The biosynthesis of storage reserves and auxin is coordinated by a hierarchical regulatory network in maize endosperm.

Grain filling in maize (Zea mays) is intricately linked to cell development, involving the regulation of genes responsible for the biosynthesis of storage reserves (starch, proteins, and lipids) and phytohormones. However, the regulatory network coordinating these biological functions remains unclear. In this study, we identified 1744 high-confidence target genes co-regulated by the transcription factors (TFs) ZmNAC128 and ZmNAC130 (ZmNAC128/130) through chromatin immunoprecipitation sequencing coupled with RNA-seq analysis in the zmnac128/130 loss-of-function mutants. We further constructed a hierarchical regulatory network using DNA affinity purification sequencing analysis of downstream TFs regulated by ZmNAC128/130. In addition to target genes involved in the biosynthesis of starch and zeins, we discovered novel target genes of ZmNAC128/130 involved in the biosynthesis of lipids and indole-3-acetic acid (IAA). Consistently, the number of oil bodies, as well as the contents of triacylglycerol, and IAA were significantly reduced in zmnac128/130. The hierarchical regulatory network centered by ZmNAC128/130 revealed a significant overlap between the direct target genes of ZmNAC128/130 and their downstream TFs, particularly in regulating the biosynthesis of storage reserves and IAA. Our results indicated that the biosynthesis of storage reserves and IAA is coordinated by a multi-TFs hierarchical regulatory network in maize endosperm.

Label-free fluorescent biosensor based on AuNPs etching releasing signal for miRNA-155 detection.

Quantitative microRNA (miRNA) detection is crucial for early breast cancer diagnosis and prognosis. However, quick and stable fluorescence sensing for miRNA identification is still challenging. This work developed a novel label-free detection method based on AuNPs etching for quantitatively detecting miRNA-155. A layer of AuNPs was grown on the surface of mesoporous silica nanoparticles (MSN) loaded with Rhodamine 6G (R6G) using seed-mediated growth, followed by probe attachment. In the presence of miRNA-155, the MSN@R6G@AuNP surface loses the protection of the attached probe, rendering AuNPs susceptible to etching by hydrochloric acid. This results in a significant fluorescent signal being released in the free space. The encapsulation with AuNPs effectively reduces signal leakage, while the rapid etching process shortens detection time. This strategy enables sensitive and fast detection with a detection range of 100 fM to 100 nM, a detection limit of 2.18 fM, and a detection time of 30 min. The recovery rate in normal human serum ranges from 99.02 % to 106.34 %. This work presents a simple biosensing strategy with significant potential for application in tumor diagnosis.

Health and wellbeing of staff working at higher education institutions globally during the post-COVID-19 pandemic period: evidence from a cross-sectional study.

BACKGROUND: The ongoing global crisis of Higher Education (HE) institutions during the post-COVID-19 pandemic period has increased the likelihood of enduring psychological stressors for staff. This study aimed to identify factors associated with job insecurity, burnout, psychological distress and coping amongst staff working at HE institutions globally. METHODS: An anonymous cross-sectional study was conducted in 2023 with staff at HE institutions across 16 countries. Job insecurity was measured using the Job Insecurity Scale (JIS), burnout using the Perceived Burnout measure question, psychological distress using the Kessler Psychological Distress Scale (K10), and coping using the Brief Resilient Coping Scale. Multivariable logistic regression with a stepwise variable selection method was used to identify associations. RESULTS: A total of 2,353 staff participated; the mean age (± SD) was 43(± 10) years and 61% were females. Most staff (85%) did not feel job insecurity, one-third (29%) perceived burnout in their jobs, more than two-thirds (73%) experienced moderate to very high levels of psychological distress, and more than half (58%) exhibited medium to high resilient coping. Perceived job insecurity was associated with staff working part-time [Adjusted Odds Ratio 1.53 (95% Confidence Intervals 1.15-2.02)], having an academic appointment [2.45 (1.78-3.27)], having multiple co-morbidities [1.86 (1.41-2.48)], perceived burnout [1.99 (1.54-2.56)] and moderate to very high level of psychological distress [1.68 (1.18-2.39)]. Perceived burnout was associated with being female [1.35 (1.12-1.63)], having multiple co-morbidities [1.53 (1.20-1.97)], perceived job insecurity [1.99 (1.55-2.57)], and moderate to very high levels of psychological distress [3.23 (2.42-4.30)]. Staff with multiple co-morbidities [1.46 (1.11-1.92)], mental health issues [2.73 (1.79-4.15)], perceived job insecurity [1.61 (1.13-2.30)], and perceived burnout [3.22 (2.41-4.31)] were associated with moderate to very high levels of psychological distress. Staff who perceived their mental health as good to excellent [3.36 (2.69-4.19)] were more likely to have medium to high resilient coping. CONCLUSIONS: Factors identified in this study should be considered in reviewing and updating current support strategies for staff at HE institutions across all countries to reduce stress and burnout and improve wellbeing.

Real world risk of discontinuing oral anticoagulation after successful catheter ablation for atrial fibrillation.

Background: Many patients with atrial fibrillation (AF) discontinued oral anticoagulation (OAC) therapy after successful catheter ablation. We aimed to determine the real-world risks and consequences of discontinuing OAC use after catheter ablation for AF. Methods: Patients who underwent successful catheter ablation for AF from January 2004 to December 2020 were divided into continued long-term OAC (On-OAC, n = 1062) and discontinued (Off-OAC, n = 1055) groups. The long-term outcomes including thromboembolic events, major bleeding, all-cause mortality and major adverse cardiovascular events (MACE), were compared between the two groups. Results: The CHA2DS2-VASc score was 3.44 ± 1.12. After a mean follow-up of 37.09 months, thromboembolism risk was higher and major bleeding risk was lower in the Off-OAC than in the On-OAC group (Both log-rank P < 0.001). CHA2DS2-VASc score-stratified subgroup analysis showed similar cumulative event rates between the two groups in men and women with scores of 2 and 3 (intermediate risk for stroke), respectively, (P > 0.05), except for a higher major bleeding rate in the On-OAC group (P = 0.002). Patients at high risk for stroke (men and women with scores ≥3 and ≥ 4) had better non-thromboembolic and non-MACE results (Both log-rank P < 0.05). Conclusion: Men with a CHA2DS2-VASc score of 2 and women with a score of 3 had a relatively low incidence of stroke events after successful catheter ablation for AF and may be safe for anticoagulation cessation. Greater benefits from long-term OAC were observed in men with CHA2DS2-VASc score ≥3 and women with score ≥4.

Assessing pain in older people with normal, mildly impaired or severely impaired cognition.

Pain is a relatively common experience among older people, but unrelieved pain has significant functional, cognitive and emotional consequences for this population. A comprehensive and accurate pain assessment is essential for effective pain management. Self-report tools are suitable to assess pain in older people with normal or mildly impaired cognition, while observational tools are suitable for use with those with significant cognitive impairment or communication difficulties. However, pain assessment in older people can be challenging. The use of one tool on its own is rarely sufficient and it is crucial to involve family carers in assessment of pain in older people with severe cognitive impairment. This article discusses different tools and strategies, including the benefits and limitations, for assessing pain in older people.

The impact of Paclitaxel-based hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer patients - interim analysis of safety and immediate efficacy of a randomized control trial (C-HOC trial).

OBJECTIVE: This study evaluates the potential superiority of combining paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) with sequential intravenous neoadjuvant chemotherapy over intravenous neoadjuvant chemotherapy alone in Chinese patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC, IVA and IVB high-grade serous ovarian/fallopian tube carcinoma (HGSOC). This interim analysis focuses on the safety and immediate efficacy of both regimens to determine the feasibility of the planned trial (C-HOC Trial). METHODS: In a single-center, open-label, randomized control trial, FIGO stage IIIC, IVA, and IVB HGSOC patients (FAGOTTI score ≥ 8 during laparoscopic exploration) unsuitable for optimal cytoreduction in primary debulking surgery (PDS) were randomized 2:1 during laparoscopic exploration. The Experiment Group (HIPEC Group) received one cycle of intraperitoneal neoadjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (paclitaxel) followed by three cycles of intravenous chemotherapy (paclitaxel plus carboplatin), while the Control Group received only three cycles of intravenous chemotherapy. Both groups subsequently underwent interval debulking surgery (IDS). The adverse effects of chemotherapy, postoperative complications, and pathological chemotherapy response scores (CRS) after IDS were compared. RESULTS: Among 65 enrolled patients, 39 HIPEC Group and 21 Control Group patients underwent IDS. Grade 3-4 chemotherapy-related adverse effects were primarily hematological with no significant differences between the two groups. The HIPEC Group exhibited a higher proportion of CRS 3 (20.5% vs. 4.8%; P = 0.000). R0 resection rates in IDS were 69.2% (HIPEC Group) and 66.7% (Control Group). R2 resection occurred in 2.6% (HIPEC Group) and 14.3% (Control Group) cases. No reoperations or postoperative deaths were reported, and complications were managed conservatively. CONCLUSIONS: Combining HIPEC with IV NACT in treating ovarian cancer demonstrated safety and feasibility, with no increased chemotherapy-related adverse effects or postoperative complications. HIPEC improved tumor response to neoadjuvant chemotherapy, potentially enhancing progression-free survival (PFS). However, the final overall survival results are pending, determining if HIPEC combined with IV NACT is superior to IV NACT alone.

Decoding cellular plasticity and niche regulation of limbal stem cells during corneal wound healing.

BACKGROUND: Dysfunction or deficiency of corneal epithelium results in vision impairment or blindness in severe cases. The rapid and effective regeneration of corneal epithelial cells relies on the limbal stem cells (LSCs). However, the molecular and functional responses of LSCs and their niche cells to injury remain elusive. METHODS: Single-cell RNA sequencing was performed on corneal tissues from normal mice and corneal epithelium defect models. Bioinformatics analysis was performed to confirm the distinct characteristics and cell fates of LSCs. Knockdown of Creb5 and OSM treatment experiment were performed to determine their roles of in corneal epithelial wound healing. RESULTS: Our data defined the molecular signatures of LSCs and reconstructed the pseudotime trajectory of corneal epithelial cells. Gene network analyses characterized transcriptional landmarks that potentially regulate LSC dynamics, and identified a transcription factor Creb5, that was expressed in LSCs and significantly upregulated after injury. Loss-of-function experiments revealed that silencing Creb5 delayed the corneal epithelial healing and LSC mobilization. Through cell-cell communication analysis, we identified 609 candidate regeneration-associated ligand-receptor interaction pairs between LSCs and distinct niche cells, and discovered a unique subset of Arg1+ macrophages infiltrated after injury, which were present as the source of Oncostatin M (OSM), an IL-6 family cytokine, that were demonstrated to effectively accelerate the corneal epithelial wound healing. CONCLUSIONS: This research provides a valuable single-cell resource and reference for the discovery of mechanisms and potential clinical interventions aimed at ocular surface reconstruction.

Assessing long-term effects of gaseous air pollution exposure on mortality in the United States using a variant of difference-in-differences analysis.

Long-term mortality effects of particulate air pollution have been investigated in a causal analytic frame, while causal evidence for associations with gaseous air pollutants remains extensively lacking, especially for carbon monoxide (CO) and sulfur dioxide (SO2). In this study, we estimated the causal relationship of long-term exposure to nitrogen dioxide (NO2), CO, SO2, and ozone (O3) with mortality. Utilizing the data from National Morbidity, Mortality, and Air Pollution Study, we applied a variant of difference-in-differences (DID) method with conditional Poisson regression and generalized weighted quantile sum regression (gWQS) to investigate the independent and joint effects. Independent exposures to NO2, CO, and SO2 were causally associated with increased risks of total, nonaccidental, and cardiovascular mortality, while no evident associations with O3 were identified in the entire population. In gWQS analyses, an interquartile range-equivalent increase in mixture exposure was associated with a relative risk of 1.067 (95% confidence interval: 1.010-1.126) for total mortality, 1.067 (1.009-1.128) for nonaccidental mortality, and 1.125 (1.060-1.193) for cardiovascular mortality, where NO2 was identified as the most significant contributor to the overall effect. This nationwide DID analysis provided causal evidence for independent and combined effects of NO2, CO, SO2, and O3 on increased mortality risks among the US general population.

One new triterpene glycoside from Cyclocarya paliurus.

One previously undescribed triterpene glycoside (1) and two known compounds were isolated from the leaves of Cyclocarya paliurus (2-3). Their structures were elucidated based on methods of spectroscopic analysis and NMR data comparison with those in the literature. Compound 1 showed a moderate inhibitory effect on melanogenesis with an IC50 value of 282.3 µM, with the positive drug arbutin showing an IC50 value of 168.5 µM.

A Clinically Feasible Diagnostic Electrochemical Micronano Motors Biosensor Built on Miniature Swimmer for Multiplex Detection and Grading of Breast Cancer Biomarkers.

Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), and Ki67 are four crucial biomarkers used in the clinical diagnosis of breast cancer. Accurate detection of these biomarkers is essential for an effective diagnosis and treatment. MOF-based micronano motors (MOFtors) are promising for various applications, including environmental remediation, targeted nanosurgery, and biomarker detection. This paper presents a clinically feasible diagnostic electrochemical micronano motor biosensor, built on a miniature swimmer, for the multiplex detection and grading of breast cancer biomarkers. We designed a biosensor, named MOFtor-MSEM, incorporating aptamers and antibodies functionalized on SiO2@Co-Fe-MOF, which acts as a miniature swimmer in solution. The SiO2@Co-Fe-MOF serves as the body, while complementary double-chain-linked antibodies function as paddles. In a homogeneous solution, when a positive voltage is applied to the working electrode, the electrostatic interaction between the neutral SiO2@Co-Fe-MOF and the negatively charged complementary double-linked antibody causes the antibody to move toward the electrode and then regress due to water resistance. This back-and-forth motion propels the miniature swimmer, enabling it to move the target analyte through the solution. The sensor features an automatic "sample-amplifying signal-output" process, achieving simultaneous signal amplification and output of four electrochemical signals on a single nanomaterial, a significant challenge in electrochemical sensing. The biosensor boasts a short detection time of 40 min, compared to approximately 1 week for current clinical tissue testing. Additionally, the bioplatform selectively detects HER2, ER, Ki67, and PR in the range of 0-1500 pg/mL, with detection limits of 0.01420, 0.03201, 0.01430, and 0.01229 pg/mL, respectively.

Unveiling the NIMBY effect in construction and demolition waste landfilling: Factors, paths, and solutions.

The construction and operation of the construction and demolition waste (C&DW) landfills often encounter significant opposition from nearby residents, which is called the "not in my backyard" (NIMBY) effect. However, little is known about the formation mechanism of the NIMBY effect in C&DW landfilling, so this research was conducted for this purpose. First, the influencing factors leading to the NIMBY effect were determined based on a literature review and questionnaire survey. Then, the interrelationship and influencing path of critical factors were revealed using expert interviews and Interpretative Structural Modelling. The results shown that 12 factors from four levels (including residents, society, government, and enterprises) caused the NIMBY effect in C&DW landfilling. These factors formed a complex network comprising 18 influencing paths. Notably, policy and responding measures as pivotal bottom-level factors that trigger the NIMBY effect by indirectly impacting residents' rights awareness and shaping public perception towards C&DW landfill operation enterprises through directly affecting personal interest, cognitive bias, distrust, disposal technology, management level, opinion leader, and other intermediate factors, ultimately triggering the NIMBY effect. Moreover, strategies for mitigating or resolving the NIMBY effect were proposed, such as protecting personal reasonable interests, understanding the potential risks of C&DW landfills rationally, reporting the C&DW landfills from an objective perspective, improving policies and promoting public participation, and enhancing supervision of the C&DW landfills. The study added new knowledge to the current public's NIMBY effect in C&DW landfilling. Meanwhile, it also provided a reference for formulating C&DW landfilling policies and selecting landfill sites.

Multi objective optimization and evaluation approach of prefabricated component combination solutions using NSGA-II and simulated annealing optimized projection pursuit method.

As a main carrier mode for the sustainable development of the construction industry in China, prefabricated building may lead to problems such as cost overruns, project delays, and waste of resources due to unreasonable selection of prefabricated components. Therefore, we quantitatively analyze the contribution rate of quality optimization of prefabricated components using QFD-SEM. Under the constraints of prefabrication rate, quality optimization contribution rate, and expected values of various sub-goals, we propose a multi-objective optimization method for prefabricated component combinations based on cost, duration, and carbon emissions. By using NSGA-II to solve the model, we can obtain a set of optimal Pareto solutions for prefabricated component combinations. Based on the optimal Pareto solution set, we establish a multi-objective evaluation model using simulated annealing optimization projection tracing method, and select the optimal prefabricated component combination solution according to the projected eigenvalues of the solutions. An empirical study is conducted using an eleven-story framed building in Shenzhen, Guangdong Province, China as a case study. The results show that: (1) Using this method, optimal solutions can be obtained in an unbounded solution space, with the optimal solution having advantages over both fully cast-in-place and fully prefabricated solutions. Compared to the fully cast-in-place solution, the duration and carbon emissions are reduced by 36.62% and 12.74% respectively, while compared to the fully prefabricated solution, costs are reduced by 4.15%. (2) There is a certain negative correlation between the cost of prefabricated component combinations and duration, carbon emissions, and quality optimization, while there is a certain positive correlation with the prefabrication rate. (3) The size of the optimal projection direction vector based on the optimization objectives indicates that carbon emissions have the greatest impact on the evaluation results of the solutions.

Preferences regarding COVID-19 vaccination among 12,000 adults in China: A cross-sectional discrete choice experiment.

Understanding public preferences concerning vaccination is critical to inform pandemic response strategies. To investigate Chinese adults' preferences regarding COVID-19 vaccine attributes, we conducted a cross-sectional online survey in 12,000 Chinese adults in June-July, 2021. Participants were requested to answer a series of discrete choice questions related to hypothetical COVID-19 vaccines. Using mixed logit models, our analysis revealed that participants had a higher preference for COVID-19 vaccines with longer duration of protection (coefficient: 1.272, 95% confidence interval [1.016 to 1.529]) and higher efficacy (coefficient: 1.063, [0.840, 1.287]). Conversely, participants demonstrated a lower preference associated with higher risk of rare but serious side-effects (coefficient: -1.158, [-1.359, -0.958]), oral administration (coefficient: -0.211, [-0.377, -0.046]), more doses (coefficient: -0.148, [-0.296, 0.000]) and imported origin (coefficient: -0.653, [-0.864, -0.443]). Moreover, preferences were heterogeneous by individual factors: highly educated participants were more sensitive to the negative vaccine attributes including price (coefficient -0.312, [-0.370, -0.253]) and imported vaccine (coefficient -0.941, [-1.186, -0.697]); there was also substantial heterogeneity in vaccine preferences with respect to age group, marital status, work status, income, chronic diagnosis history, COVID-19 vaccination history and geographic regions. As the first study of examining the public preferences for COVID-19 vaccine in China with a large nationwide sample of 12,000 adults, our results indicate that future vaccine should pose lower risk, possess longer protection period, have higher efficacy, be domestically produced, and have lower costs to increase the COVID-19 vaccination coverage. Our current study findings from this study provide insights and recommendations for not only COVID-19 vaccine design but also vaccine attribute preferences to increase vaccine uptake in potential future pandemics.

5,7,4'-Trimethoxyflavone triggers cancer cell PD-L1 ubiquitin-proteasome degradation and facilitates antitumor immunity by targeting HRD1.

Targeting the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we identified that the small molecule 5,7,4'-trimethoxyflavone (TF) from Kaempferia parviflora Wall reduces PD-L1 expression in colorectal cancer cells and enhances the killing of tumor cells by T cells. Mechanistically, TF targets and stabilizes the ubiquitin ligase HMG-CoA reductase degradation protein 1 (HRD1), thereby increasing the ubiquitination of PD-L1 and promoting its degradation through the proteasome pathway. In mouse MC38 xenograft tumors, TF can activate tumor-infiltrating T-cell immunity and reduce the immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells, thus exerting antitumor effects. Moreover, TF synergistically exerts antitumor immunity with CTLA-4 antibody. This study provides new insights into the antitumor mechanism of TF and suggests that it may be a promising small molecule immune checkpoint modulator for cancer therapy.

Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis.

Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.

Simultaneous Detection of Micro-RNAs by a Disposable Biosensor via the Click Chemistry Connection Strategy.

Simultaneous detection of multiple breast cancer-associated miRNAs significantly raises the accuracy and reliability of early diagnosis. In this work, disposable carbon fiber paper serves as the biosensing interface, linking DNA probes via click chemistry to efficiently capture targets and signals efficiently. DNA probes have multiple recognition domains that trigger a cascade reaction through the helper probes and targets, resulting in two signals output. The signals are centrally encapsulated in the pore of the MIL-88(Fe)-NH2. The signal carriers are directed by signal probes to the recognition domains that correspond to the DNA probes. The biosensor is selective and stable, and it can quantify miRNA-21 and miRNA-155 simultaneously with detection limits of 0.64 and 0.54 fmol/L, respectively. Furthermore, it demonstrates satisfactory performance in tests conducted with normal human serum and cell lysate. Overall, this method makes a satisfactory exploration to realize an inexpensive and sensitive biosensor for multiple biomarkers.

Risk of malignancy and overall survival associated with the diagnostic categories in the World Health Organization Reporting System for Pancreaticobiliary Cytopathology.

BACKGROUND: The World Health Organization (WHO) classification system revised the Papanicolaou Society of Cytopathology (PSC) system for reporting pancreaticobiliary cytopathology. To better stratify intraductal and/or cystic neoplasms by cytologic grade, the neoplastic, other category was replaced by two new categories: pancreaticobiliary neoplasm, low-risk/grade (PaN-Low) and pancreaticobiliary neoplasm, high-risk/grade (PaN-High). Low-grade malignancies were placed in the malignant category, and benign neoplasms were placed in the benign/negative for malignancy category. METHODS: An institutional pathology database search identified patients who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for pancreatic lesions from January 2015 to April 2022. The absolute risk of malignancy (ROM) was determined by histologic and/or clinical follow-up of at least 6 months, and overall survival rates were calculated across diagnostic categories, comparing the WHO and PSC systems. RESULTS: In total, 1012 cases were reviewed and recategorized. The ROM for the WHO system was 8.3% for insufficient/inadequate/nondiagnostic, 3.2% for benign/negative for malignancy, 24.6% for atypical, 9.1% for PaN-Low, 46.7% for PaN-High, 75% for suspicious for malignancy, and 100% for malignant. Comparatively, the ROM for the PSC system was 7.4% for nondiagnostic, 3.0% for negative for malignancy, 23.1% for atypical, 0% for neoplastic, benign, 7.3% for neoplastic, other, 75% for suspicious for malignancy, and 100% for malignant. The WHO system demonstrated superior stratification for overall survival. CONCLUSIONS: The WHO system significantly improves the stratification of ROM and overall survival across diagnostic categories by introducing the PaN-Low and PaN-High categories and reassigning low-grade malignancies to the malignant category. Analyzing EUS-FNA samples with the WHO system provides critical insights for guiding clinical management.

Retinoic acid receptor alpha inhibits ferroptosis by promoting thioredoxin and protein phosphatase 1F in lung adenocarcinoma.

Ferroptosis is a recently discovered form of cell death that plays an important role in tumor growth and holds promise as a target for antitumor therapy. However, evidence in the regulation of ferroptosis in lung adenocarcinoma (LUAD) remains elusive. Here, we show that retinoic acid receptor alpha (RARA) is upregulated with the treatment of ferroptosis inducers (FINs). Pharmacological activation of RARA increases the resistance of LUAD to ferroptosis according to cell viability and lipid peroxidation assays, while RARA inhibitor or knockdown (KD) does the opposite. Through transcriptome sequencing in RARA-KD cells and chromatin immunoprecipitation (CHIP)-Seq data, we identify thioredoxin (TXN) and protein phosphatase 1 F (PPM1F) as downstream targets of RARA, both of which inhibit ferroptosis. We confirm that RARA binds to the promotor region of TXN and PPM1F and promotes their transcription by CHIP-qPCR and dual-luciferase assays. Overexpression of TXN and PPM1F reverses the effects of RARA knockdown on ferroptosis in vitro and vivo. Clinically, RARA knockdown or inhibitor increases cells' sensitivity to pemetrexed and cisplatin (CDDP). Immunohistochemistry (IHC) of LUAD from our cohort shows the same expression tendency of RARA and the downstream targets. Our study uncovers that RARA inhibits ferroptosis in LUAD by promoting TXN and PPM1F, and inhibiting RARA-TXN/PPM1F axis represents a promising strategy for improving the efficacy of FINs or chemotherapy in the treatment of LUAD patients.