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IntroductionUrban green space (GS) exposure is recognized as a nature-based strategy for addressing urban challenges. However, the stress relieving effects and mechanisms of GS exposure are yet to be fully explored. The development of machine learning and street view images offers a method for large-scale measurement and precise empirical analysis.MethodsThis study focuses on the central area of Shanghai, examining the complex effects of GS exposure on psychological stress perception. By constructing a multidimensional psychological stress perception scale and integrating machine learning algorithms with extensive street view images data, we successfully developed a framework for measuring urban stress perception. Using the scores from the psychological stress perception scale provided by volunteers as labeled data, we predicted the psychological stress perception in Shanghai's central urban area through the Support Vector Machine (SVM) algorithm. Additionally, this study employed the interpretable machine learning model eXtreme Gradient Boosting (XGBoost) algorithm to reveal the nonlinear relationship between GS exposure and residents' psychological stress.ResultsResults indicate that the GS exposure in central Shanghai is generally low, with significant spatial heterogeneity. GS exposure has a positive impact on reducing residents' psychological stress. However, this effect has a threshold; when GS exposure exceeds 0.35, its impact on stress perception gradually diminishes.DiscussionWe recommend combining the threshold of stress perception with GS exposure to identify urban spaces, thereby guiding precise strategies for enhancing GS. This research not only demonstrates the complex mitigating effect of GS exposure on psychological stress perception but also emphasizes the importance of considering the “dose-effect” of it in urban planning and construction. Based on open-source data, the framework and methods developed in this study have the potential to be applied in different urban environments, thus providing more comprehensive support for future urban planning.

Abstract Objective The study aimed to identify if clinical features and survival outcomes of insular glioma patients are associated with our classification based on the tumor spread. Methods Our study included 283 consecutive patients diagnosed with histological grade 2 and 3 insular gliomas. A new classification was proposed, and tumors restricted to the paralimbic system were defined as type 1. When tumors invaded the limbic system (referred to as the hippocampus and its surrounding structures in this study) simultaneously, they were defined as type 2. Tumors with additional internal capsule involvement were defined as type 3. Results Tumors defined as type 3 had a higher age at diagnosis (p = 0.002) and a higher preoperative volume (p

Improving the resilience of rivers is a crucial method for mitigating urban flooding, restoring the ecological role of rivers, and promoting sustainable ecological development. This study specifically examines the relationship between changes in river morphology and river elasticity space, using the Xinghai Lake wetland as a case study. The MIKE 21 numerical model is employed to simulate and analyze the morphology changes of Xinghai Lake under various conditions during both the low-water and high-water periods. The findings indicated that during the period of abundant water, the inundation area of Xinghai Lake increased by 1.64 times, the average water level rose by 0.96 m, and the average flow speed decreased by approximately 11.8 % compared to the flat water period under the circulating condition within the lake. By utilizing Xinghai Lake as a channel for overflowing Yellow River water, the stability of the lake's body is improved. When Xinghai Lake is utilized as the channel for water from the Yellow River, it contributes to the increased stability of the lake. Based on the morphological characteristics of various river sections, this study identifies the potential areas for scouring, eutrophication, and flooding in the future. It also suggests specific strategic solutions to improve the resilience and ecological robustness of the river. These proposals aim to provide scientific support for enhancing the ecological robustness of urban inland lakes.

Abstract Background The three‐dimensional (3D) genome architecture plays a critical role inregulating gene expression. However, the specific alterations in thisarchitecture within somatotroph tumors and their implications for gene expression remain largely unexplored. Methods We employed Hi‐C and RNA‐seq analyses to compare the 3D genomic structures of somatotroph tumors with normal pituitary tissue. This comprehensive approachenabled the characterization of A/B compartments, topologically associateddomains (TADs), and chromatin loops, integrating these with gene expression patterns. Results We observed a decrease in both the frequency of chromosomal interactions andthe size of TADs in tumor tissue compared to normal tissue. Conversely, the number of TADs and chromatin loops was found to be increased in tumors. Integrated analysis of Hi‐C and RNA‐seq data demonstrated that changes inhigher‐order chromat in structure were associated with alterations in gene expression. Specifically, genes in A compartments showed higher density and increased expression relative to those in B compartments. Moreover, the weakand enhanced insulation boundaries were identified, and the associated genes were enriched in the Wnt/β‐Catenin signaling pathway. We identified the gainedand lost loops in tumor and integrated these differences with transcriptional changes to examine the functional relevance of the identified loops. Notably, we observed an enhanced insulation boundary and a greater number of loops in the TCF7L2 gene region within tumors, which was accompanied by an upregulation of TCF7L2 expression. Subsequently, TCF7L2 expression was confirmed through qRT‐PCR, and upregulated TCF7L2 prompted cell proliferation and growth hormone (GH) secretion in vitro. Conclusion Our results provide comprehensive 3D chromatin architecture maps of somatotroph tumors and offer a valuable resource for furthering the understanding of the underlying biology and mechanisms of gene expression regulation.

Abstract Background Pituitary neuroendocrine tumors (PitNETs) are one of the most common types of intracranial tumors. Currently, the cellular characteristics of normal pituitary and various other types of PitNETs are still not completely understood. Methods We performed single-cell RNA sequencing (scRNA-seq) on 4 normal samples and 24 PitNET samples for comprehensive bioinformatics analysis. Findings regarding the function of PBK in the aggressive tumor cells were validated by siRNA knockdown, overexpression, and transwell experiments. Results We first constructed a reference cell atlas of the human pituitary. Subsequent scRNA-seq analysis of PitNET samples, representing major tumor subtypes, shed light on the intrinsic cellular heterogeneities of the tumor cells and tumor microenvironment (TME). We found that the expression of hormone-encoding genes defined the major variations of the PIT1-lineage tumor cell transcriptomic heterogeneities. A sub-population of TPIT-lineage tumor cells highly expressing GZMK suggested a novel subtype of corticotroph tumors. In immune cells, we found two clusters of tumor-associated macrophages, which were both highly enriched in PitNETs but with distinct functional characteristics. In PitNETs, the stress response pathway was significantly activated in T cells. While a majority of these tumors are benign, our study unveils a common existence of aggressive tumor cells in the studied samples, which highly express a set of malignant signature genes. The following functional experiments confirmed the oncogenic role of selected up-regulated genes. The over-expression of PBK could promote both tumor cell proliferation and migration, and it was also significantly associated with poor prognosis in PitNET patients. Conclusions Our data and analysis manifested the basic cell types in the normal pituitary and inherent heterogeneity of PitNETs, identified several features of the tumor immune microenvironments, and found a novel epithelial cell sub-population with aggressive signatures across all the studied cases.

The role of the gut microbiome has been widely discussed in numerous works of literature. The biggest concern is the association of the gut microbiome with the central nervous system through the microbiome-brain-gut axis in the past ten years. As more and more research has been done on the relationship between the disease of the central nervous system and gut microbes. This fact is being revealed that gut microbes seem to play an important role from the onset and progression of the disease to clinical symptoms, and new treatments. As a special tumor of the central nervous system, pituitary neuroendocrine tumors (PitNETs)are closely related to metabolism, endocrinology, and immunity. These factors are the vectors through which intestinal microbes interact with the central nervous system. However, little is known about the effects of gut microbes on the PitNET. In this review, the relationship of gut microbiota in PitNETs is introduced, the potential effects of the gut-brain axis in this relationship are analyzed, and future research directions are presented.

Abstract Purpose Currently, endoscopic transsphenoidal surgery is the main treatment for pituitary neuroendocrine tumors (PitNETs). Excision of the tumor may have positive or negative effects on pituitary endocrine function, and the pituitary function of somatotroph tumors is a point of particular concern after the operation. This study aimed to conduct a meta-analysis on the effect of endoscopic transsphenoidal somatotroph tumor resection on pituitary function. Methods A systematic literature search was conducted for articles that included the evaluation of pituitary target gland before and after endoscopic transsphenoidal pituitary tumor resection and were published between 1992 and 2022 in PubMed, Cochrane, and Ovid MEDLINE. Results Sixty-eight studies that included biochemical remission rates in 4524 somatotroph tumors were concluded. According to the 2000 consensus, the biochemical remission rate after transsphenoidal endoscopic surgery was 66.4% (95% CI, 0.622–0.703; P = 0.000), the biochemical remission rate was 56.2% according to the 2010 consensus (95% CI, 0.503–0.620; P = 0.041), and with the rate of biochemical remission ranging from 30.0 to 91.7% with investigator’s definition. After endoscopic resection, adrenal axis dysfunction was slightly higher than that before surgery, but the difference was not statistically significant. Hypothyroidism was 0.712 times higher risk than that before surgery (OR = 0.712; 95% CI, 0.527–0.961; P = 0.027). Hypogonadism was 0.541 times higher risk than that before surgery (OR = 0.541; 95% CI, 0.393–0.746; P = 0.000). Hyperprolactinemia was 0.131 times higher risk than that before surgery (OR = 0.131; 95% CI, 0.022–0.783; P = 0.026). The incidence of pituitary insufficiency was 1.344 times the risk before surgery after endoscopic resection of somatotroph tumors, but the difference was not statistically significant. Conclusions In patients with somatotroph tumors after undergoing endoscopic surgery, the risk of dysfunction and pituitary insufficiency tend to increase, while preoperative thyroid insufficiency, gonadal insufficiency, and hyperprolactinemia will be partially relieved.

Global climate change has exacerbated alterations in urban thermal environments, significantly impacting the daily lives and health of city residents. Measuring and understanding urban land surface temperatures (LST) and their influencing factors is important in addressing global climate change and enhancing the well-being of residents. However, due to limitations in data precision and analytical methods, existing studies often overlook the microscale examination closely related to residents’ daily lives, and lack a deep exploration of the spatial heterogeneity of the influencing factors. This leads to these results being ineffective in guiding the planning and construction of cities. Taking Shenzhen as a case study, our study investigates the effects of various microscale build environment characteristics of LST using street view images and machine learning. A convolutional neural network model adopting the SegNet architecture is used to perform semantic segmentation on street view images, extracting features of the microscale urban-built environment. The LST is inverted through the Google Earth Engine (GEE) platform. By using Multiscale Geographically Weighted Regression (MGWR) models, our study reveals the comprehensive impact of the urban-built environment on LST and its significant spatial heterogeneity. The findings indicate that the proportions of sky, roads, and buildings are positively correlated with LST, while trees have a significant cooling effect. Although earth and water can reduce LST, their overall contribution is minimal due to limitations in their area and distribution patterns. This study not only reveals the key factors affecting urban LST at the microscale but also emphasizes the necessity of considering the spatial heterogeneity of these factors’ impacts. This suggests the need for targeted strategies for different areas to effectively improve the urban thermal environment and achieve sustainable urban development.

Territorial spatial planning requires thoughtful consideration of the scientific layout and synergistic control of production, living, and ecological spaces (PLESs). However, research in this field often neglects the human perspective and fails to account for people’s demands and behavioral characteristics. This study evaluates the level and spatial characteristics of residents’ production, living, and ecological behavioral (PLEB) flow, as well as the spatial pattern of the PLES functions, within the framework of the human–land coupling system. Therefore, to analyze the behavior–space coupling coordination relationship, the coupling coordination model is applied. The results indicate that the overall level of residents’ PLEB flow in rural–urban fringe areas is at a lower middle level and the functionality of the PLES is at a medium level, with a spatial distribution pattern of high in the northern and low in the southern areas. Most of the behavior–space matching types are in a state of mismatch between supply and demand. Meanwhile, the PLEB–PLES coupling coordination relationship is generally unbalanced, which is particularly noticeable in the production space. Regardless of whether the behavior–space matching type is a supply deficit or a supply surplus, the mismatch between supply and demand leads to uncoordinated and unreasonable spatial utilization. Overall, the findings of the study provide guidance for future research endeavors about PLESs and suggest embracing a human-centered scientific paradigm. Such a paradigm can promote high-quality, sustainable development of territorial spatial planning while strengthening the capacity and effectiveness of spatial governance and control.

ObjectiveTo investigate the clinical and pathological factors associated with preoperative hypothalamus invasion and postoperative outcomes of adamantinomatous craniopharyngiomas (ACPs) after the expanded endonasal approach (EEA) resection.MethodsNinety-three specimens of ACPs, consisting of 71 primary and 22 recurrent tumors, were investigated for the expression of TGF-β1, SMAD2, SMAD3, and β-catenin by immunohistochemistry staining. The clinical information of relevant patients, including the extent of resection, hypothalamus invasion, endocrinopathy, complications, and prognosis, was reviewed. The relationships between the expression of these immunopathological markers and clinical factors were analyzed.ResultsEndocrinological dysfunctions were more common in recurrent patients and primary patients with hypothalamus invasion in the comparisons. For recurrent patients, the rate of gross total resection (GTR) was significantly lower than for primary patients (63.6% vs. 90.1%, P = 0.007). According to radiological and intraoperative findings, invasive ACPs (IACPs) included 48 (67.6%) cases in primary tumors. The expression of TGF-β1 and β-catenin was significantly higher in recurrent tumors (P = 0.021 and P = 0.018, respectively) and IACPs (P = 0.008 and P = 0.004, respectively). The expression level of TGF-β1 was associated with hypothalamus involvement (Puget grade, P = 0.05; Vile grade, P = 0.002), postoperative endocrinopathy (P = 0.01), and pituitary stalk preservation (P = 0.008) in primary patients. In addition, the extent of resection, treatment history, hypothalamic invasion, and level of TGF-β1 expression had significant influences on tumor recurrence/progression after surgery separately.ConclusionOur study demonstrated the potential role of TGF-β1 in the regulation of hypothalamus invasion in ACPs and the prediction of prognosis after EEA surgery. The TGF-β signaling pathway may represent a crucial mechanism in the aggressive behavior and progression of ACPs.

IntroductionThe invasive behavior of nonfunctioning pituitary neuroendocrine tumors (NF-PitNEts) affects complete resection and indicates a poor prognosis. Cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The current study aimed to screen the key immune-related genes in NF-PitNEts with invasion.MethodsWe used two cohorts to explore novel biomarkers in NF-PitNEts. The immune infiltration-associated differentially expressed genes (DEGs) were obtained based on high/low immune scores, which were calculated through the ESTIMATE algorithm. The abundance of immune cells was predicted using the ImmuCellAI database. WGCNA was used to construct a coexpression network of immune cell-related genes. Random forest analysis was used to select the candidate genes associated with invasion. The expression of key genes was verified in external validation set using quantitative real-time polymerase chain reaction (qRT‒PCR).ResultsThe immune and invasion related DEGs was obtained based on the first dataset of NF-PitNEts (n=112). The immune cell-associated modules in NF-PitNEts were calculate by WGCNA. Random forest analysis was performed on 81 common genes intersected by immune-related genes, invasion-related genes, and module genes. Then, 20 of these genes with the highest RF score were selected to construct the invasion and immune-associated classification model. We found that this model had high prediction accuracy for tumor invasion, which had the largest area under the receiver operating characteristic curve (AUC) value in the training dataset from the first dataset (n=78), the self-test dataset from the first dataset (n=34), and the independent test dataset (n=73) (AUC=0.732/0.653/0.619). Functional enrichment analysis revealed that 8 out of the 20 genes were enriched in multiple signaling pathways. Subsequently, the 8-gene (BMP6, CIB2, FABP5, HOMER2, MAML3, NIN, PRKG2 and SIDT2) classification model was constructed and showed good efficiency in the first dataset (AUC=0.671). In addition, the expression levels of these 8 genes were verified by qRT‒PCR.ConclusionWe identified eight key genes associated with invasion and immunity in NF-PitNEts that may play a fundamental role in invasive progression and may provide novel potential immunotherapy targets for NF-PitNEts.

BackgroundCraniopharyngioma is a benign tumor originating from the sellar region. Damages in this area caused by the tumor itself, surgery, or radiotherapy may result in severe hypothalamic-pituitary dysfunction (HPD) and eventually lead to a significant impairment in the long-term quality of life of patients. This study aimed to investigate the characteristics of HPD in patients with adamantinomatous craniopharyngioma (ACP) or papillary craniopharyngioma (PCP) and to identify the factors affecting HPD after surgery.MethodsIn this single-center retrospective study, a total of 742 patients with craniopharyngioma were included. The neuroendocrine function of these patients before and after surgery was investigated. The differences in hypothalamic-pituitary function between the ACP and PCP groups were compared. The factors influencing the aggravation of HPD after surgery were identified.ResultsThe median follow-up after surgery was 15 months. Before surgery, the proportion of patients with diabetes insipidus (DI) and hyperprolactinemia in the PCP group was significantly higher than that in the ACP group (P

Abstract Background Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1 R625H ), but its functional effects and underlying molecular mechanisms remain largely unexplored. Methods Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1 R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1 R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA. Results Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1 R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway. Conclusions Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1 R625H mutation.

ObjectivesThe aim of this study was to establish and validate a MRI-based radiomics nomogram to predict progression-free survival (PFS) of clival chordoma.MethodsA total of 174 patients were enrolled in the study (train cohort: 121 cases, test cohort: 53 cases). Radiomic features were extracted from multiparametric MRIs. Intraclass correlation coefficient analysis and a Lasso and Elastic-Net regularized generalized linear model were used for feature selection. Then, a nomogram was established via univariate and multivariate Cox regression analysis in the train cohort. The performance of this nomogram was assessed by area under curve (AUC) and calibration curve.ResultsA total of 3318 radiomic features were extracted from each patient, of which 2563 radiomic features were stable features. After feature selection, seven radiomic features were selected. Cox regression analysis revealed that 2 clinical factors (degree of resection, and presence or absence of primary chordoma) and 4 radiomic features were independent prognostic factors. The AUC of the established nomogram was 0.747, 0.807, and 0.904 for PFS prediction at 1, 3, and 5 years in the train cohort, respectively, compared with 0.582, 0.852, and 0.914 in the test cohort. Calibration and risk score stratified survival curves were satisfactory in the train and test cohort.ConclusionsThe presented nomogram demonstrated a favorable predictive accuracy of PFS, which provided a novel tool to predict prognosis and risk stratification. Our results suggest that radiomic analysis can effectively help neurosurgeons perform individualized evaluations of patients with clival chordomas.

IntroductionInsular gliomas have complex anatomy and microvascular supply that make resection difficult. Furthermore, resection of insular glioma is associated with a significant risk of postoperative ischemic complications. Thus, this study aimed to assess the incidence of ischemic complications related to insular glioma resection, determine its risk factors, and describe a single surgeon’s experience of artery-preserving tumor resection.MethodsWe enrolled 75 consecutive patients with insular gliomas who underwent transcortical tumor resection. Preoperative and postoperative demographic, clinical, radiological [including diffusion-weighted imaging (DWI)], intraoperative neurophysiological data, and functional outcomes were analyzed. Motor evoked potentials (MEPs) and radiological characteristics like the relationship between the proximal segment of the lateral lenticulostriate arteries (LLSAs) and the tumor, the flat inner edge sign (the inner edge of the insular glioma is well-defined) or obscure inner edge sign, the distance between the lesion and posterior limb of the internal capsule and the invasion of the superior limiting sulcus by the tumor were analyzed. Strategies such as “residual triangle,” “basal ganglia outline reappearance,” and “sculpting” technique were used to preserve the LLSAs and the main branches of M2 for maximal tumor resection according to the Berger–Sinai classification.ResultsPostoperative DWI showed acute ischemia in 44 patients (58.7%). Moreover, nine patients (12%) had developed new motor deficits, as determined by the treating neurosurgeons. The flat inner edge sign [odds ratio (OR), 0.144; 95% confidence interval (CI), 0.024–0.876) and MEPs (>50%) (OR, 18.182; 95% CI, 3.311–100.00) were significantly associated with postoperative core ischemia, which affected the posterior limb of the internal capsule or corona radiata.ConclusionsInsular glioma resection was associated with a high incidence of ischemia, as detected by DWI, as well as new motor deficits that were determined by the treating neurosurgeons. Insular glioma patients with obscure inner edge signs and intraoperative MEPs decline >50% had a higher risk of developing core ischemia. With our strategies, maximal safe resection of insular gliomas may be achieved.

BackgroundThe systemic inflammation score (SIS), based on preoperative lymphocyte to monocyte ratio (LMR) and albumin (ALB), was recently developed and is demonstrated to be a novel prognostic indicator in several cancers. However, data discussing the utility of SIS in chordoma are lacking. We aimed to investigate the distribution and the prognostic role of SIS in primary skull base chordoma patients undergoing surgery.Material and methodsPreoperative SIS was retrospectively collected from 183 skull base chordoma patients between 2008 and 2014 in a single center. Its associations with clinical features and overall survival (OS) were further analyzed. The SIS-based nomogram was developed and evaluated by the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA).ResultsThe numbers of patients in the SIS 2, 1, and 0 group were 29 (15.8%), 60 (32.8%), 94 (51.4%), respectively. High SIS was associated with older age (p = 0.008), brainstem involvement of tumors (p = 0.039), and adverse OS (p < 0.001). Importantly, multivariate Cox analysis showed that high SIS independently predicts adverse OS. Furthermore, the nomogram based on SIS and clinical variables showed eligible performance for OS prediction in both training and validation cohorts.ConclusionsThe SIS is a promising, simple prognostic biomarker, and the SIS-based nomogram serves as a potential risk stratification tool for outcome in skull base chordoma patients.

ObjectiveTo determine risk factors and management for the development of a postoperative cerebrospinal fluid (CSF) leak after an endoscopic endonasal surgery (EES) for pituitary adenomas.MethodsThe clinical data of 400 patients who underwent EES for resection of pituitary adenomas from December 2018 to November 2019 in the Department of Neurosurgery of Beijing Tiantan Hospital were retrospectively reviewed. Age, gender, body mass index (BMI), tumor size, Knosp grade, suprasellar extension grade, sellar floor erosion grade, repeated transsphenoidal surgery, intraoperative CSF leak, use of pedicled nasoseptal flap and lumbar drain were collected and analyzed.ResultsPostoperative CSF leak occurred in 14 of 400 patients (3.5%). Age, gender, BMI, tumor size, Knosp grade and repeated transsphenoidal surgery were not risk factors for CSF leak. Suprasellar extension grade (≥B 6.0% vs.

ObjectiveThis study aimed to study the role of PALB2 on the prognosis of skull base chordoma patients and the proliferation, migration, and invasion of chordoma cells. Methods187 patients with primary skull base chordoma were involved in the study. Immunohistochemical analysis was used to measure the PALB2 protein expression. Kaplan-Meier analysis, univariate and multivariate Cox analysis were used to evaluate the impact of PALB2 on patient prognosis. A nomogram was established for predicting the progression free survival of chordoma patients. Cell counting kit-8, colony formation, transwell migration, and invasion assays were used to assess the proliferation, migration, and invasion of chordoma cells with PALB2 knockdown. TIMER 2.0 was used to explore the expression and prognostic role of PALB2 in cancers.ResultsHigh PALB2 expression indicated an adverse prognosis in chordoma. A nomogram involved PALB2, degree of resection, pathology, and Al-mefty classification could accurately predict the progression free survival of chordoma patients. The proliferation, migration, and invasion of chordoma cells significantly decreased after PALB2 knockdown. Additionally, PALB2 showed high expression in various cancers and was associated with a poor prognosis.ConclusionIn summary, our results reveal that high PALB2 expression indicates a poor prognosis of chordoma patients and promotes the malignant phenotypes of chordoma cells in vitro.

Background and Objectives: The diagnosis and treatment of pituitary adenomas with cavernous sinus invasion pose significant challenges for clinicians. The objective of this study is to investigate the expression profile and prognostic value of HSPB1 (heat shock protein beta-1) in pituitary adenomas with invasive and non-invasive features. Additionally, we aim to explore the potential relationship between HSPB1 expression and immunological functions in pituitary adenoma. Materials and Methods: A total of 159 pituitary adenoma specimens (73 invasive tumours and 86 non-invasive tumours) underwent whole-transcriptome sequencing. Differentially expressed genes and pathways in invasive and non-invasive tumours were analysed. HSPB1 was subjected to adequate bioinformatics analysis using various databases such as TIMER, Xiantao and TISIDB. We investigated the correlation between HSPB1 expression and immune infiltration in cancers and predicted the target drug of HSPB1 using the TISIDB database. Results: HSPB1 expression was upregulated in invasive pituitary adenomas and affected immune cell infiltration. HSPB1 was significantly highly expressed in most tumours compared to normal tissues. High expression of HSPB1 was significantly associated with poorer overall survival. HSPB1 was involved in the regulation of the immune system in most cancers. The drugs DB11638, DB06094 and DB12695 could act as inhibitors of HSPB1. Conclusions: HSPB1 may serve as an important marker for invasive pituitary adenomas and promote tumour progression by modulating the immune system. Inhibitors of HSPB1 expression are currently available, making it a potential target for therapy in invasive pituitary adenoma.

Abstract Background Pituitary adenomas are one type of intracranial tumor, which can be divided into microadenoma (≤ 1 cm), macroadenoma (> 1 cm), and giant adenoma (≥ 4 cm) according to their diametral sizes. They are benign, typically slow-progressing, whereas the biological behavior of some of them is invasive, which presents a major clinical challenge. Treatment of some pituitary adenomas is still difficult due to drug resistance or multiple relapses, usually after surgery, medication, and radiation. At present, no clear prediction and treatment biomarkers have been found in pituitary adenomas and some of them do not cause clinical symptoms, so patients are often found to be ill through physical examination, and some are even found through autopsy. With the development of research on pituitary adenomas, the immune response has become a hot spot and may serve as a novel disease marker and therapeutic target. The distribution and function of immune cells and their secreted molecules in pituitary adenomas are extremely complex. Researchers found that infiltration of immune cells may have a positive effect on the treatment and prognosis of pituitary adenomas. In this review, we summarized the advance of tumor immunity in pituitary adenomas, revealing the immunity molecules as potential biomarkers as well as therapeutic agents for pituitary adenomas. Conclusion The immune studies related to pituitary adenomas may help us find relevant immune markers. At the same time, the exploration of immunotherapy also provides new options for the treatment of pituitary adenomas.

The nature of the culture dish surface and the technique used to detach adherent cells could very likely influence the cell viability and cell membrane protein integrity of harvested macrophages. Several previous studies assessed the detachment efficacies of enzymatic and non-enzymatic methods for harvesting the single cell suspensions of macrophages, but a comprehensive study assessing different dissociation methods and culture conditions for detaching functionally different macrophage populations has not yet been reported. In this study, via the well-established GM-CSF and M-CSF differentiated bone marrow derived macrophage models (GM-BMDMs and M-BMDMs), we compared four commonly used enzymatic (trypsin and accutase) and non-enzymatic (PBS and EDTA) dissociation methods along with necessary mechanical detaching steps (scraping and pipetting) to evaluate the viable cell recovery and cell surface marker integrality of GM-BMDMs and M-BMDMs cultured on standard cell culture dish (TC dish), or on culture dish (noTC dish) that was not conditioned to enhance adherence. The data showed that accutase yielded a better recovery of viable cells comparing with PBS and EDTA, especially for tightly adherent GM-BMDMs on TC dishes, with a relatively higher level of detected cell membrane marker F4/80 than trypsin. An additional gradient centrifugation-based dead cell removal approach could increase the proportion of viable cells for TC cultured GM-BMDMs after accutase dissociation. Furthermore, transcriptome analysis was performed to evaluate the putative influence of culture dishes. At steady state, BMDMs cultured on noTC dishes exhibited more proinflammatory gene expression signatures (e.g. IL6, CXCL2 and ILlβ) and functions (e.g. TNF and IL17 signaling pathways). Similar inflammatory responses were observed upon LPS challenge regardless of culture conditions and differentiation factors. However, in LPS treated samples, the difference of gene expression patterns, signaling pathways and molecular functions between TC and noTC cultured BMDMs were largely dependent on the types of growth factors (M-CSF and GM-CSF). This observation might provide valuable information for in vitro macrophage studies.

PurposeTumor consistency is important for pituitary neuroendocrine tumors (PitNETs) resection to improve surgical outcomes. In this study, we evaluated the T2-WI of PitNETs and defined a specific T2-WI signaling manifestation, the “Mosaic sign,” to predict tumor consistency and resection of PitNETs.DesignA retrospective review of MRI and tumor histology of 137 consecutive patients who underwent endoscopic endonasal resection for PitNETs was performed.MethodsThe “Mosaic sign” was defined by the ratio of the tumor itself T2-WI signals, and characterized by multiple intratumor hyperintense dots. The degree of tumor resection was an assessment by postoperative MRI examination. The presence of the “Mosaic sign” was compared with patients' basic information, tumor consistency, tumor pathological staining, and surgical result. To determine whether the presence or absence of “Mosaic sign” could predict tumor consistency and guide surgical resection of tumors.ResultsStatistical analysis showed that the consistency of the tumor and the degree of resection were correlated with the “Mosaic sign”. In the 137 cases of T2-WI, 43 had “Mosaic sign”, 39 cases had soft tumor consistency, and 4 were classified as fibrous, of which 42 were completely resected and 1 was subtotal resected. Of the 94 patients without “Mosaic sign”, the consistency of tumor of 54 cases were classified as soft, the remaining 40 cases were fibrous, 80 cases were completely resected, and 14 cases were subtotal resected. Postoperative cerebrospinal fluid leakage occurred in 1 patient. The number of corticotroph adenomas in the group of “Mosaic sign” was higher, with the statistical difference between the two groups (P = 0.0343).ConclusionsThe presence of the “Mosaic sign” in T2-WI may provide preoperative information for pituitary adenomas consistency and effectively guide surgical approaches.

Ubiquitination is reported to be a critical biological event on ACTH secretion in corticotroph adenomas. However, the effect of ubiquitylation on ACTH secretion in silent corticotroph adenomas (SCAs) remains unclear. The aim of our study was to explore the mechanism of decreased secretion of ACTH in SCAs with ubiquitinomics. The differently expressed ubiquitinated proteins between SCAs and functioning corticotroph adenomas (FCAs) were identified by 4D label-free mass spectrometer, followed by bioinformatics analysis. The function of the candidate ubiquitinated protein ATP7A (K333) was validated in AtT20 cells. A total of 111 ubiquitinated sites corresponding to 94 ubiquitinated proteins were typically different between SCAs and FCAs. Among all the ubiquitinated sites, 102 showed decreased ubiquitination in SCAs, which mapped to 85 ubiquitinated proteins. Pathway enrichment analysis revealed that ubiquitinated proteins were mainly enriched in vesicle pathway and protein secretion pathway. ATP7A (K333) was one of the proteins enriched in vesicle pathway and protein secretion pathway with decreased ubiquitination level in SCAs. In vitro assay indicated that both ATP7A siRNA and omeprazole (ATP7A protein inhibitor) increased the secretion of ACTH in AtT20 cell supernatant compared to control groups (p

Skull base chordomas are treated with surgery and chemotherapy but often recur due to incomplete resection, understanding the molecular underpinnings of the tumours may provide additional therapeutic strategies. Here, the authors carry out whole genome sequencing of 80 skull base chordoma tumours and identify the SWI/SNF component—PBRM1—as a frequently mutated gene.

Chordomas are very rare malignant bone tumors. Following surgery, their effects on neurological, physical, psychological, social, and emotional functioning are substantial and can have a major impact on a patients’ quality of life (QOL). In this survey, we aimed to characterize the postoperation health-related QOL and emotional problem in patients with chordoma using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and Hamilton Depression Rating Scale (HAMD). The cohort included 100 patients who underwent resection surgery between 2014 and 2020. Being single or divorced, living in a rural area, receiving a diagnosis of sacrococcygeal chordoma, Karnofsky performance status (KPS) ≤ 70, and weight loss were associated with increased likelihood of depression (p < 0.05). Patients who were single or divorced, with KPS ≤ 70, and experiencing weight loss had a higher likelihood of a worse QOL (p < 0.05). The uni- and multivariate logistic regression analyses indicated that the KPS level (p = 0.000) and postoperative radiation therapy (p = 0.009) were related to depression; marital status (p = 0.029), KPS level (p = 0.006), and tumor location (p = 0.033) were related to worse QOL. Certain characteristics placed patients with chordoma at increased risk of emotional problems, which are associated with a lowered QOL and a higher symptom burden. Further knowledge regarding emotional problems is key to improving the QOL for patients with chordoma.

Abstract Background Dysregulated lncRNA PCAT6 was discovered in many cancers excluding pituitary adenomas (PA). Therefore, we explored the role of PCAT6 in PA in this research. Methods Abnormally expressed miRNAs were analyzed by bioinformatics and RT-qPCR. The target and regulator of miR-139-3p were determined by bioinformatics, dual-luciferase reporter assay, or RIP. The correlation among PCAT6, miR-139-3p, and BRD4 was further analyzed. The viability, apoptosis, cell cycle distribution of PA cells, as well as their ability to invade, migrate, and proliferate, were tested after transfection through CCK-8, flow cytometry, transwell, wound healing, and colony formation assays. After construction of transplanted-tumor model in nude mice, cell apoptosis in the tumor was detected by TUNEL. The expressions of PCAT6, BRD4, miR-139-3p, and apoptosis-related factors in PA tissues, cells, or tumor tissues were detected by RT-qPCR, Western blot, or IHC. Results PCAT6 and BRD4 were high-expressed but miR-139-3p was low-expressed in PA. Both the 3′-untranslated regions of PCAT6 and BRD4 mRNAs were demonstrated to contain a potential binding site for miR-139-3p. PCAT6 was positively correlated to BRD4, and miR-139-3p was negatively correlated to PCAT6 and BRD4. MiR-139-3p mimic, shPCAT6 and siBRD4 inhibited the viability, migration, invasion, and proliferation of PA cells while inducing apoptosis. MiR-139-3p mimic and shPCAT6 inhibited the cell cycle progression of PA cells, decreased the weight and volume of the xenotransplanted tumor, and reduced the levels of Bcl-2 and BRD4 while enhancing the levels of Bax, miR-139-3p, and Cleaved caspase-3. MiR-139-3p inhibitor caused the opposite effect of miR-139-3p mimic and further reversed the effect of shPCAT6 on on PA cells. Conclusion PCAT6 regulated the progression of PA via modulating the miR-139-3p/BRD4 axis, which might provide a novel biomarker for the prevention, diagnosis, and treatment of PA.

Rheumatoid arthritis (RA) occurs in about 5 per 1,000 people and can lead to severe joint damage and disability. However, the knowledge of pathogenesis and treatment for RA remains limited. Here, we found that histone demethylase inhibitor GSK-J4 relieved collagen induced arthritis (CIA) symptom in experimental mice model, and the underlying mechanism is related to epigenetic transcriptional regulation in macrophages. The role of epigenetic regulation has been introduced in the process of macrophage polarization and the pathogenesis of inflammatory diseases. As a repressive epigenetic marker, tri-methylation of lysine 27 on histone H3 (H3K27me3) was shown to be important for transcriptional gene expression regulation. Here, we comprehensively analyzed H3K27me3 binding promoter and corresponding genes function by RNA sequencing in two differentially polarized macrophage populations. The results revealed that H3K27me3 binds on the promoter regions of multiple critical cytokine genes and suppressed their transcription, such as IL6, specifically in M-CSF derived macrophages but not GM-CSF derived counterparts. Our results may provide a new approach for the treatment of inflammatory and autoimmune disorders.

Abstract Background Increasing studies have demonstrated that activated platelets play an essential role in tumour progression. However, the level and prognostic role of platelet indices in chordoma patients remain unclear. The aim of the current study was to characterize the prognostic performance of platelet count (PLT), mean platelet volume (MPV) and platelet distribution width (PDW) in skull base chordoma patients. Methods 187 primary skull base chordoma patients between January 2008 and September 2014 were enrolled in this retrospective study. The optimal cut-off values were determined by X-tile software, and the correlations between PLT, MPV, PDW and clinicopathological features were further analysed. Kaplan-Meier curve and Cox regression analysis were used for survival analysis. Results The values of preoperative PTL, MPV and PDW ranged from 104 to 501 × 109/L, 6.7 to 14.2 fl, and 7.8 to 26.2%, respectively. Elevated PLT was associated with larger tumour volume (p = 0.002). Kaplan-Meier survival analysis revealed that increased MPV and PDW were associated with shorter overall survival (p = 0.022 and 0.008, respectively). Importantly, multivariate Cox analysis demonstrated that elevated PDW was an independent unfavourable predictive factor for overall survival (hazard ratio (HR), 2.154, 95% confidence interval (CI), 1.258–3.688, p = 0.005). Conclusions Our data show that elevated MPV and PDW are associated with poor outcomes in skull base chordoma and that PDW may be helpful to identify patients with high risk.

Abstract Background Endonasal endoscopic skull base surgery has undergone rapid technological developments and is now widely performed, but its strengths and weaknesses deserve further investigation and deliberation. This study was performed to investigate the surgical indications, complications, and technical advantages and disadvantages of endonasal endoscopic skull base surgery. Methods The clinical data of 1886 endoscopic endonasal skull base surgeries performed in our ward at Beijing Tiantan Hospital from June 2006 to June 2016 were retrospectively analyzed. Results One thousand ninety-three (73.4%, 1490) pituitary adenomas, 54 (24.9%, 217) chordomas, 28 (80.0%, 35) craniopharyngiomas, and 15 (83.3%, 18) meningiomas underwent total resection. Two patients died postoperatively, both having pituitary adenomas. Other postoperative complications included olfactory disorders (n = 226, 11.9%), postoperative cerebrospinal fluid leakage (n = 78, 4.1%), hypopituitarism (n = 74, 3.9%), diabetes insipidus (n = 64, 3.4%), intracranial infection (n = 36, 1.9%), epistaxis (n = 24, 1.3%), vascular injury (n = 8, 0.4%), optic nerve injury (n = 8, 0.4%), and oculomotor movement impairment (n = 4, 0.2%). In total, 1517 (80.4%) patients were followed up for 6 to 126 months (average, 42.5 months) postoperatively. A total of 196 (13.2%) pituitary adenomas and 13 (37.1%) craniopharyngiomas recurred but no meningiomas recurred. Chordomas recurred in 97 (44.7%) patients, in whom 5-year survival rate was 65%. Conclusion Endoscopic surgery is an innovative surgical technique and the first choice for most midline extradural lesions such as chordomas, and an excellent choice for pituitary adenomas. It probably will be a good technique for many kinds of craniopharyngiomas and a common technique for most of skull base meningiomas, so the surgical indications of these cases should be chosen carefully to make good use of its respective advantages.

The genetic basis of prolactinomas remains poorly understood. Here, the authors find a recurrent hotspot somatic mutation in the splicing factor 3 subunit B1 (SF3B1 R625H ) in prolactinomas, and show that this mutation causes aberrant splicing of ESRRG mRNA leading to up-regulation of prolactin.

IntroductionOwing to the close vicinity of the optic chiasma, visual dysfunction is known as one of the most common surgical indications and postoperative complications in adult patients with craniopharyngiomas, probably leading to poor quality of life. Historically, very few consistent predictive factors associated with the visual outcome are identified, which may not be helpful for patient counseling and preoperative decision making. Recently, optical coherence tomography (OCT) serving as a novel high-resolution imaging technique can assess the retinal morphology by measuring the circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell complex thickness. However, few studies have examined the prognostic utility of OCT parameters for visual outcome after surgery for craniopharyngiomas. This study aims to use the largest series to evaluate the association between OCT parameters and visual outcome after extended endoscopic endonasal surgery (EEES) for primary craniopharyngiomas in adults.Material and MethodsFrom October 2018 to October 2020, one hundred and seventy eyes in 88 adult patients with newly confirmed craniopharyngiomas were retrospectively reviewed and pertinent prognostic factors were analyzed.ResultsGross total resection was performed in 82 (93.2%) patients. The median postoperative follow-up time was 10.9 months. Multiple logistic regression analysis showed that increased temporal cpRNFL thickness was associated with higher odds of visual acuity (VA) improvement and maintenance (OR = 1.070; 95% CI, 1.005–1.140; p = 0.035), and greater inferior cpRNFL thickness was significantly associated with visual field (VF) improvement and maintenance (OR = 1.034; 95% CI, 1.001–1.068; p = 0.046). Furthermore, tight adhesion between optic nerves and craniopharyngiomas was demonstrated as an independent adverse factor for either postoperative VA or VF (p = 0.048, p = 0.030, respectively). The ROC results further verified the robustness of the prediction model either in VA (AUC = 0.843; 95% CI, 0.734–0.952; p < 0.001) or VF (AUC = 0.849; 95% CI, 0.741–0.958; p < 0.001).ConclusionPreoperative OCT can effectively predict visual outcome after EEES for adult craniopharyngiomas. It can also serve as a reliable alternative to evaluate preoperative visual field defects, especially for patients with lower compliance. Tight adhesion was confirmed as an independent risk factor for postoperative visual outcome. The OCT-based multivariable prediction models developed in the present study may contribute to patient counseling on visual prognosis.

Previous studies have shown that the insula is closely related to addiction, and the structure’s role in delay discounting can be measured by a specific task, but the specific role of the insula has been less studied. In this study, we first conducted a lesion study in which we recruited healthy controls (n = 30) and patients with unilateral insula injury (n = 16) to complete a behavioral delay discounting task. Then we conducted a functional magnetic resonance imaging (fMRI) study, and a separate group healthy volunteers (n = 51) completed a delay discounting task during the fMRI scan. The lesion study showed a significant difference between the two groups in the delay discounting task, which revealed that insula injury was associated with impaired decision making. The fMRI study revealed choice-sensitive insula activation that was modulated by delayed time and delayed reward, indicating an important role of the insula in delay discounting. Overall, our results provide evidence for a role of the insular lobe in delay discounting and suggests that this structure may be considered an important factor in the future treatment and diagnosis of addiction disorders.

Adamantinomatous craniopharyngioma (ACPs) are rare embryonic tumors and often involve the hypothalamus. The underlying neural substrate of the hypothalamic involvement (HI)-related cognitive decline in patients with ACP is still unclear. We aimed to combine the multi-modal neuroimaging and histological characteristics of the ACP to explore the potential neural substrate of the HI-related cognitive decline. 45 patients with primary ACPs (invasive, 23; noninvasive, 22) and 52 healthy control subjects (HCs) were admitted to the cross-sectional study. No significant difference in cognitive domains was observed between HCs and patients with noninvasive ACPs (NACP). Patients with invasive ACPs (IACP) showed significantly lower working memory performance (WM, p = 0.002) than patients with NACP. The WM decline was correlated with the disruption of the medial temporal lobe (MTL) subsystem in the default mode network (DMN) (r = 0.45, p = 0.004). The increased radial diffusivity of the fornix, indicating demyelinating process, was correlated with the disruption of the MTL subsystem (r = -0.48, p = 0.002). Our study demonstrated that the fornix alterations link DMN disruption to HI-related cognitive decline in patients with ACPs. ACPs that invade the hypothalamus can provide a natural disease model to investigate the potential neural substrate of HI-related cognitive decline.

Abstract Background Tumor surrounding the internal carotid artery or invading to the cavernous sinus is an important characteristic of invasive pituitary adenoma, and a pivotal factor of tumor residue and regrowth. Without specific changes in serum hormone related to the adenohypophyseal cell of origin, clinically non-functioning pituitary adenoma is more likely to be diagnosed at invasive stages compared with functioning pituitary adenoma. The underlying mechanism of tumor invasion remains unknown. In this study, we aimed to identify key genes in tumor invasion by integrating analyses of DNA methylation and gene expression profiles. Method Genome-wide DNA methylation and mRNA microarray analysis were performed for tumor samples from 68 patients at the Beijing Tiantan Hospital. Differentially expressed genes and methylated probes were identified based on an invasive vs non-invasive grouping. Differentially methylated probes in the promoter region of targeted genes were assessed. Pearson correlation analysis was used to identify genes with a strong association between DNA methylation status and expression levels. Pyrosequencing and RT-PCR were used to validate the methylation status and expression levels of candidate genes, respectively. Results A total of 8842 differentially methylated probes, located on 4582 genes, and 661 differentially expressed genes were identified. Both promoter methylation and expression alterations were observed for 115 genes with 58 genes showing a negative correlation between DNA methylation status and expression level. Nineteen genes that exhibited notably negative correlations between DNA methylation and gene expression levels, are involved in various gene ontologies and pathways, or played an important role in different diseases, were regarded as candidate genes. We found an increased methylation with a decreased expression of PHYHD1, LTBR, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6, and a decreased methylation with an increased expression of MYBPHL. The methylation status and expression levels of these genes were validated by pyrosequencing and RT-PCR. Conclusions The DNA methylation and expression levels of PHYHD1, LTBR, MYBPHL, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6 are associated with tumor invasion, and these genes may become the potential genes for targeted therapy.

ObjectThe trans lamina terminalis approach (TLTA) has been described as a way to remove third ventricular tumors. The aim of this paper was to analyze the feasible outcomes of TLTA applied to tumors extending into the third ventricle in our institute.MethodsSuprasellar tumors (n = 149) were treated by the extended endonasal approach from September 2019 to December 2020 in Beijing Tiantan Hospital. Eleven of the tumors were treated by TLTA or TLTA via the trans-chiasm-pituitary corridor (TCPC). The surgical technique notes of TLTA were described and indications and outcomes of the approach were analyzed.ResultsThere were 11 patients enrolled in the study, six with papillary craniopharyngiomas, two with adamantinomatous craniopharyngiomas, one with a germinal cell tumor (GCT), one with cavernous malformation and one with chordoid glioma. Four of the patients received a radical resection by TLTA alone, while seven of them received TLTA via the TCPC. Gross total resection was achieved in eight patients (72.7%), and partial resection in three patients (27.3%). Visual function was improved in four of the 11 patients (36.4%), was unchanged in five patients (45.5%), and deteriorated in two patients (18.2%). New-onset hypopituitarism occurred in seven patients (63.3%) and new-onset diabetes insipidus occurred in two patients (18.2%). Electrocyte imbalance were observed in six patients (54.5%) at post-operative week 2. There were no surgery-related deaths or cerebrospinal fluid leaks. Postoperative intracranial infection was observed in one patient (9.1%), and during the follow-up period, tumor recurrence occurred in one patient (9.1%).ConclusionThe expanded TLTA provides a feasible suprachiasm corridor to remove tumors extending into the third ventricle, especially for craniopharyngiomas. Sound understanding of the major strengths and limitations of this approach, as well as strategies for complication avoidance, is necessary for its safe and effective application.

The nonfunctioning pituitary adenoma (NFPA) recurrence rate is relatively high after surgical resection. Here, we constructed effective long noncoding RNA (lncRNA) signatures to predict NFPA prognosis. LncRNAs expression microarray sequencing profiles were obtained from 66 NFPAs. Sixty-six patients were randomly separated into a training (n = 33) and test group (n = 33). Univariable Cox regression and a machine learning algorithm was used to filter lncRNAs. Time-dependent receiver operating characteristic (ROC) analysis was performed to improve the prediction signature. Three lncRNAs (LOC101927765, RP11-23N2.4 and RP4-533D7.4) were included in a prognostic signature with high prediction accuracy for tumor recurrence, which had the largest area under ROC curve (AUC) value in the training/test group (AUC = 0.87/0.73). The predictive ability of the signature was validated by Kaplan-Meier survival analysis. A signature-based risk score model divied patients into two risk group, and the recurrence-free survival rates of the groups were significantly different (log-rank p < 0.001). In addition, the ROC analysis showed that the lncRNA signature predictive ability was significantly better than that of age in the training/testing/entire group (AUC = 0.87/0.726/0.798 vs. AUC = 0.683/0.676/0.679). We constructed and verified a three-lncRNA signature predictive of recurrence, suggesting potential therapeutic targets for NFPA.

BackgroundThe prognostic factors of skull base chordoma associated with outcomes of patients after surgery remain inadequately identified. This study was designed to identify a novel prognostic factor for patients with skull base chordoma.MethodUsing a proteomic technique, the tumor biomarkers that were upregulated in the rapid-recurrence group of chordoma were screened and then narrowed down by bioinformatic analysis. Finally one potential biomarker was chosen for validation by immunohistochemistry using tissue microarray (TMA). A total of 187 patients included in TMA were randomly divided into two cohorts, the training cohort included 93 patients and the validation cohort included 94 patients. Kaplan-Meier survival analysis was used to assess the patients’ survival. Univariable and multivariable Cox regression analysis were used to identify prognostic factors predicting recurrence-free survival (RFS). CCK-8 assay, clonal formation assay and transwell assay were used to test the effect of asparagine synthetase (ASNS) on the proliferation, migration and invasion in chordoma cell lines.ResultsAmong 146 upregulated proteins, ASNS was chosen as a potential prognostic biomarker after bioinformatics analysis. The H-scores of ASNS ranged from 106.27 to 239.58 in TMA. High expression of ASNS was correlated with shorter RFS in both the training cohort (p = 0.0093) and validation cohort (p < 0.001). Knockdown of ASNS by small interfering RNA (siRNA) inhibited the growth, colony formation, migration and invasion of chordoma cells in vitro.ConclusionThis study indicates that high expression of ASNS is correlated with poor prognosis of patients with skull base chordoma. ASNS may be a useful prognostic factor for patients with skull base chordoma.

BackgroundSkull base chordomas (SBCs) are rare malignant bone tumors with dismal long-term local control. Endoscopic endonasal surgeries (EESs) are increasingly adopted to resect SBCs recently. Gross total resection (GTR) favors good outcomes. However, the SBCs often invade the skull base extensively and hide behind vital neurovascular structures; the tumors were challenging to remove entirely. To improve the GTR, we established a surgical strategy for EES according to the tumor growth directions.MethodsA total of 112 patients with SBCs from 2018 to 2019 were classified into the derivation group. We retrospectively analyzed their radiologic images and operation videos to find the accurate tumor locations. By doing so, we confirmed the tumor growth directions and established a surgical strategy. Fifty-five patients who were operated on in 2020 were regarded as the validation group, and we performed their operations following the surgical strategy to verify its value.ResultsIn the derivation group, 78.6% of SBCs invade the dorsum sellae and posterior clinoid process region. 62.5% and 69.6% of tumors extend to the left and right posterior spaces of cavernous ICA, respectively. 59.8% and 61.6% of tumors extend to the left and right posterior spaces of paraclival and lacerum ICA (pc-la ICA), respectively. 30.4% and 28.6% of tumors extended along the left and right petroclival fissures that extend toward the jugular foramen, respectively. 30.4% of tumors involved the foramen magnum and craniocervical junction region. The GTR was achieved in 60.8% of patients with primary SBCs in the derivation group. Based on the tumors’ growth pattern, pituitary transposition and posterior clinoidectomy techniques were adopted to resect tumors that hid behind cavernous ICA. Paraclival ICA transposition was used when the tumor invaded the posterior spaces of pc-la ICA. Lacerum fibrocartilage resection and eustachian tube transposition may be warranted to resect the tumors that extended to the jugular foramen. GTR was achieved in 75.0% of patients with primary SBCs in the validation group.ConclusionBesides the midline clival region, the SBCs frequently grow into the eight spaces mentioned above. The surgical strategy based on the growth pattern contributes to increasing the GTR rate.

Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2β (EIF2β) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2β in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2β was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p < 0.001) for EIF2β and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p < 0.001) for GCN2, and r = 0.732 (p < 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2β was greater than that in patients with a low EIF2β (7/10 vs. 4/18, p = 0.038), with a lower immune-cell infiltration probability (p < 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p < 0.001). In in vitro experiments, the knockdown of EIF2β changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies.

Abstract Background Pituitary adenoma and meningioma are the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease and the clinical features and mechanisms of PAM are unclear. Methods We summarized the clinical data of 57 PAM patients and compared with sporadic pituitary adenoma (SPA) and sporadic meningioma (SM). 5 pituitary adenomas of PAM and 5 SPAs were performed ceRNA microarray. qRT-PCR, Western Blot, siMEN1 and rapamycin inhibition experiment were validated for ceRNA microarray. Results Clinical variable analyses revealed that significant correlations between PAM and female sex as well as older age when compared with SPA and significant correlations between PAM and transitional meningioma as well as older age when compared with SM. Additionally, the characteristics of PAM were significantly different for MEN1 patients. Functional experiments showed lower expression of MEN1 can upregulate mTOR signaling, in accordance with the result of ceRNA microarray. Rapamycin treatment promotes apoptosis in primary pituitary adenoma and meningioma cells of PAM. Conclusions MEN1 plays an important role in PAM by upregulating mTOR signaling pathway. Rapamycin represents a potential therapeutic strategy for PAM in the future.

Abstract Background To investigate the relationship between cyclin B1 (CCNB1) gene expression and cavernous sinus invasion in pituitary adenomas. Methods Twenty-four pituitary adenoma tissue samples were examined by RT-qPCR and Western blot to assess the mRNA expression levels and protein levels of CCNB1, E-cadherin and N-cadherin. Correlation analyses between the expression levels of E-cadherin, N-cadherin and CCNB1 were performed. After lentivirus-mediated knockdown of CCNB1 in rat pituitary adenoma cell lines (GH3 and GT1-1), cell function changes were studied. The relationship between CCNB1 and epithelial-mesenchymal transition (EMT) was further verified by animal experiments. Results CCNB1 and N-cadherin gene expression were significantly higher in the invasive pituitary adenomas than in the non-invasive pituitary adenomas. Conversely, E-cadherin expression in the invasive pituitary adenomas was significantly lower. CCNB1 gene expression was downregulated in the GH3 and GT1-1 pituitary adenoma cell lines; N-cadherin expression was also decreased, but E-cadherin expression was increased. These results were confirmed in vivo. After downregulation of CCNB1, cell invasion and migration was significantly reduced in Transwell experiments. Conclusion High CCNB1 expression in pituitary adenoma affects cavernous sinus invasion through EMT.

Abstract Background Pituitary adenomas are common brain tumors. Although transsphenoidal surgery are able to achieve extensive tumor removal, the rate of recurrence ranges from 5 to 20% depending on the different subtype. Further understanding of these tumors is needed to develop novel strategies to improve the prognosis of patients. But their metabolic characteristics are largely unknown. Methods We used metabolomic, transcriptomic, and proteomic approaches to systematically investigate eight subtypes of pituitary adenomas and normal pituitary glands. By blocking IDH2, we investigate IDH2 play an inhibitory role in GH tumor cell growth and tumor secretion. Results We found that all of the pituitary adenomas displayed downregulated glucose metabolism and glycolysis compared to normal tissues. Together with the differences in amino acids and fatty acids, we categorized these tumors into three clusters. We then re-established the reprogrammed metabolic flux in pituitary adenomas based on multiomic analyses. Take growth hormone-secreting pituitary adenomas as an example, we revealed that IDH2 is a key player in the reprogrammed metabolism of such tumors. By blocking IDH2, we confirmed that IDH2 is a potential target for the inhibition of tumor cell growth and tumor secretion. Conclusions Our study first uncovered the metabolic landscape of pituitary adenomas and demonstrated a possible way to inhibit tumor growth by regulating aberrant metabolism.

Prolactinomas are the most frequently observed pituitary adenomas (PAs), and 5%–18% tumors were resistant to the dopamine agonists (DAs). MicroRNAs (miRNAs) dysfunction play a key role in tumorigenesis. Agilent miRNA and an expression chip were used for six prolactinomas and three normal pituitary specimens. Differentially expressed genes were confirmed by RT-qPCR. The level of DDR1 and SAT1 was determined with tissue micro-array (TMA) and western blot. A MMQ cell line was used for functional experiments. We have identified 5-miRNA and 12 target gene signatures of prolactinomas through gene ontology analysis. miRNA-199a-5p was selected for experiments that integrated the results from prolactinomas specimens and a rat prolactinoma model induced by 17-b-estradiol. Tumors with low miRNA-199a-5p had a significantly invasive behavior and a higher tumor volume (p

Abstract Background Compared with clinically functioning pituitary adenoma (FPA), clinically non-functioning pituitary adenoma (NFPA) lacks of detectable hypersecreting serum hormones and related symptoms which make it difficult to predict the prognosis and monitoring for postoperative tumour regrowth. We aim to investigate whether the expression of selected tumour-related proteins and clinical features could be used as tumour markers to effectively predict the regrowth of NFPA. Method Tumour samples were collected from 295 patients with NFPA from Beijing Tiantan Hospital. The expression levels of 41 tumour-associated proteins were assessed using tissue microarray analyses. Clinical characteristics were analysed via univariate and multivariate logistic regression analyses. Logistic regression algorithm was applied to build a prediction model based on the expression levels of selected proteins and clinical signatures, which was then assessed in the testing set. Results Three proteins and two clinical signatures were confirmed to be significantly related to the regrowth of NFPA, including cyclin-dependent kinase inhibitor 2A (CDKN2A/p16), WNT inhibitory factor 1 (WIF1), tumour growth factor beta (TGF-β), age and tumour volume. A prediction model was generated on the training set, which achieved a fivefold predictive accuracy of 81.2%. The prediction ability was validated on the testing set with an accuracy of 83.9%. The area under the receiver operating characteristic curves (AUC) for the signatures were 0.895 and 0.881 in the training and testing sets, respectively. Conclusion The prediction model could effectively predict the regrowth of NFPA, which may facilitate the prognostic evaluation and guide early interventions.

Abstract Mitochondria are energy factories of cells and are important pivots for intracellular interactions with other organelles. They interact with the endoplasmic reticulum, peroxisomes, and nucleus through signal transduction, vesicle transport, and membrane contact sites to regulate energy metabolism, biosynthesis, immune response, and cell turnover. However, when the communication between organelles fails and the mitochondria are dysfunctional, it may induce tumorigenesis. In this review, we elaborate on how mitochondria interact with the endoplasmic reticulum, peroxisomes, and cell nuclei, as well as the relation between organelle communication and tumor development .

BackgroundThe growth hormone (GH) and insulin-like-growth factor 1 (IGF-1) axis has long been recognized for its critical role in brain growth, development. This study was designed to investigate microstructural pathology in the cortex and white matter in growth hormone-secreting pituitary adenoma, which characterized by excessive secretion of GH and IGF-1.Methods29 patients with growth hormone-secreting pituitary adenoma (acromegaly) and 31 patients with non-functional pituitary adenoma as controls were recruited and assessed using neuropsychological test, surface-based morphometry, T1/T2-weighted myelin-sensitive magnetic resonance imaging, neurite orientation dispersion and density imaging, and diffusion tensor imaging.ResultsCompared to controls, we found 1) acromegaly had significantly increased cortical thickness throughout the bilateral cortex (pFDR < 0.05). 2) T1/T2-weighted ratio in the cortex were decreased in the bilateral occipital cortex and pre/postcentral central gyri but increased in the bilateral fusiform, insular, and superior temporal gyri in acromegaly (pFDR < 0.05). 3) T1/T2-weighted ratio were decreased in most bundles, and only a few areas showed increases in acromegaly (pFDR < 0.05). 4) Neurite density index (NDI) was significantly lower throughout the cortex and bundles in acromegaly (pTFCE < 0.05). 5) lower fractional anisotropy (FA) and higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in extensive bundles in acromegaly (pTFCE < 0.05). 6) microstructural pathology in the cortex and white matter were associated with neuropsychological dysfunction in acromegaly.ConclusionsOur findings suggested that long-term persistent and excess serum GH/IGF-1 levels alter the microstructure in the cortex and white matter in acromegaly, which may be responsible for neuropsychological dysfunction.

Neuroplasticity may preserve neurologic function in insular glioma, thereby improving prognosis following resection. However, the anatomic and molecular bases of this phenomenon are not known. To address this gap in knowledge, the present study investigated contralesional compensation in different molecular pathologic subtypes of insular glioma by high-resolution three-dimensional T1-weighted structural magnetic resonance imaging. A total of 52 patients with insular glioma were examined. We compared the gray matter volume (GMV) of the contralesional insula according to histological grade [low-grade glioma (LGG) and high-grade glioma (HGG)] and molecular pathology status [isocitrate dehydrogenase (IDH) mutation, telomerase reverse-transcriptase (TERT) promoter mutation, and 1p19q codeletion] by voxel-based morphometry (VBM). A cluster of 320 voxels in contralesional insula with higher GMV was observed in glioma with IDH mutation as compared to IDH wild-type tumors by region of interest-based VBM analysis (family-wise error-corrected at p < 0.05). The GMV of the entire contralesional insula was also larger in insular glioma patients with IDH mutation than in patients with wild-type IDH. However, there was no association between histological grade, TERT promoter mutation, or 1p19q codeletion and GMV in the contralesional insula. Thus, IDH mutation is associated with greater structural compensation in insular glioma. These findings may be useful for predicting neurocognitive and functional outcomes in patients undergoing resection surgery.

PurposeNon-functioning pituitary adenoma (NFPA) is a very common type of intracranial tumor, which can be locally invasive and can have a high recurrence rate. The tumor microenvironment (TME) shows a high correlation with tumor pathogenesis and prognosis. The current study aimed to identify microenvironment-related genes in NFPAs and assess their prognostic value.Methods73 NFPA tumor samples were collected from Beijing Tiantan Hospital and transcriptional expression profiles were obtained through microarray analysis. The immune and stromal scores of each sample were calculated through the ESTIMATE algorithm, and the patients were divided into high and low immune/stromal score groups. Intersection differentially expressed genes (DEGs) were then obtained to construct a protein–protein interaction (PPI) network. Potential functions and pathways of intersection DEGs were then analyzed through Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The prognostic value of these genes was evaluated. The quantitative real-time polymerase chain reaction in another set of NFPA samples was used to confirm the credibility of the bioinformatics analysis.ResultsThe immune/stromal scores were significantly correlated with cavernous sinus (CS) invasion. The Kaplan–Meier curve indicated that the high immune score group was significantly related to poor recurrence-free survival. We identified 497 intersection DEGs based on the high vs. low immune/stromal score groups. Function enrichment analyses of 497 DEGs and hub genes from the PPI network showed that these genes are mainly involved in the immune/inflammatory response, T cell activation, and the phosphatidylinositol 3 kinase-protein kinase B signaling pathway. Among the intersection DEGs, 88 genes were further verified as significantly expressed between the CS invasive group and the non-invasive group, and five genes were highly associated with NFPA prognosis.ConclusionWe screened out a series of critical genes associated with the TME in NFPAs. These genes may play a fundamental role in the development and prognosis of NFPA and may yield new therapeutic targets.