Hsa_circ_0079875 functions as a competitive endogenous RNA to promote hepatocellular carcinoma progression.

Circular RNA (circRNA) can influence the development of hepatocellular carcinoma (HCC) as a competitive endogenous RNA (ceRNA). However, there are still many circRNAs whose functions are unknown. Our research explores the role of a novel circRNA, hsa_circ_0079875, in HCC. The expression of hsa_circ_0079875 in HCC was verified by next-generation sequencing, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and fluorescence in situ hybridization (FISH). The distribution of hsa_circ_0079875 in HCC cells was investigated by RNA subcellular isolation and FISH assays. The functional effects on HCC proliferation, invasion, migration, cell cycle, and apoptosis were verified by overexpression and knockdown of hsa_circ_0079875. Moreover, xenograft mouse models and immunohistochemistry experiments were used to assess the function of hsa_circ_0079875 in vivo. Hsa_circ_0079875 was up-regulated in HCC tissues and mainly distributed in the cytoplasm. Higher hsa_circ_0079875 leads to larger tumor tissue, more microvascular invasion(MVI) and higher AFP levels, which in turn leads to a poor prognosis. Overexpression of hsa_circ_0079875 can promote the proliferation, migration, and invasion of HCC cells and inhibit apoptosis in vitro and in vivo. Knocking down hsa_circ_0079875 has the opposite effect. Sequencing and biological information predicted the target miRNA and mRNA of hsa_circ_0079875. Further bioinformatics and clinical correlation analysis revealed that hsa_circ_0079875 promote the malignant biological behaviors of HCC through hsa_circ_0079875/miR-519d-59/NRAS ceRNA net. Therefore, hsa_circ_0079875 can be a potential prognostic marker and therapeutic target for HCC.

Substrate-induced condensation activates plant TIR domain proteins.

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain mediate recognition of strain-specific pathogen effectors, typically via their C-terminal ligand-sensing domains1. Effector binding enables TIR-encoded enzymatic activities that are required for TIR-NLR (TNL)-mediated immunity2,3. Many truncated TNL proteins lack effector-sensing domains but retain similar enzymatic and immune activities4,5. The mechanism underlying the activation of these TIR domain proteins remain unclear. Here we show that binding of the TIR substrates NAD+ and ATP induces phase separation of TIR domain proteins in vitro. A similar condensation occurs with a TIR domain protein expressed via its native promoter in response to pathogen inoculation in planta. The formation of TIR condensates is mediated by conserved self-association interfaces and a predicted intrinsically disordered loop region of TIRs. Mutations that disrupt TIR condensates impair the cell death activity of TIR domain proteins. Our data reveal phase separation as a mechanism for the activation of TIR domain proteins and provide insight into substrate-induced autonomous activation of TIR signalling to confer plant immunity.

The effectiveness and safety of rectal modular dissection for male middle and low rectal cancer after neoadjuvant chemoradiation therapy: the short-term outcome.

Background: The purpose of this study was to assess the efficacy and safety of rectal modular dissection (RMD) in male patients with middle and low rectal cancer. RMD is a technique used to guide the surgical procedure for rectal mobilization, with the ultimate goal of achieving total mesorectal excision. In order to evaluate the effectiveness of RMD, a single-center, non-inferiority randomized clinical trial was carried out. Methods: Eligible patients were randomly assigned into two groups: the RMD group and the traditional rectal mobilization (TRM) group. Demographic characteristics, perioperative data and pathological results of the surgical specimens were collected for analysis. additionally, assessments of urogenital function and defecation function were conducted for all participants. Results: A total of 103 patients (RMD group 53 patients and TRM group 50 patients) were included to analyzed. There were no significant differences in age, body mass index, ASA classification, and tumor characteristics between two groups. The RMD group had significantly lower blood loss (P = 0.00), shorter operative duration (P = 0.00), and shorter hospital stay (P = 0.04) compared to the TRM group. The complete rate of mesorectal excision was higher in the RMD group (98.1%) compared to the TRM group (86.0%, P = 0.02). In terms of functional outcomes, the RMD group had better evaluation scores for urethral function (IPSS score, P = 0.01), erectile function (IIEF-5 score, P = 0.00) and defecation function (LARS score, P = 0.00) at the one-year postoperative follow-up. The 1-year disease-free survival rate was similar between the two groups (P = 0.28). Conclusions: These results suggest that RMD is an effective and safe approach for achieving total mesorectal excision while promoting better functional outcomes for patients. The trial was registered in Chinese Clinical Trial Registry (ChiCTR2100052094).

The prognostic significance of right paratracheal lymph node dissection numbers in right upper lobe non-small cell lung cancer.

BACKGROUND: The number of dissected lymph nodes is closely related to the prognosis of patients with non-small cell lung cancer. This study explored the optimal number of right paratracheal lymph nodes dissected in right upper non-small cell lung cancer patients and its impact on prognosis. METHODS: Patients who underwent radical surgery for right upper lobe cancer between 2012 and 2017 were retrospectively enrolled. The optimal number of right paratracheal lymph nodes and the relationship between the number of dissected right paratracheal lymph nodes and the prognosis of right upper non-small cell lung cancer were analysed. RESULTS: A total of 241 patients were included. The optimal number of dissected right paratracheal lymph nodes was 6. The data were divided according to the number of dissected right paratracheal lymph nodes into groups RPLND + (≥ 6) and RPLND- (< 6). In the stage II and III patients, the 5-year overall survival rates were 39.0% and 48.2%, respectively (P = 0.033), and the 5-year recurrence-free survival rates were 32.8% and 41.8%, respectively (P = 0.043). Univariate and multivariate analyses revealed that among the stage II and III patients, ≥ 6 right paratracheal dissected lymph nodes was an independent prognostic factor for overall survival (HR = 0.53 95% CI 0.30-0.92 P = 0.025) and recurrence-free survival (HR = 1.94 95% CI 1.16-3.24 P = 0.011). CONCLUSIONS: Resection of 6 or more right paratracheal lymph nodes may be associated with an improved prognosis in patients with right upper non-small cell lung cancer, especially in patients with stage II or III disease.

End-to-end deep learning method for predicting hormonal treatment response in women with atypical endometrial hyperplasia or endometrial cancer.

Purpose: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and atypical endometrial hyperplasia (AEH) is considered a high-risk precursor to EC. Hormone therapies and hysterectomy are practical treatment options for AEH and early-stage EC. Some patients prefer hormone therapies for reasons such as fertility preservation or being poor surgical candidates. However, accurate prediction of an individual patient's response to hormonal treatment would allow for personalized and potentially improved recommendations for these conditions. This study aims to explore the feasibility of using deep learning models on whole slide images (WSI) of endometrial tissue samples to predict the patient's response to hormonal treatment. Approach: We curated a clinical WSI dataset of 112 patients from two clinical sites. An expert pathologist annotated these images by outlining AEH/EC regions. We developed an end-to-end machine learning model with mixed supervision. The model is based on image patches extracted from pathologist-annotated AEH/EC regions. Either an unsupervised deep learning architecture (Autoencoder or ResNet50), or non-deep learning (radiomics feature extraction) is used to embed the images into a low-dimensional space, followed by fully connected layers for binary prediction, which was trained with binary responder/non-responder labels established by pathologists. We used stratified sampling to partition the dataset into a development set and a test set for internal validation of the performance of our models. Results: The autoencoder model yielded an AUROC of 0.80 with 95% CI [0.63, 0.95] on the independent test set for the task of predicting a patient with AEH/EC as a responder vs non-responder to hormonal treatment. Conclusions: These findings demonstrate the potential of using mixed supervised machine learning models on WSIs for predicting the response to hormonal treatment in AEH/EC patients.

SIRT7 promotes the proliferation and migration of anaplastic thyroid cancer cells by regulating the desuccinylation of KIF23.

OBJECTIVE: This study was designed to investigate the regulatory effects of kinesin family member (KIF) 23 on anaplastic thyroid cancer (ATC) cell viability and migration and the underlying mechanism. METHODS: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze the levels of KIF23 in ATC cells. Besides, the effects of KIF23 and sirtuin (SIRT) 7 on the viability and migration of ATC cells were detected using cell counting kit-8, transwell and wound healing assays. The interaction between SIRT7 and KIF23 was evaluated by co-immunoprecipitation (Co-IP) assay. The succinylation (succ) of KIF23 was analyzed by western blot. RESULTS: The KIF23 expression was upregulated in ATC cells. Silencing of KIF23 suppressed the viability and migration of 8505C and BCPAP cells. The KIF23-succ level was decreased in ATC cells. SIRT7 interacted with KIF23 to inhibit the succinylation of KIF23 at K537 site in human embryonic kidney (HEK)-293T cells. Overexpression of SIRT7 enhanced the protein stability of KIF23 in HEK-293T cells. Besides, overexpression of KIF23 promoted the viability and migration of 8505C and BCPAP cells, which was partly blocked by silenced SIRT7. CONCLUSIONS: SIRT7 promoted the proliferation and migration of ATC cells by regulating the desuccinylation of KIF23.

Conditional Survival of Patients with Limited-Stage Small Cell Lung Cancer After Surgery: A National Real-World Cohort Study.

BACKGROUND: The prognosis of limited-stage small cell lung cancer (LS-SCLC) after surgery usually is estimated at diagnosis, but how the prognosis actually evolves over time for patients who survived for a predefined time is unknown. METHODS: Data on patients with a diagnosis of LS-SCLC after surgery between 2004 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. The 5-year conditional cancer-specific survival (CCSS) and conditional overall survival (COS) were calculated. RESULTS: This study analyzed 997 patients (555 women, 55.7%) with a median age, of 67 years (interquartile range [IQR], 60-73 years). The 5-year CCSS and COS increased from 44.7% and 38.3%, respectively, at diagnosis to 83.7% and 67.9% at 5 years after diagnosis. Although there were large differences with different stages (stages I, II, and III) at diagnosis (respectively 59.5%, 28.4%; 28.1% for CCSS and 50.6%, 24.8%, and 23.6% for COS), the gap decreased with time, and the rates were similar after 5 years (respectively 85.0%, 80.3%, and 79.4% for CCSS; 65.6%, 56.9%, and 61.3% for COS). The 5-year conditional survival for the patients who received lobectomy was better than for those who received sublobectomy or pneumonectomy. Multivariable analyses showed that only age and resection type were independent predictors for CCSS and COS, respectively, throughout the period. CONCLUSION: Conditional survival estimates for LS-SCLC generally increased over time, with the most significant improvement in patients with advanced stage of disease. Resection type and old age represented extremely important determinants of prognosis after a lengthy event-free follow-up period.

Construction and validation of a risk-scoring model to predict lymph node metastasis in T1b-T2 esophageal cancer.

BACKGROUND: Lymph node status is an important factor in determining preoperative treatment strategies for stage T1b-T2 esophageal cancer (EC). Thus, the aim of this study was to investigate the risk factors for lymph node metastasis (LNM) in T1b-T2 EC and to establish and validate a risk-scoring model to guide the selection of optimal treatment options. METHODS: Patients who underwent upfront surgery for pT1b-T2 EC between January 2016 and December 2022 were analyzed. On the basis of the independent risk factors determined by multivariate logistic regression analysis, a risk-scoring model for the prediction of LNM was constructed and then validated. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminant ability of the model. RESULTS: The incidence of LNM was 33.5% (214/638) in our cohort, 33.4% (169/506) in the primary cohort and 34.1% (45/132) in the validation cohort. Multivariate analysis confirmed that primary site, tumor grade, tumor size, depth, and lymphovascular invasion were independent risk factors for LNM (all P < 0.05), and patients were grouped based on these factors. A 7-point risk-scoring model based on these variables had good predictive accuracy in both the primary cohort (AUC, 0.749; 95% confidence interval 0.709-0.786) and the validation cohort (AUC, 0.738; 95% confidence interval 0.655-0.811). CONCLUSION: A novel risk-scoring model for lymph node metastasis was established to guide the optimal treatment of patients with T1b-T2 EC.

Abnormal p16 expression and prognostic significance in esophageal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to analyze p16 expression status and evaluate whether abnormal p16 expression was associated with prognosis in a large-scale esophageal squamous cell carcinoma (ESCC) cohort of patients. METHODS: We retrospectively evaluated p16 expression status of 525 ESCC samples using immunohistochemistry. Associations between abnormal p16 expression and survival were analyzed. RESULTS: P16 negative, focal expression and overexpression were found in 87.6%, 6.9% and 5.5% of ESCC patients. No significant association was observed between abnormal p16 expression and age, sex, tumor site and location, differentiation, vessel and nerve invasion, T stage and lymph node metastasis. In all patients, the survival of p16 focal expression group tended to be better compared with negative group (disease free survival/DFS P=0.040 and overall survival/OS P=0.052) and overexpression group (DFS P=0.201 and OS P=0.258), and there was no survival difference between negative group and overexpression group. The multivariate analysis for OS and DFS found that only clinical stage was a significantly independent prognostic factor (P<0.001). When patients were divided into I-II stage (n=290) and III-IVa stage (n=235), the survival of focal expression group was better compared with negative group (DFS P=0.015 and OS P=0.019), and tended to be better compared with overexpression group (DFS P=0.405 and OS P=0.432) in I-II stage ESCC, which was not found in III-IVa stage ESCC. CONCLUSION: P16 overexpression or negative expression tend to be associated with unfavorable outcomes, especially in I-II stage ESCC. Our study will help to identify a subgroup of ESCC patients with excellent prognosis after surgical therapy.

Radiomics-based machine learning and deep learning to predict serosal involvement in gallbladder cancer.

OBJECTIVE: Our study aimed to determine whether radiomics models based on contrast-enhanced computed tomography (CECT) have considerable ability to predict serosal involvement in gallbladder cancer (GBC) patients. MATERIALS AND METHODS: A total of 152 patients diagnosed with GBC were retrospectively enrolled and divided into the serosal involvement group and no serosal involvement group according to paraffin pathology results. The regions of interest (ROIs) in the lesion on all CT images were drawn by two radiologists using ITK-SNAP software (version 3.8.0). A total of 412 features were extracted from the CT images of each patient. The Mann‒Whitney U test was applied to identify features with significant differences between groups. Seven machine learning algorithms and a deep learning model based on fully connected neural networks (f-CNNs) were used for radiomics model construction. The prediction efficacy of the models was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Through the Mann‒Whitney U test, 75 of the 412 features extracted from the CT images of patients were significantly different between groups (P < 0.05). Among all the algorithms, logistic regression achieved the highest performance with an area under the curve (AUC) of 0.944 (sensitivity 0.889, specificity 0.8); the f-CNN deep learning model had an AUC of 0.916, and the model showed high predictive power for serosal involvement, with a sensitivity of 0.733 and a specificity of 0.801. CONCLUSION: Radiomics models based on features derived from CECT showed convincing performances in predicting serosal involvement in GBC.

Chondroprotective effects of bone marrow mesenchymal stem cell-derived exosomes in osteoarthritis.

Chondrocyte ferroptosis constitutes a major cause of the development of osteoarthritis (OA). Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have a protective role against ferroptosis in various diseases. Hence, we aimed to determine whether BMSC-Exos alleviated chondrocyte ferroptosis and its effect on OA, and to dissect out the possible mechanisms. An OA rat chondrocyte model was established by interleukin-1ß (IL-1ß) exposure, and treated with BMSC-Exos/ferroptosis inhibitor Ferrostatin-1. Cell viability/ferroptosis-related index levels [reactive oxygen species (ROS)/malondialdehyde (MDA)/glutathione (GSH)]/cell death/ACSL4 mRNA and protein levels and METTL3 levels were assessed by MTT/kits/immunohistochemical method and TUNEL staining/RT-qPCR and Western blot. METTL3/ACSL4 were overexpressed in rat chondrocytes to evaluate their role in BMSC-Exo-produced repression on chondrocyte ferroptosis. Bioinformatics website predicted the presence of m6A modification sites on ACSL4 mRNA, with the m6A level enriched on it assessed by MeRIP/RT-qPCR. ACSL4 mRNA stability was detected by actinomycin D assay. A surgical destabilized medial meniscus rat OA model was also established, followed by injection with BMSC-Exos to verify their function. IL-1ß stimulation in rat chondrocytes inhibited cell viability, elevated Fe2+/ROS/MDA levels, declined GSH levels and increased TUNEL positive cell number and ACSL4 level, which were neutralized by BMSC-Exos. BMSC-Exos limited chondrocyte ferroptosis by down-regulating METTL3, with the effect abrogated by METTL3 overexpression. METTL3 regulated the m6A modification of ACSL4 mRNA, increasing ACSL4 mRNA stability and ACSL4 expression. BMSC-Exos reduced chondrocyte ferroptosis and prevented OA progression via disruption of the METTL3-m6A-ACSL4 axis. BMSC-Exos might exert a chondroprotective effect by attenuating chondrocyte ferroptosis and alleviate OA progression.

The association between histological subtypes and lymph node metastasis and prognosis in early esophageal cancer: a population-based study.

BACKGROUND: There is still a lack of high-level clinical evidence and uniform conclusions on whether there are differences in lymph node metastasis (LNM) and prognosis between early esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). METHODS: Patients with surgically resected, histologically diagnosed, pT1 EAC or ESCC in the Surveillance, Epidemiology and End Results registries database from 2004 to 2015 were included. Multivariable logistic regression, Cox regression, multivariate competing risk model, and propensity score matching were used to analyze association the histology and LNM or prognosis. RESULTS: A total of 570 early esophageal cancer patients were included. The LNM rates were 13.8% and 15.1% for EAC and ESCC ( P  = 0.757), respectively. Multivariate logistic regression analysis showed no significant association between histological type and LNM (odds ratio [OR], 1.209; 95% CI, 0.538-2.715; P  = 0.646). Moreover, the prognosis of early EAC and ESCC was shown to be comparable in both multivariate Cox regression (hazard ratio [HR], 1.483; 95% CI, 0.699-3.150; P  = 0.305) and the multivariate competing risk model (subdistribution HR, 1.451; 95% CI, 0.628-3.354; P  = 0.383). After propensity score matching, there were no significant differences between early EAC and ESCC in terms of LNM (10.6% vs.18.2%, P  = 0.215), 5-year CSS (89.8% [95% CI, 81.0%-98.6%] vs. 79.1% [95% CI, 67.9%-90.3%], P  = 0.102) and 5-year cumulative incidence of CSS (10.2% [95% CI, 1.4%-19.0%] vs. 79.1% [95% CI, 9.7%-32.1%], P  = 0.124). CONCLUSION: The risk of LNM and prognosis of early ESCC and EAC are comparable, so the treatment choice for early esophageal cancer does not depend on the histologic type.

Prognostic Factors and Outcomes in Elderly Esophagectomy Patients with Esophageal Cancer.

BACKGROUND: Choosing the appropriate treatment for elderly patients with esophageal cancer remains a contentious issue. While surgery is still a valid option, we aimed to identify predictors and outcomes in elderly esophagectomy patients with esophageal cancer. PATIENTS AND METHODS: We analyzed characteristics, surgical outcomes, survival rates, cause-specific mortality, and recurrence in 120 patients with stage I-IV esophageal cancer. Univariate and multivariate analyses were used to identify risk factors for event-free survival (EFS) and overall survival (OS). RESULTS: The median follow-up period was 31 months, with 5-year overall survival (OS) and event-free survival (EFS) rates standing at 45.2% and 41.5%, respectively. Notably, lower body mass index (BMI ≤ 22 kg/m2) and reduced preoperative albumin levels (pre-ALB < 40 g/L) led to a significant decrease in OS rates. Postoperative pulmonary complications resulted in higher in-hospital and 90-day mortality rates. After about 31 months post-surgery, the rate of cancer-specific deaths stabilized. The most common sites for distant metastasis were the lungs, supraclavicular lymph nodes, liver, and bone. The study identified lower BMI, lower pre-ALB levels, and postoperative pulmonary complications as independent risk factors for poorer EFS and OS outcomes. CONCLUSIONS: Esophagectomy remains a safe and feasible treatment for elderly patients, though the prevention of postoperative pulmonary infection is crucial. Factors such as lower BMI, lower pre-ALB levels, advanced tumor stage, postoperative pulmonary complications, and certain treatment modalities significantly influence the outcomes in elderly esophagectomy patients. These findings provide critical insights into the characteristics and outcomes of this patient population.

Integrated Metabolomics, Transcriptome and Functional Analysis Reveal Key Genes Are Involved in Tree Age-Induced Amino Acid Accumulation in Torreya grandis Nuts.

Torreya grandis is native Chinese tree species of economic significance, renowned for its long lifespan and the rich nutritional value of its nuts. In this study, we analyzed the morphological characteristics, metabolites, associated gene expressions, and regulatory mechanism in nuts from young (10 years old) and old (1000 years old) T. grandis trees. We observed that the length, width, and weight of nuts from older trees were considerably greater than those from younger trees. Metabolomic analysis revealed that the concentrations of 18 amino acids and derivatives (including histidine and serine) in nuts from older trees were markedly higher than those in nuts from younger trees. Transcriptome and metabolomic correlation analysis identified 16 genes, including TgPK (pyruvate kinase), TgGAPDH (glyceraldehyde 3-phosphate dehydrogenase), and others, which exhibit higher expression levels in older trees compared to younger trees, as confirmed by qRT-PCR. These genes are associated with the biosynthesis of histidine, glutamic acid, tryptophan, and serine. Transient expression of TgPK in tobacco led to increased pyruvate kinase activity and amino acid content (histidine, tryptophan, and serine). Additionally, dual-luciferase assays and yeast one-hybrid results demonstrated that TgWRKY21 positively regulates TgPK expression by directly binding to the TgPK promoter. These findings not only demonstrate the nutritional differences between nuts from young and old trees but also offer fresh insights into the development of nutritional sources and functional components based on nuts from old trees, enriching our understanding of the potential benefits of utilizing nuts from older trees.

Construction of a ceRNA regulatory network to explore potential pathogenesis mechanisms involved in human hepatocellular carcinoma.

Worldwide, primary liver cancer is the third leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Recent studies have shown that circular RNAs (circRNAs) that interact with microRNAs (miRNAs) are involved in the occurrence and development of various tumours. Transcriptional profile analysis was used to analyse expression of circRNAs in HCC in this study. The top ten upregulated circRNAs were selected and validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in another 34 HCC patients. MiRNAs and mRNAs downstream of these circRNAs were explored through database analysis, and finally, the competitive endogenous RNA (ceRNA) networks were constructed for 5 selected circRNAs. We identified 9658 differentially expressed circRNAs by transcriptional profile analysis. QRT-PCR was performed to validate the top ten upregulated circRNAs, and five circRNAs were selected for further analysis. The miRNAs and mRNAs downstream of these five circRNAs were predicted to construct ceRNA network diagrams. Further analysis revealed five circRNA-miRNA-mRNA axes that correlate negatively with HCC prognosis. Numerous differentially expressed circRNAs exist in HCC, and they can regulate the biological behaviour of HCC through ceRNA networks. Bioinformatics analysis showed that ceRNA regulatory axes involved in HCC have high diagnostic and prognostic value and deserve further exploration.

The mechanism of Shenbing Decoction II against IgA nephropathy renal fibrosis revealed by UPLC-MS/MS, network pharmacology and experimental verification.

Background: IgA nephropathy (IgAN) is a major and growing public health problem. Renal fibrosis plays a vital role in the progression of IgAN. This study is to investigate the mechanisms of action underlying the therapeutic effects of Shenbing Decoction II (SBDII) in IgAN renal fibrosis treatment based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), network pharmacology and experimental verification. Method: We first used UPLC-MS/MS to explore the main compounds of SBDII, and then used network pharmacology to predict the targets and key pathways of SBDII in the treatment of IgAN renal fibrosis. Next, bovine serum albumin (BSA), lipopolysaccharide (LPS), and carbon tetrachloride (CCL4) were used to induce IgAN in rats, and then biochemical indicators, renal tissue pathology, and renal fibrosis-related indicators were examined. At the same time, part of the results predicted by network pharmacology were also verified. Result: A total of 105 compounds were identified in SBDII by UPLC-MS/MS. Network pharmacology results showed that the active compounds such as acacetin, eupatilin, and galangin may mediate the therapeutic effects of SBDII in treating IgAN by targeting tumor protein p53 (TP53) and regulating phosphatidylinositol 3-kinase (PI3K)-Akt kinase (Akt) signaling pathway. Animal experiments showed that SBDII not only significantly improved renal function and fibrosis in IgAN rats, but also significantly downregulated the expressions of p53, p-PI3K and p-Akt. Conclusion: This UPLC-MS/MS, network pharmacological and experimental study highlights that the TP53 as a target, and PI3K-Akt signaling pathway are the potential mechanism by which SBDII is involved in IgAN renal fibrosis treatment. Acacetin, eupatilin, and galangin are probable active compounds in SBDII, these results might provide valuable guidance for further studies of IgAN renal fibrosis treatment.

Molecular subtyping and characterization of clear cell renal cell carcinoma by tumor differentiation trajectories.

Previous bulk RNA sequencing or whole genome sequencing on clear cell renal cell carcinoma (ccRCC) subtyping mainly focused on ccRCC cell origin or the complex tumor microenvironment (TME). Based on the single-cell RNA sequencing (scRNA-seq) data of 11 primary ccRCC specimens, cancer stem-cell-like subsets could be differentiated into five trajectories, whereby we further classified ccRCC cells into three groups with diverse molecular features. These three ccRCC subgroups showed significantly different outcomes and potential targets to tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). Tumor cells in three differentiation directions exhibited distinct interactions with other subsets in the ccRCC niches. The subtyping model was examined through immunohistochemistry staining in our ccRCC cohort and validated the same classification effect as the public patients. All these findings help gain a deeper understanding about the pathogenesis of ccRCC and provide useful clues for optimizing therapeutic schemes based on the molecular subtype analysis.

The MR Imaging of Primary Intrahepatic Lymphoepithelioma-like Cholangiocarcinoma: A Diagnostic Challenge.

PURPOSE: To characterize the magnetic resonance imaging features of primary intrahepatic lymphoepithelioma-like cholangiocarcinoma (LELCC). MATERIALS AND METHODS: Thirty-four patients with 38 histologically confirmed LELCCs were enrolled retrospectively from January 2014 to August 2022. We evaluated the clinical features, histologic findings, and imaging manifestations on dynamic enhanced MRI. RESULTS: 74% (25/34) of the cases were associated with EBV infection. Moreover, patients infected with EBV exhibited a lower level of Ki-67 proliferation. The serum CA199 level was elevated in 10 patients. The median tumor diameter was 2.8 cm (range, 1.1-8.7 cm). Most tumors were well-defined with a smooth or lobulated margin and showed peripheral hyperintensity and central hypointensity on T2-weighted imaging (T2WI). T2 hyperintense foci were recognized in 8 patients. In the dynamic enhanced MRI, 21 tumors demonstrated Type A enhancement pattern (rim enhancement), 10 demonstrated Type B (rapid wash-in and wash-out), and seven demonstrated Type C (rapid wash-in without wash-out). Capsular enhancement in PVP or DP was found in 22 tumors. A few patients had satellite lesions, portal vein thrombosis, bile duct dilatation, and distal metastasis. Lymph node metastases were discovered pathologically in 11 patients. CONCLUSIONS: MRI findings of LELCC vary and are non-specific. While a majority of LELCCs exhibit typical features of intrahepatic cholangiocarcinoma (iCCA), unique findings like T2 hyperintense foci or capsular enhancement could suggest LELCC. EBV infection and elevated tumor markers can aid in differentiation. However, given the mimics of some cases of liver hypervascular lesions, histological examination remains essential for definitive diagnosis.

Melatonin alleviates aluminum toxicity by regulating aluminum-responsive and nonresponsive pathways in hickory.

Aluminum (Al) toxicity is a significant constraint on agricultural productivity worldwide. Melatonin (MT) has been shown to alleviate Al toxicity in plants; however, the underlying mechanisms remain largely unknown. Here, we employed a combination of physiological and molecular biology techniques to examine the role of MT in mitigating Al toxicity of hickory. We found that MT decreased the contents of cell wall pectin, hemicellulose, Al, and Al-induced massive reactive oxygen species accumulation in the roots of hickory. Transcriptomic analysis revealed that MT may alleviate root tip Al stress by regulating Al-responsive and nonresponsive pathways. Co-expression regulatory network and dual-luciferase receptor assays revealed that transcription factors, CcC3H12 and CcAZF2, responded to MT and significantly activated the expression of two cell wall pectin-related genes, CcPME61 and CcGAE6, respectively. Further, yeast one-hybrid and electrophoretic mobility shift assay (EMSA) assays verified that CcC3H12 and CcAZF2 regulated CcPME61 and CcGAE6, respectively, by directly binding to their promoters. Overexpression of CcPME61 enhanced the Al sensitivity of Arabidopsis thaliana. Our results indicate that MT can improve Al tolerance of hickory via multiple pathways, which provides a new perspective for the study of the mechanism of MT in alleviating abiotic stress.