Real-time monitoring of glucose metabolism and effects of metformin on HepG2 cells using 13C in-cell NMR spectroscopy.

Metformin is currently a strong candidate antitumor agent for multiple cancers, and has the potential to inhibit cancer cell viability, growth, and proliferation. Metabolic reprogramming is a critical feature of cancer cells. However, the effects of metformin which targets glucose metabolism on HepG2 cancer cells remain unclear. In this study, to explore the effects of metformin on glucose metabolism in HepG2 cells, we conducted real-time metabolomic monitoring of live HepG2 cells treated with metformin using 13C in-cell NMR spectroscopy. Metabolic tracing with U-13C6-glucose revealed that metformin significantly increased the production of 13C-G3P and 13C-glycerol, which were reported to attenuate liver cancer development, but decreased the production of potential oncogenesis-supportive metabolites, including 13C-lactate, 13C-alanine, 13C-glycine, and 13C-glutamate. Moreover, the expression levels of enzymes associated with the measured metabolites were carried out. The results showed that the levels of ALT1, MCT4, GPD2 and MPC1 were greatly reduced, which were consistent with the changes of measured metabolites in 13C in-cell NMR spectroscopy. Overall, our approach directly provides fundamental insights into the effects of metformin on glucose metabolism in live HepG2 cells, and highlights the potential mechanism of metformin, including the increase in production of G3P and glycerol derived from glucose, as well as the inhibition of glucose incorporation into lactate, alanine, glutamate, and glycine.

The development of a combined clinico-radiomics model for predicting post-operative recurrence in atypical meningiomas: a multicenter study.

PURPOSE: Atypical meningiomas could manifest early recurrence after surgery and even adjuvant radiotherapy. We aimed to construct a clinico-radiomics model to predict post-operative recurrence of atypical meningiomas based on clinicopathological and radiomics features. MATERIALS AND METHODS: The study cohort was comprised of 224 patients from two neurosurgical centers. 164 patients from center I were divided to the training cohort for model development and the testing cohort for internal validation. 60 patients from center II were used for external validation. Clinicopathological characteristics, radiological semantic, and radiomics features were collected. A radiomic signature was comprised of four radiomics features. A clinico-radiomics model combining the radiomics signature and clinical characteristics was constructed to predict the recurrence of atypical meningiomas. RESULTS: 1920 radiomics features were extracted from the T1 Contrast and T2-FLAIR sequences of patients in center I. The radiomics signature was able to differentiate post-operative patients into low-risk and high-risk groups based on tumor recurrence (P < 0.001). A clinic-radiomics model was established by combining age, extent of resection, Ki-67 index, surgical history and the radiomics signature for recurrence prediction in atypical meningiomas. The model achieved a good prediction performance with the integrated AUC of 0.858 (0.802-0.915), 0.781 (0.649-0.912) and 0.840 (0.747-0.933) in the training, internal validation and external validation cohort, respectively. CONCLUSIONS: The present study established a radiomics signature and a clinico-radiomics model with a favorable performance in predicting tumor recurrence for atypical meningiomas.

Distinct clinical outcome of microcystic meningioma as a WHO grade 1 meningioma subtype.

OBJECTIVE: To evaluate the clinicopathological characteristics, radiology, and long-term outcomes of microcystic meningiomas (MM) and compare it with other subtypes of meningiomas managed at a single neurosurgical center. METHODS: A total of 87 consecutive patients who underwent surgical resection and were diagnosed as MM between 2005 and 2016 were enrolled for analysis. Clinicopathological, radiology, and prognostic information was collected and analyzed. Progression free survival (PFS) was compared with 659 patients with other subtypes of WHO grade 1 meningiomas and 167 patients with atypical meningiomas treated during the same period. RESULTS: Fifty six females and 31 males with MM were analyzed. Peri-tumor brain edema was frequent on T2 WI (85%).12 patients (13.8%) experienced tumor progression during the mean follow-up of 101.66 ± 40.92 months. The median PFS was unavailable, and the 5, 10, and 15 year progression-free rates were 96.9%, 84.0%, and 73.9%, respectively. Univariate COX analysis demonstrated skull base location and higher Ki-67 index as significant negative prognostic factors for PFS (P < 0.05); multivariate analysis identified tumor location and Ki-67 index as independent factors (P < 0.01), as well. Of note, the PFS of MM was worse than other WHO grade 1 subtypes (P < 0.001), but better than atypical meningiomas (P < 0.001), and the PFS differences were retained even when the analysis was limited to the patients receiving GTR (P < 0.05). CONCLUSION: The PFS of MM was worse than other WHO grade 1 subtypes and better than atypical meningiomas. Skull base location and higher Ki-67 index were independent negative prognostic factors in MM.

Loss of H3K27me3 expression enriches in recurrent grade 1&2 meningiomas and maintains as a biomarker stratifying progression risk.

PURPOSE: To determine if loss of H3K27me3 could predict higher risk of re-recurrence in recurrent meningiomas. METHODS: A retrospective, single-center cohort study was performed for patients who underwent resection of recurrent grade 1 (N = 132) &2 (N = 32) meningiomas from 2009 to 2013. Association of H3K27me3 staining and clinical parameters was analyzed. Additionally, H3K27me3 staining was performed from 45 patients whose tumors recurred and were resected during the follow-up, to evaluate H3K27me3 change during tumor progression. Survival analysis was performed as well. RESULTS: Loss of H3K27me3 expression was observed in 83 patients, comprising 63 grade 1 (47.7%) and 20 grade 2 patients (62.5%). Both grade 1 (p < 0.001) and grade 2 recurrent meningiomas (p < 0.001) had a higher frequency of H3K27me3 loss, compared to de novo meningiomas. 8 of 27 tumors with retained H3K27me3 lost H3K27me3 during re-recurrence (29.6%), while no gain of H3K27me3 was observed in progressive disease from 18 tumors with H3K27me3 loss. Loss of H3K27me3 expression was associated with an earlier re-recurrence in recurrent meningiomas grade 1 and 2 (p < 0.001), and was an independent prognostic factor for PFS in recurrent grade 1 meningiomas (p = 0.005). CONCLUSION: Compared to primary meningiomas, recurrent meningiomas more predominantly had loss of H3K27me3 expression, and further loss can occur during the progression of recurrent tumors. Our results further demonstrated that loss of H3K27me3 predicted shorter PFS in recurrent grade 1 and grade 2 meningiomas. Our work thus supports clinical testing of H3K27me3 in recurrent meningiomas WHO grade 1 and 2.

Long-term outcomes of multimodality management for parasagittal meningiomas.

PURPOSE: The aim of this study was to systematically analyze the clinical characteristics of a large cohort of parasagittal meningioma (PM) and to evaluate the patients' outcomes and best treatment strategies based on tumor features. METHODS: To minimize selection bias we performed a single-institutional review of PM with restricted criteria. One hundred and ninety-two consecutive patients who met criteria for inclusion were reviewed from 2003 to 2011 in our general hospital. RESULTS: A total of 131 cases (68.2%) were with WHO grade I, while grade II and grade III PMs constituted 40 (20.8%) and 21 cases (10.9%). Higher histological grade was associated with loss of trimethylation of H3K27 (P = 0.000). For WHO grade I PMs, GTR was significantly associated with a better PFS (P = 0.023); however, adjuvant radiotherapy did not benefit patients with STR (P = 0.215). For de novo high-grade (WHO grade II and III) PMs (n = 37), adjuvant radiotherapy was associated with a significantly longer OS (P = 0.013), while no difference was observed between GTR and STR (P = 0.654). In recurrent high-grade PM patients (n = 24), GTR combined with adjuvant radiotherapy increased PFS (P = 0.005). CONCLUSIONS: This study demonstrated that PMs were a heterogeneous group of tumors with a high proportion of high-grade tumors that often displayed aggressive clinical behaviors. Low-grade PM benefited from radical resection, whereas high-grade de novo PM did not. Adjuvant radiotherapy significantly prolonged OS for high-grade primary PM, but did not impact survival of patients with subtotally resected low-grade tumors. Long-term outcome of high-grade recurrent PMs was dismal. We thus show that extent of tumor resection, tumor grade and tumor recurrent status inform therapeutic decisions for PMs.

Hybrid representations of asymmetrically excited surface plasmon self-interference at a planar dielectric/metal interface.

We introduce a hybrid representation to describe asymmetrically excited surface plasmon (SP) self-interference at a planar dielectric/metal interface. The hybrid representation combines a ray model, angular spectrum representation, near-field spatial frequency analysis, and parameter characterization to investigate the incidence coupling and spatial resolution degradation of the SP self-interference. We also propose SP numerical aperture for self-interference virtual probe imaging. We explain the shift in the main peak in asymmetrical excitation. Individual models are used to study the various characteristic features in detail, and physical insights are gained. We examine the consistency of the results obtained using the different models and demonstrate the effectiveness of the hybrid representation for describing the asymmetrically excited SP self-interference.

Paraxial models for the surface plasmon self- interference at off-axis excitation.

The surface plasmon self-interference excited by a strongly focused, linearly polarized vortex beam at off-axis illumination in a paraxial regime is analytically studied. The off-axis excitation is investigated using a geometrical model. The combination of an angular spectrum representation and homogeneous transformation is applied to derive the integral expressions of the surface plasmon polariton fields for off-axis directions both parallel and perpendicular to polarization plane, and an off-axis convergence angle is used to compute the integral. The surface plasmon excitation is represented by the relative peak intensity of the longitudinal field, while its standing wave is characterized by the full width at half-maximum of the transmitted field intensity distribution profile. Both models consistently show that even in ideal Gaussian microscopic imaging systems, self-interference degradation exists. When the off-axis angle increases, the surface plasmon interference disappears and the fields detune out of surface plasmon resonance.

Effect of Mailuoning injection on 8-iso-prostaglandin F2 alpha and superoxide dismutase in rabbits with extremity ischemia-reperfusion injury.

BACKGROUND: To date, there are no effective treatments for extremity ischemia-reperfusion (IR) injury. The objective of the present study was to explore the protective effect of Mailuoning on IR injury by investigating the plasma levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF2α) and the activity of superoxide dismutase (SOD) in rabbits. MATERIALS AND METHODS: The experimental models of posterior limb IR injury were established in thirty rabbits that were divided into three groups: the sham, IR, and IR + Mailuoning groups. At the end of ischemia, Mailuoning was injected intravenously into the rabbits in the IR + Mailuoning group, and normal saline solution was administered to the rabbits in the sham and IR groups. Venous blood samples were collected to measure the levels of 8-iso-PGF2α and the activity of SOD in the plasma at the following time points: at the onset of ischemia, the end of ischemia, and 2, 4, 8, 12, and 24 h after reperfusion. The skeletal muscles were harvested to examine the ultrastructure. RESULTS: The levels of 8-iso-PGF2α increased significantly and SOD activity decreased in the IR group at every time point after reperfusion (P <0.01 or P <0.05). In contrast, the levels of 8-iso-PGF2α and SOD activity were not significantly different after reperfusion in the IR + Mailuoning group (P >0.05) but were significantly different compared with the IR group (P <0.01). Using electron microscopy, the skeletal muscle injury was shown to be milder in the IR+ Mailuoning group after reperfusion compared with the IR group. CONCLUSIONS: The Mailuoning is capable of decreasing the excessive production of 8-iso-PGF2α and protecting SOD activity, thereby exhibiting a protective effect on extremity IR injury.

Diffusion tensor magnetic resonance imaging for predicting the consistency of intracranial meningiomas.

BACKGROUND: The ability of preoperative MRI-sequences to predict the consistency of intracranial meningiomas has not yet been clearly defined. We aim to demonstrate that diffusion tensor imaging (DTI) improves the prediction of intracranial meningiomas consistency. METHODS: We prospectively studied 110 meningioma patients operated on in a single center from March 1st to the 25th of May 2012. Demographic data, location and size of the tumor, peritumoral edema, T1WI, T2WI, proton density weighted (PDWI), fluid-attenuated inversion recover (FLAIR) sequences, and arterial spin labeling (ASL) perfusion were studied and compared with the gray matter signal to predict meningioma consistency. Diffusion tensor imaging (DTI) with fractional anisotropy (FA) and mean diffusivity (MD) maps were included in the preoperative MRI. Meningioma consistency was evaluated by the operating surgeon who was unaware of the neuroradiological findings. RESULTS: In univariate analysis, meningioma size (diameter > 2 cm) and supratentorial or sphenoidal wing location were more frequently associated with hard-consistency meningiomas (p < 0.05). In addition, isointense signal on MD maps (p = 0.009), hyperintense signal on FA maps, and FA value > 0.3 (p = 0.00001) were associated with hard-consistency tumors. Age and sex, T1WI, T2WI, PDWI, FLAIR, or ASL perfusion sequences and peritumoral edema were not significantly associated with meningioma consistency. In logistic regression analysis, the most accurate model (AUC: 0.9459) for predicting a hard-consistency meningioma shows that an isointense signal in MD-maps, a hyperintense signal in FA-maps, and an FA value of more than 0.3 have a significant predictive value. CONCLUSIONS: FA value and MD and FA maps are useful for prediction of meningioma consistency and, therefore, may be considered in the preoperative routine MRI examination of all patients with intracranial meningiomas.

Application of CUSA Excel ultrasonic aspiration system in resection of skull base meningiomas.

BACKGROUND: Here, we introduced our short experience on the application of a new CUSA Excel ultrasonic aspiration system, which was provided by Integra Lifesciences corporation, in skull base meningiomas resection. METHODS: Ten patients with anterior, middle skull base and sphenoid ridge meningioma were operated using the CUSA Excel ultrasonic aspiration system at the Neurosurgery Department of Shanghai Huashan Hospital from August 2014 to October 2014. There were six male and four female patients, aged from 38 to 61 years old (the mean age was 48.5 years old). Five cases with tumor located at anterior skull base, three cases with tumor on middle skull base, and two cases with tumor on sphenoid ridge. RESULTS: All the patents received total resection of meningiomas with the help of this new tool, and the critical brain vessels and nerves were preserved during operations. All the patients recovered well after operation. CONCLUSIONS: This new CUSA Excel ultrasonic aspiration system has the advantage of preserving vital brain arteries and cranial nerves during skull base meningioma resection, which is very important for skull base tumor operations. This key step would ensure a well prognosis for patients. We hope the neurosurgeons would benefit from this kind of technique.

Association of frequent NF2 mutations with spinal location predominance and worse outcomes in psammomatous meningiomas.

OBJECTIVE: Psammomatous meningiomas (PMs) are a rare histological subtype of meningioma but are rather frequent in spinal meningiomas. The authors aimed to analyze the incidence, clinical features, molecular alterations, long-term outcomes, and prognostic factors of PMs. METHODS: In total, 151 patients with PMs were included in this study. Clinical characteristics, molecular alterations, and progression-free survival (PFS) were analyzed in PMs. Clinical characteristics were compared between PMs and other WHO grade 1 meningiomas. Targeted sequencing of meningioma-relevant genes was performed to determine the molecular alterations in PMs. RESULTS: PMs accounted for 1.34% of all meningiomas. Clinically, spinal location (p < 0.001) and female predominance (p < 0.001) were statistically significant in PMs when compared with the other grade 1 subtypes. Radiologically, calcification was frequently found in PMs (88.24%). Genetically, NF2 was the most frequently mutated gene in PMs (59.7%), followed by TRAF7 and AKT1. Ten patients experienced recurrence during the long-term follow-up. Multivariate analysis demonstrated that age (p = 0.009), extent of resection (p < 0.001), Ki-67 index (p = 0.007), and NF2 status (p < 0.001) were independent prognostic factors in the cohort of PMs. Interestingly, NF2 mutation was detected in all (48/48) spinal PMs (SPMs) but in only 38.46% (35/91) of cranial PMs (CPMs), revealing a significant difference (p < 0.001). The mean Ki-67 index (p = 0.044) and proportion of PMs with PR-positive expression (p = 0.048) were significantly higher in SPMs than in CPMs. The frequent NF2 mutations are associated with spinal location predominance and worse PFS in PMs. CONCLUSIONS: Female sex and spinal location predominance were statistically significant in PMs. NF2 mutation was an independent predictor for worse PFS of PMs. Of note, NF2 mutation was detected in all SPMs but in only 38.46% of CPMs, revealing a significant difference.

Early changes in GMRP1 after intracerebral hemorrhage: involvement in brain damage and cell apoptosis.

Glucose metabolism-related protein 1 (GMRP1), also known as BTBD10, has been reported to inhibit apoptosis of neuronal and islet beta cells via the Akt pathway. The present study attempted to investigate whether GMRP1 and its mediated Akt pathway were involved in brain injury of rats after intracerebral hemorrhage (ICH). Rat models of ICH had been established successfully. Western blotting was used to investigate the levels of GMRP1 protein in the caudate nuclei tissues of the hemorrhagic and contralateral sides at 6 h, day 1, day 3, day 5, and day 7 after ICH. Phosphorylations of Akt was determined in caudate nuclei mentioned above. TUNEL assay was used to measure the cell apoptosis. GMRP1 protein levels, as well as phosphorylations of Akt, significantly decreased in caudate nuclei of the hemorrhagic side, compared with those of the contralateral side on day 1 and day 3 after ICH. Enhanced cell apoptosis was observed on the hemorrhagic side using TUNEL assay. We presented here evidence that a decreased GMRP1-mediated Akt pathway contributed to cell apoptosis on the hemorrhagic side, suggesting that GMRP1 plays an important role in brain damage after ICH.

Alteration of intracellular calcium and its modulator SLC24A6 after experimental intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) can lead to tragic disability and mortality. Accumulating evidence has shown that sodium calcium exchanger (NCX) may contribute to the secondary injury of a stroke. Recently, a novel member of NCX, SLC24A6, was discovered with knowledge of its abundant distribution in brain. In the present study, we examined the time course of expression of SLC24A6 and its mediated intracellular calcium concentration ([Ca(2+)]i) to investigate its potential roles in brain damage after ICH. An ICH model was established as previously reported. Real-time PCR and Western blotting were used to test the mRNA and protein levels of SLC24A6 on the hemorrhagic side and on the contralateral side caudate nucleus tissues at 6 h, and on days 1, 3, 5, and 7 after ICH. Immunohistochemistry was used to analyze the morphological changes. Fura-2/AM loaded, dual wavelength spectrophotofluorometry was used to test [Ca(2+)]i. The data presented a remarkable decrease in SLC24A6 early after ICH, along with a comparable increase in [Ca(2+)]i. Our results indicated that SLC24A6 presents specific and remarkable alterations in both mRNA and protein levels after ICH. Decreases in SLC24A6 level were correlated with [Ca(2+)]i elevation. These data suggest that SLC24A6-mediated calcium overload plays an important role in brain damage after ICH.

Intraoperative ultrasound assistance in resection of intracranial meningiomas.

OBJECTIVE: Intracranial meningiomas, especially those located at anterior and middle skull base, are difficult to be completely resected due to their complicated anatomy structures and adjacent vessels. It's essential to locate the tumor and its vessels precisely during operation to reduce the risk of neurological deficits. The purpose of this study was to evaluate intraoperative ultrasonography in displaying intracranial meningioma and its surrounding arteries, and evaluate its potential to improve surgical precision and minimize surgical trauma. METHODS: Between December 2011 and January 2013, 20 patients with anterior and middle skull base meningioma underwent surgery with the assistance of intraoperative ultrasonography in the Neurosurgery Department of Shanghai Huashan Hospital. There were 7 male and 13 female patients, aged from 31 to 66 years old. Their sonographic features were analyzed and the advantages of intraoperative ultrasonography were discussed. RESULTS: The border of the meningioma and its adjacent vessels could be exhibited on intraoperative ultrasonography. The sonographic visualization allowed the neurosurgeon to choose an appropriate approach before the operation. In addition, intraoperative ultrasonography could inform neurosurgeons about the location of the tumor, its relation to the surrounding arteries during the operation, thus these essential arteries could be protected carefully. CONCLUSIONS: Intraoperative ultrasonography is a useful intraoperative technique. When appropriately applied to assist surgical procedures for intracranial meningioma, it could offer very important intraoperative information (such as the tumor supplying vessels) that helps to improve surgical resection and therefore might reduce the postoperative morbidity.

Clinicopathological analysis of metaplastic meningioma: report of 15 cases in Huashan Hospital.

OBJECTIVE: Metaplastic meningioma is a rare subtype of benign meningiomas, classified as WHO grade I with well prognosis. Here we presented our experiences on 15 cases of metaplastic meningioma, to investigate the clinicopathological features, therapies and prognosis of these cases. METHODS: 15 patients underwent surgical treatment for intracranial metaplastic meningioma between 2001 and 2010 at Neurosurgery Department of Huashan Hospital, Shanghai, China. The clinical data, radiological manifestation, treatment strategy, pathological findings and prognosis of all patients were analyzed retrospectively. RESULTS: Among the 15 cases (10 males and 5 females), the age ranged from 22 to 74 years old (the mean age was 50.67-year old). The clinical manifestations include headache, dizziness, seizure attack, vision decrease, and weakness of bilateral lower limbs. All the patients received surgical treatment, combined with radiotherapy in some cases. In the follow-up period, recurrence occurred in 2 cases, of which 1 patient died of other system complications. CONCLUSIONS: Metaplastic meningiomas are characterized by focal or widespread mesenchymal differentiation with formation of bone, cartilage, fat, and xanthomatous tissue elements. Surgical removal is the optimal therapy, and the overall prognosis is well. But recurrence may occur in some cases, thus radiotherapy is necessary for such kind of patients.

Organoids: Construction and Application in Gastric Cancer.

Gastric organoids are biological models constructed in vitro using stem cell culture and 3D cell culture techniques, which are the latest research hotspots. The proliferation of stem cells in vitro is the key to gastric organoid models, making the cell subsets within the models more similar to in vivo tissues. Meanwhile, the 3D culture technology also provides a more suitable microenvironment for the cells. Therefore, the gastric organoid models can largely restore the growth condition of cells in terms of morphology and function in vivo. As the most classic organoid models, patient-derived organoids use the patient's own tissues for in vitro culture. This kind of model is responsive to the 'disease information' of a specific patient and has great effect on evaluating the strategies of individualized treatment. Herein, we review the current literature on the establishment of organoid cultures, and also explore organoid translational applications.

Favorable Long-Term Outcomes of Chordoid Meningioma Compared With the Other WHO Grade 2 Meningioma Subtypes.

BACKGROUND: WHO grade 2 meningiomas, including atypical, chordoid, and clear cell subtypes, form a heterogenous group of meningiomas with varying aggressiveness and clinical behavior. OBJECTIVE: To demonstrate the differences of clinical-histopathological characteristics and long-term outcomes among these 3 subtypes. METHODS: A total of 609 consecutive patients diagnosed with WHO grade 2 meningiomas (543 atypical meningiomas [AMs], 36 chordoid meningiomas [CMs], and 30 clear cell meningiomas [CCMs]) from 2010 to 2018 were enrolled in this study. We compared the clinical-histopathological characteristics and long-term outcomes in these 3 subtypes and assessed survival differences among the subtypes. Targeted panel sequencing of meningioma-relevant genes was performed in the cases of CM. RESULTS: The patients with CCM were significantly younger than those with AM ( P < .001) and CM ( P = .016). CMs were more likely to receive gross total resection than AMs and CCMs ( P = .033). The Ki-67 index was lower ( P < .001) while the progesterone receptors-positive rate was higher ( P = .034) in CM than in AM and CCM. Importantly, survival analysis demonstrated that CM had better progression-free survival ( P = .022) and overall survival ( P = .0056) than non-CM tumors. However, the PFS of CM was still worse than WHO grade 1 meningiomas ( P < .001). Alterations in NF2 (20.6%) and KMT2C (26.5%) were associated with poorer PFS in CM ( P = .013 for NF2 ; P = .021 for KMT2C ). CONCLUSION: Patients with CM had better long-term postoperative outcomes than the other WHO grade 2 subtypes. A lower Ki-67 index, higher PR status, higher extent of resection, and lower frequency of NF2 alteration might contribute to favorable clinical outcomes of CM.

Progesterone receptor expression and prediction of benefits of adjuvant radiotherapy in de novo atypical meningiomas after gross-total resection.

OBJECTIVE: Benefits of adjuvant radiotherapy (ART) after gross-total resection (GTR) of de novo atypical meningiomas (AMs) are controversial, and factors predictive of radiotherapy benefits in patients with de novo AMs after GTR are unknown. The authors aimed to evaluate the benefits of ART and explore potential factors sensitizing AMs to ART. METHODS: A total of 231 consecutive patients who were pathologically diagnosed with de novo AMs and treated with GTR (Simpson class I-III resections) from 2010 to 2018 were enrolled in the study. Clinicopathological and prognostic information was collected and analyzed. Univariate and multivariate Cox analyses were used to evaluate prognostic predictors and compare the response to radiotherapy. Propensity score matching (PSM) was used to balance the confounding bias in subgroups. RESULTS: A total of 138 patients (59.74%) received ART. Progesterone receptor (PR) expression was positive in 157 patients (67.97%). During the mean follow-up period of 76.25 months, 65 patients (28.14%) experienced recurrence and 38 (16.45%) died of tumor progression. For disease-specific survival (DSS), ART was a better prognostic factor via univariate (p = 0.003) and multivariate (p = 0.025) analyses. For progression-free survival (PFS), univariate Cox analysis showed that ART improved PFS (p = 0.013), but multivariate analysis did not (p = 0.068). Positive PR expression (p = 0.019), age 53.5 years or younger (p = 0.012), and Ki-67 7.5% or lower (p = 0.025) were independent prognostic predictors for better PFS. In the subcohort analysis, the beneficial impact of ART was observed in the PR-negative cohort (p = 0.002) but not in the PR-positive cohort (p = 0.86). The heterogeneity analysis demonstrated that the PR-negative cohort was more sensitive to ART than the PR-positive cohort (p = 0.036). ART was not found to be associated with better PFS in younger patients (≤ 53.5 years, p = 0.14), older patients (> 53.5 years, p = 0.085), those with a Ki-67 index ≤ 7.5% (p = 0.068), or those with a Ki-67 > 7.5% (p = 0.13). The contrasting effects of ART in the PR-negative versus PR-positive cohorts remained true even after PSM, confirming that PR-negative, but not PR-positive, de novo AMs benefited from ART after GTR. CONCLUSIONS: ART was an independent prognostic factor for DSS of patients with de novo AMs treated with GTR (p = 0.025), but not for PFS (p = 0.068). Negative PR expression was a radiosensitive biomarker on PFS for de novo AM patients after GTR.

Identification of the Key Immune Cells and Genes for the Diagnostics and Therapeutics of Meningioma.

BACKGROUND: Dysregulation of immune infiltration critically contributes to the tumorigenesis and progression of meningiomas. However, the landscape of immune microenvironment and key genes correlated with immune cell infiltration remains unclear. METHODS: Four Gene Expression Omnibus data sets were included. CIBERSORT algorithm was utilized to analyze the immune cell infiltration in samples. Wilcoxon test, Random Forest algorithm, and Least Absolute Shrinkage and Selection Operator regression were adopted in identifying significantly different infiltrating immune cells and differentially expressed genes (DEGs). Functional enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology. The correlation between genes and immune cells was evaluated via Spearman's correlation analysis. Receiver Operator Characteristic curve analysis evaluated the markers' diagnostic effectiveness. The mRNA-miRNA and Drug-Gene-Immune cell interaction networks were constructed to identify potential diagnostic and therapeutic targets. RESULTS: Plasma cells, M1 macrophages, M2 macrophages, neutrophils, eosinophils, and activated NK cells were the significantly different infiltrating immune cells in meningioma. A total of 951 DEGs, associated with synaptic function and structure, ion transport regulation, brain function, and immune-related pathways, were identified. Among 11 hub DEGs, RYR2 and TTR were correlated with plasma cells; SNCG was associated with NK cells; ADCY1 exhibited excellent diagnostic effectiveness; and ADCY1, BMX, KCNA5, SLCO4A1, and TTR could be considered as therapeutic targets. CONCLUSIONS: ADCY1 can be identified as a diagnostic marker; ADCY1, BMX, KCNA5, SLCO4A1, and TTR are potential therapeutic targets, and their associations with macrophages, neutrophils, NK cells, and plasma cells might impact the tumorigenesis of meningiomas.

STAT1 suppresses the transcriptional activity of TRIM21 in gastric cancer.

PURPOSE: Tripartite motif-containing protein 21 (TRIM21) has E3 ubiquitin ligase activity and is involved in the regulation of various biological processes in vivo. TRIM21 has been found to have strong associations with various cancers. However, its role in gastric cancer is unclear. METHODS: The TCGA database was screened to obtain TRIM21 using WGCNA and PPI analyses. The TCGA database was used to evaluate the correlation of TRIM21 expression with patients' clinical characteristics, prognosis, functional enrichment and immune cell infiltration. The role of TRIM21 in cell proliferation, apoptosis and invasion was verified by in vivo and in vitro assays. The UCSC and JASPAR databases were used to evaluate the regulatory role of STAT1 on TRIM21 transcription. Finally, dual-luciferase reporter assay was used to confirm the regulation of TRIM21 transcriptional activity by STAT1. RESULTS: As a key gene, high expression of TRIM21 inhibited the gastric cancer growth and was significantly enriched in apoptosis, cell proliferation, and JAK/STAT signaling pathways. TRIM21 expression was positively correlated with a variety of TICs, including T cells, NK cells, and DCs. In vivo assays, TRIM21 inhibited functions in gastric cancer cell lines, including inhibition of proliferation and migration, and promotion of apoptosis. Database analysis and dual-luciferase reporter assay showed that STAT1 inhibited the transcriptional activity of TRIM21. In vivo assays confirmed that TRIM21 inhibited tumor growth, and STAT1 expression was negatively correlated with STAT1. CONCLUSION: TRIM21 is a tumor-suppressive gene in gastric cancer, and its transcriptional activity is inhibited by STAT1.