Inhibitory mechanisms of decoy receptor 3 in cecal ligation and puncture-induced sepsis.

Despite its high mortality, specific and effective drugs for sepsis are lacking. Decoy receptor 3 (DcR3) is a potential biomarker for the progression of inflammatory diseases. The recombinant human DcR3-Fc chimera protein (DcR3.Fc) suppresses inflammatory responses in mice with sepsis, which is critical for improving survival. The Fc region can exert detrimental effects on the patient, and endogenous peptides are highly conducive to clinical application. However, the mechanisms underlying the effects of DcR3 on sepsis are unknown. Herein, we aimed to demonstrate that DcR3 may be beneficial in treating sepsis and investigated its mechanism of action. Recombinant DcR3 was obtained in vitro. Postoperative DcR3 treatment was performed in mouse models of lipopolysaccharide- and cecal ligation and puncture (CLP)-induced sepsis, and their underlying molecular mechanisms were explored. DcR3 inhibited sustained excessive inflammation in vitro, increased the survival rate, reduced the proinflammatory cytokine levels, changed the circulating immune cell composition, regulated the gut microbiota, and induced short-chain fatty acid synthesis in vivo. Thus, DcR3 protects against CLP-induced sepsis by inhibiting the inflammatory response and apoptosis. Our study provides valuable insights into the molecular mechanisms associated with the protective effects of DcR3 against sepsis, paving the way for future clinical studies. IMPORTANCE: Sepsis affects millions of hospitalized patients worldwide each year, but there are no sepsis-specific drugs, which makes sepsis therapies urgently needed. Suppression of excessive inflammatory responses is important for improving the survival of patients with sepsis. Our results demonstrate that DcR3 ameliorates sepsis in mice by attenuating systematic inflammation and modulating gut microbiota, and unveil the molecular mechanism underlying its anti-inflammatory effect.

Research on a machine learning-based adaptive and efficient screening model for psychological symptoms of community correctional prisoners.

Community correction institutions in China frequently employ the Symptom Checklist-90 (SCL-90) and the health survey brief (SF-12) as primary tools for psychological assessment of community correctional prisoners. However, in practical application, the SCL-90 Checklist faces issues such as complex item numbers, overall low cultural level of the subjects, and insufficient professional level of the administrators. The SF-12 health survey brief, as a preliminary screening tool, although only has 12 questions, to some extent simplifies the evaluation process and improves work efficiency, it is prone to missed screening. The research team collected 17-dimensional basic characteristic data and corresponding SCL-90 and SF-12 data from 25,480 samples of community correctional prisoners in Zhejiang Province, China. This study explored the application of multi-label multi-classification algorithms and oversampling techniques in building machine learning models to delve into the correlation between the psychological health risks of community correctional prisoners and their characteristic data. Inspired by computerized adaptive testing (CAT), we constructed an adaptive and efficient screening model for community correctional prisoners through experimental comparisons, based on the binary relevance algorithm with sample oversampling. This screening model personalize the assessment process by dynamically matching participants with the most relevant subset (s) of the nine dimensions of the SCL-90 based on their individual characteristics. Thus, adaptive dynamic simplification and personalized recommendation of the SCL-90 scale between question groups were achieved for the specific group of community correctional prisoners. As a screening tool for psychological symptoms of community correctional prisoners, this model significantly simplifies the number of questions compared to SCL-90, with a simplification rate of up to 65%. However, it achieves this simplification while maintaining excellent performance. The accuracy reached 0.66, with a sensitivity of 0.754, and an F1 score of 0.649. This innovation simplified the assessment process, reduced the assessment time, improved work efficiency, and enhanced the ability to judge the specificity of community correctional prisoners population. Compared to the SF-12, although the simplification rate and accuracy of the model are slightly lower than those of the SF-12, the sensitivity increased by 42.26%, and the F1 score improved by 15.28%. This means the model greatly reduces the possibility of missed screening, effectively preventing prisoners with abnormal psychological or mental states from losing control due to missed screening, and even committing suicide, self injury, or injuring others.

The inflammation score predicts the prognosis of gastric cancer patients undergoing Da Vinci robot surgery.

Neutrophil-to-lymphocyte ratio (NLR), calculated from peripheral blood immune-inflammatory cell counts, is considered a predictor of survival in various cancers. Nevertheless, there is a lack of research into the predictive value of NLR specifically in gastric cancer patients following surgery using the Da Vinci robot. Investigate the objectives of this research, confirm the positive predictive value of NLR in the prognosis of gastric cancer patients undergoing Da Vinci robotic-assisted surgery by comparing its prognostic ability with other inflammation markers and tumor biomarkers. In this retrospective analysis, information from 128 individuals diagnosed with gastric cancer and treated with da Vinci robot-assisted surgery was examined. The study examined various markers in the peripheral blood, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), systemic immune-inflammatory index (SII) prognostic nutrition index (PNI), cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4), carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP).To ascertain the prognostic ability and optimal cutoff values of each parameter, operating characteristic curves and the area under the curve were utilized in the analysis. For evaluation of independent prognostic factors, we utilized Kaplan-Meier curves and multifactorial Cox analysis. The variables from the multifactorial Cox analysis were used to construct a nomogram. NLR, LMR, CEA, AFP, primary location, largest tumor size and TNM stage were all found to be significant predictive elements for overall survival (OS). Multivariate Cox identified NLR (P = 0.005), LMR (P = 0.03) and AFP (P = 0.007) as the only separate predictive variables among hematological indicators. The nomogram built using NLR demonstrates excellent predictive performance at 1 year (AUC = 0.778), 3 years (AUC = 0.773), and 5 years (AUC = 0.781). Cross-validation demonstrates that this model has favorable predictive performance and discriminative ability. NLR is an uncomplicated yet potent marker for forecasting the survival result of individuals with gastric cancer following da Vinci robotic surgery, and it possesses considerable predictive significance. The nomogram based on NLR provides patients with a visual and accurate prognosis prediction.

Presurgical Medical Treatment in Prolactinomas: Surgical Implications and Pathological Characteristics From 290 Cases.

OBJECTIVE: To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. METHODS: A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. RESULTS: Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P < .001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P = .047). CONCLUSION: This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging.

MiR-138-5p Inhibits Thyroid Cancer Cell Growth and Stemness by Targeting TRPC5/Wnt/ß-Catenin Pathway.

MicroRNAs play a key role in the pathogenesis of many types of cancer, including thyroid cancer (TC). MiR-138-5p has been confirmed to be abnormally expressed in TC tissues. However, the role of miR-138-5p in TC progression and its potential molecular mechanism need to be further explored. In this study, quantitative real-time PCR was used to examine miR-138-5p and TRPC5 expression, and western blot analysis was performed to examine the protein levels of TRPC5, stemness-related markers, and Wnt pathway-related markers. Dual-luciferase reporter assay was used to assess the interaction between miR-138-5p and TRPC5. Cell proliferation, stemness, and apoptosis were examined using colony formation assay, sphere formation assay, and flow cytometry. Our data showed that miR-138-5p could target TRPC5 and its expression was negatively correlated with TRPC5 expression in TC tumor tissues. MiR-138-5p decreased proliferation, stemness, and promoted gemcitabine-induced apoptosis in TC cells, and this effect could be reversed by TRPC5 overexpression. Moreover, TRPC5 overexpression abolished the inhibitory effect of miR-138-5p on the activity of Wnt/ß-catenin pathway. In conclusion, our data showed that miR-138-5p suppressed TC cell growth and stemness via the regulation of TRPC5/Wnt/ß-catenin pathway, which provided some guidance for studying the potential function of miR-138-5p in TC progression.

Assessment of quality of life in patients with craniopharyngioma and identification of risk factors for compromised overall wellness

ABSTRACT Objective: Quality of Life (QoL) has been a multifactorial concerning issue in oncology. We aimed to inspect the pre-operative QoL among patients with craniopharyngioma and to explore the potential correlations between parameters of QoL and clinical indices. Subjects and methods: We enrolled a total of 109 patients with craniopharyngioma. We utilized Short Form 36 (SF-36), Symptom Check List-90, Generalized Anxiety Disorder Questionnaire scale (GAD7), Patient Health Questionnaire Depression (PHQ9) and Pittsburgh Sleep Quality Index to prospectively evaluated their QoL. Parameters of QoL along with clinical indices were compared among sub-groups divided according to Puget classification. Correlation analyses and regression analyses were performed to detect influential determinants to self-reported wellness. Results: Patients presented impaired QoL compared with general population ( p < 0.001), as assessed by SF-36. Correlation analyses indicated the detrimental influence resulting from central diabetes insipidus (CDI). Multivariate linear regression unveiled the adverse effect of CDI on Mental Component Summary (coefficient = −13.869, p = 0.007), GAD7 total score (coefficient = 2.072, p = 0.049) as well as PHQ9 total score (coefficient = 3.721, p = 0.001). Multivariate logistic regression verified CDI as a risk factor of developing depressive symptoms (OR = 6.160, p = 0.001). Conclusion: QoL of patients with craniopharyngioma was remarkably compromised before operation. CDI exerted detrimental influences on patients' QoL and it might serve as a marker for early identification of patients at risk of depression.

Assessment of quality of life in patients with craniopharyngioma and identification of risk factors for compromised overall wellness.

Objective: Quality of Life (QoL) has been a multifactorial concerning issue in oncology. We aimed to inspect the pre-operative QoL among patients with craniopharyngioma and to explore the potential correlations between parameters of QoL and clinical indices. Subjects and methods: We enrolled a total of 109 patients with craniopharyngioma. We utilized Short Form 36 (SF-36), Symptom Check List-90, Generalized Anxiety Disorder Questionnaire scale (GAD7), Patient Health Questionnaire Depression (PHQ9) and Pittsburgh Sleep Quality Index to prospectively evaluated their QoL. Parameters of QoL along with clinical indices were compared among sub-groups divided according to Puget classification. Correlation analyses and regression analyses were performed to detect influential determinants to self-reported wellness. Results: Patients presented impaired QoL compared with general population (p < 0.001), as assessed by SF-36. Correlation analyses indicated the detrimental influence resulting from central diabetes insipidus (CDI). Multivariate linear regression unveiled the adverse effect of CDI on Mental Component Summary (coefficient = -13.869, p= 0.007), GAD7 total score (coefficient = 2.072, p = 0.049) as well as PHQ9 total score (coefficient = 3.721, p = 0.001). Multivariate logistic regression verified CDI as a risk factor of developing depressive symptoms (OR = 6.160, p = 0.001). Conclusion: QoL of patients with craniopharyngioma was remarkably compromised before operation. CDI exerted detrimental influences on patients' QoL and it might serve as a marker for early identification of patients at risk of depression.

Effects of Moracizine Combined with Metoprolol on Hemodynamic Indices of the Left Atrium and Quality of Life in Patients with Atrial Fibrillation.

BACKGROUND: Drugs are the first choice of treatment for atrial fibrillation (AF), but there is currently a lack of efficient drug treatment options. The aim of this study was to investigate a combination drug treatment plan which may serve as a reference for the treatment of AF. METHODS: A total of 316 AF patients admitted to Jiaozhou Central Hospital in Qingdao from October 2020 to October 2022 were selected for this retrospective study. They were divided into a control group (CG, metoprolol, n = 156) and an observation group (OG, moracizine combined with metoprolol, n = 160) based on the treatment they received. The CG and OG groups were compared for clinical efficacy, occurrence of AF, cardiac output (CO), cardiac indexes (CI), stroke volume (SV), stroke indexes (SI) and improvement in QOL. RESULTS: The OG had a better effective rate of treatment, higher levels of CO, CI, SV and SI, and higher QOL scores compared to the CG, as well as a lower AF recurrence rate and AF burden (all p < 0.05). CONCLUSION: Moracizine combined with metoprolol is an effective treatment for AF patients. This drug combination was found to reduce the AF recurrence rate and burden in AF patients, and to improve their hemodynamic indices and QOL.

Transcription factors, cap 'n' collar isoform C regulates the expression of CYP450 genes involving in insecticides susceptibility in Locusta migratoria.

BACKGROUND: The cap 'n' collar (Cnc) belongs to the Basic Leucine Zipper (bZIP) transcription factor super family. Cap 'n' collar isoform C (CncC) is highly conserved in the animal kingdom. CncC contributes to the regulation of growth, development, and aging and takes part in the maintenance of homeostasis and the defense against endogenous and environmental stress. Insect CncC participates in the regulation of various kinds of stress-responsive genes and is involved in the development of insecticide resistance. RESULTS: In this study, one full-length CncC sequence of Locusta migratoria was identified and characterized. Upon RNAi silencing of LmCncC, insecticide bioassays showed that LmCncC played an essential role in deltamethrin and imidacloprid susceptibility. To fully investigate the downstream genes regulated by LmCncC and further identify the LmCncC-regulated genes involved in deltamethrin and imidacloprid susceptibility, a comparative transcriptome was constructed. Thirty-five up-regulated genes and 73 down-regulated genes were screened from dsLmCncC-knockdown individuals. We selected 22 LmCncC-regulated genes and verified their gene expression levels using RT-qPCR. Finally, six LmCYP450 genes belonging to the CYP6 family were selected as candidate detoxification genes, and LmCYP6FD1 and LmCYP6FE1 were further validated as detoxification genes of insecticides via RNAi, insecticide bioassays, and metabolite identification. CONCLUSIONS: Our data suggest that the locust CncC gene is associated with deltamethrin and imidacloprid susceptibility via the regulation of LmCYP6FD1 and LmCYP6FE1, respectively.

A meta-analysis of the Zilongjin tablets for non-small cell lung cancer and its network pharmacology of action against NSCLC and COVID-19.

Objective: To objectively evaluate the efficacy of the Zilongjin tablets in non-small cell lung cancer (NSCLC) and to explore its potential mechanism of action against NSCLC and COVID-19 based on network pharmacology. Methods: The database was searched for randomized controlled trials (RCTs) of the Zilongjin tablets for NSCLC published up to 22 August 2022. The quality of included trials was assessed using Cochrane standard guidelines, and a meta-analysis was performed using Rev Man 5.3. Gene targets for intersections of NSCLC and COVID-19 (the NC) and drugs were obtained from the TCMSP database, HERB database, GeneCards database, and the NCBI database for network pharmacology research. Results: Meta-analysis included 14 articles with 2,430 patients. The meta-analysis showed that the Zilongjin tablets combined with conventional chemotherapy were significantly more effective than chemotherapy alone in the treatment of NSCLC. A total of 29 drug-disease intersecting targets were identified in the network pharmacology. The "ingredient-target-pathway" diagram component-target-pathway network contained 119 nodes and 429 edges, with the majority of targets associated with inflammatory responses. Conclusion: The efficacy and quality of life of the Zilongjin tablets combined conventional chemotherapy for NSCLC were significantly better than chemotherapy alone, alleviating various adverse effects. At the same time, the Zilongjin tablets may modulate the inflammatory response to alleviate NSCLC and COVID-19.

Establishment of a prognostic model related to tregs and natural killer cells infiltration in bladder cancer.

BACKGROUND: Regulatory T cells (Tregs) and natural killer (NK) cells play an essential role in the development of bladder urothelial carcinoma (BUC). AIM: To construct a prognosis-related model to judge the prognosis of patients with bladder cancer, meanwhile, predict the sensitivity of patients to chemotherapy and immunotherapy. METHODS: Bladder cancer information data was obtained from The Cancer Genome Atlas and GSE32894. The CIBERSORT was used to calculate the immune score of each sample. Weighted gene co-expression network analysis was used to find genes that will have the same or similar expression patterns. Subsequently, multivariate cox regression and lasso regression was used to further screen prognosis-related genes. The prrophetic package was used to predict phenotype from gene expression data, drug sensitivity of external cell line and predict clinical data. RESULTS: The stage and risk scores are independent prognostic factors in patients with BUC. Mutations in FGFR3 lead to an increase in Tregs percolation and affect the prognosis of the tumor, and additionally, EMP1, TCHH and CNTNAP3B in the model are mainly positively correlated with the expression of immune checkpoints, while CMTM8, SORT1 and IQSEC1 are negatively correlated with immune checkpoints and the high-risk group had higher sensitivity to chemotherapy drugs. CONCLUSION: Prognosis-related models of bladder tumor patients, based on Treg and NK cell percolation in tumor tissue. In addition to judging the prognosis of patients with bladder cancer, it can also predict the sensitivity of patients to chemotherapy and immunotherapy. At the same time, patients were divided into high and low risk groups based on this model, and differences in genetic mutations were found between the high and low risk groups.

Knockdown of circADAM9 inhibits cell progression and glycolysis by targeting the miR-1236-3p/FGF7 axis in breast cancer.

BACKGROUND: Circular RNAs (circRNAs) are closely associated with the development of breast cancer (BC). In this study, we aimed to clarify how differentially expressed circRNAs affect the development of BC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of circADAM9, miR-1236-3p and fibroblast growth factor 7 (FGF7). Colony formation, 5-ethynyl-2'-deoxyuridine (EdU), wound healing, transwell, and flow cytometry were used to assess cell proliferation, migration, invasion, and apoptosis. Glucose consumption, lactic acid production and ATP levels were assessed using glycolysis metabolism analysis. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to verify the relationship between miR-1236-3p and circADAM9 or FGF7. The roles of cirADAM9 on tumor growth were analyzed using a xenograft tumor model. Ki-67 and FGF7 expression was measured via immunohistochemistry (IHC) assay. Apoptosis-related proteins and exosome markers were detected by western blot. RESULTS: CircADAM9 was highly expressed in BC cells, and circADAM9 silencing inhibited BC cell proliferation, migration, invasion, and glycolysis, and promoted cell apoptosis. Furthermore, miR-1236-3p inhibition could overturn circADAM9 knockdown-mediated BC inhibition. Moreover, the negative influences of miR-1236-3p overexpression on BC progression were restrained via FGF7 overexpression. CircADAM9 silence also inhibited BC tumor growth in vivo. CONCLUSION: CircADAM9 promoted BC development partly by the miR-1236-3p/FGF7 axis, highlighting a potential prognostic biomarker and therapeutic target for BC patients.

Ectopic recurrence craniopharyngioma: series report and literature review.

BACKGROUND: Craniopharyngioma is a common intracranial tumor located in the sellar-suprasellar region. Due to the involvement of adjacent structures, it can lead to increased intracranial pressure, visual impairment, and endocrine deficiencies. Surgical resection is the primary treatment, but it is a tough challenge to achieve total resection, which will led to the frequency of recurrences and progressions. Among them, distant spread is extremely rare, but important complication, identifying and providing proper therapy, is crucial. METHODS: We report two cases of ectopic recurrence craniopharyngioma and make a literature review for the published similar case reports. RESULTS: Our literature review revealed 63 cases (including our patient). The onset age in children group and adult group ranges from 2-14 years old (6.70 ± 3.33) to 17-73 years old (40.63 ± 15.58), while the interval year between tumor initiation and ectopic recurrence ranges from 0.17-20 (7.28 ± 6.76) years to 0.3-34 (6.85 ± 7.29). Achieving gross total resection seems not to prevent the ectopic recurrence. The major pathology of ectopic recurrence craniopharyngioma is adamantinomatous type. The most common site of ectopic recurrence is frontal lobe. According to the pathogenesis, 35 cases were seeding along the surgical approach, and 28 cases were seeding via the CSF pathway. CONCLUSION: Ectopic recurrence craniopharyngioma is rare, but it can lead to serious symptoms. Delicate surgical procedure can help to reduce the risk of ectopic recurrence, and standardized follow-up can provide valuable information for treatment.

Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET.

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors with variable recurrence rate. Currently, the recurrence prediction is unsatisfying and can be improved by understanding the cellular origins and differentiation status. Here, to comprehensively reveal the origin of PitNET, we perform comparative analysis of single-cell RNA sequencing data from 3 anterior pituitary glands and 21 PitNETs. We identify distinct genes representing major subtypes of well and poorly differentiated PitNETs in each lineage. To further verify the predictive value of differentiation biomarkers, we include an independent cohort of 800 patients with an average follow-up of 7.2 years. In both PIT1 and TPIT lineages, poorly differentiated groups show significantly higher recurrence rates while well-differentiated groups show higher recurrence rates in SF1 lineage. Our findings reveal the possible origin and differentiation status of PitNET based on which new differentiation classification is proposed and verified to predict tumor recurrence.

Gut microbiota in brain tumors: An emerging crucial player.

In recent decades, various roles of the gut microbiota in physiological and pathological conditions have been uncovered. Among the many interacting pathways between the host and gut flora, the gut-brain axis has drawn increasing attention and is generally considered a promising way to understand and treat brain tumors, one of the most lethal neoplasms. In this narrative review, we aimed to unveil and dissect the sophisticated mechanisms by which the gut-brain axis exerts its influence on brain tumors. Furthermore, we summarized the latest research regarding the gastrointestinal microbial landscape and the effect of gut-brain axis malfunction on different brain tumors. Finally, we outlined the ongoing developing approaches of microbial manipulation and their corresponding research related to neuro-malignancies. Collectively, we recapitulated the advances in gut microbial alterations along with their potential interactive mechanisms in brain tumors and encouraged increased efforts in this area.

Integrated proteogenomic characterization across major histological types of pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors. Due to its extensive tumor heterogeneity and the lack of high-quality tissues for biomarker discovery, the causative molecular mechanisms are far from being fully defined. Therefore, more studies are needed to improve the current clinicopathological classification system, and advanced treatment strategies such as targeted therapy and immunotherapy are yet to be explored. Here, we performed the largest integrative genomics, transcriptomics, proteomics, and phosphoproteomics analysis reported to date for a cohort of 200 PitNET patients. Genomics data indicate that GNAS copy number gain can serve as a reliable diagnostic marker for hyperproliferation of the PIT1 lineage. Proteomics-based classification of PitNETs identified 7 clusters, among which, tumors overexpressing epithelial-mesenchymal transition (EMT) markers clustered into a more invasive subgroup. Further analysis identified potential therapeutic targets, including CDK6, TWIST1, EGFR, and VEGFR2, for different clusters. Immune subtyping to explore the potential for application of immunotherapy in PitNET identified an association between alterations in the JAK1-STAT1-PDL1 axis and immune exhaustion, and between changes in the JAK3-STAT6-FOS/JUN axis and immune infiltration. These identified molecular markers and alternations in various clusters/subtypes were further confirmed in an independent cohort of 750 PitNET patients. This proteogenomic analysis across traditional histological boundaries improves our current understanding of PitNET pathophysiology and suggests novel therapeutic targets and strategies.

Single-cell transcriptome reveals cellular hierarchies and guides p-EMT-targeted trial in skull base chordoma.

Skull base chordoma (SBC) is a bone cancer with a high recurrence rate, high radioresistance rate, and poorly understood mechanism. Here, we profiled the transcriptomes of 90,691 single cells, revealed the SBC cellular hierarchies, and explored novel treatment targets. We identified a cluster of stem-like SBC cells that tended to be distributed in the inferior part of the tumor. Combining radiated UM-Chor1 RNA-seq data and in vitro validation, we further found that this stem-like cell cluster is marked by cathepsin L (CTSL), a gene involved in the packaging of telomere ends, and may be responsible for radioresistance. Moreover, signatures related to partial epithelial-mesenchymal transition (p-EMT) were found to be significant in malignant cells and were related to the invasion and poor prognosis of SBC. Furthermore, YL-13027, a p-EMT inhibitor that acts through the TGF-ß signaling pathway, demonstrated remarkable potency in inhibiting the invasiveness of SBC in preclinical models and was subsequently applied in a phase I clinical trial that enrolled three SBC patients. Encouragingly, YL-13027 attenuated the growth of SBC and achieved stable disease with no serious adverse events, underscoring the clinical potential for the precision treatment of SBC with this therapy. In summary, we conducted the first single-cell RNA sequencing of SBC and identified several targets that could be translated to the treatment of SBC.

Global changes in chromatin accessibility and transcription in growth hormone-secreting pituitary adenoma.

PURPOSE: Growth hormone-secreting pituitary adenoma (GHPA) is an insidious disease with persistent hypersecretion of growth hormone and insulin-like growth factor 1, causing increased morbidity and mortality. Previous studies have investigated the transcription of GHPA. However, the gene regulatory landscape has not been fully characterized. The objective of our study was to unravel the changes in chromatin accessibility and transcription in GHPA. METHODS: Six patients diagnosed with GHPA in the Department of Neurosurgery at Huashan Hospital were enrolled in our study. Primary pituitary adenoma tissues and adjacent normal pituitary specimens with no morphologic abnormalities from these six patients were obtained at surgery. RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were applied to investigate the underlying relationship between gene expression and chromatin accessibility changes in GHPA. RESULTS: Totally, 1528 differential expression genes (DEGs) were identified by transcriptomics analyses, including 725 up-regulated and 803 down-regulated. Further, we obtained 64 significantly DEGs including 10 DEGs were elevated and 54 DEGs were negligibly expressed in tumors tissues. The up-regulated DEGs were mainly involved in terms related to synapse formation, nervous system development and secretory pathway. In parallel, 3916 increased and 2895 decreased chromatin-accessible regions were mapped by ATAC-seq. Additionally, the chromatin accessible changes were frequently located adjacent to transcription factor CTCF and Rfx2 binding site. CONCLUSIONS: Our results are the first to demonstrate the landscape of chromatin accessibility in GHPA, which may contribute to illustrate the underlying transcriptional regulation mechanism of this disease.

Transcription Factor ASCL1 Acts as a Novel Potential Therapeutic Target for the Treatment of the Cushing's Disease.

BACKGROUND: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway. METHODS: RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation, and apoptosis were studied in vitro. The effectiveness of an ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells on Ascl1 knockdown combined with published chromatin immunoprecipitation sequencing data and dual luciferase assays were used to explore downstream pathways. RESULTS: ASCL1 was exclusively overexpressed in USP8-mutant and wild-type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. An ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. CONCLUSION: Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target the treatment of CD. SUMMARY: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. Moreover, few effective medical therapies are currently available for the treatment of CD. Here, using a multiomics approach, we first report the aberrant overexpression of the transcription factor gene ASCL1 in USP8-mutant and wild-type tumors of CD. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in mouse AtT-20 cells. Notably, an ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. Importantly, ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Thus, our findings improve understanding of CD pathogenesis and suggest that ASCL1 is a potential therapeutic target the treatment of CD.