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JOURNAL/nrgr/04.03/01300535-202507000-00032/figure1/v/2024-09-09T124005Z/r/image-tiff A microgravity environment has been shown to cause ocular damage and affect visual acuity, but the underlying mechanisms remain unclear. Therefore, we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity. After 4 weeks of tail suspension, there were no notable alterations in retinal function and morphology, while after 8 weeks of tail suspension, significant reductions in retinal function were observed, and the outer nuclear layer was thinner, with abundant apoptotic cells. To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina, proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension. The results showed that the expression levels of fibroblast growth factor 2 (also known as basic fibroblast growth factor) and glial fibrillary acidic protein, which are closely related to Müller cell activation, were significantly upregulated. In addition, Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks, respectively, of simulated weightlessness. These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.

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BACKGROUND: Efforts to shorten rifampicin-resistant tuberculosis (RR-TB) treatment have led to concerns about hepatotoxicity in shorter regimens. We evaluated hepatotoxicity in two novel regimens against the standard shorter regimen recommended by WHO. METHODS: Participants from the TB-TRUST and TB-TRUST plus trials were assigned to the WHO shorter regimen, a levofloxacin-based regimen, or a bedaquiline-based regimen. Liver function was tested bi-weekly in the first month, then monthly until treatment ended. Eligibility required receiving at least one drug dose and undergoing at least two liver function tests. RESULTS: Of 429 patients, hepatotoxicity was most prevalent in the WHO shorter group (26.7% of 169), compared to 4.7% in the levofloxacin group (172 patients), and 5.7% in the bedaquiline group (88 patients). The median peak ALT levels were 1.67 × ULN for WHO, 0.82 × ULN for levofloxacin, and 0.88 × ULN for bedaquiline groups. The incidence of drug-induced liver injury was significantly higher in the WHO group (18.3%) than in the levofloxacin (3.5%) and bedaquiline (4.6%) groups. Time to significant ALT elevation was about 2.8 months, with no differences between groups. CONCLUSIONS: Two novel regimens demonstrated lower hepatotoxicity compared to the WHO shorter regimen. Entire course management monitoring is recommended in RR-TB treatment.

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Immobilization of enzymes improves their stability and recoverability and is therefore crucial for scientific research and industrial applications. In this study, phospholipase LM (PLLM) and phospholipase 3G (PL3G) were immobilized using Fe3O4@SiO2@CS-COOH polycarboxylated magnetic nanoparticles (MNPs-COOH) as carriers and then used for degumming soybean crude oil. The immobilization rates and relative enzyme activities of these immobilized phospholipases were evaluated to determine the optimal immobilization parameters. The enzyme activities of PLLM-MNPs-COOH and PL3G-MNPs-COOH were 2830.87 and 1162.25 U/g, respectively. Enzymatic properties of the free and immobilized enzymes were compared. Both immobilized phospholipases exhibited higher condition tolerance and stability after immobilization. After 30-day storage at 4 °C, both immobilized phospholipases retained approximately 1.3 times the residual activity of the corresponding free phospholipases. When the degumming conditions were optimized, the residual phosphorus contents of the PLLM-MNPs-COOH- and PL3G-MNPs-COOH-degummed oils were 4.91 and 7.41 mg/kg, respectively, which were consistent with the safety standards for oil products. After 6 cycles, PLLM-MNPs-COOH and PL3G-MNPs-COOH continued to preserve 71.88 % and 70.00 % of their initial activities, respectively. The immobilized phospholipases are thus suitable for degumming soybean crude oil, and the mixed enzymes exhibited better degumming potential.

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Piezocatalysis offers an encouraging alternative for the sustainable, on-demand, and decentralized production of hydrogen peroxide (H2O2), underscoring the importance of enhancing piezocatalytic efficiency. Enhancing piezocatalysts through defect engineering has shown considerable potential in boosting H2O2 production efficiency. However, the impact of oxygen vacancies on piezocatalytic activity remains unclear. Herein, we used a chemical probe method to quantify negative charges (q-) and superoxide radicals (O2-) to explore the relation between the oxygen vacancy concentration and piezocatalytic performance of bismuth titanate (Bi4Ti3O12) based catalysts. Results indicate that piezocatalytic H2O2 production in pure water demonstrates a volcanic trend with increasing oxygen vacancy concentration. This trend is attributed to the dual role of oxygen vacancies, which reduce the piezoelectric property of the piezocatalyst while simultaneously increasing the concentration of O2-, which is crucial for H2O2 formation through the O2 reduction pathway. This study provides insights into the interplay between oxygen vacancies, piezoelectric properties, and piezocatalytic activity, offering valuable guidance for the design of piezocatalysts for sustainable H2O2 production.

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The concept of integrating physics-based and data-driven approaches has become popular for modeling sustainable energy systems. However, the existing literature mainly focuses on the data-driven surrogates generated to replace physics-based models. These models often trade accuracy for speed but lack the generalizability, adaptability, and interpretability inherent in physics-based models, which are often indispensable in modeling real-world dynamic systems for optimization and control purposes. We propose a novel machine learning architecture, termed model-integrated neural networks (MINN), that can learn the physics-based dynamics of general autonomous or non-autonomous systems consisting of partial differential-algebraic equations (PDAEs). The obtained architecture systematically solves an unsettled research problem in control-oriented modeling, i.e., how to obtain optimally simplified models that are physically insightful, numerically accurate, and computationally tractable simultaneously. We apply the proposed neural network architecture to model the electrochemical dynamics of lithium-ion batteries and show that MINN is extremely data-efficient to train while being sufficiently generalizable to previously unseen input data, owing to its underlying physical invariants. The MINN battery model has an accuracy comparable to the first principle-based model in predicting both the system outputs and any locally distributed electrochemical behaviors but achieves two orders of magnitude reduction in the solution time.

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Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder, and chemokines have been shown to be dysregulated in autoimmune disorders. We conducted a prospective analysis to identify potential chemokines that could enhance the diagnostic accuracy and bleeding evaluation in ITP patients. In the discovery cohort, a Luminex-based assay was employed to quantify concentrations of plasma multiple chemokines. These levels were subjected to comparative analysis using a cohort of 60 ITP patients and 17 patients with thrombocytopenia other than ITP (non-ITP). Additionally, comparative evaluation was conducted between a subgroup of 12 ITP patients characterised by bleeding episodes (ITP-B, as defined by an ITP-2016 bleeding grade ≥2) and 33 ITP patients without bleeding episodes (ITP-NB, as defined by an ITP-2016 bleeding grade ≤1). Machine learning algorithms further identified CCL20, interleukin-2, CCL26, CCL25, and CXCL1 as promising indicators for accurate diagnosis of ITP and CCL21, CXCL8, CXCL10, CCL8, CCL3, and CCL15 as biomarkers for assessing bleeding risk in ITP patients. The results were confirmed using enzyme-linked immunosorbent assays in a validation cohort (43 ITP patients and 19 non-ITP patients). Overall, the findings suggest that specific chemokines show promise as potential biomarkers for diagnosis and bleeding evaluation in ITP patients.

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BACKGROUND: Bacillus inaquosorum strains is widely recognized for their plant-growth-promoting and biocontrol capabilities, yet their roles in protease production remain unclear. The present study aimed to comprehensively assess the protease-producing performance of B. inaquosorum strain E1-8, at the same time as exploring the novel application of agricultural Bacillus proteases in the preparation of protein hydrolysates for fresh-cut fruits preservation. RESULTS: First, genomic sequencing revealed the diversity of E1-8 proteases, indicating 15 putative extracellular proteases. Subsequently, the fermentation conditions for E1-8 protease production were optimized, with sweet potato powder and soybean meal identified as the most suitable carbon and nitrogen sources, respectively, resulting in a maximum protease activity of 321.48 U mL-1. Upon culturing the strain under these optimized conditions, only an S8 family serine protease and an M48 family metalloprotease were revealed by secretomic analysis and protease inhibitor assays. Additionally, the optimal protease conditions for generating protein hydrolysates from soy, pea, fish and porcine proteins were determined. The molecular weight of the hydrolysates primarily ranged from 2000 to 180 Da, with a total of 17 amino acids identified. The application of these hydrolysates demonstrated a 2,2-diphenyl-1-picrylhydrazyl (i.e. DPPH) scavenging activity ranging from 58.64% to 84.12%, significantly reducing of the melting peaks and the freezing points. Furthermore, the browning index of apple slices stored at 4 °C decreased by 14.81% to 22.15% on the second day, and similar effects were observed in fresh-cut banana stored at 4 °C for 7 days. CONCLUSION: The protein hydrolysates obtained exhibit remarkable antioxidant, antifreeze and anti-browning properties for fresh-cut fruits. © 2024 Society of Chemical Industry.

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Conjugative dissemination of mobile genetic elements (MGEs) among bacteria is initiated by assembly of the relaxosome at the MGE's origin-of-transfer (oriT) sequence. A critical but poorly defined step of relaxosome assembly involves recruitment of the catalytic relaxase to its DNA strand-specific nicking site within oriT. Here, we present evidence by AlphaFold modeling, affinity pulldowns, and in vivo site-directed photocrosslinking that the TraK Ribbon-Helix-Helix DNA-binding protein recruits TraI to oriT through a dynamic interaction in which TraI's C-terminal unstructured domain (TraICTD) wraps around TraK's C-proximal tetramerization domain. Upon relaxosome assembly, conformational changes disrupt this contact, and TraICTD instead self-associates as a prerequisite for relaxase catalytic functions or substrate engagement with the transfer channel. These findings delineate key early-stage processing reactions required for conjugative dissemination of a model MGE.

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Psoriasis is a prevalent chronic disease affecting 2-3% of the global population. Cyclosporine A (CyA) has been widely used with great promise in the treatment of moderate to severe psoriasis despite various side effects associated with its systemic administration. Topical administration of CyA circumvents systemic side effects; however, the poor water solubility and large molecular weight of CyA pose challenges for dermal delivery. In this study, choline-based ionic liquids (ILs) were used to enhance the dermal delivery of CyA for the potential treatment of psoriasis. All four ILs tested significantly improved the solubility of CyA, which was greater than that of the control group with dimethyl sulfoxide (DMSO) as a solubilizer (20%, w/w). The saturated solubility of CyA in two of the ILs, choline geranate ([Ch][Ge]) and choline ricinoleate ([Ch][Ra]), reached more than 90 mg/mL, and the solubilization capability of the ILs except [Ch][Ci] was resistant to water dilution. The negligible change in CyA content determined by high-performance liquid chromatography and the secondary structure detected by circular dichroism spectroscopy confirmed the stability of CyA in the ILs. At 4 h in the in vitro penetration test, the amount of CyA retained in the skin in the IL groups was slightly greater than that in the control group (20% DMSO). The water content of the ILs significantly affected their penetration ability. When the water content increased from 10 to 70%, the dermal delivery of CyA first increased, peaked at a water content of 30%, and then decreased. The dermal delivery ability of [Ch][Ge] and [Ch][Ra] with a water content of 70% was still comparable to that of 20% DMSO. Moreover, CyA-loaded ILs (0.5%, w/w) significantly relieved the symptoms of psoriasis in an imiquimod (IMQ)-induced mouse model, and the levels of inflammatory factors, including tumor necrosis factor α, interleukin 22 and interleukin 17, in the affected area were reduced by 71.7%, 75.6%, and 89.3%, respectively. The IL tested, choline sorbate ([Ch][So]), showed low cytotoxicity to human immortalized epidermal cells (HaCaT). After 7 days of consecutive application, [Ch][So] did not cause significant irritation. In conclusion, ILs demonstrate promising potential for the dermal delivery of CyA for the treatment of psoriasis.

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Coconut milk products are susceptible to bacterial damage, necessitating sterilization methods that often compromise nutrient and aroma integrity. This study investigates the effects of different thermal sterilisation methods on coconut milk aroma using headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS) and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). We assessed the impact of pasteurisation (PAS, 70 °C, 25 min), high-temperature sterilisation (HTS, 121.1 °C, 15 min), and ultra-high temperature sterilisation (UHT, 130 °C, 5 s) through clustered heat maps and correlation analyses. Significant differences were observed (p < 0.05), with 37 and 52 substances detected by HS-GC-IMS and HS-SPME-GC-MS, respectively, identifying 12 key aroma compounds. UHT treatment primarily reduced 8 acids, maintaining a compositional structure and sensory profile similar to raw coconut milk. PAS and HTS treatments decreased the sensory intensity of overall coconut milk aroma, creamy, and floral notes, correlating with the presence of 2-heptanol, nonanal, 4-methylvaleric acid, and 2-tridecanone. These methods increased cooked notes, associated with 5-methyl-3-heptanone, 3-butyn-1-ol, hydroxyacetone, and acetoin. Rancidity was linked to acids such as isobutyric acid, isovaleric acid, and heptanoic acid, with high temperatures effectively reducing these compounds. Prolonged temperature changes in PAS and HTS accelerated lipid oxidative degradation and the Maillard reaction, involving free fatty acids in the formation of alcohols, aldehydes, esters, and lactones. These findings provide a theoretical basis for studying coconut milk flavour deterioration.

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Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologically active tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs. Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix. Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and good degradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation, and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widely recognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair. This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, the modification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissue engineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of the use and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future research directions for clinical treatment.

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Purpose: The goal of the study was to create a nomogram based on clinical risk factors to forecast the rate of locoregional recurrence-free survival (LRFS) in patients with esophageal squamous cell carcinoma (ESCC) who underwent radiotherapy (RT). Methods: In this study, 574 ESCC patients were selected as participants. Following radiotherapy, subjects were divided into training and validation groups at a 7:3 ratio. The nomogram was established in the training group using Cox regression. Performance validation was conducted in the validation group, assessing predictability through the C-index and AUC curve, calibration via the Hosmer-Lemeshow (H-L) test, and evaluating clinical applicability using decision curve analysis (DCA). Results: T stage, N stage, gross tumor volume (GTV) dose, location, maximal wall thickness (MWT) after RT, node size (NS) after RT, Δ computer tomography (CT) value, and chemotherapy were found to be independent risk factors that impacted LRFS by multivariate cox analysis, and the findings could be utilized to create a nomogram and forecast LRFS. the area under the receiver operating characteristic (AUC) curve and C-index show that for training and validation groups, the prediction result of LRFS using nomogram was more accurate than that of TNM. The LRFS in both groups was consistent with the nomogram according to the H-L test. The DCA curve demonstrated that the nomogram had a good prediction effect both in the groups for training and validation. The nomogram was used to assign ESCC patients to three risk levels: low, medium, or high. There were substantial variations in LRFS between risk categories in both the training and validation groups (p<0.001, p=0.003). Conclusions: For ESCC patients who received radiotherapy, the nomogram based on clinical risk factors could reliably predict the LRFS.

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PURPOSE: Conventional minimally invasive surgery requires mini-laparotomy to extract the pathological specimen. However, by using a natural orifice as the delivery route, natural orifice specimen extraction (NOSE) surgery avoids the need for a large incision. This study analyzed the short-term outcome of NOSE compared with conventional mini-laparotomy (CL) for colorectal cancer surgery. METHODS: We conducted a retrospective analysis of 1,189 patients who underwent surgery for primary colorectal cancer between the cecum and upper rectum. Propensity score analyses were applied to the NOSE and CL groups in a 1:1 matched cohort. RESULTS: After propensity score matching, each group included 201 patients. The NOSE group and CL group did not differ significantly in terms of baseline characteristics. Postoperative morbidity and mortality rates were comparable. Compared with the CL group, the NOSE group experienced a shorter time to first flatus (1.6 ± 0.8 vs. 2.0 ± 1.2 days, p < 0.001), first stool (2.7 ± 1.5 vs. 4.1 ± 1.9, p < 0.001), liquid diet (2.3 ± 1.3 vs. 3.6 ± 1.8 days, p < 0.001), soft diet (3.9 ± 2.0 vs. 5.2 ± 1.9 days, p < 0.001) and a shorter hospital stay (5.1 ± 3.5 vs. 7.4 ± 4.8 days, p < 0.001). The NOSE group exhibited lower mean pain intensity and lower highest pain intensity on postoperative days 1, 2, and 3. CONCLUSION: NOSE has several advantages over conventional mini-laparotomy following minimally invasive surgery for colon cancer. These advantages include reduced time to oral intake, shorter hospital stays, and less postoperative pain. NOSE can be adopted and applied to highly selective patients without additional risk of short-term complications.

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High-energy gamma rays produced in inertial confinement fusion (ICF) experiments are crucial for studying implosion dynamics. These gamma rays, characterized by their extremely short durations, represent the least disturbed products of fusion, preserving vital birth information. To detect such γ-rays, ultrafast radiation detectors with high time resolution are necessary. This study introduces a newly developed Cherenkov optical image screen designed for ultra-fast gamma-ray imaging. Composed of pure quartz fiber material, the imaging screen features a single fiber pixel size of 0.6 mm and a thickness of 3 cm. Theoretical investigations explore the luminous time response and efficiency of the Cherenkov optical imaging screen under gamma-ray irradiation. Experimental validation was conducted using a steady-state gamma-ray source with an average energy of 1.25 MeV. Results demonstrate that the image screen achieves a spatial resolution limit of 0.75 mm. The temporal response exhibits a full width at half maximum of less than 0.4 ns when excited by a high-energy electron beam with a single pulse duration of several picoseconds.

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Background: Sepsis-induced acute lung injury (ALI) leads to severe hypoxemia and respiratory failure, contributing to poor prognosis in septic patients. Endotoxin dissemination triggers oxidative stress and the release of inflammatory cytokines in macrophages, initiating diffuse alveolar damage. The role of epigenetic histone modifications in organ injury is increasingly recognized. The present study aimed to investigate the use of a histone modification inhibitor to alleviate sepsis-induced ALI, revealing a new strategy for improving sepsis patient survival. Methods: In vivo models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated in vitro by stimulating Tamm-Horsfall protein-1 (THP-1) cells with lipopolysaccharide. Hematoxylin and eosin staining, blood gas analysis and pulmonary function tests were utilized to assess the extent of lung tissue damage. Western blot analysis, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence were used to measure the levels and distribution of the indicated indicators within cells and tissues. Reactive oxygen species and autophagic flux alterations were detected using specific probes. Results: BRD3308, which is a inhibitor of histone deacetylase 3, improved lung tissue damage, inflammatory infiltration and edema in ALI by inhibiting Nod-like receptor protein3-mediated pyroptosis in macrophages. By upregulating autophagy, BRD3308 improved the disruption of redox balance in macrophages and reduced the accumulation of reactive oxygen species. Mechanistically, BRD3308 inhibited histone deacetylase 3 activity by binding to it and altering its conformation. Following histone deacetylase 3 inhibition, acetylation of H3K27 was significantly increased. Moreover, the increase in H3K27Ac led to the upregulation of autophagy-related gene 5, a key component of autophagosomes, thereby activating autophagy. Conclusions: BRD3308 inhibits oxidative stress and pyroptosis in macrophages by modulating histone acetylation, thereby preventing sepsis-induced ALI. The present study provides a potential strategy and theoretical basis for the clinical treatment of sepsis-induced ALI.

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Multifunctional responsive hydrogels hold significant promise for diabetic foot ulcer (DFU) treatment, though their complex design and manufacturing present challenges. This study introduces a novel supramolecular guanosine-phenylboronic-chlorogenic acid (GBC) hydrogel developed using a dynamic covalent strategy. The hydrogel forms through guanosine quadruplex assembly in the presence of potassium ions and chlorogenic acid (CA) linkage via dynamic borate bonds. GBC hydrogels exhibit pH and glucose responsiveness, releasing more chlorogenic acid under acidic and high glucose conditions due to borate bond dissociation and G-quadruplex (G4) hydrogel disintegration. Experimental results indicate that GBC hydrogels exhibit good self-healing, shear-thinning, injectability, and swelling properties. Both in vitro and in vivo studies demonstrate the GBC hydrogel's good biocompatibility, ability to eliminate bacteria and reactive oxygen species (ROS), facilitate macrophage polarization from the M1 phenotype to the M2 phenotype (decreasing CD86 expression and increasing CD206 expression), exhibit anti-inflammatory effects (reducing TNF-α expression and increasing IL-10 expression), and promote angiogenesis (increasing VEGF, CD31, and α-SMA expression). Thus, GBC hydrogels accelerate DFU healing and enhance tissue remodeling and collagen deposition. This work provides a new approach to developing responsive hydrogels to expedite DFU healing.

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Calcium oxalate (CaOx) kidney stones are common and recurrent, lacking pharmacological prevention. Randall's plaques (RPs), calcium deposits in renal papillae, serve as niduses for some CaOx stones. This study explores the role of osteogenic-like cells in RP formation resembling ossification. CaP crystals deposit around renal tubules, interstitium, and blood vessels in RP tissues. Human renal interstitial fibroblasts (hRIFs) exhibit the highest osteogenic-like differentiation potential compared to chloride voltage-gated channel Ka positive tubular epithelial cells, aquaporin 2 positive collecting duct cells, and vascular endothelial cells, echoing the upregulated osteogenic markers primarily in hRIFs within RP tissues. Utilizing RNA-seq, osteomodulin (OMD) is found to be upregulated in hRIFs within RP tissues and hRIFs following osteogenic induction. Furthermore, OMD colocalizes with CaP crystals and calcium vesicles within RP tissues. OMD can enhance osteogenic-like differentiation of hRIFs in vitro and in vivo. Additionally, crystal deposits are attenuated in mice with Omd deletion in renal interstitial fibroblasts following CaOx nephrocalcinosis induction. Mechanically, a positive feedback loop of OMD/BMP2/BMPR1A/RUNX2/OMD drives hRIFs to adopt osteogenic-like fates, by which OMD induces osteogenic-like microenvironment of renal interstitium to participate in RP formation. We identify OMD upregulation as a pathological feature of RP, paving the way for preventing CaOx stones.

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Spinal cord injury (SCI) is a severe neurological disorder that can lead to paralysis or death. Oxidative stress during SCI is a critical phase causing extensive nerve cell damage and apoptosis, thereby impairing spinal cord healing. Thus, a primary goal of SCI drug therapy is to mitigate oxidative stress. Curculigoside (CUR), a phenolic glucoside extracted from the dried root and rhizome of Curculigo orchioides Gaertn, possesses neuroprotective and antioxidant properties. This study aimed to investigate whether CUR effectively promotes the recovery of spinal cord tissue following SCI and elucidate its mechanism. We employed a hydrogen peroxide (H2O2)-induced PC12 cell model and an SCI rat model to observe the effects of CUR on oxidation and apoptosis. The results demonstrated that CUR significantly reduced the expression of apoptosis-related proteins (Bax and Caspase-3), Annexin V/propidium iodide (PI), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), while increasing the expression of the anti-apoptotic protein Bcl-2. Moreover, CUR effectively enhanced levels of antioxidants (glutathione [GSH)] and decreased reactive oxygen species (ROS) in vitro. Furthermore, CUR facilitated functional recovery through its anti-apoptotic and anti-oxidative stress effects on spinal cord tissues in SCI rats. These effects were mediated via the Nrf2/NQO1 signaling pathway. Therefore, our study showed that CUR acted as an anti-apoptotic and anti-oxidative stress agent, inhibiting astrocyte activation and promoting neuronal reconstruction and functional recovery. These findings may contribute significantly to the development of SCI treatments and advance the field of SCI drug therapy.

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Introduction: Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce. Methods: We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing. Results: Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFR exon 21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0-17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2-29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0-5.9 mo). Conclusions: SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.