The hippocampal salt-inducible kinase 2-CREB-regulated transcription co-activator 1 system mediates the antidepressant actions of paroxetine in mice.

The hippocampal salt-inducible kinase 2 (SIK2)-CREB-regulated transcription co-activator 1 (CRTC1) system has been demonstrated to participate in not only the pathogenesis of depression but also the antidepressant mechanisms of several antidepressant medications including fluoxetine, paroxetine, and mirtazapine. Like fluoxetine, paroxetine is also a widely used selective serotonin (5-HT) reuptake inhibitor (SSRI). Recent studies have indicated that paroxetine also modulates several pharmacological targets other than the 5-HT system. Here, we speculate that paroxetine regulates the hippocampal SIK2-CRTC1 system. Chronic stress models of depression, various behavioral tests, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription PCR, and genetic knockdown were used together in the present study. Our results show that the antidepressant actions of paroxetine in mice models of depression were accompanied by its preventing effects against chronic stress on hippocampal SIK2, CRTC1, and CRTC1-CREB binding. In contrast, genetic knockdown of hippocampal CRTC1 notably abrogated the antidepressant effects of paroxetine in mice. In summary, regulating hippocampal SIK2 and CRTC1 participates in the antidepressant mechanism of paroxetine, extending the knowledge of its pharmacological targets.

Comparison of the Endoscopic Endonasal Approach with the Endoscopic Supraorbital Keyhole Approach to the Tuberculum Sellae Region: A Quantitatively Cadaveric Study.

BACKGROUND: The endoscopic endonasal approach (EEA) and the endoscopic supraorbital keyhole approach (eSKA) provide minimally invasive access to tuberculum sellae (TS) tumors. Evaluation of the operating maneuverability is helpful for approach selection. Herein, we compared the two approaches and aimed to provide quantitative anatomic data for surgical decision-making in the management of TS lesions. METHODS: Fifteen dissections were performed on five silicone-injected cadaveric heads. The EEA and eSKA (both right and left) were performed on each head. Surgical freedom and working angles in the axial and sagittal planes were calculated using the stereotactic navigation system in the selected six targets: the midpoint of the leading edge of the sphenoid sinus (leSS), the midpoint of the edge of the dorsum sellae (eDS), the ipsilateral medial opticocarotid recess (imOCR), the contralateral medial opticocarotid recess (cmOCR), the ipsilateral lateral opticocarotid recess (ilOCR), and the contralateral lateral opticocarotid recess (clOCR). RESULTS: The surgical freedom at the ilOCR and the axial working angles at the leSS, ilOCR, and imOCR (imOCR with excessive manipulation of the optic apparatus) were greater in the eSKA. The EEA provided greater surgical freedom and/or working angles at most targets than eSKA (the surgical freedom at the imOCR, cmOCR, clOCR, and eDS; the axial working angles at the cmOCR and clOCR; and the sagittal working angles at the leSS, imOCR, cmOCR, clOCR, and eDS). CONCLUSION: The EEA provides greater surgical freedom and working angles for paramedian lesions, whereas the eSKA provides better surgical maneuverability for lesions with lateral extension.

Safety Assessment and Hepatic-Renal Protection of Cajanus cajan (L.) Millsp. Root and Its Soy Isoflavone Contents.

Cajanus cajan (L.) Millsp., also known as pigeon pea, has roots that have exhibited much pharmacological potential. The present study was conducted to assess the safe dose of the ethanolic extract of C. cajan roots (EECR95) and to analyze the main soy isoflavones contents. In vitro, we investigated the mutagenicity and cytotoxic effect of EECR95 on Salmonella typhimurium-TA98 and TA100 (by Ames tests) and RAW 264.7, L-929, and HGF-1 cell lines (by MTT tests) for 24 h of incubation. We found no mutagenic or cytotoxic effects of EECR95. After administration of 0.2 or 1.0 g/kg bw of EECR95 to both male and female Wistar rats for 90 days, there were no significant adverse effects on the behaviors (body weight, water intake, and food intake), organ/tissue weights, or immunohistochemical staining, and the urine and hematological examinations of the rats were within normal ranges. EECR95 potentially decreases renal function markers in serum (serum uric acid, BUN, CRE, and GLU) or liver function markers (cholesterol, triglyceride, and glutamic-pyruvate-transaminase (GPT)). We also found that EECR95 contained five soy isoflavones (genistein, biochanin A, daidzein, genistin, and cajanol), which may be related to its hepatorenal protection. Based on the high dose (1.0 g/kg bw) of EECR95, a safe daily intake of EECR95 for human adults is estimated to be 972 mg/60 kg person/day.

A Preoperative Nomogram for Prediction of Postoperative Hypocortisolism in Patients with Pituitary Adenomas: A Single-Center Retrospective Cohort Study.

BACKGROUND: Patients with pituitary adenomas (PAs) are at an increased risk preoperatively and postoperatively for hypopituitarism. Postoperative hypocortisolism is associated with increased mortality and morbidity as well as poor quality of life. However, research about the risk factors for postoperative hypocortisolism is limited, and a predictive nomogram for postoperative hypocortisolism has not yet been developed. We aimed to investigate the predictive factors for postoperative hypocortisolism and construct a dynamic online nomogram. METHODS: Our database included 438 consecutive PA patients who were hospitalized and treated with transsphenoidal surgery by experienced neurosurgeons from the different medical teams in the Neurosurgery Department, Jinling Hospital, between January 2018 and October 2020. The final study group included 238 eligible patients. Data on possible predictors, including age, sex, treatment history of PAs, preoperative signs and symptoms, primary recurrence subtype, and clinical subtypes, were collected. Univariable and multivariable logistic regression analyses were applied to identify independent predictors, which were included in constructing the nomogram model. The calibration curve and receiver operating characteristic curve were computed to evaluate the predictive performance of the nomogram model. RESULTS: The incidence of postoperative hypocortisolism was 12.08%. Three preoperative predictors were identified to construct the nomogram: surgical type (microscopic or endoscopic, with endoscopic surgery proven to be the protective factor) (odds ratio, 0.24; 95% confidence interval [CI], 0.093-0.610; P = 0.003), prothrombin time (odds ratio, 2.40; 95% CI, 1.332-4.326; P = 0.004), and basophil cell count (odds ratio, 5.25; 95% CI, 1.270-21.816; P = 0.022,). The area under the curve of receiver operating characteristic curve for the constructed nomogram was 0.749 (95% CI, 0.640-0.763); a well-fixed calibration curve was generated for the nomogram model. An interactive web-based dynamic nomogram application was also constructed. CONCLUSIONS: In this study, surgical type, prothrombin time, and basophil cell count were the most relevant predictive factors for postoperative hypocortisolism. A predictive nomogram that can preoperatively assess the risk of hypocortisolism after surgical treatment of PAs was developed. This nomogram could be helpful in identifying high-risk patients who require close monitoring of serum cortisol levels and initiating clinical procedures for patients requiring cortisol administration therapy as a lifesaving strategy.

Comprehensive analysis of m6A subtype classification for immune microenvironment of pituitary adenomas.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation and tumor immune microenvironment (IME) have an essential role in tumor development. However, their relationships in pituitary adenomas (PAs) remains unclear. METHODS: PA datasets from the Gene Expression Omnibus (GEO) and European Bioinformatics Institute (EMBL-EBI) were used. We utilized hierarchical clustering algorithms based on the m6A regulator gene set to identify m6A subtypes. ESTIMATE and CIBERSORT algorithms were applied to explore the compositions of stromal and immune cells. A nomogram model was constructed for the prediction of m6A subtypes in PAs. Immunohistochemistry and multiplex immunofluorescence staining were used to analyze the expression level of m6A regulator YTHDF2 in relation to M2 macrophages and immune checkpoints in PAs. RESULTS: We concluded the IME landscape of m6A subtype classification and characterized two emerging m6A subtypes. Different IME between these two m6A subtypes were identified. Simultaneously, a polygenic nomogram model was constructed for predicting m6A subtype classification, with excellent predictive performance (training set, AUC = 0.984; validation set, AUC = 0.986). YTHDF2 was highly expressed in PAs and accompanied by upregulated M2 macrophages and expression of PD-L1. CONCLUSIONS: We proposed two novel m6A subtypes in PAs for the first time and constructed a reliable and clinically accessible nomogram model for them. Meanwhile, YTHDF2 was first identified as a promising biomarker for immunotherapy and potential molecular target in PAs.

Predictors and dynamic online nomogram for postoperative delayed hyponatremia after endoscopic transsphenoidal surgery for pituitary adenomas: a single-center, retrospective, observational cohort study with external validation.

BACKGROUND: Postoperative delayed hyponatremia (PDH) is a major cause of readmission after endoscopic transsphenoidal surgery (eTSS) for pituitary adenomas (PAs). However, the risk factors associated with PDH have not been well established, and the development of a dynamic online nomogram for predicting PDH is yet to be realized. We aimed to investigate the predictive factors for PDH and construct a dynamic online nomogram to aid in its prediction. METHODS: We analyzed the data of 226 consecutive patients who underwent eTSS for PAs at the Department of Neurosurgery in Jinling Hospital between January 2018 and October 2020. An additional 97 external patients were included for external validation. PDH was defined as a serum sodium level below 137 mmol/L, occurring on the third postoperative day (POD) or later. RESULTS: Hyponatremia on POD 1-2 (OR = 2.64, P = 0.033), prothrombin time (PT) (OR = 1.78, P = 0.008), and percentage of monocytes (OR = 1.22, P = 0.047) were identified as predictive factors for PDH via multivariable logistic regression analysis. Based on these predictors, a nomogram was constructed with great discrimination in internal validation (adjusted AUC: 0.613-0.688) and external validation (AUC: 0.594-0.617). Furthermore, the nomogram demonstrated good performance in calibration plot, Brier Score, and decision curve analysis. Subgroup analysis revealed robust predictive performance in patients with various clinical subtypes and mild to moderate PDH. CONCLUSIONS: Preoperative PT and the percentage of monocytes were, for the first time, identified as predictive factors for PDH. The dynamic nomogram proved to be a valuable tool for predicting PDH after eTSS for PAs and demonstrated good generalizability. Patients could benefit from early identification of PDH and optimized treatment decisions.

Advances in Optogenetics Applications for Central Nervous System Injuries.

Injuries to the central nervous system (CNS) often lead to severe neurological dysfunction and even death. However, there are still no effective measures to improve functional recovery following CNS injuries. Optogenetics, an ideal method to modulate neural activity, has shown various advantages in controlling neural circuits, promoting neural remapping, and improving cell survival. In particular, the emerging technique of optogenetics has exhibited promising therapeutic methods for CNS injuries. In this review, we introduce the light-sensitive proteins and light stimulation system that are important components of optogenetic technology in detail and summarize the development trends. In addition, we construct a comprehensive picture of the current application of optogenetics in CNS injuries and highlight recent advances for the treatment and functional recovery of neurological deficits. Finally, we discuss the therapeutic challenges and prospective uses of optogenetics therapy by photostimulation/photoinhibition modalities that would be suitable for clinical applications.

One-and-a-half nostril versus binostril endoscopic transsphenoidal approach to the pituitary adenomas: A prospective randomized controlled trial.

Background: Binostril endoscopic transsphenoidal approach (BETA) is the most used approach for sellar lesions nowadays, while its damage to the nasal structures may cause nasal discomfort and affect nasal functions including respiration and olfaction. With the purpose to improve the post-operative sinonasal quality of life (QoL), we introduced the one-and-a-half nostril endoscopic transsphenoidal approach (OETA) in 2016 which preserved more natural structures and registered a prospective randomized controlled trial (ChiCTR-IOR-16008222) to compare the two approaches regarding the surgical outcomes and complications. Methods: Sixty patients with pituitary adenomas were recruited and randomly assigned to the OETA group and the BETA group between April 2016 and May 2017 in Jinling Hospital. The tumor resection rate, endocrinal and visual outcomes, and surgical complications between the OETA and BETA groups were analyzed. Besides, the questionnaire Anterior Skull Base Nasal Inventory-12 (ASK Nasal-12) was used to evaluate patients' sinonasal QoL at seven time points (pre-operative; 2-weeks, 1-month, 3-months, 6-months, 12-months, and long-term post-operatively). The Sniffin' Sticks were used to assess patients' olfactory function objectively in a long term. Each patient was followed for at least 12 months post-operatively. Results: There was no significant difference in tumor resection rate, hormonal and visual outcomes, and surgical complications between the two groups. Regarding the ASK Nasal-12, patients in the OETA group complained less about dried nasal material at 2 weeks after surgery (P = 0.017). One month after surgery, the OETA group had better olfaction function (P = 0.019) compared with the BETA group. However, there was no significant difference in early and long-term postoperative sinonasal QoL between the two approaches according to the entire ASK Nasal-12 metric. The results of the Sniffin' Sticks showed that the two groups had a similar olfactory performance at long-time follow-up. Conclusion: In this single tertiary center trial, the results showed that the OETA achieved the same surgical outcomes and post-operative sinonasal QoL as the BETA. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=13852, identifier: ChiCTR-IOR-16008222.

N6-methyladenosine-related microRNAs risk model trumps the isocitrate dehydrogenase mutation status as a predictive biomarker for the prognosis and immunotherapy in lower grade gliomas.

Aim: Lower grade gliomas [LGGs; World Health Organization (WHO) grades 2 and 3], owing to the heterogeneity of their clinical behavior, present a therapeutic challenge to neurosurgeons. The aim of this study was to explore the N6-methyladenosine (m6A) modification landscape in the LGGs and to develop an m6A-related microRNA (miRNA) risk model to provide new perspectives for the treatment and prognostic assessment of LGGs. Methods: Messenger RNA (mRNA) and miRNA expression data of LGGs were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. An m6A-related miRNA risk model was constructed via least absolute shrinkage and selection operator (LASSO), univariate, and multivariate Cox regression analysis. Next, Kaplan-Meier analysis, principal-component analysis (PCA), functional enrichment analysis, immune infiltrate analysis, dynamic nomogram, and drug sensitivity prediction were used to evaluate this risk model. Results: Firstly, six m6A-related miRNAs with independent prognostic value were selected based on clinical information and used to construct a risk model. Subsequently, compared with low-risk group, LGGs in the high-risk group had a higher m6A writer and reader scores, but a lower eraser score. Moreover, LGGs in the high-risk group had a significantly worse clinical prognosis than those in the low-risk group. Simultaneously, this risk model outperformed other clinicopathological variables in the prognosis prediction of LGGs. Immune infiltrate analysis revealed that the proportion of M2 macrophages, regulatory T (Treg) cells, and the expression levels of exhausted immune response markers were significantly higher in the high-risk group than in the low-risk group. Finally, this study constructed an easy-to-use and free dynamic nomogram to help clinicians use this risk model to aid in diagnosis and prognosis assessment. Conclusions: This study developed a m6A-related risk model and uncovered two different m6A modification landscapes in LGGs. Moreover, this risk model may provide guidance and help in clinical prognosis assessment and immunotherapy response prediction for LGGs.

BTB domain and CNC homolog 1 promotes glioma invasion mainly through regulating extracellular matrix and increases ferroptosis sensitivity.

BTB Domain and CNC Homolog 1 (Bach1) has been implicated in cancer progression, particularly in invasion, but little is unknown about its effect on glioma. Here, we confirmed that highly expressed Bach1 prominently promoted glioma invasion. Similar to the reported mechanisms in other tumors, Bach1 upregulation was also correlated with epithelial mesenchymal transition (EMT) in glioma cells. More importantly, proteomic analysis indicated that the main mechanism of Bach1 promoting invasion in glioma involved extracellular matrix (ECM). We further found thatBach1 upregulation was associated with the multiple mechanisms of ECM remodeling in glioma, including increasing the expression and deposition of ECM components, activating TGFBR2-smad2/3 signaling, promoting invadopodia formation and inducing the expression and secretion of MMP2. Meanwhile, Bach1 overexpression increased ferroptosis sensitivity in glioma cells. The ferroptosis inducer (sulfasalazine) obviously suppressed the gliomas with Bach1 upregulation in vitro and in vivo. Overall, Bach1 has a two-faced role in glioma. Highly expressed Bach1 promotes glioma invasion. Conversely, Bach1 upregulation is also a potential indicator of the sensitivity of ferroptosis inducers.

Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses.

Purpose: Glioblastoma multiforme (GBM) is a common and aggressive form of brain tumor. The N6-methyladenosine (m6A) mRNA modification plays multiple roles in many biological processes and disease states. However, the relationship between m6A modifications and the tumor microenvironment in GBM remains unclear, especially at the single-cell level. Experimental Design: Single-cell and bulk RNA-sequencing data were acquired from the GEO and TCGA databases, respectively. We used bioinformatics and statistical tools to analyze associations between m6A regulators and multiple factors. Results: HNRNPA2B1 and HNRNPC were extensively expressed in the GBM microenvironment. m6A regulators promoted the stemness state in GBM cancer cells. Immune-related BP terms were enriched in modules of m6A-related genes. Cell communication analysis identified genes in the GALECTIN signaling network in GBM samples, and expression of these genes (LGALS9, CD44, CD45, and HAVCR2) correlated with that of m6A regulators. Validation experiments revealed that MDK in MK signaling network promoted migration and immunosuppressive polarization of macrophage. Expression of m6A regulators correlated with ICPs in GBM cancer cells, M2 macrophages and T/NK cells. Bulk RNA-seq analysis identified two expression patterns (low m6A/high ICP and high m6A/low ICP) with different predicted immune infiltration and responses to ICP inhibitors. A predictive nomogram model to distinguish these 2 clusters was constructed and validated with excellent performance. Conclusion: At the single-cell level, m6A modification facilitates the stemness state in GBM cancer cells and promotes an immunosuppressive microenvironment through ICPs and the GALECTIN signaling pathway network. And we also identified two m6A-ICP expression patterns. These findings could lead to novel treatment strategies for GBM patients.

Are dopamine agonists still the first-choice treatment for prolactinoma in the era of endoscopy? A systematic review and meta-analysis.

BACKGROUND: For prolactinoma patients, dopamine agonists (DAs) are indicated as the first-line treatment and surgery is an adjunctive choice. However, with the development of surgical technique and equipment, the effect of surgery has improved. The aim of this study was to assess the efficacy and safety of surgery versus DAs in patients with different types of prolactinomas. METHODS: A systematic search of literature using Web of Science, PubMed, Cochrane Library, and Clinical Trial databases was conducted until July 12, 2019. Prolactinoma patients treated with DAs (bromocriptine or cabergoline) or surgery (microscopic or endoscopic surgery) were included. Outcomes included the biochemical cure rate, recurrence rate, prolactin level, improvement rates of symptoms, and incidence rates of complications. A random-effects model was used to pool the extracted data. Qualitative comparisons were conducted instead of quantitative comparison. RESULTS: DAs were better than surgery in terms of the biochemical cure rate (0.78 versus 0.66), but surgery had a much lower recurrence rate (0.19 versus 0.57). Full advantages were not demonstrated in improvement rates of symptoms and incidence rates of complications with both treatment options. In microprolactinoma patients, the biochemical cure rate of endoscopic surgery was equal to the average cure rate of DAs (0.86 versus 0.86) and it surpassed the biochemical cure rate of bromocriptine (0.86 versus 0.76). In macroprolactinoma patients, endoscopic surgery was slightly higher than bromocriptine (0.66 versus 0.64) in terms of the biochemical cure rate. CONCLUSION: For patients with clear indications or contraindications for surgery, choosing surgery or DAs accordingly is unequivocal. However, for patients with clinical equipoise, such as surgery, especially endoscopic surgery, in microprolactinoma and macroprolactinoma patients, we suggest that neurosurgeons and endocrinologists conduct high-quality clinical trials to address the clinical equipoise quantitatively.

Reconstruction strategies for intraoperative CSF leak in endoscopic endonasal skull base surgery: systematic review and meta-analysis.

BACKGROUND: Endoscopic endonasal surgery (EES) is one of the preferred options for skull base pathologies. Cerebrospinal fluid (CSF) leak is a significant complication of EES and neurosurgeons have proposed various reconstructive strategies to decrease this morbidity. We describe and compare the efficacy of these strategies. METHODS: We searched PubMed, Cochrane Library, and Web of Science for publications between 1990 and November 2019. We defined a reconstruction hierarchy of seven levels from inside to outside: fat graft, intracranial intradural layer (inlay), intracranial extradural layer (onlay), buttress, mucosal flap, nasal packing and lumbar drainage. A single-arm analysis was performed for the primary outcome of CSF leak rate. RESULTS: Of 3641 records identified, 48 studies met the inclusion criteria. Pituitary tumors had lower postoperative CSF leak rate than other diseases (1.8% vs. 6.5%, RD = -4.7% [-7.1%, -2.1%]). In high CSF flow group, the post-operative leak rate was reduced by application of mucosal flap (4.3% vs. without mucosal flap at 12.8%, RD = -8.5% [-15.1%, -1.9%]). The use of inlay showed potential of decreasing the post-operative leak rate (5.0% vs. 7.2%, RD = -2.2% [-7.7%, 3.3%]). In low CSF flow group, tampon was better than balloon for nasal packing (1.0% vs. 10.5%, RD = -9.5% [-16.5%, -2.4%]). CONCLUSIONS: Mucosal flap and inlay for high-flow intraoperative CSF leak and tampon (compared with balloon) for low-flow intraoperative CSF leak, improved the postoperative CSF leak rate. Further studies are required to establish more robust evidence.

BACH1 as a potential target for immunotherapy in glioblastomas.

Glioblastoma (GBM, WHO grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor. BTB domain and CNC homology 1 (BACH1) is a transcription factor, and it plays an essential role in regulating tumor metastasis, tumor metabolism, and tumor stem cell self-renewal. However, its role in glioma is still unclear. In this research, we confirmed that BACH1 as an independent prognostic indicator was enriched in GBMs. BACH1 was strongly correlated with immune responses in GBMs, especially the M0 and M2 tumor-associated macrophage (TAM) mediated immune responses. GBMs with high expression of BACH1 express high levels of immune checkpoints (ICs), glioma cell-derived TAM chemokines, and M2 TAM markers. Interestingly, single cell RNA-seq analysis showed that the expression level of BACH1 in TAMs was higher than that in the other cell types in GBM. Transcriptome analysis of U87-MG cells showed that compared with the BACH1-vector U87-MG group, glioma cell-derived TAM chemokines (including monocyte chemotactic protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and EGF) and ICs (including CD276, TIM-3, LAG3, TIGIT and LGALS9) were enriched in the BACH1-overexpressing U87-MG group. In addition, we constructed a polygenic risk scoring model and compound nomogram model based on BACH1, which might provide a reliable prognosis assessment tool for clinicians and aid in treatment decision-making in the clinic. In conclusion, this research identified that BACH1 might be a potential molecular signature for survival and immunotherapy response. GBMs with high expression of BACH1 have a stronger immunosuppressive tumor microenvironment (TME). Overexpression of BACH1 can upregulate the expression of glioma cell-derived TAM chemokines and ICs in vitro. Moreover, the risk model and nomogram model based on BACH1 can provide a reliable prognosis assessment tool. Therefore, BACH1 is a promising therapeutic target for GBMs.

A Novel Immune Classification for Predicting Immunotherapy Responsiveness in Patients With Adamantinomatous Craniopharyngioma.

Adamantinomatous craniopharyngioma (ACP) is the most common tumor of the sellar region in children. The aggressive behavior of ACP challenges the treatment for it. However, immunotherapy is rarely studied in ACP. In this research, we performed unsupervised cluster analysis on the 725 immune-related genes and arrays of 39 patients with ACP patients in GSE60815 and GSE94349 databases. Two novel immune subtypes were identified, namely immune resistance (IR) subtype and immunogenic (IG) subtype. Interestingly, we found that the ACPs with IG subtype (34.78%, 8/23) were more likely to respond to immunotherapy than the ACPs with IR subtype (6.25%, 1/16) via tumor immune dysfunction and exclusion (TIDE) method. Simultaneously, the enrichment analysis indicated that the differentially expressed genes (DEGs) (p < 0.01, FDR < 0.01) of the IG subtype were chiefly involved in inflammatory and immune responses. However, the DEGs of the IR subtype were mainly involved in RNA processing. Next, immune infiltration analysis revealed a higher proportion of M2 macrophage in the IG subtype than that in the IR subtype. Compared with the IR subtype, the expression levels of immune checkpoint molecules (PD1, PDL1, PDL2, TIM3, CTLA4, Galectin9, LAG3, and CD86) were significantly upregulated in the IG subtype. The ssGSEA results demonstrated that the biofunction of carcinogenesis in the IG subtype was significantly enriched, such as lymphocyte infiltration, mesenchymal phenotype, stemness maintenance, and tumorigenic cytokines, compared with the IR subtype. Finally, a WDR89 (the DEG between IG and IR subtype)-based nomogram model was constructed to predict the immune classification of ACPs with excellent performance. This predictive model provided a reliable classification assessment tool for clinicians and aids treatment decision-making in the clinic.

Development and Validation of Nomogram to Preoperatively Predict Intraoperative Cerebrospinal Fluid Leakage in Endoscopic Pituitary Surgery: A Retrospective Cohort Study.

BACKGROUND: Pituitary adenomas (PAs) are the most common tumor of the sellar region. PA resection is the preferred treatment for patients with clear indications for surgery. Intraoperative cerebrospinal fluid (iCSF) leakage is a major complication of PA resection surgery. Risk factors for iCSF leakage have been studied previously, but a predictive nomogram has not yet been developed. We constructed a nomogram for preoperative prediction of iCSF leakage in endoscopic pituitary surgery. METHODS: A total of 232 patients who underwent endoscopic PA resection at the Department of Neurosurgery in Jinling Hospital between January of 2018 and October of 2020 were enrolled in this retrospective study. Patients treated by a board-certified neurosurgeon were randomly classified into a training cohort or a validation cohort 1. Patients treated by other qualified neurosurgeons were included in validation cohort 2. A range of demographic, clinical, radiological, and laboratory data were acquired from the medical records. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm and uni- and multivariate logistic regression were utilized to analyze these features and develop a nomogram model. We used a receiver operating characteristic (ROC) curve and calibration curve to evaluate the predictive performance of the nomogram model. RESULTS: Variables were comparable between the training cohort and validation cohort 1. Tumor height and albumin were included in the final prediction model. The area under the curve (AUC) of the nomogram model was 0.733, 0.643, and 0.644 in training, validation 1, and validation 2 cohorts, respectively. The calibration curve showed satisfactory homogeneity between the predicted probability and actual observations. Nomogram performance was stable in the subgroup analysis. CONCLUSIONS: Tumor height and albumin were the independent risk factors for iCSF leakage. The prediction model developed in this study is the first nomogram developed as a practical and effective tool to facilitate the preoperative prediction of iCSF leakage in endoscopic pituitary surgery, thus optimizing treatment decisions.

ACT001 reverses resistance of prolactinomas via AMPK-mediated EGR1 and mTOR pathways.

Dopamine agonist (DA) is the first choice for the treatment of prolactinomas, and drug resistance is unavoidable during treatment due to the heterogeneity of tumors. The two prolactinoma cell lines (GH3 cells and MMQ cells) were found to have different sensitivity and responding modes to the cabergoline (CAB) and bromocriptine (BRC). In this research, we disclosed the capability of ACT001, a derivative of parthenolide analogs, to activate AMPK by increasing the intracellular reactive oxygen species (ROS) level and AMP/ATP ratio to reverse DA resistance through dual pathways in prolactinoma cells. The results indicated that ACT001 could reverse the CAB resistance in GH3 cells by inhibiting the mTOR signaling pathway, inducing cell death through autophagy, and reverse the BRC resistance in MMQ cells by activating the EGR1 signaling pathway, inducing cell death through apoptosis. Our results suggested that ACT001 is a promising therapeutic compound for treating DA-resistant prolactinomas.

Curcumin Sensitizes Prolactinoma Cells to Bromocriptine by Activating the ERK/EGR1 and Inhibiting the AKT/GSK-3ß Signaling Pathway In Vitro and In Vivo.

Although bromocriptine (BRC) as first-line drug is recommended for treating patients with prolactinoma, a minority of patients with prolactinoma are resistance to BRC. Moreover, our previous study showed the difference in drug sensitivity in BRC-treated rat prolactinoma cells, MMQ cells are more resistant to BRC, and GH3 cells are more sensitive to BRC. Curcumin (Cur) has been shown to inhibit proliferation of prolactinoma cell lines. The aim of this study is to further investigate whether Cur could enhance the growth-inhibitory effect of BRC resistance on prolactinoma cell lines and its possible mechanism. CCK-8 kit was used to test cell growth. Cell cycle analysis and apoptosis were performed by flow cytometry. Electron microscopy was used to test autophagosome. The mRNA expression profiles were analyzed using the Affymetrix Gene-Chip array. Western blot was used to test protein expression. Our data showed that Cur enhanced the growth-inhibitory effect of BRC on GH3 and MMQ cell proliferation. BRC and Cur both induced cell apoptosis, and Cur could significantly increase the apoptosis of BRC on pituitary adenoma cells through the ERK/EGR1 signaling pathway. Moreover, Cur could enhance the autophagic cell death (ACD) of BRC on tumor cells by inhibiting the AKT/GSK-3ß signaling pathway. The same results were confirmed invivo study. Taken together, Cur sensitizes rat prolactinoma cells to BRC by activating the ERK/EGR1 and inhibiting the AKT/GSK-3ß signaling pathway.

A Nomogram for Preoperatively Predicting the Ki-67 Index of a Pituitary Tumor: A Retrospective Cohort Study.

BACKGROUND: The Ki-67 index is an indicator of proliferation and aggressive behavior in pituitary adenomas (PAs). This study aims to develop and validate a predictive nomogram for forecasting Ki-67 index levels preoperatively in PAs. METHODS: A total of 439 patients with PAs underwent PA resection at the Department of Neurosurgery in Jinling Hospital between January 2018 and October 2020; they were enrolled in this retrospective study and were classified randomly into a training cohort (n = 300) and a validation cohort (n = 139). A range of clinical, radiological, and laboratory characteristics were collected. The Ki-67 index was classified into the low Ki-67 index (<3%) and the high Ki-67 index (≥3%). Least absolute shrinkage and selection operator algorithm and uni- and multivariate logistic regression analyses were applied to identify independent risk factors associated with Ki-67. A nomogram was constructed to visualize these risk factors. The receiver operation characteristic curve and calibration curve were computed to evaluate the predictive performance of the nomogram model. RESULTS: Age, primary-recurrence subtype, maximum dimension, and prolactin were included in the nomogram model. The areas under the curve (AUCs) of the nomogram model were 0.694 in the training cohort and 0.658 in the validation cohort. A well-fitted calibration curve was also generated for the nomogram model. A subgroup analysis revealed stable predictive performance for the nomogram model. A correlation analysis revealed that age (R = -0.23; p < 0.01), maximum dimension (R = 0.17; p < 0.01), and prolactin (R = 0.16; p < 0.01) were all significantly correlated with the Ki-67 index level. CONCLUSIONS: Age, primary-recurrence subtype, maximum dimension, and prolactin are independent predictors for the Ki-67 index level. The current study provides a novel and feasible nomogram, which can further assist neurosurgeons to develop better, more individualized treatment strategies for patients with PAs by predicting the Ki-67 index level preoperatively.

Glioma-Associated Stromal Cells Stimulate Glioma Malignancy by Regulating the Tumor Immune Microenvironment.

BACKGROUND: The glioma-associated stromal cell (GASC) is a recently identified type of cell in the glioma microenvironment and may be a prognostic marker for glioma. However, the potential mechanisms of GASCs in the glioma microenvironment remain largely unknown. In this work, we aimed to explore the mechanisms of GASCs in gliomas, particularly in high-grade gliomas (HGG). METHODS: We used glioma datasets from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We utilized the Single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm to discriminate between patients with high or low GASC composition. The xCELL and CIBERSORT algorithms were used to analyze the composition of stromal cells and immune cells. Risk score and a nomogram model were constructed for prognostic prediction of glioma. RESULTS: We observed for the first time that the levels of M2 macrophages and immune checkpoints (PD-1, PD-L1, PD-L2, TIM3, Galectin-9, CTLA-4, CD80, CD86, CD155, and CIITA) were significantly higher in the high GASC group and showed positive correlation with the GASC score in all glioma population and the HGG population. Copy number variations of DR3 and CIITA were higher in the high-GASC group. THY1, one of the GASC markers, exhibited lower methylation in the high GASC group. The constructed risk score was an independent predictor of glioma prognostics. Finally, a credible nomogram based on the risk score was established. CONCLUSIONS: GASCs stimulate glioma malignancy through the M2 macrophage, and are associated with the level of immune checkpoints in the glioma microenvironment. The methylation of THY1 could be used as prognostic indicator and treatment target for glioma. However, further studies are required to verify these findings.