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Background: Sorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell death underlying the mechanism of sorafenib. Iron is crucial for synthesis of cofactors essential to mitochondrial enzymes and necessary for HCC proliferation, while mitochondrial iron overload and oxidative stress are associated with sorafenib induced ferroptosis. However, the crosstalk among iron homeostasis and sorafenib resistance is unclear. Methods: We conducted bioinformatics analysis of sorafenib treated HCC datasets to analyze GCN5L1 and iron related gene expression with sorafenib resistance. GCN5L1 deleted HCC cell lines were generated by CRISPR technology. Sorafenib resistant HCC cell line was established to validate dataset analysis and evaluate the effect of potential target. Results: We identified GCN5L1, a regulator of mitochondrial acetylation, as a modulator in sorafenib-induced ferroptosis via affecting mitochondrial iron homeostasis. GCN5L1 deficiency significantly increased sorafenib sensitivity in HCC cells by down-regulating mitochondrial iron transporters CISD1 expression to induce iron accumulation. Mitochondrial iron accumulation leads to an acceleration in cellular and lipid ROS. Sorafenib resistance is related to CISD1 overexpression to release mitochondrial iron and maintaining mitochondrial homeostasis. We combined CISD1 inhibitor NL-1 with sorafenib, which significantly enhanced sorafenib-induced ferroptosis by promoting mitochondrial iron accumulation and lipid peroxidation. The combination of NL-1 with sorafenib enhanced sorafenib efficacy in vitro and in vivo. Conclusions: Our findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC. [ABSTRACT FROM AUTHOR]

Background: Research into the acute kidney disease (AKD) after acute ischemic stroke (AIS) is rare, and how clinical features influence its prognosis remain unknown. We aim to employ interpretable machine learning (ML) models to study AIS and clarify its decision-making process in identifying the risk of mortality. Methods: We conducted a retrospective cohort study involving AIS patients from January 2020 to June 2021. Patient data were randomly divided into training and test sets. Eight ML algorithms were employed to construct predictive models for mortality. The performance of the best model was evaluated using various metrics. Furthermore, we created an artificial intelligence (AI)-driven web application that leveraged the top ten most crucial features for mortality prediction. Results: The study cohort consisted of 1633 AIS patients, among whom 257 (15.74%) developed subacute AKD, 173 (10.59%) experienced AKI recovery, and 65 (3.98%) met criteria for both AKI and AKD. The mortality rate stood at 4.84%. The LightGBM model displayed superior performance, boasting an AUROC of 0.96 for mortality prediction. The top five features linked to mortality were ACEI/ARE, renal function trajectories, neutrophil count, diuretics, and serum creatinine. Moreover, we designed a web application using the LightGBM model to estimate mortality risk. Conclusions: Complete renal function trajectories, including AKI and AKD, are vital for fitting mortality in AIS patients. An interpretable ML model effectively clarified its decision-making process for identifying AIS patients at risk of mortality. The AI-driven web application has the potential to contribute to the development of personalized early mortality prevention. Keypoints: What was known: Acute kidney disease (AKD) defines patients with acute kidney injury (AKI) or subacute loss of kidney function lasting for more than 7 days, which links well AKI to subsequent chronic kidney disease (CKD). Little is known about the risk and prognosis of AKD in acute ischemic stroke (AIS) patients. This study adds: Renal function trajectories, including both AKI and AKD, play a crucial role in predicting mortality in AIS patients. The LightGBM model elucidates decision processes by providing explanations at both global and local levels. The AI web application aids in reducing mortality rates and helps physicians make informed treatment decisions. Potential impact: Adding AKD as a definition for renal failure lasting > 7 days up to 90 days is of clinical importance in addition to the existing definitions for AKI and CKD. Research activities and clinical practice should also focus on AKD, which is far more accurate to predict prognosis especially mortality. [ABSTRACT FROM AUTHOR]

Background: Pulmonary high-grade neuroendocrine carcinomas(pHGNEC) encompassing small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are clinically aggressive tumors with poor prognosis. The role of surgery and prognostic factors guiding management remain unclear. We aimed to analyze prognosis following resection and identify predictive variables. Methods: This retrospective study analyzed 259 patients undergoing pHGNEC resection from 2001–2023. Overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan–Meier curves. Prognostic factors were assessed with Cox regression and visualized using nomogram tools. Results: Minimally invasive surgery was associated with better OS (p = 0.001) and DFS (p = 0.001). Higher T stage predicted worse OS (T2 p = 0.044, T4 p = 0.007) and DFS (T2 p = 0.020, T4 p = 0.004). Advanced TNM stage III (OS p = 0.018; DFS p = 0.015) and IV (OS p < 0.001; DFS p < 0.001) also correlated with poorer prognosis. In the SCLC subgroup, elevated preoperative CEA independently predicted worse OS (p = 0.012) and DFS (p = 0.004). T4 disease (OS p < 0.001; DFS p = 0.002) and advanced TNM staging (stage III OS p = 0.043; DFS p = 0.045; stage IV OS p < 0.001, DFS p < 0.001) were associated with worse outcomes. In LCNEC patients, VATS resection improved OS (p = 0.048) and DFS (p = 0.027) despite conversion. Prior malignancy predicted worse OS (p < 0.001). Advanced TNM disease (stage III OS p = 0.047; stage IV OS p = 0.003, DFS p = 0.005) were also negative prognostic factors. The prognostic nomogram incorporating above variables effectively stratified risk. Calibration plots revealed good correlation between predicted and actual survival. Conclusions: We identified minimally invasive surgery, early TNM stage, younger age, and normal preoperative CEA as positive prognostic factors following pHGNEC resection. Our study provides an applicable prognostic nomogram to facilitate personalized pHGNEC management. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4+ effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment. Methods: The therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model. Results: We find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8+ T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8+ T cells in mice with tumor lung metastasis and induces peripheral CD8+ T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1β and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1β signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models. Conclusions: Collectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Background: We investigated the real-world efficacy of adjuvant therapy for stage I lung adenocarcinoma patients with pathological high-risk factors. Methods: Study participants were enrolled from November 1, 2016 and December 31, 2020. Clinical bias was balanced by propensity score matching. Disease-free survival (DFS) outcomes were compared by Kaplan–Meier analysis. The Cox proportional hazards regression was used to identify survival-associated factors. p ≤ 0.05 was the threshold for statistical significance. Results: A total of 454 patients, among whom 134 (29.5%) underwent adjuvant therapy, were enrolled in this study. One hundred and eighteen of the patients who underwent adjuvant therapy were well matched with non-treatment patients. Prognostic outcomes of the treatment group were significantly better than those of the non-treatment group, as revealed by Kaplan-Meier analysis after PSM. Differences in prevention of recurrence or metastasis between the targeted therapy and chemotherapy groups were insignificant. Adjuvant therapy was found to be positive prognostic factors, tumor size and solid growth patterns were negative. Conclusions: Adjuvant therapy significantly improved the DFS for stage I lung adenocarcinoma patients with high-risk factors. Larger prospective clinical trials should be performed to verify our findings. [ABSTRACT FROM AUTHOR]

Background: Prenatal diagnosis of Berry syndrome, a rare combination of cardiac anomalies including aortopulmonary window (APW), aortic origin of the right pulmonary artery (RPA), interrupted aortic arch (IAA), hypoplastic aortic arch, or coarctation of the aorta (COA), poses a significant challenge. Due to the rarity of the disease, and the limited case reports available to features the complex malformation of Berry syndrome postpartum, this article introduces an innovative approach to visually showcase this unusual disease. The proposed method provides a comprehensive display of the structural deformities, offering valuable insights for clinical practitioners seeking to comprehend this condition. Case presentation: In this report, we present a case where fetal echocardiography aided in diagnosing Berry syndrome, which was later confirmed through postpartum cardiovascular casting. Our experience highlights the importance of using the three-vessel view to diagnose APW and aortic origin of the right pulmonary artery. Additionally, obtaining true cross-sectional and sagittal views by continuously scanning from the three-vessel-trachea view to the long-axis view of the aortic arch is necessary to image IAA or coarctation of the aortic arch. Conclusions: Early and accurate prenatal diagnosis of Berry syndrome is feasible and our cardiovascular cast can perfectly display the microvascular morphology of the fetal heart, which may have great application prospects for postpartum diagnosis and teaching of complex cardiac abnormalities. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of metformin (MET) monotherapy and pioglitazone plus MET (PIOMET) therapy on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome (PCOS). Methods: Sixty normal-weight women with PCOS were recruited between January and September 2022 at the Shengjing Hospital of China Medical University. They were randomly assigned to the MET or PIOMET groups for 12 weeks of MET monotherapy or PIOMET therapy. Anthropometric measurements, menstrual cycle changes, gonadal profiles, and the oral glucose insulin-releasing test (OGIRT) were performed at baseline and after the 12-week treatment. Results: Thirty-six participants completed the trial. MET and PIOMET therapies improved menstrual cycles after the 4- and 12-week treatments; however, there was no statistical difference between the two groups. PIOMET therapy improved luteinizing hormone (LH), luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, and free androgen index (FAI) levels after the 4-week treatment, whereas MET monotherapy only improved total testosterone (TT) levels compared to baseline (P < 0.05). Both MET and PIOMET therapies improved TT and anti-Mullerian hormone (AMH) levels after the 12-week treatment (P < 0.05). In addition, only PIOMET therapy significantly improved sex hormone-binding globulin (SHBG), FAI, and androstenedione (AND) levels than the baseline (P < 0.05). PIOMET therapy improved SHBG and AMH levels more effectively than MET monotherapy (P < 0.05). Furthermore, PIOMET treatment was more effective in improving blood glucose levels at 120 and 180 min of OGIRT compared to MET monotherapy (P < 0.05). Conclusions: In normal-weight women with PCOS, PIOMET treatment may have more benefits in improving SHBG, AMH, and postprandial glucose levels than MET monotherapy, and did not affect weight. However, the study findings need to be confirmed in PCOS study populations with larger sample sizes. [ABSTRACT FROM AUTHOR]

Background: Cardiac masses can encompass a variety of conditions, such as tumors, thrombi, vegetations, calcific lesions, and other rare diseases. Treatment and management of these types of cardiac masses differ considerably. Thus, accurately distinguishing among thrombi, benign tumors, and malignant tumors in the heart is of great importance. Contrast echocardiography (CE) has emerged as a promising technology. Although published guidelines suggest that CE can enhance image quality and assist in differentiating between benign and malignant lesions, most studies on CE diagnosis of cardiac masses are limited to case reports or retrospective/small-sample-sized prospective cohorts. This study aims to evaluate the diagnostic accuracy of CE in patients with suspected cardiac masses and address the insufficient evidence for differential diagnosis using CE. Methods: Between April 2018 and July 2022, a prospective multicenter study was conducted, which included 145 consecutive patients suspected to have cardiac masses based on transthoracic echocardiography. All patients underwent CE examinations. The echocardiographic diagnosis relied on qualitative factors such as echogenicity, boundary, morphology of the base, mass perfusion, pericardial effusion, and motility as well as quantitative factors such as the area of the masses and the peak intensity ratio of the masses to adjacent myocardium (A1/A2). Results: The final confirmed diagnoses were as follows: 2 patients had no cardiac mass, 4 patients had pseudomass, 43 patients had thrombus, 66 patients had benign tumors, and 30 patients had malignant tumors. The receiver operating characteristic (ROC) analysis indicated that an optimal A1/A2 cutoff value of 0.499 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.977, 97.9%, 90.7%, 95.9%, and 95.1%, respectively. The optimal A1/A2 cutoff value of 1.583 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.950, 93.3%, 93.9%, 87.5%, and 96.9%, respectively. Conclusions: Combined with qualitative and quantitative analyses, CE has the potential to accurately differentiate among different types of cardiac masses. [ABSTRACT FROM AUTHOR]

Fish live in an aquatic environment rich in various microorganisms and pathogens. Fish mucosal-associated lymphoid tissue (MALT) plays a very important role in immune defence. This study was conducted to characterize the immune response mediated by CcIgZ3 in common carp (Cyprinus carpio.) and investigate the proliferating CcIgZ3+ B lymphocytes in gill. We determined the expression of CcIgZ3 in many different tissues of common carp following stimulation by intraperitoneal injection of TNP-LPS (2,4,6-Trinitrophenyl hapten conjugated to lipopolysaccharide) or TNP-KLH (2,4,6-Trinitrophenyl hapten conjugated to Keyhole Limpet Hemocyanin). Compared with TNP-KLH, TNP-LPS can induce greater CcIgZ3 expression in the head kidney, gill and hindgut, especially in the gill. The results indicate that the gill is one of the main sites involved in the immune response mediated by CcIgZ3. To examine the distribution of CcIgZ3+ B lymphocytes, immunohistochemistry (IHC) experiments were performed using a polyclonal antibody against CcIgZ3. The results indicated that CcIgZ3 was detected in the head kidney, hindgut and gill. To further examine whether CcIgZ3+ B lymphocytes proliferate in the gills, proliferating CcIgZ3+ B cells were analysed by immunofluorescence staining using an anti-CcIgZ3 polyclonal antibody and an anti-PCNA monoclonal antibody. CcIgZ3 and PCNA (Proliferating Cell Nuclear Antigen) double-labelled cells in the gills were located within the epithelial cells of the gill filaments of common carp stimulated with TNP-LPS at 3 dps and 7 dps, and relatively more proliferating CcIgZ3+ B cells appeared in the gills of common carp at 7 dps. These data imply that CcIgZ3+ B cells in the gills might be produced by local proliferation following TNP-LPS stimulation. In summary, compared with those in TNP-KLH, CcIgZ3 preferentially affects the gills of common carp following challenge with TNP-LPS. CcIgZ3+ B cells proliferate in the gills to quickly produce the CcIgZ3 antibody. In addition, CcIgZ3+ B cells can be activated to induce a strong immune response very early locally in the gill and produce the antibody CcIgZ3, which helps exert an immune-protective effect. These results suggest that an effective vaccine can be designed to promote production of the mucosal antibody CcIgZ3. [ABSTRACT FROM AUTHOR]

The immune-related microenvironment of thymic carcinoid has rarely been reported. We analyzed the expression of PD-L1 and VISTA, and the distribution of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the thymic carcinoid by immunohistochemical staining, and showed the correlation between these markers and clinical survival, indicating the potential therapeutic prospects. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic ovulation dysfunction and overabundance of androgens; it affects 6–20% of women of reproductive age. PCOS involves various pathophysiological factors, and affected women usually have significant insulin resistance (IR), which is a major cause of PCOS. IR and compensatory hyperinsulinaemia have differing pathogeneses in various tissues, and IR varies among different PCOS phenotypes. Genetic and epigenetic changes, hyperandrogenaemia, and obesity aggravate IR. Insulin sensitization drugs are a new treatment modality for PCOS. We searched PubMed, Google Scholar, Elsevier, and UpToDate databases in this review, and focused on the pathogenesis of IR in women with PCOS and the pathophysiology of IR in various tissues. In addition, the review provides a comprehensive overview of the current progress in the efficacy of insulin sensitization therapy in the management of PCOS, providing the latest evidence for the clinical treatment of women with PCOS and IR. [ABSTRACT FROM AUTHOR]

Background: Transcranial magnetic stimulation (TMS) has attracted plenty of attention as it has been proved to be effective in facilitating motor recovery in patients with stroke. The aim of this study was to systematically review the effects of repetitive TMS (rTMS) and theta burst stimulation (TBS) protocols in modulating cortical excitability after stroke.Methods: A literature search was carried out using PubMed, Medline, EMBASE, CINAHL, and PEDro, to identify studies that investigated the effects of four rTMS protocols-low and high frequency rTMS, intermittent and continuous TBS, on TMS measures of cortical excitability in stroke. A random-effects model was used for all meta-analyses.Results: Sixty-one studies were included in the current review. Low frequency rTMS was effective in decreasing individuals' resting motor threshold and increasing the motor-evoked potential of the non-stimulated M1 (affected M1), while opposite effects occurred in the stimulated M1 (unaffected M1). High frequency rTMS enhanced the cortical excitability of the affected M1 alone. Intermittent TBS also showed superior effects in rebalancing bilateral excitability through increasing and decreasing excitability within the affected and unaffected M1, respectively. Due to the limited number of studies found, the effects of continuous TBS remained inconclusive. Motor impairment was significantly correlated with various forms of TMS measures.Conclusions: Except for continuous TBS, it is evident that these protocols are effective in modulating cortical excitability in stroke. Current evidence does support the effects of inhibitory stimulation in enhancing the cortical excitability of the affected M1. [ABSTRACT FROM AUTHOR]

Background: SQUAMOSA PROMOTER BINDING PROTEIN (SBP)-box genes encode a family of plant-specific transcription factors (TFs) that play important roles in many growth and development processes including phase transition, leaf initiation, shoot and inflorescence branching, fruit development and ripening etc. The SBP-box gene family has been identified and characterized in many species, but has not been well studied in Petunia, an important ornamental genus. Results: We identified 21 putative SPL genes of Petunia axillaris and P. inflata from the reference genome of P. axillaris N and P. inflata S6, respectively, which were supported by the transcriptome data. For further confirmation, all the 21 genes were also cloned from P. hybrida line W115 (Mitchel diploid). Phylogenetic analysis based on the highly conserved SBP domains arranged PhSPLs in eight groups, analogous to those from Arabidopsis and tomato. Furthermore, the Petunia SPL genes had similar exon-intron structure and the deduced proteins contained very similar conserved motifs within the same subgroup. Out of 21 PhSPL genes, fourteen were predicted to be potential targets of PhmiR156/157, and the putative miR156/157 response elements (MREs) were located in the coding region of group IV, V, VII and VIII genes, but in the 3’-UTR regions of group VI genes. SPL genes were also identified from another two wild Petunia species, P. integrifolia and P. exserta, based on their transcriptome databases to investigate the origin of PhSPLs. Phylogenetic analysis and multiple alignments of the coding sequences of PhSPLs and their orthologs from wild species indicated that PhSPLs were originated mainly from P. axillaris. qRT-PCR analysis demonstrated differential spatiotemperal expression patterns of PhSPL genes in petunia and many were expressed predominantly in the axillary buds and/or inflorescences. In addition, overexpression of PhSPL9a and PhSPL9b in Arabidopsis suggested that these genes play a conserved role in promoting the vegetative-to-reproductive phase transition. Conclusion: Petunia genome contains at least 21 SPL genes, and most of the genes are expressed in different tissues. The PhSPL genes may play conserved and diverse roles in plant growth and development, including flowering regulation, leaf initiation, axillary bud and inflorescence development. This work provides a comprehensive understanding of the SBP-box gene family in Petunia and lays a significant foundation for future studies on the function and evolution of SPL genes in petunia. [ABSTRACT FROM AUTHOR]