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Cui-Ping Li,1,* Lei Li,2,* Lin-Ming Su,3,* Shu-Sheng Zhu,4 Meng-Jie Li5 1Department of Pathology, Renmin Hospital of Qingxian, Cangzhou, People’s Republic of China; 2Department of the First Surgery, Wuhan Jin-Yin-Tan Hospital, Wuhan, People’s Republic of China; 3Department of Radiology, Renmin Hospital of Qingxian, Cangzhou, People’s Republic of China; 4Department of Thoracic Surgery, Taizhou Hospital of Traditional Chinese Medicine, Taizhou, People’s Republic of China; 5Department of Respiratory Oncology, Renmin Hospital of Qingxian, Cangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shu-Sheng Zhu; Meng-Jie Li, Email lwb421223@163.com; lmjnkdf@163.comAbstract: Schwannomas are benign slow-growing tumors arising from the embryonic neural crest cells of the nerve sheaths of peripheral and cranial nerves, and they are a rare type of soft tissue mass that is usually always solitary. Generally, it grows in the head, neck, and flexor portions of the limbs, where many nerves are located. Schwannomas of the lung are extremely rare. Fewer than ten cases of schwannomas in this organ region have been reported in the existing literature. In this case report, a 40-year-old male non-smoker was hospitalized with occasional chest pain. His chest computed tomographic scan revealed a 3.8 cm space occupying lesion in the upper lobe of the right lung. This lesion has clear boundaries and uneven internal density. And it was concluded as a benign lesion possibility, it is preferred to be considered as a haematoma. This space occupying lesion was eventually confirmed as a schwannoma by needle biopsy tissues. Due to the presence in rare locations, such as the lung, the clinical presentation of this space occupying lesion is non-specific, making diagnosis difficult. The data presented in this case report can help clinicians to obtain information on the identification of this disease, which highlighted lung schwannoma as a differential diagnosis for patients with intermittent pain. It can also alert clinicians and radiologists to observe every detail of the radiology imaging findings.Keywords: diagnosis, schwannoma, lung cancer, thoracic radiology, solitary pulmonary nodule

Yin Dong,1,* Ming-Jing Li,2,* Yan-Zhu Hong,3 Wen-Jie Li4 1Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 4Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Zhu Hong, Xiamen University, No. 422, Siming South Road, Siming District, Xiamen, Fujian, 361005, People’s Republic of China, Tel +86 13671617025, Email hongyanzhu2020@sina.com Wen-Jie Li, Shanghai University of Traditional Chinese Medicine, No. 1200 Cai-lun Road, Pudong District, Shanghai, 201203, People’s Republic of China, Tel +86 15397687742, Email liwenjie@shutcm.edu.cnAbstract: Dysmenorrhea, classified as primary dysmenorrhea and secondary dysmenorrhea, is a common gynecological symptom that seriously affects female daily life. At present, studies on dysmenorrhea are numerous and complex. To better reflect the trend and innovative progress of dysmenorrhea-related research, this study screened papers on the Web of Science from January 1, 1992, to December 31, 2022. A total of 1012 papers were selected and analyzed for their affiliated countries, institutions, authors, keywords, etc. China is the country with the most academic output, Beijing University of Traditional Chinese Medicine is the most influential institution, and Yang Jie, from Chengdu University of Traditional Chinese Medicine, China, is the scholar with the most papers. We consider that the current research focus is on pathogenesis, treatment, epidemiology, and self-management. With increasing research on functional connectivity between dysmenorrhea and various brain regions, functional connectivity has gradually become the forefront of research. We hope our study can promote the further study of dysmenorrhea.Keywords: pathogenesis, treatment, management, traditional Chinese medicine

Wan-Ling Liu,1– 4,* Yong-Qu Zhang,1– 5,* Xiang-Jie Luo,6 Yuan-Yuan Zhu,1– 4 Liang Song,7 Zi-He Ming,1– 4 Li-Xin Zhang,1– 4 Meng-Jun Li,1– 4 Rui-Chan Lv,8 Guo-Jun Zhang,1– 4,9,* Min Chen2– 4,* 1Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer, Xiang’an Hospital of Xiamen University, Xiamen, People’s Republic of China; 3Xiamen Key Laboratory of Endocrine-Related Cancer Precision Medicine, Xiamen, People’s Republic of China; 4Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, People’s Republic of China; 5Department of Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, People’s Republic of China; 6College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, People’s Republic of China; 7Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences and Technology University, Xiamen, People’s Republic of China; 8Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shanxi, People’s Republic of China; 9Cancer Research Center, School of Medicine, Xiamen University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min Chen; Guo-Jun Zhang, Email mchen@xah.xmu.edu.cn; gjzhang@xah.xmu.edu.cnBackground: Durable responses to immune-checkpoint blocking therapy (ICT) targeting programmed cell death protein-1/ligand-1 (PD-1/PD-L1) have improved outcomes for patients with triple negative breast cancer (TNBC). Unfortunately, only 19– 23% of patients benefit from ICT. Hence, non-invasive strategies evaluating responses to therapy and selecting patients who will benefit from ICT are critical issues for TNBC immunotherapy.Methods: We developed a novel nanoparticle-Atezolizumab (NPs-Ate) consisting of indocyanine green (ICG), gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), human serum albumin (HSA), and Atezolizumab. The efficiency of Gd-DTPA linking was verified using mass spectrometry, and the size of NPs-Ate was characterized using Nano-flow cytometry. The synthesized NPs-Ate were evaluated for fluorescence stability, penetration depth, and target specificity. TNBC cell lines and tumor-bearing mice models were used to identify the feasibility of this dual-modal second near-infrared/magnetic resonance imaging (NIR-II/MRI) system. Additionally, ICT combination with chemotherapy or radiotherapy in TNBC tumor-bearing mice models were used to assess dynamic changes of PD-L1 and predicted therapeutic responses with NPs-Ate.Results: Atezolizumab, a monoclonal antibody, was successfully labeled with ICG and Gd-DTPA to generate NPs-Ate. This demonstrated strong fluorescence signals in our NIR-II imaging system, and relaxivity (γ 1) of 9.77 mM− 1 s− 1. In tumor-bearing mice, the NIR-II imaging signal background ratio (SBR) reached its peak of 11.51 at 36 hours, while the MRI imaging SBR reached its highest as 1.95 after 12 hours of tracer injection. NPs-Ate specifically targets cells and tumors expressing PD-L1, enabling monitoring of PD-L1 status during immunotherapy. Combining therapies led to inhibited tumor growth, prolonged survival, and increased PD-L1 expression, effectively monitored using the non-invasive NPs-Ate imaging system.Conclusion: The NIR-II/MRI NPs-Ate effectively reflected PD-L1 status during immunotherapy. Real-time and non-invasive immunotherapy and response/prognosis monitoring under NIR-II/MRI imaging guidance in TNBC is a promising and innovative technology with potential for extensive clinical applications in the future.Keywords: dual-modal imaging, triple-negative breast cancer, immune-checkpoint blocking therapy, programmed cell death protein ligand-1, monitoring therapeutic response

Meng-Jie Li,1,* Jun Wei,2,* Guo-Ping Ai,3,* Ying Liu,4 Jian Zhu4 1Department of Respiratory Oncology, Renmin Hospital of Qingxian, Cangzhou, 062650, People’s Republic of China; 2Department of the First Surgery, Wuhan Jin-Yin-Tan Hospital, Wuhan, 430011, People’s Republic of China; 3Department of Radiology, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China; 4Department of Thoracic Cardiovascular Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Zhu; Ying Liu, Department of Thoracic Cardiovascular Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China, Tel +86-13871166489, Fax +86-27-50772388, Email zhujian0718@163.com; xxwkly@163.comIntroduction: Molecular targeted therapy has shown certain therapeutic effects on various cancer types, especially lung cancer. Here, we report a case of a patient with unresectable non-small cell lung cancer (NSCLC) with bone metastases and metastatic lesions that disappeared after molecular targeted therapy.Patient Information: A 49-year-old male patient’s chest CT scan showed a patchy, slightly high-density shadow on the upper lobe of the left lung with an unclear boundary. The multiple thoracic vertebrae, 4th lumbar vertebrae, multiple ribs, right sacroiliac joint, right hip joint, right inferior ramus of pubis, left middle and upper femur, and right proximal radial bone showed nodular and slightly high-density shadows.Interventions: The patient was not considered eligible for tumor resection due to his metastatic lesions. A resected lymph node biopsy was performed. The pathologic findings suggested lung adenocarcinoma, and the gene detection results indicated NM-005228:exon19:c.2235– 2249del:p. GLu746-Ala750del (15.31%), NM-005228:exon20:c. G2356A: p. V786M (1.67%). The patient received the icotinib hydrochloride molecular targeted therapy.Outcomes: After two months of treatment, pulmonary nodules were basically absent on chest CT scan re-examination. After nine months of treatment, no obvious abnormalities in the thoracic vertebral bone were found on 99mTc-MDP bone scan and CT scan re-examination. No obvious structural abnormalities, such as enlarged lymph nodes, could be found by ultrasound re-examination, and the patient remained alive without recurrence at the five-year follow-up.Conclusion: This case report may provide a clue for the future development of molecular targeted therapy for lung cancer. It will allow surgeons to collaborate with oncologists and raise awareness of the benefit of the multidisciplinary approach to the diagnosis and treatment of cancer. Moreover, our results will help patients to fully understand the effect of nonsurgical treatments and improve confidence in the diagnosis and treatment of advanced lung cancer.Keywords: bone metastases, lung cancer, molecular targeted therapy, gene therapy

Lei Li,1,* Meng-Jie Li,2,* Liu Sun,3,* Yuan-Liang Jiang,4 Jian Zhu5 1Department of the First Surgery, Wuhan Jin-Yin-Tan Hospital, Wuhan, 430011, People’s Republic of China; 2Department of Respiratory Oncology, Renmin Hospital of Qingxian, Cangzhou, 062650, People’s Republic of China; 3Department of Otolaryngology-Head and Neck Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China; 4Department of Radiology, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China; 5Department of Thoracic Cardiovascular Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Zhu; Yuan-Liang Jiang, General Hospital of Central Theater Command of the People’s Liberation Army, 627#, Wuluo Road, Wuchangqu, Wuhan, Hubei, 430070, People’s Republic of China, Tel +86-13871166489, Fax +86-27-50772388, Email zhujian0718@163.com; whzyyjyl@126.comAbstract: Foreign body aspiration (FBA) occurs less frequently in adults than in children. Case reports of FBAs occurring in adults after lung surgery are not found in the literature, and this particular condition is often misdiagnosed. We report a case in which the patient was diagnosed after various events. A 56-year-old female patient had undergone robotic-assisted resection of the right upper lobe. The patient recovered well after the operation, with a slight irritant dry cough. Chest computed tomography (CT) examination of the patient showed no obvious abnormality early postoperatively. However, she developed intermittent cough and hemoptysis at six months. Repeat chest CT showed a soft tissue shadow near the bronchus in the lower lobe of the right lung. Cancer recurrence, surgery-related foreign body residue, lymphoid reactive hyperplasia, or other reasons was considered. Further examination revealed a piece of watermelon seed shell blocking the bronchial opening of the lower lung. This case highlights the importance of medical history, careful physical examination and fiberoptic bronchoscopic examination after lung cancer surgery due to lung cancer recurrence risk or FBA.Keywords: foreign body aspiration, cancer recurrence, fiberoptic bronchoscopy, diagnosis

Bo Yang,1– 3,* Lin-Lin Ji,1,2,* Hong-Liang Xu,1,* Xiao-Ping Li,3 Hong-Gang Zhou,4 Ting Xiao,4 Xiao-He Li,4 Zhou-Yong Gao,1,2 Jian-Zhong Li,5 Wei-Dong Zhang,3 Guang-Shun Wang,1 Ming-Jiang Li3 1Department of Thoracic Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People’s Republic of China; 2State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, People’s Republic of China; 3Department of Thoracic Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, People’s Republic of China; 4State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key, Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People’s Republic of China; 5Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guang-Shun WangDepartment of Thoracic Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People’s Republic of ChinaEmail wgs@bddhospital.comMing-Jiang LiDepartment of Thoracic Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, People’s Republic of ChinaEmail mingjiangli@nankai.edu.cnBackground: Zc3h12d is a negative regulator which plays a crucial role in immune modulation. However, the role of zc3h12d in lung adenocarcinoma (LUAD) remains unclear. We aim to explore the prognostic of zc3h12d and investigate the relationship between zc3h12d expression and immune infiltration in LUAD.Methods: TIMER site was used to analyze the expression of zc3h12d in LUAD. The zc3h12d protein levels in patient tissue samples were detected by immunohistochemistry staining assays. Meanwhile, based on UALCAN database and samples’ data from our cohort, we explored the relationship of clinicopathological features and zc3h12d expression to determine the clinical effect of zc3h12d in LUAD. Several databases including GEPIA, Kaplan–Meier plotter and our samples’ data were used to explore the prognostic value of zc3h12d in LUAD. Cox regression analysis was established to further evaluate the prognostic value of zc3h12d in LUAD. In addition, zc3h12d promoter methylation was analyzed by UALCAN database. Genetic alteration analysis was observed in the cBioPortal web. GO and KEGG analyses were conducted to elucidate the underlying mechanisms. Finally, the correlation between zc3h12d and tumor-infiltrating immune cells in LUAD was investigated by TIMER database. The B cells level was investigated by flow cytometry analysis of peripheral blood from our LUAD cohort.Results: Zc3h12d expression was significantly higher in LUAD, compared with adjacent normal tissues. The clinical data from the UALCAN database demonstrated that zc3h12d expression was closely related with cancer stage and nodal metastasis. However, patient sample detection revealed that zc3h12d expression was closely related to pathological N (p = 0.0431) and grade (p = 0.004). Moreover, low zc3h12d expression was associated with poorer overall survival in LUAD. We analyzed the methylation level of zc3h12d in LUAD and found that the methylation levels of zc3h12d promoter in LUAD were significantly reduced. In addition, zc3h12d genetic alterations, including deep deletion, could be found in LUAD. GO and KEGG pathway analysis results indicated that zc3h12d has a certain value in immune infiltration. We investigated the expression of zc3h12d in tumor-immune interactions. It was found that zc3h12d might be associated with the immune infiltration and markers of infiltrating immune cells of LUAD. The results of patient sample detection confirmed that B cells level was significantly lower in the patients with low zc3h12d expression than those in the patients with high zc3h12d expression.Conclusion: zc3h12d might be considered as a potential biomarker for determining prognosis and immune-related therapeutic target in LUAD.Keywords: zc3h12d, lung adenocarcinoma, hypomethylation, tumor microenvironment, prognosis

Qintai Yang,1 Hui Li,2,* Weijun Wu,2,* Xuekun Huang,1 Bo Tu,2 Yukun Ma,2 Huiyi Deng,1 Meijiao Li,1 Hongfeng He,2 Can Li,2 Yongqi Yang2 1Department of Otorhinolaryngology – Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Otorhinolaryngology – Head and Neck Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: The effect of continuous positive airway pressure (CPAP) on nasal symptoms in patients with obstructive sleep apnea–hypopnea syndrome (OSAHS) remains controversial. In addition, possible mechanism(s) remains unclear. Objective: To examine whether CPAP contributes to the onset and exacerbation of allergic rhinitis (AR) in OSAHS patients based on patient-reported changes in nasal symptoms with and without CPAP therapy and the detection of house dust mites (HDMs) in CPAP filters and household environments. Materials and methods: In a cohort of OSAHS patients, 350 patients who were undergoing CPAP therapy and 100 patients who declined CPAP therapy were retrospectively analyzed. These patients were contacted by telephone and asked to compare their nasal symptoms before and after CPAP therapy. HDMs in air conditioner and CPAP device filters and in household dust samples were detected using enzyme-linked immunosorbent assays. Results: The prevalence of AR was higher in the CPAP group vs the non-CPAP group (15.8% vs 7.0%, respectively; P = 0.025). The onset of AR among the OSAHS patients with no previous history of AR significantly increased within the first year of CPAP therapy compared with the control group (5.7% vs 0%, respectively; P = 0.031). Meanwhile, the patients with a history of AR were more likely to experience exacerbated rhinitis symptoms within the second year of treatment compared with the control group (7.5% vs 0%, respectively; P = 0.005). There was no significant difference in HDM concentrations between the CPAP and air conditioner filters, yet the concentrations in both the filters were higher than the concentrations in the bedroom dust samples (all P < 0.05). Conclusion: CPAP is associated with the onset and exacerbation of AR in OSAHS patients. Long-term exposure to high concentrations of HDM allergens may be a significant factor. Keywords: obstructive sleep apnea–hypopnea syndrome, continuous positive airway pressure, allergic rhinitis, house dust mites, allergens

Objective: To study the anatomical and biomechanical features of sacral pedicle and lateral mass so as to provide reference for clinical screw fixation technology of sacral pedicle and lateral mass.Methods: A total of 60 adult patients'spiral CT images of the sacrum and coccyx were selected randomly. The entry points of sacral pedicle and lateral mass screws were determined, and the screw trajectory was measured using the three dimensional reconstruction method. Meanwhile, the gross anatomy was scrutinized in 15 adult cadaver specimens to determine the sacral pedicle and lateral mass screw entry points. The length, width and angle of sacral pedicle and lateral mass screw trajectory were measured. Eight of 15 cadaver specimens were selected to test the maximal extraction force of sacral pedicle and lateral mass screws. The clinical data of 15 cases treated by pedicle and lateral mass screw technology were collected and analyzed.Results: The diameter and length of S(1)-S(5) sacral pedicle and lateral mass screw trajectory were regular, with about 20 degree inclination angle. The S(1) pedicle screw entry point was located at the intersection point of the basal lateral part of articular process and median line of transverse process, and no significant difference was found for the maximal extraction force between pedicle and lateral mass screws (P larger than 0.05). The entry points of S(2)-S(5) pedicle screws were located at the intersection point of the line connecting adjacent posterior sacral foramina and median line of the transverse process. The lateral mass screw entry point of S(2)-S(5) was on the median side of intersection point between median line of the transverse process and lateral sacral crest. The maximal extraction force of pedicle screws was significantly greater than that of lateral mass screws (P less than 0.05).Conclusion: Both the sacral pedicle and the lateral mass screw fixation techniques can offer effective fixation and reconstruction for fracture of the sacrum and coccyx, but pedicle screw fixation may be more convenient, safe and reliable than lateral mass screw fixation. [ABSTRACT FROM AUTHOR]

Unraveling the causal variants from genome wide association studies (GWASs) is pivotal for understanding genetic underpinnings of complex traits and diseases. Despite continuous efforts, tools to refine and prioritize GWAS signals need enhancement to address the direct causal implications of genetic variations. To overcome challenges related to statistical fine-mapping in identifying causal variants, CAUSALdb has been updated with novel features and comprehensive datasets, morphing into CAUSALdb2. This expanded repository integrates 15 057 updated GWAS summary statistics across 10 839 unique traits and implements both LD-based and LD-free fine-mapping approaches, including innovative applications of approximate Bayes Factor and SuSiE. Additionally, by incorporating larger LD reference panels such as TOPMED and UK Biobank, and integrating functional annotations via PolyFun, CAUSALdb2 enhances the accuracy and context of fine-mapping results. The database now supports interrogation of additional causal signals and offers sophisticated visualizations to aid researchers in deciphering complex genetic architectures. By facilitating a deeper and more precise characterisation of causal variants, CAUSALdb2 serves as a crucial tool for advancing the genetic analysis of complex diseases. Available freely, CAUSALdb2 continues to set benchmarks in the post-GWAS era, fostering the development of targeted diagnostics and therapeutics derived from responsible genetic research. Explore these advancements at http://mulinlab.org/causaldb., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Transcriptome-wide association study (TWAS) has successfully identified numerous complex disease susceptibility genes in the post-genome-wide association study (GWAS) era. Over the past 3 years, the focus of TWAS algorithms has shifted from merely identifying associations to understanding how single nucleotide polymorphisms (SNPs) regulate gene expression, with a growing emphasis on incorporating fine-mapping techniques. Additionally, the rapid increase in GWAS summary statistics, driven largely by the UK Biobank and other consortia, has made it essential to update our webTWAS resource. To address these challenges and meet the growing needs of researchers, we developed webTWAS 2.0, an updated platform for identifying susceptibility genes for human complex diseases using TWAS. Additionally, webTWAS 2.0 provides an online TWAS analysis tool that simplifies conducting TWAS analyses. The updated resource includes 7247 GWAS summary statistics covering 1588 complex human diseases from 192 publications. It also incorporates multiple TWAS methods, such as sTF-TWAS, 3'aTWAS and GIFT, along with an updated interactive visualization tool that allows users to easily explore significant associations across different methods. Other upgrades include a personalized online analysis tool for user-submitted GWAS data and a refined search function that makes it easier to identify relevant associations and meet diverse user needs more efficiently. webTWAS 2.0 is freely accessible at http://www.webtwas.net., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: In the United States, most (~ 70%) annual newly diagnosed HIV infections are among substance-using sexual minority men (SMM) and gender minority transgender women (trans women). Trans women and SMM are more likely to report or be diagnosed with a substance use disorder (SUD) than their cisgender or heterosexual counterparts and the presence of an SUD substantially increases the risk of HIV infection in both groups. Although Pre-Exposure Prophylaxis (PrEP) is highly effective, initiation, adherence, and persistence are exclusively behavioral outcomes; thus, the biomedical benefits of PrEP are abrogated by substance use. SUD is also associated with reduced quality-of-life, and increased overdose deaths, utilization of high-cost healthcare services, engagement in a street economy, and cycles of incarceration., Objective: To determine the optimal (considering efficacy and cost-effectiveness) strategy for advancement along the PrEP Care Continuum among trans women and SMM with an SUD., Methods: This study will implement a randomized controlled trial, evaluating two Stepped Care approaches involving A.S.K.-PrEP vs. standard of care (SOC) to determine optimal intervention strategies for trans women and SMM with an SUD (N = 250; n = 83 trans women; n = 167 SMM) for advancement along the PrEP Care Continuum. Participants will be randomized (3:1) to Stepped Care (n = 187) or SOC (n = 63). Participants in the Stepped Care arm will be assessed at 3-months for intervention response; responders will be maintained in A.S.K.-PrEP, while non-responders will receive added attention to their SUD via Contingency Management (CM). Non-responders will be re-randomized (1:1) to either (a) receive A.S.K.-PrEP + CM, or (b) shift the primary focus to their SUD (CM alone)., Results: Recruitment and enrollment began in May 2023. Recruitment will span approximately 36 months. Data collection, including all follow-up assessments, is expected to be completed in April 2027., Discussion: Trans women and SMM with an SUD have the two highest HIV prevalence rates in the United States, which underscores the urgent need for effective measures to develop scalable behavioral interventions that can encourage advancement along the PrEP Care Continuum. To improve public health, researchers must identify scalable and cost-effective behavioral interventions to promote PrEP initiation, adherence, and persistence among trans women and SMM who use substances., Trial Registration: This trial has been registered at ClinicalTrials.gov under the number NCT05934877., (© 2024. The Author(s).)

Purpose: Retinal neovascularization poses heightened risks of vision loss and blindness. Despite its clinical significance, the molecular mechanisms underlying the pathogenesis of retinal neovascularization remain elusive. This study utilized single-cell multiomics profiling in an oxygen-induced retinopathy (OIR) model to comprehensively investigate the intricate molecular landscape of retinal neovascularization., Methods: Mice were exposed to hyperoxia to induce the OIR model, and retinas were isolated for nucleus isolation. The cellular landscape of the single-nucleus suspensions was extensively characterized through single-cell multiomics sequencing. Single-cell data were integrated with genome-wide association study (GWAS) data to identify correlations between ocular cell types and diabetic retinopathy. Cell communication analysis among cells was conducted to unravel crucial ligand-receptor signals. Trajectory analysis and dynamic characterization of Müller cells were performed, followed by integration with human retinal data for pathway analysis., Results: The multiomics dataset revealed six major ocular cell classes, with Müller cells/astrocytes showing significant associations with proliferative diabetic retinopathy (PDR). Cell communication analysis highlighted pathways that are associated with vascular proliferation and neurodevelopment, such as Vegfa-Vegfr2, Igf1-Igf1r, Nrxn3-Nlgn1, and Efna5-Epha4. Trajectory analysis identified a subset of Müller cells expressing genes linked to photoreceptor degeneration. Multiomics data integration further unveiled positively regulated genes in OIR Müller cells/astrocytes associated with axon development and neurotransmitter transmission., Conclusions: This study significantly advances our understanding of the intricate cellular and molecular mechanisms underlying retinal neovascularization, emphasizing the pivotal role of Müller cells. The identified pathways provide valuable insights into potential therapeutic targets for PDR, offering promising directions for further research and clinical interventions.

Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC-and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro . In vivo , while deletion of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby metastatic cancer cells awake locally-generated developmental cues for metabolically reprograming, suggesting novel therapeutic approaches.

Covalent organic frameworks are a type of crystalline porous materials that linked through covalent bond, and they have numerous potential applications in adsorption, separation, catalysis, and more. However, there are rarely relevant reported on photochromism. Fortunately, a hydrazone-linked DBTB-DETH-COF is rapidly generated through ultrasound method. The DBTB-DETH-COF is found to exhibit reversible photochromism (at least 50 cycles) from yellow to olive in the presence of light and air, and subsequently back to the original color upon heating. In addition, the structure of DBTB-DETH-COF remains unchanged after 15 days of light illumination. Furthermore, the reason of photochromic process is discussed by electron paramagnetic resonance, X-ray photoelectron spectroscopy, electrochemistry characterizations and transient absorption measurements. The reversible photochromic DBTB-DETH-COF can be used as anti-counterfeiting ink and optical switch in the presence of air. This work expands a stable organic photochromic material and broadens the applications of COFs., (© 2024. The Author(s).)

Background: Myocardial fibrosis, a hallmark of heart disease, is closely associated with macrophages, yet the genetic pathophysiology remains incompletely understood. In this study, we utilized integrated single-cell transcriptomics and bulk RNA-seq analysis to investigate the relationship between macrophages and myocardial fibrosis across omics integration., Methods: We examined and curated existing single-cell data from dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), myocardial infarction (MI), and heart failure (HF), and analyzed the integrated data using cell communication, transcription factor identification, high dimensional weighted gene co-expression network analysis (hdWGCNA), and functional enrichment to elucidate the drivers of macrophage polarization and the macrophage-to-myofibroblast transition (MMT). Additionally, we assessed the accuracy of single-cell data from the perspective of driving factors, cell typing, anti-fibrosis performance of left ventricular assist device (LVAD). Candidate drugs were screened using L1000FWD., Results: All four heart diseases exhibit myocardial fibrosis, with only MI showing an increase in macrophage proportions. Macrophages participate in myocardial fibrosis through various fibrogenic molecules, especially evident in DCM and MI. Abnormal RNA metabolism and dysregulated transcription are significant drivers of macrophage-mediated fibrosis. Furthermore, profibrotic macrophages exhibit M1 polarization and increased MMT. In HF patients, those responding to LVAD therapy showed a significant decrease in driver gene expression, M1 polarization, and MMT. Drug repurposing identified cinobufagin as a potential therapeutic agent., Conclusion: Using integrated single-cell transcriptomics, we identified the drivers of macrophage-mediated myocardial fibrosis in four heart diseases and confirmed the therapeutic effect of LVAD on improving HF with single-cell accuracy, providing novel insights into the diagnosis and treatment of myocardial fibrosis., (© 2024. The Author(s).)

Introduction: Hybrid rice demonstrated superior performance in enhancing yield and efficiency in rice production compared to inbred rice. Nevertheless, the underlying mechanism responsible for the increased yield and efficiency of hybrid rice in South China's double-cropping rice region remains understudied., Methods: Field experiments over two consecutive years were conducted. Firstly, yield variations among 20 inbred and 15 hybrid rice cultivars prevalent in South China's double-cropping rice system were examined. Secondly, selecting representative hybrid and inbred rice cultivars with significant yield disparities were carried out on further analyzing dry-matter production, source-sink relationships, and nutrient absorption and utilization in both rice types., Results: Hybrid rice displayed an average grain yield of 8.07 and 7.22 t hm -2 in the early and late seasons, respectively, which corresponds to a 12.29% and 13.75% increase over inbred rice with statistically significant differences. In comparison to inbred rice, hybrid rice exhibited enhanced nitrogen concentration in leaves at the heading stage (15.48-16.20%), post-heading dry matter accumulation (52.62-73.21%), post-heading dry matter conversion rate (29.23-34.12%), and harvest index (17.31-18.37%). Additionally, grain nitrogen and phosphorus uptake in hybrid rice increased by 11.88-22.50% and 16.38-19.90%. Hybrid rice mainly improved post-heading nitrogen and phosphorus uptake and transport, while not total nitrogen and phosphorus uptake. Internal nitrogen and phosphorus use efficiency enhanced by 9.83%-14.31% and 10.15%-13.66%, respectively. Post-heading dry matter accumulation, harvest index, grain nitrogen and phosphorus uptake, and internal nitrogen and phosphorus use efficiency exhibited significant positive linear correlations with grain yield., Discussion: The period from heading to maturity is critical for enhancing hybrid rice yield and efficiency. Improving photosynthetic capacity during this period and promoting nutrient transport to grains serve as crucial pathways for increasing grain yield and efficiency. This study is of great significance for further improvement grain yield and breeding rice cultivars with high-yield and high nutrients use efficiency for South China's double-cropped rice system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fu, Lu, Zhong, Liang, Pan, Liu, Hu, Hu, Li, Wang, Ye, Yin, Huang and Huang.)

We administered a questionnaire to participants who received different vaccination regimens to evaluate the effectiveness of Ad5-vectored COVID-19 vaccines. The results showed that administration of intramuscular Ad5-nCoV provided 21.32% more protection against SARS-CoV-2 infection than that of the inactivated COVID-19 vaccine in people who had received only one type of COVID-19 vaccine. Furthermore, aerosolized Ad5-nCoV exhibited good protection, whether it was administered as a homologous booster to people vaccinated with the intramuscular Ad5-nCoV or as a heterologous booster to people vaccinated with inactivated COVID-19 vaccines. Our research indicates that Ad5-nCoV is an effective booster. This finding supports the future selection of COVID-19 immunization strategies.

In patients with liver cirrhosis, approximately one-third experience pigmented cholelithiasis. In parallel to this, cirrhotics consequently encounter a greater prevalence of acute cholecystitis. Traditionally, the definitive treatment for acute cholecystitis in non-cirrhotic patients is cholecystectomy. However, decompensated cirrhosis and portal hypertension pose a surgical challenge, as these comorbidities increase the risk of postoperative complications such as bleeding, infection, and multi-organ failure. Therefore, it is of utmost importance to consider patient risk factors, anatomy, and acuity of patient cholecystitis on an individual basis and develop a surgical (or non-surgical) plan that minimizes risk to patients with decompensated cirrhosis and portal hypertension. We present the management strategies of a case of a 50-year-old male who presents with a history of decompensated liver cirrhosis and portal hypertension complicated by acute cholecystitis. Upon initial presentation, he was critically ill, and a percutaneous cholecystostomy tube was placed for management and the patient was instructed to follow up in the clinic. Then, the patient later returned to the emergency department with a fever, UTI, and sepsis. At that time, his cholecystostomy tube continued to have bilious drainage and he had tenderness in the right upper quadrant. The decision was made to proceed with surgery. Because of his significant comorbid conditions and underlying cirrhosis, surgery posed an increased risk. For this patient, it was especially important to evaluate the risk of complications and the decision of open vs laparoscopic cholecystectomy. In this patient, robotic-assisted laparoscopic cholecystectomy was eventually performed. Due to the patient's hepatomegaly, splenomegaly, and portal hypertension, special consideration was needed for trocar placement. In this case, we aim to exemplify that is of utmost importance to consider patient anatomy by using imaging and marking organ borders to inform trocar placement as part of the surgical approach., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Li et al.)

Coreopsis tinctoria Nutt. is an important medicinal plant in traditional Uyghur medicine. The skin-lightening potential of the flower has been recognized recently; however, the active compounds responsible for that are not clear. In this work, tyrosinase, a target protein for regulating melanin synthesis, was immobilized on the Whatman paper for the first time to screen skin-lightening compounds present in the flower. Quercetagetin-7- O -glucoside ( 1 ), marein ( 2 ), and okanin ( 3 ) were found to be the enzyme inhibitors. The IC 50 values of quercetagetin-7- O -glucoside ( 1 ) and okanin ( 3 ) were 79.06 ± 1.08 μM and 30.25 ± 1.11 μM, respectively, which is smaller than 100.21 ± 0.11 μM of the positive control kojic acid. Enzyme kinetic analysis and molecular docking were carried out to investigate their inhibition mechanism. Although marein ( 2 ) showed a weak inhibition effect in vitro, it inhibited the intracellular tyrosinase activity and diminished melanin production in melanoma B16 cells as did the other two inhibitors. The paper-based ligand fishing method developed in this work makes it effective to quickly screen tyrosinase inhibitors from natural products. This is the first report on the tyrosinase inhibitory effect of those three compounds, showing the promising potential of Coreopsis tinctoria for the development of herbal skin-lightening products.

Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Lepr db/db mice and Lepr db/+ mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications., Competing Interests: QH, MZ, ML, XL, JJ, YF, LZ, WH, FY, JY No competing interests declared, (© 2024, He, Zhao et al.)

The pursuit of effective treatments for brain tumors has increasingly focused on the promising area of nanoparticle-enhanced radiotherapy (NERT). This review elucidates the context and significance of NERT, with a particular emphasis on its application in brain tumor therapy-a field where traditional treatments often encounter obstacles due to the blood-brain barrier (BBB) and tumor cells' inherent resistance. The aims of this review include synthesizing recent advancements, analyzing action mechanisms, and assessing the clinical potential and challenges associated with nanoparticle (NP) use in radiotherapy enhancement. Preliminary preclinical studies have established a foundation for NERT, demonstrating that nanoparticles (NPs) can serve as radiosensitizers, thereby intensifying radiotherapy's efficacy. Investigations into various NP types, such as metallic, magnetic, and polymeric, have each unveiled distinct interactions with ionizing radiation, leading to an augmented destruction of tumor cells. These interactions, encompassing physical dose enhancement and biological and chemical radio sensitization, are crucial to the NERT strategy. Although clinical studies are in their early phases, initial trials have shown promising results in terms of tumor response rates and survival, albeit with mindful consideration of toxicity profiles. This review examines pivotal studies affirming NERT's efficacy and safety. NPs have the potential to revolutionize radiotherapy by overcoming challenges in targeted delivery, reducing off-target effects, and harmonizing with other modalities. Future directions include refining NP formulations, personalizing therapies, and navigating regulatory pathways. NERT holds promise to transform brain tumor treatment and provide hope for patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Li, Liang, Sun, Shao, Hu and Xing.)

Lymphoma-associated hemophagocytic syndrome is aggressive with rapid progression, particularly in NK/T cell lymphoma. The MINE regimen is a salvage treatment for aggressive non-Hodgkin lymphoma. In our center, the modified MINE regimen was applied to treat three patients with hemophagocytic syndrome secondary to aggressive NK cell leukemia and T-cell lymphoma. The modified MINE regimen showed good efficacy against NK/T cell lymphoma, control of the inflammatory state of secondary hemophagocytic syndrome, and good tolerability.

Genome organization is thought to underlie cell type specific gene expression, yet how it is regulated in progenitors to produce cellular diversity is unknown. In Drosophila, a developmentally-timed genome reorganization in neural progenitors terminates competence to produce early-born neurons. These events require downregulation of Distal antenna (Dan), part of the conserved pipsqueak DNA-binding superfamily. Here we find that Dan forms liquid-like condensates with high protein mobility, and whose size and subnuclear distribution are balanced with its DNA-binding. Further, we identify a LARKS domain, a structural motif associated with condensate-forming proteins. Deleting just 13 amino acids from LARKS abrogates Dan's ability to retain the early-born neural fate gene, hunchback, in the neuroblast nuclear interior and maintain competence in vivo. Conversely, domain-swapping with LARKS from known phase-separating proteins rescues Dan's effects on competence. Together, we provide in vivo evidence for condensate formation and the regulation of progenitor nuclear architecture underlying neuronal diversification., (© 2024. The Author(s).)

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous., Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes., Results: Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells : (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted P = 1.17E-02), (2) CD25++ CD45RA- CD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted P = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted P = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted P = 1.17E-02) was related to dendritic cells (DCs)., Conclusion: These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zuo, Hu, Hao, Li, Shi, Guo, Ma, Li, Liang, Zhang, Mao, Xu and Shi.)

Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones., (© 2024. The Author(s).)

Nocardia disease is an opportunistic infection, the occurrence is rare and mostly occurs in patients with immune deficiency. Even if the patient is immunocompetent, it can still be life-threatening. This case report describes a previously healthy 78-year-old male farmer with lung lesions discovered on a computerized tomography scan. Combined with the patient's history of fever and the results of elevated laboratory markers associated with inflammation, the patient was diagnosed with a lung infection. After escalating empirical broad-spectrum antibiotics, antiviral and antifungal therapy, the patient continued to deteriorate to septic shock. In the meanwhile, the patient's sputum was cultured repeatedly, and no obvious positive pathogenic bacteria were found. Considering the patient was elderly and that these lesions were solid with burr signs, as well as the progression after antimicrobial therapy cancer was considered in the differential diagnosis. Artificial intelligence (YITU, Hangzhou Yitu Medical Technology Limited Company) was also applied, and it also calculated that these lesions were cancerous. The patient received a puncture biopsy of the largest lung lesion. During the puncture pus was withdrawn from largest lung lesion. Culture and metagenome next-generation sequencing (mNGS) detection performed on pus indicated Nocardia otitidiscaviarum . The test report of the mNGS is also attached with a susceptibility report of commonly used clinical antibiotics to this Nocardia spp. Using this result, the patient's disease was quickly controlled after selecting the targeted drug compound sulfamethoxazole and intravenous meropenem for treatment. In view of the high misdiagnosis rate and poor sensitivity of culture for Nocardia spp., this case emphasized mNGS playing a key role in the diagnosis and selection of effective antibiotics for the treatment of Nocardia spp. lung infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fan, Fang, Huang, Zhou, Liu, Li and Ding.)

Glioblastoma multiforme (GBM) is one of the most lethal brain tumors, characterized by profound heterogeneity. While single-cell transcriptomic studies have revealed extensive intra-tumor heterogeneity, shed light on intra-tumor diversity, spatial intricacies remain largely unexplored. Leveraging clinical GBM specimens, this study employs spatial transcriptomics technology to delve into gene expression heterogeneity. Our investigation unveils a significant enrichment of tissue stem cell signature in regions bordering necrosis and the peritumoral area, positively correlated with the mesenchymal subtype signature. Moreover, upregulated genes in these regions are linked with extracellular matrix (ECM)-receptor interaction, proteoglycans, as well as vascular endothelial growth factor (VEGF) and angiopoietin-Tie (ANGPT) signaling pathways. In contrast, signatures related to glycogen metabolism and oxidative phosphorylation show no relevance to pathological zoning, whereas creatine metabolism signature is notably exclusive to vascular-enriched areas. These spatial profiles not only offer valuable references but also pave the way for future in-depth functional and mechanistic investigations into GBM progression., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Aims: This study compared the prevalences of metabolic syndrome and of cardiac or kidney comorbidities among patients with hepatocellular carcinoma (HCC) associated with metabolic dysfunction-related fatty liver disease (MAFLD), chronic infection with hepatitis B or C virus (HBV or HCV), or the combination of MAFLD and chronic HBV infection., Methods: Medical records were retrospectively analyzed for patients with HCC who underwent hepatectomy between March 2013 and March 2023. Patients with HCC of different etiologies were compared in terms of their clinicodemographic characteristics and laboratory data before surgery., Results: Of the 2422 patients, 1,822 (75.2%) were chronically infected with HBV without MAFLD and HCV, 415 (17.2%) had concurrent MAFLD and chronic HBV infection but no HCV infection, 121 (5.0%) had MAFLD without hepatitis virus infection, and 64 (2.6%) were chronically infected with HCV in the presence or absence of MAFLD and HBV infection. Compared to patients chronically infected with HBV without MAFLD and HCV, those with MAFLD but no hepatitis virus infection showed significantly lower prevalence of cirrhosis, ascites, portal hypertension, alpha-fetoprotein concentration ≥ 400 ng/mL, tumor size > 5 cm, multinodular tumors and microvascular invasion. Conversely, they showed significantly higher prevalence of metabolic syndrome, hypertension, type 2 diabetes, abdominal obesity, history of cardiovascular disease, T-wave alterations, hypertriglyceridemia and hyperuricemia, as well as higher risk of arteriosclerotic cardiovascular disease. Compared to patients with MAFLD but no hepatitis virus infection, those with concurrent MAFLD and chronic infection with HBV showed significantly higher prevalence of cirrhosis, ascites and portal hypertension, but significantly lower prevalence of hypertension and history of cardiovascular disease. Compared to patients with other etiologies, those chronically infected with HCV in the presence or absence of MAFLD and HBV infection, showed significantly higher prevalence of cirrhosis, portal hypertension, ascites, and esophagogastric varices., Conclusion: Patients with HCC associated with MAFLD tend to have a background of less severe liver disease than those with HCC of other etiologies, but they may be more likely to suffer metabolic syndrome or comorbidities affecting the heart or kidneys., (© 2024. The Author(s).)

Objectives: Combination therapy of lenvatinib and immune checkpoint inhibitors (CLICI) has emerged as a promising approach for managing unresectable hepatocellular carcinoma (HCC). However, the response to such treatment is observed in only a subset of patients, underscoring the pressing need for reliable methods to identify potential responders., Materials & Methods: This was a retrospective analysis involving 120 patients with unresectable HCC. They were divided into training (n = 72) and validation (n = 48) cohorts. We developed an interpretable deep learning model using multiphase computed tomography (CT) images to predict whether patients will respond or not to CLICI treatment, based on the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). We evaluated the models' performance and analyzed the impact of each CT phase. Critical regions influencing predictions were identified and visualized through heatmaps., Results: The multiphase model outperformed the best biphase and uniphase models, achieving an area under the curve (AUC) of 0.802 (95% CI = 0.780-0.824). The portal phase images were found to significantly enhance the model's predictive accuracy. Heatmaps identified six critical features influencing treatment response, offering valuable insights to clinicians. Additionally, we have made this model accessible via a web server at http://uhccnet.com/ for ease of use., Conclusions: The integration of multiphase CT images with deep learning-generated heatmaps for predicting treatment response provides a robust and practical tool for guiding CLICI therapy in patients with unresectable HCC., Competing Interests: The authors have no conflicts of interest to declare that are relevant to the content of this article., (© 2024 The Authors.)

This study aimed to investigate the association between irritable bowel syndrome (IBS) and Parkinson's disease (PD) utilizing prospective cohort study and Mendelian randomization. The dataset contained a substantial cohort of 426,911 participants from the UK Biobank, discussing the association between IBS and PD with Cox proportional hazards models and case-control analysis while adjusting for covariates such as age, gender, ethnicity and education level. In univariate Cox regression model, the risk of PD was reduced in IBS patients (HR: 0.774, 95%CI: 0.625-0.956, P = 0.017), but the statistical significance diminished in the three models after adjusting for other variables. In a few subgroup analyses, IBS patients are less likely to develop into PD, and patients diagnosed with IBS after 2000 also had a lower risk (HR: 0.633, 95%CI: 0.403-0.994, P = 0.047) of subsequently developing PD. In addition, we matched five healthy control participants based on gender and age at the end of the study for each IBS patient diagnosed during the follow-up period, and logistic regression results (OR:1.239, 95%CI: 0.896-1.680, P = 0.181) showed that IBS was not associated with the risk of PD. Mendelian randomization did not find significant evidence of the causal relationship between IBS and Parkinson's disease (OR: 0.801, 95%CI: 0.570-1.278, P = 0.204). Overall, we suggest that IBS status is not associated with the risk of developing PD, and that these findings provide valuable insights into the clinical management and resource allocation of patients with IBS., (© 2024. The Author(s).)

Background: Sarcoma is a highly heterogeneous malignancy with a poor prognosis. Although chemotherapy and targeted therapy have improved the prognosis to some extent, the efficacy remains unsatisfactory in some patients. The efficacy and safety of immunotherapy in sarcoma need further evaluation., Methods: We conducted a two-center study of sarcoma patients receiving PD-1 immunotherapy at Tianjin Medical University Cancer Institute and Hospital and Henan Provincial Cancer Hospital. The treatment regimens included PD-1 inhibitor monotherapy and combination therapy based on PD-1 inhibitors. The observed primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS). Survival curves were compared using the Kaplan-Meier method., Results: A total of 43 patients were included from the two centers. The median follow-up time for all patients was 13 months (range, 1-48 months). In the group of 37 patients with advanced or unresectable sarcoma, the mPFS was 6 months (95%CI: 5-12 months), and the mOS was 16 months (95%CI: 10-28 months). The ORR was 10.8% (4/37), and the DCR was 18.9% (7/37). Subgroup analysis showed no significant differences in mPFS (p=0.11) and mOS (p=0.88) between patients with PD-L1 negative/positive expression. There were also no significant differences in mPFS (p=0.13) or mOS (p=0.72) between PD-1 inhibitor monotherapy and combination therapy. Additionally, there were no significant differences in mPFS (p=0.52) or mOS (p=0.49) between osteogenic sarcoma and soft tissue sarcoma. Furthermore, the results showed no significant differences in mPFS (p=0.66) or mOS (p=0.96) between PD-1 inhibitors combined with targeted therapy and PD-1 inhibitors combined with AI chemotherapy. Among the 6 patients receiving adjuvant therapy after surgery, the mPFS was 15 months (95%CI: 6-NA months), and the mOS was not reached. In terms of safety, most adverse events were mild (grade 1-2) and manageable. The most severe grade 4 adverse events were bone marrow suppression, which occurred in 4 patients but resolved after treatment. There was also one case of a grade 4 adverse event related to hypertension., Conclusion: Immunotherapy is an effective treatment modality for sarcoma with manageable safety. Further inclusion of more patients or prospective clinical trials is needed to validate these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BL declared a shared parent affiliation with the author WY to the handling editor at the time of review., (Copyright © 2024 Liao, Teng, Li, Liu, Li, Zhang, Xing, Teng, Yang, Zhao, Xiao, Zhang, Li, Yao and Yang.)

Background: Patient education (PE) is essential for improving patients' knowledge, anxiety, and satisfaction, and supporting their postoperative recovery. However, the advantages of video-assisted thoracoscopic surgery (VATS)-smaller incisions and faster recovery-can result in shorter hospital stays, making PE more challenging to implement effectively. Multimedia PE can potentially enhance PE, but its effectiveness for patients undergoing VATS is unclear., Objective: This study developed a scenario-based PE web app for lung tumor patients undergoing VATS (SPE-VATS) to facilitate the PE process and evaluated its usability through a clinical trial., Methods: The SPE-VATS provided the experimental group (EG: 32 participants) with interactive scenario, query guidance, diagnostic analysis, experience sharing, and active reminder, while the control group (CG: 32 participants) used pamphlets and videos. The usability of SPE-VATS in terms of postoperative anxiety reduction and patient satisfaction with the app was evaluated using self-reported questionnaires based on the state-trait anxiety inventory, technology acceptance model, system usability scale, and task load index., Results: There was no statistically significant difference in postoperative anxiety reduction between the EG and CG, possibly because 90% of the participants underwent a low-risk surgical type, and VATS is known to be advantageous in alleviating surgical anxiety. However, females and higher educated EG participants showed a non-significant but favorable reduction than their CG counterparts. Moreover, the EG was highly satisfied with the app (rated 4.2 to 4.4 out of 5.0), with no significant gender and education level difference. They particularly valued the interactive scenario, experience sharing, and diagnostic analysis features of SPE-VATS., Conclusions: The SPE-VATS demonstrated its usability and high patient satisfaction, particularly for female and higher educated patients. Low-risk patient predominance and VATS's advantages may explain non-significant postoperative anxiety reduction, warranting further studies on high-risk patients to evaluate the impact of SPE-VATS on clinical practice., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Mapping of expression quantitative trait loci (eQTLs) and other molecular QTLs can help characterize the modes of action of disease-associated genetic variants. However, current eQTL databases present data from bulk RNA-seq approaches, which cannot shed light on the cell type- and environment-specific regulation of disease-associated genetic variants. Here, we introduce our Single-cell eQTL Interactive Database which collects single-cell eQTL (sc-eQTL) datasets and provides online visualization of sc-eQTLs across different cell types in a user-friendly manner. Although sc-eQTL mapping is still in its early stage, our database curates the most comprehensive summary statistics of sc-eQTLs published to date. sc-eQTL studies have revolutionized our understanding of gene regulation in specific cellular contexts, and we anticipate that our database will further accelerate the research of functional genomics. Database URL: http://www.sqraolab.com/scqtl., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The data of the prognostic role of V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in early-stage lung adenocarcinoma (LUAD) patients is scarce. This study aimed to investigate the proportion, clinicopathological features, and prognostic significance of patients with stage I LUAD carrying BRAF mutations., Methods: We collected 431 patients with pathological stage I LUAD from cBioPortal for Cancer Genomics and 1604 LUAD patients tested for BRAF V600E and epidermal growth factor receptor (EGFR) mutations from Shanghai Pulmonary Hospital. Survival curves were drawn by the Kaplan-Meier method and compared by log-rank test. Cox proportional hazard models, propensity-score matching (PSM), and overlap weighting (OW) were performed in this study. The primary endpoint was recurrence-free survival (RFS)., Results: The proportion of BRAF mutations was estimated at 5.6% in a Caucasian cohort. BRAF V600E mutations were detected in six (1.4%) patients in Caucasian populations and 16 (1.0%) patients in Chinese populations. Two BRAF V600E-mutant patients were detected to have concurrent EGFR mutations, one for 19-del and one for L858R. For pathological stage I LUAD patients, BRAF mutations were not significantly associated with worse RFS than wild-type BRAF patients (HR = 1.111; p = 0.885). After PSM and OW, similar results were presented (HR = 1.352; p = 0.742 and HR = 1.246; p = 0.764, respectively). BRAF V600E mutation status also lacked predictive significance for RFS (HR, 1.844; p = 0.226; HR = 1.144; p = 0.831 and HR = 1.466; p = 0.450, respectively)., Conclusions: In this study, we demonstrated that BRAF status may not be capable of predicting prognosis in stage I LUAD patients. There is a need for more data to validate our findings., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.

Glutathione (GSH), homocysteine (Hcy) and cysteine (Cys) play important roles in many physiological processes. However, due to their structural and functional similarities, it is still a challenge to develop a probe that can differentiate between GSH and Hcy/Cys simultaneously. In this work, a luminescent probe Ir-NBD was designed and synthesized, which emit weakly due to the presence of photo induced electron transfer (PET) interaction. When it reacted with the three biothiols, NBD dissociated and luminescence of Ir-OH was enhanced in the near-infrared (NIR) region due to the disappearance of the PET effect. On the other hand, the products obtained from the reaction of GSH with NBD were hardly luminescent, but the products from the reaction of Hcy/Cys with NBD could undergo an intramolecular rearrangement, resulting in an enhanced luminescence of the solution in the visible region. Ir-NBD enabled highly selective and sensitive detection of GSH and Cys/Hcy in a relatively short time (15 min). The two luminescent colors were clearly differentiated without spectral interference and the detection limit reached 1.32 μM (GSH), 0.42 μM (Hcy) and 0.51 μM (Cys), respectively. Ir-NBD also had low cytotoxicity, it realized the simultaneous detection of GSH and Hcy/Cys by dual-channel luminescence, and also provided ideas for the design of multifunctional luminescent probes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hitherto, research on iron(III)-reduction has mainly focused on bacteria rather than fungal communities. To acquire insight into fungi involved in iron(III) reduction, typical organic matters (containing cellulose, glucose, lactate, and acetate) and ferrihydrite were used as electron donors and acceptors, respectively, in the presence of antibiotics. After antibiotic addition, microbial iron(III) reduction was still detected at quite high rates. In comparison, rates of iron(III) reduction were significantly lower in cellulose-amended groups than those with glucose, lactate, and acetate under the antibiotic-added condition. Patterns of intermediate (e.g., acetate, pyruvate, glucose) turnover were markedly different between treatments with and without antibiotics during organic degradation. A total of 20 genera of potential respiratory and fermentative iron(III)-reducing fungi were discovered based on ITS sequencing and genome annotation. This study provided an insight into the diversity of iron(III)-reducing fungi, indicating the underestimated contribution of fungi to iron and the coupled carbon biogeochemical cycling in environments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Ye, Da, Sun and Zhou.)

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes ( CD38 , GPNMB , RAB29 , TMEM175 , TTC19 ) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Telomere length (TL) shortening is a pivotal indicator of biological aging and is associated with many human diseases. The genetic determinates of human TL have been widely investigated, however, most existing studies were conducted based on adult tissues which are heavily influenced by lifetime exposure. Based on the analyses of terminal restriction fragment (TRF) length of telomere, individual genotypes, and gene expressions on 166 healthy placental tissues, we systematically interrogate TL-modulated genes and their potential functions. We discover that the TL in the placenta is comparatively longer than in other adult tissues, but exhibiting an intra-tissue homogeneity. Trans-ancestral TL genome-wide association studies (GWASs) on 644,553 individuals identify 20 newly discovered genetic associations and provide increased polygenic determination of human TL. Next, we integrate the powerful TL GWAS with placental expression quantitative trait locus (eQTL) mapping to prioritize 23 likely causal genes, among which 4 are functionally validated, including MMUT, RRM1, KIAA1429, and YWHAZ. Finally, modeling transcriptomic signatures and TRF-based TL improve the prediction performance of human TL. This study deepens our understanding of causal genes and transcriptomic determinants of human TL, promoting the mechanistic research on fine-grained TL regulation., (© 2023. The Author(s).)

Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41 -/- ) or type 1 interferon receptor IFNAR1 (Ifnar1 -/- ) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life., (© 2023. The Author(s).)

Unscheduled R-loops are a major source of replication stress and DNA damage. R-loop-induced replication defects are sensed and suppressed by ATR kinase, whereas it is not known whether R-loop itself is actively involved in ATR activation and, if so, how this is achieved. Here, we report that the nuclear form of RNA-editing enzyme ADAR1 promotes ATR activation and resolves genome-wide R-loops, a process that requires its double-stranded RNA-binding domains. Mechanistically, ADAR1 interacts with TOPBP1 and facilitates its loading on perturbed replication forks by enhancing the association of TOPBP1 with RAD9 of the 9-1-1 complex. When replication is inhibited, DNA-RNA hybrid competes with TOPBP1 for ADAR1 binding to promote the translocation of ADAR1 from damaged fork to accumulate at R-loop region. There, ADAR1 recruits RNA helicases DHX9 and DDX21 to unwind R-loops, simultaneously allowing TOPBP1 to stimulate ATR more efficiently. Collectively, we propose that the tempo-spatially regulated assembly of ADAR1-nucleated protein complexes link R-loop clearance and ATR activation, while R-loops crosstalk with blocked replication forks by transposing ADAR1 to finetune ATR activity and safeguard the genome., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma., Results: Here, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions., Conclusions: Our study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies., (© 2023. The Author(s).)

The gut microbiota, a complex ecosystem integral to host wellbeing, is modulated by environmental triggers, including exposure to heavy metals such as chromium. This study aims to comprehensively explore chromium-induced gut microbiota and metabolomic shifts in the quintessential lepidopteran model organism, the silkworm ( Bombyx mori ). The research deployed 16S rDNA sequence analysis and LC/MS metabolomics in its experimental design, encompassing a control group alongside low (12 g/kg) and high (24 g/kg) feeding chromium dosing regimens. Considerable heterogeneity in microbial diversity resulted between groups. Weissella emerged as potentially resilient to chromium stress, while elevated Propionibacterium was noted in the high chromium treatment group. Differential analysis tools LEfSe and random forest estimation identified key species like like Cupriavidus and unspecified Myxococcales , offering potential avenues for bioremediation. An examination of gut functionality revealed alterations in the KEGG pathways correlated with biosynthesis and degradation, suggesting an adaptive metabolic response to chromium-mediated stress. Further results indicated consequential fallout in the context of metabolomic alterations. These included an uptick in histidine and dihydropyrimidine levels under moderate-dose exposure and a surge of gentisic acid with high-dose chromium exposure. These are critical players in diverse biological processes ranging from energy metabolism and stress response to immune regulation and antioxidative mechanisms. Correlative analyses between bacterial abundance and metabolites mapped noteworthy relationships between marker bacterial species, such as Weissella and Pelomonas , and specific metabolites, emphasizing their roles in enzyme regulation, synaptic processes, and lipid metabolism. Probiotic bacteria showed robust correlations with metabolites implicated in stress response, lipid metabolism, and antioxidant processes. Our study reaffirms the intricate ties between gut microbiota and metabolite profiles and decodes some systemic adaptations under heavy-metal stress. It provides valuable insights into ecological and toxicological aspects of chromium exposure that can potentially influence silkworm resilience., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Rong, Qin, Lu, Liu, Li, Xin, Li and Guan.)

Background: Many patients with neuromuscular scoliosis (NMS) experience a variety of difficult medical problems that aggravate the development effects of progressive scoliosis and pelvic obliquity (PO). The objective of the current study was to assess the safety and effectiveness of multi-rod posterior correction only (MRPCO) with halo-femoral traction (HFT) for the management of adult NMS (> 100°) with severe PO., Methods: From 2012 to 2017, 13 adult patients who suffered from NMS (> 100°) with severe PO underwent MRPCO with HFT. The radiography parameters in a sitting position, such as the coronal Cobb angle of the main curve, the PO and the trunk shift (TS), were measured at the preoperative, postoperative and final follow-up stages. The preoperative and final follow-up assessment of the Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) was taken., Results: The average follow-up span was 68.15 ± 6.78 months. There was decreased postoperative coronal Cobb angle with an average mean of 125.24° ± 11.78° to 47.55° ± 12.10°, with a correction rate of 62.43%; the PO was reduced to 6.25° ± 1.63° from 36.93° ± 4.25° with a correction rate of 83.07%; the TS was reduced to 2.41 cm ± 1.40 cm from 9.19 cm ± 3.07 cm. There was significant improvement in all parameters compared to the preoperative data. The VAS score reduced from 4.77 ± 0.93 to 0.69 ± 0.75, and the ODI score reduced from 65.38 ± 16.80 to 28.62 ± 12.29 at the final follow-up., Conclusions: Treatment of adult NMS (> 100°) with severe PO could be safe and effective with MRPCO with HFT. In order to obtain the optimum sitting balance, this could reduce the prevalence of complications and rectify the curvature and the correction of PO., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: The actin cytoskeleton plays an essential role in maintaining podocyte functions. However, whether the urinary exosome proteins related to the regulation of the actin cytoskeleton are changed in diabetic nephropathy (DN) is still unknown. This study was to investigate the possibility that related proteins can be applied as diagnostic biomarkers for DN., Methods: Urinary exosomes were obtained from 144 participants (Discovery phase: n = 72; Validation phase: n = 72) by size exclusion chromatography methods. Proteomic analysis of urinary exosome by LC-MS/MS. Western blot and ELISA were applied to validate the selected urinary exosome proteins. The clinical value of selected urinary exosome proteins was evaluated using correlation and receiver operating characteristic curve analyses., Results: Fifteen urinary proteins related to the regulation of the actin cytoskeleton were identified in urinary exosomes. Three upregulated proteins were selected, including Serine/threonine-protein kinase PAK6 (PAK6), Epidermal growth factor receptor (EGFR), and SHC-transforming protein 1(SHC1). The expression level of PAK6 and EGFR was negatively correlated with estimated glomerular filtration rate and positively correlated with serum creatinine levels. For diagnosing DN in the discovery phase: the area under curve (AUC) of PAK6 was 0.903, EGFR was 0.842, and the combination of two proteins was 0.912. These better performances were also observed in the validation phase (For PAK6: AUC = 0.829; For EGFR: AUC = 0.797; For PAK6 + EGFR: AUC = 0.897)., Conclusions: Urinary exosome proteins PAK6 and EGFR may be promising and noninvasive biomarkers for diagnosing DN., (© 2023. BioMed Central Ltd., part of Springer Nature.)