improved atherosclerosis and non-alcoholic fatty liver disease and reduced serum low-density lipoprotein levels in the high-dose group. The high- and low-dose groups showed upregulated ABCA1, MerTK, and LXR-α expression in blood vessels and the liver, respectively. GQD decreased serum TNF-α and increased IL-13 levels. PPAR-γ expression was elevated in the high-, and low-dose groups. In the high-and low-dose groups, ABCA7, GAS6, SCARB1, and LXR-α, ABCA1 and MerTK, and ABCG1 gene expression were upregulated, respectively. Both low- and high-dose serum-containing drugs promoted LXR-ß gene expression, and LXR-α protein expression was improved in the high-dose group. CONCLUSION: GQD improves rat atherosclerosis and hepatic lipid metabolism by regulating PPAR-γ, LXR-α, LXR-ß, ABCA1, ABCA7, and ABCG1 expression and augmenting cellular intercalation through the GAS6/TAM pathway.

Comprehensive review on the elaboration of payloads derived from natural products for antibody-drug conjugates.

Antibody-drug conjugates (ADCs) have arisen as a promising class of biotherapeutics for targeted cancer treatment, combining the specificity of monoclonal antibodies with the cytotoxicity of small-molecule drugs. The choice of an appropriate payload is crucial for the success development of ADCs, as it determines the therapeutic efficacy and safety profile. This review focuses on payloads derived from natural products, including cytotoxic agents, DNA-damaging agents, and immunomodulators. These offer several advantages such as diverse chemical structures, unique mechanism of actions, and potential for improved therapeutic index. Challenges and opportunities associated with their development were highlighted. This review underscores the significance of natural product payloads in the elaboration of ADCs, which serves as a valuable resource for researchers involved in developing and optimizing next-generation ADCs for cancer treatment.

Straw with different fermentation degrees mediate Se/Cd bioavailability by governing the putative iron reducing bacteria.

Straw returning is a crucial agronomic practice in fields due to its various benefits. However, effects and mechanisms of straw with different fermentation degrees on Se and Cd bioavailability have not been sufficiently investigated. In this study, straw with different fermentation degrees were applied to a Cd-contaminated seleniferous soil to investigate their effects on Se and Cd bioavailability. Results revealed that the effects of straw application on Se/Cd bioavailability in soil depended on the fermentation degrees of straw. Both original and slightly fermented straw had pronounced impacts on microbial iron reduction compared to fully fermented straw, and thus led to a significant increase in Se and Cd bioavailability. The linear discriminant analysis effect size (LEfSe) showed that norank_f_Symbiobacteraceae, Micromonospora, WCHB1-32, Ruminiclostrdium, and Cellulomonas were the major biomarkers at genus level in straw application soils, additional network analysis and random forest analysis suggested that Ruminiclostrdium and Cellulomonas might be implicated in microbial iron reduction. Furthermore, the microbial iron reduction had negative effects on mineral-associated Se with coefficient of -0.81 and positive effects on mineral-associated Cd with coefficient of 0.72, while Mn fractions exhibited positive effects on mineral-associated Se with a coefficient of 0.53 and negative effects on mineral-associated Cd. In conclusion, straw with different fermentation degrees governed Se and Cd mobility by regulating abundance of Ruminiclostrdium and Cellulomonas, subsequently affecting Fe and Mn fractions and consequently influencing Se and Cd bioavailability.

Genome-Wide Identification and Characterization of the Medium-Chain Dehydrogenase/Reductase Superfamily of Trichosporon asahii and Its Involvement in the Regulation of Fluconazole Resistance.

The medium-chain dehydrogenase/reductase (MDR) superfamily contains many members that are widely present in organisms and play important roles in growth, metabolism, and stress resistance but have not been studied in Trichosporon asahii. In this study, bioinformatics and RNA sequencing methods were used to analyze the MDR superfamily of T. asahii and its regulatory effect on fluconazole resistance. A phylogenetic tree was constructed using Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans, and T. asahii, and 73 MDRs were identified, all of which contained NADPH-binding motifs. T. asahii contained 20 MDRs that were unevenly distributed across six chromosomes. T. asahii MDRs (TaMDRs) had similar 3D structures but varied greatly in their genetic evolution at different phylum levels. RNA-seq and gene expression analyses revealed that the fluconazole-resistant T. asahii strain upregulates xylitol dehydrogenase, and downregulated alcohol dehydrogenase and sorbitol dehydrogenase concluded that the fluconazole-resistant T. asahii strain was less selective toward carbon sources and had higher adaptability to the environment. Overall, our study contributes to our understanding of TaMDRs, providing a basis for further analysis of the genes associated with drug resistance in T. asahii.

Mitochondrial Artificial K+ Channel Construction Using MPTPP@5F8 Nanoparticles for Overcoming Cancer Drug Resistance via Disrupting Cellular Ion Homeostasis.

Mitochondrial potassium ion channels have become a promising target for cancer therapy. However, in malignant tumors, their low expression or inhibitory regulation typically leads to undesired cancer therapy, or even induces drug resistance. Herein, this work develops an in situ mitochondria-targeted artificial K+ channel construction strategy, with the purpose to trigger cancer cell apoptosis by impairing mitochondrial ion homeostasis. Considering the fact that cancer cells have a lower membrane potential than that of normal cells, this strategy can selectively deliver artificial K+ channel molecule 5F8 to the mitochondria of cancer cells, by using a mitochondria-targeting triphenylphosphine (TPP) modified block polymer (MPTPP) as a carrier. More importantly, 5F8 can further specifically form a K+ -selective ion channel through the directional assembly of crown ethers on the mitochondrial membrane, thereby inducing mitochondrial K+ influx and disrupting ions homeostasis. Thanks to this design, mitochondrial dysfunction, including decreased mitochondrial membrane potential, reduced adenosine triphosphate (ATP) synthesis, downregulated antiapoptotic BCL-2 and MCL-1 protein levels, and increased reactive oxygen species (ROS) levels, can further effectively induce the programmed apoptosis of multidrug-resistant cancer cells, no matter in case of pump or nonpump dependent drug resistance. In short, this mitochondria-targeted artificial K+ -selective ion channel construction strategy may be beneficial for potential drug resistance cancer therapy.

Electromagnetic interference shielding of flexible carboxymethyl cellulose/MWCNT@Fe3O4 composite film with ultralow reflection loss.

Nowadays, various high-performance electromagnetic interference (EMI) shielding materials have enormous application potential in electronic field. However, traditional EMI shielding materials often have high conductivity, resulting in the serious mismatch between the impedance of the material surface and the free space, which will cause a large amount of reflection of electromagnetic (EM) waves, leading to secondary reflection pollution. In this paper, we report a novel flexible EMI shielding composite film with extremely low reflection loss and efficient EM wave absorption, which was prepared by assisted self-assembly based on simple vacuum filtration using carboxymethyl cellulose as the matrix and MWCNT@Fe3O4 synthesized by chemical coprecipitation as the composite functional filler. By adjusting the Fe3O4 coating degree of MWCNTs in the filler, the composite film achieved the construction of a conductive network with high Fe3O4 content. Benefit by the good adaptability of conductivity and magnetic permeability, the composite film has good impedance matching ability and microwave absorption performance. The reflection loss of the composite film with the thickness of 28 µm in the X-band was only 0.23 dB, accounting for 1.7 % of the total loss. This work provides new insights for the development of EMI materials and effective mitigation secondary EM wave reflection pollution.

Fibroblasts in immune-mediated inflammatory diseases: The soil of inflammation.

As one of the most abundant stromal cells, fibroblasts are primarily responsible for the production and remodeling of the extracellular matrix. Traditionally, fibroblasts have been viewed as quiescent cells. However, recent advances in multi-omics technologies have demonstrated that fibroblasts exhibit remarkable functional diversity at the single-cell level. Additionally, fibroblasts are heterogeneous in their origins, tissue locations, and transitions with stromal cells. The dynamic nature of fibroblasts is further underscored by the fact that disease stages can impact their heterogeneity and behavior, particularly in immune-mediated inflammatory diseases such as psoriasis, inflammatory bowel diseases, and rheumatoid arthritis, etc. Fibroblasts can actively contribute to the disease initiation, progression, and relapse by responding to local microenvironmental signals, secreting downstream inflammatory factors, and interacting with immune cells during the pathological process. Here we focus on the development, plasticity, and heterogeneity of fibroblasts in inflammation, emphasizing the need for a developmental and dynamic perspective on fibroblasts.

Formylpeptide receptor 1 contributes to epidermal barrier dysfunction-induced skin inflammation through NOD-like receptor C4-dependent keratinocyte activation.

BACKGROUND: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. OBJECTIVES: We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms. METHODS: Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated. RESULTS: Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1ß secretion through modulation of ER stress via the PERK-eIF2α-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. CONCLUSIONS: In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.

Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by perineural invasion (PNI), which is associated with excruciating neuropathic pain and malignant progression. However, the relationship between PNI and tumour stromal cells has not been clarified. METHODS: The dorsal root ganglia or sciatic nerves nerve model was used to observe the paracrine interaction and the activation effect among Schwann cells, tumour-associated macrophages (TAMs), and pancreatic cancer cells in vitro. Next generation sequencing, enzyme-linked immunosorbent assay and chromatin immunoprecipitation were used to explore the specific paracrine signalling between TAMs and Schwann cells. RESULTS: We demonstrated that more macrophages were expressed around nerves that have been infiltrated by pancreatic cancer cells compared with normal nerves in murine and human PNI specimens. In addition, high expression of CD68 or GFAP is associated with an increased incidence of PNI and indicates a poor 5-year survival rate in patients with PDAC. Mechanistically, tumour-associated macrophages (TAMs) activate Schwann cells via the bFGF/PI3K/Akt/c-myc/GFAP pathway. Schwann cells secrete IL-33 to recruit macrophages into the perineural milieu and facilitate the M2 pro-tumourigenic polarisation of macrophages. CONCLUSIONS: Our study demonstrates that the bFGF/IL-33 positive feedback loop between Schwann cells and TAMs is essential in the process of PNI of PDAC. The bFGF/PI3K/Akt/c-myc/GFAP pathway would open potential avenues for targeted therapy of PDAC.

Assembly of porous filaments by interfacial complexation of nanochitin-based Pickering emulsion and seaweed alginate.

Interfacial polyelectrolyte complexation spinning is an all-water, easy-to-operate method for production of composite filaments. Herein, this concept is extended to interfacial polyelectrolyte-emulsion complexation (IPEC) that better encodes structural and functional attributes of biomass substances into the filaments. This allows for formation of composite filaments by drawing contacting oppositely-charged chitin nanofiber-stabilized Pickering emulsion and seaweed alginate solution. The parameters affecting spinnability of the system including water-to-oil ratio, alginate concentration, and pH are comprehensively elucidated to support the design and application of IPEC. The composite filaments exhibit varied diameters and diverse porous structures that are adjustable by properties of Pickering droplets. The droplet diameter of precursor emulsion and pore size in the filaments are well correlated, revealing controllability of the IPEC spinning. The filaments are mechanically robust in dry condition and show stable performance even in wet condition. The release rate of filaments that is pre-loaded with hydrophilic drug is regulated by the internal pore size, showing capability on sustained release. This study offers a new perspective toward dry spinning via interfacial complexation of complicated nanochitin-based structural building blocks, aiming at developing high-performance fiber materials for advanced applications.

Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.

ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.

The TLR2/TLR6 ligand FSL-1 mitigates radiation-induced hematopoietic injury in mice and nonhuman primates.

Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS.

Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.

Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.

[Distribution Characteristics and Risk Assessment of Microplastics in Soil in Danjiangkou Reservoir Area of South-to-North Water Diversion Project].

To explore the occurrence characteristics and influencing factors of microplastics in soil in the Danjiangkou Reservoir area, this study collected soil samples from orchards, dryland, paddy fields, and wetland and identified microplastics in soil via density sorting, microscope observation, and Raman spectrometry. The results showed that microplastics were detected in 64 samples collected in the study area, and the abundance ranged from 645 to 15161 n·kg-1. The spatial distribution of microplastics in the bottom of the reservoir was higher than those in the middle and head of the reservoir, and the abundance of microplastics in the surface soil(0-20 cm) was significantly lower than that in the bottom soil(20-40 cm). The main types of microplastics were polypropylene(26.4%) and polyamide(20.2%), the particle size was mainly concentrated between 50-500 µm(75%), and the common shape was fragments(66.2%). Correlation analysis showed that soil microplastic abundance was closely related to land use, distance from water and housing, population density, and soil properties. From the perspective of microplastic pollution risk, 72.1% of the region's microplastic polymer risk index was at level Ⅲ and level Ⅳ, and there was a certain risk of microplastic pollution in the Danjiangkou Reservoir area. The results of this study can provide support for risk assessment of microplastics.

Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via DIO2-TH signaling.

Metastasis of lung adenocarcinoma (LUAD) is a major cause of death in patients. Aryl hydrocarbon receptor (AHR), an important transcription factor, is involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, acts as an oncogene promoting the malignancy of multiple cancer types. However, the interaction between these two factors and their significance in lung cancer remain to be determined. In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events. RNA-seq analyses reveal that type 2 deiodinase (DIO2) is responsible for EMT and enhanced metastatic potential. DIO2 converts tetraiodothyronine (T4) to triiodothyronine (T3), activating thyroid hormone (TH) signaling. In vitro and in vivo experiments demonstrate that treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or a deiodinase inhibitor disrupts this property. Taking together, our results identify the AHR phosphorylation by PLK1 and subsequent activation of DIO2-TH signaling as mechanisms leading to LUAD metastasis. These findings can inform possible therapeutic interventions for this event.

Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas.

Approximately half of patients with cancer receive radiotherapy and, as cancer survivorship increases, the low rate of radiation-associated sarcomas is rising. Pharmacologic inhibition of p53 has been proposed as an approach to ameliorate acute injury of normal tissues from genotoxic therapies, but how this might impact the risk of therapy-induced cancer and normal tissue injuries remains unclear. We utilized mice that express a doxycycline (dox)-inducible p53 short hairpin RNA to reduce Trp53 expression temporarily during irradiation. Mice were placed on a dox diet 10 days prior to receiving 30 or 40 Gy hind limb irradiation in a single fraction and then returned to normal chow. Mice were examined weekly for sarcoma development and scored for radiation-induced normal tissue injuries. Radiation-induced sarcomas were subjected to RNA sequencing. Following single high-dose irradiation, 21% of animals with temporary p53 knockdown during irradiation developed a sarcoma in the radiation field compared with 2% of control animals. Following high-dose irradiation, p53 knockdown preserves muscle stem cells, and increases sarcoma development. Mice with severe acute radiation-induced injuries exhibit an increased risk of developing late persistent wounds, which were associated with sarcomagenesis. RNA sequencing revealed radiation-induced sarcomas upregulate genes related to translation, epithelial-mesenchymal transition (EMT), inflammation, and the cell cycle. Comparison of the transcriptomes of human and mouse sarcomas that arose in irradiated tissues revealed regulation of common gene programs, including elevated EMT pathway gene expression. These results suggest that blocking p53 during radiotherapy could minimize acute toxicity while exacerbating late effects including second cancers. SIGNIFICANCE: Strategies to prevent or mitigate acute radiation toxicities include pharmacologic inhibition of p53 and other cell death pathways. Our data show that temporarily reducing p53 during irradiation increases late effects including sarcomagenesis.

The effect of annulus fibrosus incision and foraminoplasty on lumbar biomechanics in percutaneous endoscopic lumbar discectomy: a finite element analysis.

The objective of this study was to analyze the effects of annulus fibrosus incision and foraminoplasty on lumbar biomechanics during posterior lateral approach translaminar percutaneous endoscopic lumbar discectomy (PELD) using a lumbar 4/5 segment model and three-dimensional finite element analysis (FEA). We created a model of the L4 to L5 segment and performed simulated foraminoplasty, annulus fibrosus incision, and a combined operation. The models were tested under six working conditions, and we recorded the deformation and equivalent strain/stress of each group. Results showed that foraminoplasty can affect the stability and rotation axis of the segment during rotation without significantly impacting discal stress. Conversely, annulus fibrosus incision significantly increases discal stress except for when the patient is doing a forward flexion movement. We recommend that surgical maneuvers minimize the removal and destruction of the annulus fibrosus and that rotation movements are avoided during the short-term recovery period following PELD surgery.