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A two-year field experiment was conducted to clarify the regulatory effects of nitrogen (N), phosphorus (P), and potassium (K) combined with drip fertigation on the yield, yield components, and grain quality of winter wheat in lime concretion black soil (Calcaric Cambisols). The objective was to screen a sustainable fertilization model for coordinating high yield and quality in the Huang-Huai-Hai Plain. An L16(43) orthogonal design was adopted to investigate yield, protein content, wet gluten, test weight (TW), and grain hardness. Range analysis and ANOVA were used to evaluate factor effects and interactions. The results showed that N was the dominant factor affecting yield and quality (Rank 1), followed by K (Rank 2), while P showed the weakest effect. Compared to the control (N0P0K0), the optimized N–P–K combination increased grain yield by an average of 315.0% and enhanced grain crude protein by 55.3% over the two seasons. The optimal combination for maximum yield was N170P30K120 (kg/ha), which optimized the source–sink relationship by balancing spike density and 1000-grain weight. High N (220 kg/ha) combined with low P and high K achieved the best nutritional quality. The 3D response surface analysis confirmed significant synergistic interactions between N–K and N–P in promoting grain filling and protein synthesis. Rational NPK drip fertigation, particularly when synchronized with critical growth stages (jointing and grain filling), can simultaneously enhance grain yield and quality in this soil type. The optimized combination provides theoretical support and a robust fertilization strategy for green and efficient wheat production in the region.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal, and aging-associated interstitial lung disease with a poor prognosis and limited treatment options, while the pathogenesis remains elusive. In this study, we found that the expression of nuclear receptor subfamily 2 group F member 2 (NR2F2), a member of the steroid thyroid hormone superfamily of nuclear receptors, was reduced in both IPF and bleomycin-induced fibrotic lungs, markedly in bleomycin-induced senescent epithelial cells. Inhibition of NR2F2 expression increased the expression of senescence markers such as p21 and p16 in lung epithelial cells, and activated fibroblasts through epithelial-mesenchymal crosstalk, inversely overexpression of NR2F2 alleviated bleomycin-induced epithelial cell senescence and inhibited fibroblast activation. Subsequent mechanistic studies revealed that overexpression of NR2F2 alleviated DNA damage in lung epithelial cells and inhibited cell senescence. Adenovirus-mediated Nr2f2 overexpression attenuated bleomycin-induced lung fibrosis and cell senescence in mice. In summary, these data demonstrate that NR2F2 is involved in lung epithelial cell senescence, and targeting NR2F2 may be a promising therapeutic approach against lung cell senescence and fibrosis.

Hepatocellular carcinoma (HCC) remains one of the most common and highly lethal malignancies globally. Conventional therapeutic approaches are often limited by suboptimal efficacy and significant toxicity, driving the search for alternative strategies, particularly those derived from natural products. This study aimed to evaluate the antitumor activity and underlying molecular mechanisms of the ethyl acetate extract of “Origanum vulgare” L (EAO) in human hepatocellular carcinoma cells. Our findings demonstrate that EAO markedly suppressed HepG2 and Huh7 cell proliferation and promoted apoptosis, accompanied by increased reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential, and ATP depletion. Additionally, EAO inhibited autophagy, as indicated by decreased LC3-II expression and increased p62 accumulation. Mechanistic investigations revealed that EAO inactivated the PI3K/AKT signaling pathway, and these effects were reversed by the ROS scavenger N-acetylcysteine (NAC), confirming ROS-dependent suppression of this pathway. Both network pharmacology and RNA-sequencing analyses further supported PI3K/AKT as a critical regulatory node. In summary, EAO exerts potent antitumor effects against hepatocellular carcinoma by inducing mitochondrial dysfunction and apoptosis, while concurrently suppressing autophagy through ROS-mediated inhibition of the PI3K/AKT pathway. These results highlight EAO as a promising low-toxicity candidate for the treatment of liver cancer.

Background This study investigated Th17 cells, an important part of adaptive immunity in multiple myeloma (MM). Methods Newly diagnosed MM patients ( n  = 30) were included, along with 30 healthy subjects matched in age and gender who underwent routine examination. Th17 cell proportion in patient’s peripheral blood mononuclear cells was determined by flow cytometry. Interleukin (IL)-17 and IL-18 were measured by ELISA method. Results MM patients expressed a higher Th17 cell proportion and increased IL-17/-18. Th17 cell proportion and IL-17/-18 levels were correlated with tumor stage, serum lactate dehydrogenase concentration, and serum creatinine concentration. Th17 cell proportion and IL-17/-18 levels were reduced in MM patients with complete response. Conclusion Th17 cells may be a therapeutic target for MM and promote better outcomes of tumor immunotherapy.

Immune checkpoint inhibitors (ICIs) only benefit a subset of cancer patients, underlining the need for predictive biomarkers for patient selection. Given the limitations of tumor tissue availability, flow cytometry of peripheral blood mononuclear cells (PBMCs) is considered a noninvasive method for immune monitoring. This study explores the use of spectrum flow cytometry, which allows a more comprehensive analysis of a greater number of markers using fewer immune cells, to identify potential blood immune biomarkers and monitor ICI treatment in non-small-cell lung cancer (NSCLC) patients. PBMCs were collected from 14 non-small-cell lung cancer (NSCLC) patients before and after ICI treatment and 4 healthy human donors. Using spectrum flow cytometry, 24 immune cell markers were simultaneously monitored using only 1 million PBMCs. The results were also compared with those from clinical flow cytometry and bulk RNA sequencing analysis. Our findings showed that the measurement of CD4+ and CD8+ T cells by spectrum flow cytometry matched well with those by clinical flow cytometry (Pearson R ranging from 0.75 to 0.95) and bulk RNA sequencing analysis (R=0.80, P=1.3 x 10-4). A lower frequency of CD4+ central memory cells before treatment was associated with a longer median progression-free survival (PFS) [Not reached (NR) vs. 5 months; hazard ratio (HR)=8.1, 95% confidence interval (CI) 1.5-42, P=0.01]. A higher frequency of CD4-CD8- double-negative (DN) T cells was associated with a longer PFS (NR vs. 4.45 months; HR=11.1, 95% CI 2.2-55.0, P=0.003). ICIs significantly changed the frequency of cytotoxic CD8+PD1+ T cells, DN T cells, CD16+CD56dim and CD16+CD56- natural killer (NK) cells, and CD14+HLDRhigh and CD11c+HLADR + monocytes. Of these immune cell subtypes, an increase in the frequency of CD16+CD56dim NK cells and CD14+HLADRhigh monocytes after treatment compared to before treatment were associated with a longer PFS (NR vs. 5 months, HR=5.4, 95% CI 1.1-25.7, P=0.03; 7.8 vs. 3.8 months, HR=5.7, 95% CI 169 1.0-31.7, P=0.04), respectively. Our preliminary findings suggest that the use of multicolor spectrum flow cytometry helps identify potential blood immune biomarkers for ICI treatment, which warrants further validation.

Background: Acne vulgaris (AV) is a chronic inflammatory disease of the pilosebaceous unit. Many factors are involved in the occurrence of acne. It has been confirmed that some adipokines play an important role in the development of AV. Irisin is a novel adipokine, which is highly expressed in skeletal muscle, liver, and fat. It improves insulin resistance (IR) by inducing the browning of white adipose tissue, increasing heat production and energy expenditure. Objective: The purpose of this study was to investigate the role of serum irisin as an adipokine to explore its function in the pathogenesis of AV and its correlation with IR, and whether it can be used as a potential biomarker of insulin sensitivity. Although the hyperinsulinemic-euglycemic clamp remains the gold standard for accurate determination of IR, it cannot be performed routinely. Various alternative simpler measures have been used, the most common being homeostasis model assessment. However, these metrics are limited by their accuracy, cost, and blood collection requirements.[1] Therefore, an effective and feasible serum biomarker is an attractive and relatively straightforward method, which may provide clinicians with a more accurate and simple method for the prediction and diagnosis of IR. IR can often be detected before other symptoms appear, so establishing an early diagnosis method will allow for the appropriate treatment of patients before the disease develops. Patients and Methods: The study included 171 subjects; 115 patients with newly diagnosed AV and 56 apparently healthy subjects. The contents of irisin and interleukin-1 alpha in serum were determined by enzyme-linked immunosorbent assay. The IR index was calculated by the homeostasis model. Results: Serum irisin levels in AV patients and control group were (24.0 ± 11.3) and (104.3 ± 27.0) ng/dl, respectively, which were significantly lower than those in control group (P < 0.001). Serum irisin was negatively correlated with IR (r = −0.711, P 0.001). The sensitivity of irisin was 100.0%, the specificity was 92.8%, and the cutoff point was 53.32. The decrease of serum irisin level could predict the patients with IR in acne. Conclusion: Serum irisin levels in AV patients were significantly decreased. Serum irisin showed acceptable performance criteria in the diagnosis of AV with IR. Serum irisin seems to be a good diagnostic and prognostic marker for IR. Further multi-center studies are needed to confirm this link, which could pave the way for new treatment options.

BackgroundAdenocarcinomas represent nearly 40% of all cancer types, and account for more than 70% of cancer-related deaths. Next generation sequencing (NGS) has been increasingly used for precision treatment in patients with adenocarcinomas. Labyrinthin (LAB) is a novel cancer neoantigen expressed on the surface of adenocarcinoma cells of various cancer types including lung adenocarcinoma (LUAD) and breast cancer. LabVax 3(22)-23 is a novel anti-tumor vaccine that contains four synthetic labyrinthin-based peptides designed to elicit both B-cell and T-cell responses. The objective of this study is to establish biomarker assays to identify candidate patients for a first-in-human phase I/II trial of peptide vaccine LabVax 3(22)-23 alone or in combination with pembrolizumab (NCT051013560).MethodsIHC assay for LAB expression on archived clinical tumor specimens was developed using a mouse monoclonal anti-LAB antibody MCA 44–3A6 (HB-8986TM, ATCC). LAB expression was scored on tumor cells by percentage and intensity on sections of tissue microarrays (TMAs) derived from 256 non-small cell lung cancer (NSCLC) and 97 breast cancer tissue blocks. LAB-specific mRNA expression was assessed in The Cancer Genome Atlas (TCGA) LUAD dataset by averaging expression of LAB-specific exons, excluding the related splice variant aspartyl/asparaginyl beta-hydroxylase (ASPH). The results were validated in an independent clinical NGS dataset of adenocarcinoma patients and selected tumor samples by IHC expression.ResultsWe found that LAB was expressed in 105/128 (82.0%) of LUAD by IHC. LAB expression is an independent poor prognostic factor for LUAD.1 High prevalence of LAB expression was also found in breast cancer samples (95.8%, 93/97). There was no significant difference in the LAB expression among the ER, PR, and HER2 positive subgroups. IHC assay was used to detect LAB expression on 11 out of 12 (91.7%) patients screened for the phase I trial. Tumor origins included colon or rectum (8), ovarian (1), scalp (1), and prostate (1). LAB RNA was expressed in both oncogene-driven and non-oncogene-driven adenocarcinomas. Furthermore, LAB RNA expression was positively correlated with PD-L1 RNA expression across these LUAD subgroups. There was a good correlation between RNA seq expression with IHC expression in the initial 10 patients. Ongoing studies are validating these results with more patients with NGS data.ConclusionsWe have established IHC and RNA assays to identify patients with LAB-positive adenocarcinomas in the ongoing phase I/II study (UCDCC#296, NCT051013560) evaluating the safety and efficacy of the LAB vaccine in combination with pembrolizumab.AcknowledgementsThis research was supported by the Personalized Cancer Therapy Gift Fund and Novel Treatment Strat for Adenocarcinoma (T.L.), and the Biostatistics Shared Resource funded by the UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded bythe National Cancer Institute (NCI P30CA093373) (S.C.).Trial RegistrationNCT051013560ReferenceMa W, Zeng J, Montoya DJ, Toomey K, Zhou C, Chen S, Liu D, Babich M, Radosevich JA, Li T, Labyrinthin Expression Is Associated with Poor Prognosis in Patients with Non-Small-Cell Lung Cancer. Cancers 2023; 15:924.Ethics ApprovalThe study was conducted according to the guidelines of the declaration of helsinki and approved by the institutional review board (or ethics committee) of the university of california, davis (UC davis cancer center biorepository protocol# 293828).ConsentPatient consent was waived with the IRB approval.

High gain greater than 106 is crucial for the preamplifiers of joule-class high-energy lasers. In this work, we present a specially designed compact amplifier using 0.5%Nd,5%Gd:SrF2 and 0.5%Nd,5%Y:SrF2 crystals. The irregular crystal shape enhances the gain length of the laser beam and helps suppress parasitic oscillations. The amplified spontaneous emission (ASE) induced by the high gain is analyzed through ray tracing. The balance between gain and ASE is estimated via numerical simulation. The gain spectral characteristics of the two-stage two-pass amplifier are examined, demonstrating the advantages of using different crystals, with bandwidths up to 8 nm and gains over 106. In addition, the temperature and stress distributions in the Nd,Gd:SrF2 crystal are simulated. This work is expected to contribute to the development of high-peak-power ( $\\ge$ terawatt-class) high-energy (joule-class) laser devices.

BackgroundImmune checkpoint inhibitors (ICIs) have inferior clinical response in patients with oncogene-driven lung adenocarcinoma (LUAD). There is also an unmet need for patients with non-oncogene-driven LUAD who failed first line ICI-containing treatment. Labyrinthin (LAB) is a novel cancer neoantigen expressed on the surface of adenocarcinoma cells of various cancer types including LUAD. We recently showed that LAB was expressed in LUAD by immunohistochemistry and is an independent prognostic factor for LUAD. The objective of this study was to determine if LAB is a target in different LUAD subgroups.MethodsLAB mRNA expression was assessed in The Cancer Genome Atlas (TCGA) LUAD dataset. LAB-specific mRNA expression was determined by averaging expression of exons specific to LAB and not the related splice variant aspartyl/asparaginyl beta-hydroxylase (ASPH). Patients with tyrosine-kinase inhibitor (TKI)-sensitive driver oncogenes were defined as those with an FDA-approved targeted therapy (e.g., mutations in EGFR, BRAF V600E, MET E14SP, ERBB2 and gene fusions in ALK, ROS1 and RET). Patients with other oncogenes included other BRAF mutations, KRAS, HRAS, NRAS and MAP2K).The results are validated in an independent cohort of clinically annotated patients with LUAD.ResultsAs expected, TKI-sensitive oncogene-driven LUAD (n=54) had statistically lower tumor mutational burden (TMB) (2.8 mut/MB, p<0.001) compared to other oncogene-driven LUAD (n=89,7.0 mut/MB) and non-oncogene-driven LUAD (n=87, 9.2 mut/MB), which is associated with poor response to ICIs. LAB RNA expression was higher in primary tumors than normal tissue specimens across different subgroups of TCGA-LUAD (figure 1). Furthermore, LAB expression was found to positively correlate with PD-L1 mRNA expression across these LUAD subgroups. RNA sequencing analysis of blood mononuclear cells of two pts enrolled in phase I trial revealed that LabVax 3(22)-23 and adjuvant GM-CSF treatment modulated the activity of immune cells and PD-1 pathway.ConclusionsLAB is a promising cancer neoantigen for both oncogene-driven and non-oncogene-driven LUAD, which warrant further study.AcknowledgementsThis research was supported by the Personalized Cancer Therapy Gift Fund and Novel Treatment Strat for Adenocarcinoma (T.L.), and the Biostatistics Shared Resource funded by the UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373) (S.C.).Ethics ApprovalUCD IRB#937274.Biomarkers for Patients with Advanced Solid Tumors. Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 1140 Figure 1LAB-FC expression in tumor vs normal tissues and correlation with PD-L1 (CD274) mRNA expression across different LUAD groups.