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Linoleic-acid-substituted polyethylenimine to silence heat shock protein 90B1 (HSP90B1) to inhibit migration of breast cancer cells.

Breast cancer continues to be one of the leading causes of death in women, and the lack of treatment options for distant metastasis warrants the need to identify and develop more effective approaches. The aim of this study was to identify and validate targets that are associated with the survival and migration of the breast cancer cells in vitro through RNA interference (RNAi) approach. Linoleic-acid-modified polyethylenimine (PEI) polymer was used to screen a short interfering RNA (siRNA) library against numerous cell adhesion and cytoskeleton genes in MDA-MB-231 triple-negative breast cell line, and the functional outcome of silencing was determined by growth and migration inhibition with further target validation studies. Heat shock protein 90B1 (HSP90B1) was identified as a crucial gene that is known to be involved in various breast cancer machineries, including uncontrolled proliferation and brain metastasis. The success of this approach was also due to the use of hyaluronic acid (HA) additive in lipopolymer complexes that showed a profound impact in reducing the cell viability (50%), migration (40%), and mRNA transcript levels (80%) with a physiologically relevant siRNA concentration of 60 nM. The use of Dicer-substrate siRNA proved to be beneficial in target silencing, and a combinational treatment of integrin-β1 (ITGB1) and HSP90B1 was effective in reducing the migration of the MDA-MB-231 and MDA-MB-436 breast cancer cells. This study demonstrates the potential to identify and silence targets using a lipid-modified PEIsiRNA system and highlights the importance of HSP90B1 in the growth and migration of breast cancer cells.

Retrospective and integrative analyses of molecular characteristics and their specific imaging parameters in pediatric grade 1 gliomas.

Pediatric low-grade gliomas (PLGG) are the most common brain tumors diagnosed during childhood and represent a heterogeneous group associating variable molecular abnormalities. To go further and develop specific statistical patterns between tumor molecular background, imaging features, and patient outcome, a retrospective study was performed in a group of non-neurofibromatosis type 1 (non-NF1) grade 1 PLGGs. Seventy-eight children, followed from 2004 to 2017, were retrospectively reported. In this population, we analyzed radiological and molecular parameters. Their therapeutic management comprised surgery or surgery plus chemotherapies. Considering all 78 patients, 59 had only a surgical removal and 19 patients were treated with postoperative chemotherapy. Twelve progressions were reported in the partially resected and chemotherapeutic groups, whereas four deaths occurred only in the highly treated patients. As expected, in the global cohort, PLGG with BRAF p.V600E andor CDKN2A loss exhibited poor outcomes and we evidenced significant associations between those molecular characteristics and their imaging presentation. In the chemo-treated patients, when associating initial and 6-month magnetic resonance imaging (MRI) parameters to the molecular features, the good risk situations were significantly linked to the presence of a large tumor cyst at diagnosis and the appearance during treatment of a higher cystic proportion that we called cystic conversion. So, additionally to the presence of BRAF p.V600E or CDKN2A deletion in grade 1 PLGGs, the absence on diagnostic MRI of cystic parts andor cystic conversion at 6-month chemotherapy were significantly linked to a worst prognosis and response to treatment. These imaging features should be considered as prognostic markers in future PLGG studies.

Systemic inflammatory biomarkers in primary central nervous system lymphoma versus high-grade glioma exploratory, comparative and correlative analysis.

There exists a complex interplay between cancer and inflammation that can manifest as increased inflammatory biomarkers in blood. However, utility of systemic inflammatory biomarkers in the non invasive differential diagnosis of primary brain lymphoma from high-grade glioma is generally lacking. Two simple serum biomarkers, absolute lymphocyte count and prognostic nutritional index, easily derived from routine pretreatment blood tests have fair correlation and acceptable diagnostic accuracy in differentiating brain lymphoma from glioma in patients with similar morphology on MRI.

Successful treatment of refractory brain metastases from ALK-positive lung cancer with lorlatinib.

A 44-year-old woman with ALK-positive advanced adenocarcinoma of the lung was treated with crizotinib, and the lung lesions disappeared. The patient was treated with alectinib and chemotherapy, but brain metastases worsened therefore, we performed an ALK resistance gene mutation test using plasma samples. Since no ALK resistance gene mutations were detected, we speculated that ALK inhibitors failed to achieve therapeutic effects due to poor transport to the central nervous system. Therefore, we switched to lorlatinib, and found a reduction in brain metastases. In ALK-positive advanced lung cancer, plasma-based resistance gene testing may be useful for treatment decisions.

Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment ProtecT study).

To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 padday, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes.

Evaluation of Lorlatinib Cerebrospinal Fluid Concentrations in Relation to Target Concentrations for Anaplastic Lymphoma Kinase (ALK) Inhibition.

Lorlatinib is a third-generation, brain-penetrant anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with robust intracranial activity in patients with ALK- or ROS1-positive non-small cell lung cancer (NSCLC). Data from the ongoing open-label, single-arm, multicenter, phase-12 study of lorlatinib in patients with metastatic ALK- or ROS1-positive NSCLC were used to further investigate the potential brain penetration of lorlatinib. Patients received escalating lorlatinib doses (10-200 mg once daily or 35-100 mg twice daily) or the approved dosing (100 mg daily). Plasma was collected from all patients, and cerebrospinal fluid (CSF) was collected at baseline and during the study from 5 patients with suspected or confirmed leptomeningeal carcinomatosis or carcinomatous meningitis. For those 5 patients, lorlatinib concentrations ranged from 2.64 to 125 ngmL in the CSF and from 12.7 to 457 ngmL in the plasma free plasma concentrations ranged from 4.318 to 155.385 ngmL. The CSFfree plasma ratio was 0.77 (R

Aspirin resistance and blood biomarkers in predicting ischemic stroke recurrence An exploratory study.

Recurrent strokes cause greater complications and worse outcomes by adding to the existing neurological deficit. There is the paucity of data on serum markers of inflammation as predictors of recurrent stroke. This study was planned to analyze the clinico-etiological profile of recurrent noncardioembolic ischemic stroke, estimate aspirin resistance among regular aspirin users and evaluate blood biomarkers high-sensitivity C-reactive protein (hsCRP), Tumor necrosis factor-alpha (TNF-α), Lipoprotein-associated phospholipase A Patients of recurrent noncardioembolic ischemic stroke fulfilling the inclusion criteria were enrolled. Detailed history, clinical examination, and investigations were obtained as per protocol. Aspirin resistance was determined by light transmission aggregometry. Serum hsCRP, TNF-α, and Lp-PLA2 levels were estimated. This study included 34 males and 16 females. Majority of the patients were > 60 years ( Majority of patients with recurrent stroke were elderly (>60 years), hypertensive, and non-compliant with aspirin. Aspirin resistance was an important factor in patients with antiplatelet compliance. Inflammatory biomarkers hsCRP, PLA2, and TNF-α were found to be significantly elevated in patients compared to controls.

Siglec-9, a Putative Immune Checkpoint Marker for Cancer Progression Across Multiple Cancer Types.

Siglec-9, a cell surface transmembrane receptor mainly expressed on B cells, CD56

A Novel Prediction Model for Brain Glioma Image Segmentation Based on the Theory of Bose-Einstein Condensate.

The input image of a blurry glioma image segmentation is, usually, very unclear. It is difficult to obtain the accurate contour line of image segmentation. The main challenge facing the researchers is to correctly determine the area where the points on the contour line belong to the glioma image. This article highlights the mechanism of formation of glioma and provides an image segmentation prediction model to assist in the accurate division of glioma contour points. The proposed prediction model of segmentation associated with the process of the formation of glioma is innovative and challenging. Bose-Einstein Condensate (BEC) is a microscopic quantum phenomenon in which atoms condense to the ground state of energy as the temperature approaches absolute zero. In this article, we propose a BEC kernel function and a novel prediction model based on the BEC kernel to detect the relationship between the process of the BEC and the formation of a brain glioma. Furthermore, the theoretical derivation and proof of the prediction model are given from micro to macro through quantum mechanics, wave, oscillation of glioma, and statistical distribution of laws. The prediction model is a distinct segmentation model that is guided by BEC theory for blurry glioma image segmentation. Our approach is based on five tests. The first three tests aimed at confirming the measuring range of T and μ in the BEC kernel. The results are extended from -10 to 10, approximating the standard range to T ≤ 0, and μ from 0 to 6.7. Tests 4 and 5 are comparison tests. The comparison in Test 4 was based on various established cluster methods. The results show that our prediction model in image evaluation parameters of P, R, and F is the best amongst all the existent ten forms except for only one reference with the mean value of F that is between 0.88 and 0.93, while our approach returns between 0.85 and 0.99. Test 5 aimed to further compare our results, especially with CNN (Convolutional Neural Networks) methods, by challenging Brain Tumor Segmentation (BraTS) and clinic patient datasets. Our results were also better than all reference tests. In addition, the proposed prediction model with the BEC kernel is feasible and has a comparative validity in glioma image segmentation. Theoretical derivation and experimental verification show that the prediction model based on the BEC kernel can solve the problem of accurate segmentation of blurry glioma images. It demonstrates that the BEC kernel is a more feasible, valid, and accurate approach than a lot of the recent year segmentation methods. It is also an advanced and innovative model of prediction deducing from micro BEC theory to macro glioma image segmentation.

Cerebral Intraparenchymal Hemorrhage Changes Patients Gut Bacteria Composition and Function.

Gut bacteria consists of 150 times more genes than humans that are vital for health. Several studies revealed that gut bacteria are associated with disease status and influence human behavior and mentality. Whether human brain injury alters the gut bacteria is yet unclear, we tested 20 fecal samples from patients with cerebral intraparenchymal hemorrhage and corresponding healthy controls through metagenomic shotgun sequencing. The composition of patients gut bacteria changed significantly at the phylum level Verrucomicrobiota was the specific phylum colonized in the patients gut. The functional alteration was observed in the patients gut bacteria, including high metabolic activity for nutrients or neuroactive compounds, strong antibiotic resistance, and less virulence factor diversity. The changes in the transcription and metabolism of differential species were more evident than those of the non-differential species between groups, which is the primary factor contributing to the functional alteration of patients with cerebral intraparenchymal hemorrhage.

Risk Factors on the Incidence and Prognostic Effects of Colorectal Cancer With Brain Metastasis A SEER-Based Study.

Colorectal cancer (CRC) with brain metastases (BM) is uncommon and often diagnosed at a late stage. The aims of this study were to identify the clinical factors that can influence the incidence of CRC patients with BM (CRCBM) and to investigate the impact of clinical factors and therapies on the outcomes of CRCBM. Between 2010 and 2018, patients with CRCBM were enrolled under the Surveillance, Epidemiology, and End Results (SEER) program. Multivariable logistic and Cox regression models were used to identify risk factors and prognostic factors of BM. Kaplan-Meier curve and log-rank test were used to evaluate overall survival (OS) and tumor-specific survival (CSS) of CRCBM patients. A total of 195 (0.34%) CRC patients initially diagnosed with BM were included for analysis. The positive level of CEA, pN2a-b, and additional organ metastases were positively associated with developing BM from the CRC cohort ( Although the overall prognosis of CRCBM patients was extremely poor, the positive level of CEA, pN2a-b, and distant metastases could be bad risk factors for the incidence of CRCBM. In addition, only systematic treatment was found to be a negative prognostic factor for CRCBM patients. These related factors can provide more valuable reference for clinical individualized treatments.

The Role of m5C-Related lncRNAs in Predicting Overall Prognosis and Regulating the Lower Grade Glioma Microenvironment.

Glioma is the most lethal primary brain tumor with a poor prognosis and high recurrence rate. Enormous efforts have been made to find therapeutic targets for gliomas. In the current study, we identified m5C-related lncRNAs through Pearson correlation analysis by the criteria R>0.5 and p<0.001 in TCGA LGG and CGGA325 datasets. We then established an eight-lncRNA m5C-related prognostic signature (m5C LPS) through lasso cox regression analysis and multivariate analysis. The performance of the signature was confirmed in the CGGA325 dataset and evaluated in differential subgroups divided by relevant clinicopathological characteristics. Patients were then divided into high and low risk groups using risk scores calculated with the signature. Next, we performed GO, KEGG and gene set enrichment analysis (GSEA) and identified the m5C LPS to be related with glioma microenvironment, immune response, EMT, cell cycle, and hypoxia. Correlation of the risk groups with immune cell infiltration, somatic mutation, and CNVs was then explored. Responses to immuno- and chemotherapies in different risk groups were evaluated using submap and pRRophetic R packages respectively. The high-risk group was more sensitive to anti-CTLA4 therapy and to compounds including Temozolomide, Bleomycin, Cisplatin, Cyclopamine, A.443654 (Akt inhibitor), AZD6482 (PI3K inhibitor), GDC0941(PI3K inhibitor), and metformin. We present for the first time a m5C-related lncRNA signature for lower grade glioma patient prognosis and therapy response prediction with validated performance, providing a promising target for future research.

Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis.

Mutation or loss of the tumor suppressor gene

NCAPG Promotes Tumor Progression and Modulates Immune Cell Infiltration in Glioma.

Glioma is one of the most deadly types of brain cancer. As it is highly invasive, the prognosis for glioma patients remains dismal, with median survival rarely exceeding 16 months. Thus, developing a new prognostic biomarker for glioma and investigating its molecular mechanisms is necessary for the development of an efficient treatment strategy. In this study, we analyzed a cohort of 1,131 glioma patients using RNA-seq data from The Cancer Genome Atlas (TCGA project) and Gene Expression Omnibus (GSE4290 and GSE16011 datasets), and validated the results using the RNA-seq data of 1,018 gliomas from the Chinese Glioma Genome Atlas (CGGA project). We used the R language as the main tool for statistical analysis and data visualization. We found that NCAPG, a mitosis-associated chromosomal condensing protein, is highly expressed in glioma tissues. Furthermore, the expression of NCAPG increased significantly with the increase in tumor grade, and high NCAPG expression was found to be a predictor of poor overall survival in glioma patients (

The Minimal Subcortical Electronic Threshold Predicts the Motor Deficit and Survivals in Non-Awake Surgery for Gliomas Involving the Motor Pathway.

Direct subcortical motor mapping is the golden criterion to detect and monitor the motor pathway during glioma surgery. Minimal subcortical monopolar threshold (MSCMT) means the minimal distance away from the motor pathway and is critical to decide to continue or interrupt glioma resection. However, the optimal cutoff value of MSCMT for glioma resection in non-awake patients has not been reported discreetly. In this study, we try to establish the safe cutoff value of MSCMT for glioma resection and analyzed its relationship with postoperative motor deficit and long-term survivals. We designed this prospective study with high-frequency electronic stimulus method. The cutoff MSCMT of postoperative motor deficits was statistically calculated by receiver operating characteristic (ROC) curve, and its relationship with motor deficit and survivals was analyzed by logistic and Cox regression, respectively. The cutoff MSCMT to predict motor deficit after surgery was 3.9 mA on day 1, 3.7 mA on day 7, 5.2 mA at 3 months, and 5.2 mA at 6 months. MSCMT ≤3.9 mA and MSCMT ≤5.2 mA independently predicted postoperative motor deficits at four times after surgery ( This study showed strong cause-effect relation between MSCMT and postoperative motor deficit and prognoses. The cutoff MSCMT was dug out to avoid postoperative motor deficit. Further studies are needed to establish the results above.

The Potential Role of Exosomes in the Treatment of Brain Tumors, Recent Updates and Advances.

Exosomes are small endosomal derived membrane extracellular vesicles that contain cell-specific cargos such as lipid, protein, DNA, RNA, miRNA, long non-coding RNA, and some other cell components that are released into surrounding body fluids upon the fusion of multivesicular bodies (MVB) and the plasma membrane. Exosomes are a one-of-a-kind cell-to-cell communication mechanism that might pave the way for target therapy. The use of exosomes as a therapeutic potential in a variety of cancers has been and is still being investigated. One of the most important of these has been the use of exosomes in brain tumors therapy. Exosome contents play a crucial role in brain tumor progression by providing a favorable niche for tumor cell proliferation. Also, exosomes that are secreted from tumor cells, lead to the protection of tumor cells and their proliferation in the tumor environment by reducing the inflammatory response and suppression of the immune system. Although some treatment protocols such as surgery, chemotherapy, and radiotherapy are common in brain tumors, they do not result in complete remission in the treatment of some malignant and metastatic brain tumors. Identifying, targeting, and blocking exosomes involved in the progression of brain tumors could be a promising way to reduce brain tumor progression. On the other way, brain tumor therapy with effective therapeutic components such as siRNAs, mRNAs, proteins, could be developed. Finally, our research suggested that exosomes of nanoscale sizes might be a useful tool for crossing the blood-brain barrier and delivering effective content. However, further research is needed to fully comprehend the potential involvement of the exosome in brain tumor therapy protocols.

Paradoxical Association Between Relative Cerebral Blood Volume Dynamics Following Chemoradiation and Increased Progression-Free Survival in Newly Diagnosed IDH Wild-Type MGMT Promoter Methylated Glioblastoma With Measurable Disease.

While relative cerebral blood volume (rCBV) may be diagnostic and prognostic for survival in glioblastoma (GBM), changes in rCBV during chemoradiation in the subset of newly diagnosed GBM with subtotal resection and the impact of MGMT promoter methylation status on survival have not been explored. This study aimed to investigate the association between rCBV response, MGMT methylation status, and progression-free (PFS) and overall survival (OS) in newly diagnosed GBM with measurable enhancing lesions. 1,153 newly diagnosed IDH wild-type GBM patients were screened and 53 patients (4.6%) had measurable post-surgical tumor (>1mL). rCBV was measured before and after patients underwent chemoradiation. Patients with a decrease in rCBV >10% were considered rCBV Responders, while patients with an increase or a decrease in rCBV <10% were considered rCBV Non-Responders. The association between change in enhancing tumor volume, change in rCBV, MGMT promotor methylation status, and PFS or OS were explored. A decrease in tumor volume following chemoradiation trended towards longer OS (p0.12 median OS26.8 vs. 16.3 months). Paradoxically, rCBV Non-Responders had a significantly improved PFS compared to Responders (p0.047 median PFS9.6 vs. 7.2 months). MGMT methylated rCBV Non-Responders exhibited a significantly longer PFS compared to MGMT unmethylated rCBV Non-Responders (p<0.001 median PFS0.5 vs. 7.1 months), and MGMT methylated rCBV Non-Responders trended towards longer PFS compared to methylated rCBV Responders (p0.089 median PFS20.5 vs. 13.8 months). This preliminary report demonstrates that in newly diagnosed IDH wild-type GBM with measurable enhancing disease after surgery (5% of patients), an enigmatic non-response in rCBV was associated with longer PFS, particularly in MGMT methylated patients.

The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness.

Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor survival. In GBM, ADAM8 affects intracellular kinase signaling and increases expression levels of osteopontinSPP1 and matrix metalloproteinase 9 (MMP9) by an unknown mechanism. Here we explored whether microRNA (miRNA) expression levels could be regulators of MMP9 expression in GBM cells expressing ADAM8. Initially, we identified several miRNAs as dysregulated in ADAM8-deficient U87 GBM cells. Among these, the tumor suppressor miR-181a-5p was significantly upregulated in ADAM8 knockout clones. By inhibiting kinase signaling, we found that ADAM8 downregulates expression of miR-181a-5p

TransConver transformer and convolution parallel network for developing automatic brain tumor segmentation in MRI images.

Medical image segmentation plays a vital role in computer-aided diagnosis (CAD) systems. Both convolutional neural networks (CNNs) with strong local information extraction capacities and transformers with excellent global representation capacities have achieved remarkable performance in medical image segmentation. However, because of the semantic differences between local and global features, how to combine convolution and transformers effectively is an important challenge in medical image segmentation. In this paper, we proposed TransConver, a U-shaped segmentation network based on convolution and transformer for automatic and accurate brain tumor segmentation in MRI images. Unlike the recently proposed transformer and convolution based models, we proposed a parallel module named transformer-convolution inception (TC-inception), which extracts local and global information via convolution blocks and transformer blocks, respectively, and integrates them by a cross-attention fusion with global and local feature (CAFGL) mechanism. Meanwhile, the improved skip connection structure named skip connection with cross-attention fusion (SCCAF) mechanism can alleviate the semantic differences between encoder features and decoder features for better feature fusion. In addition, we designed 2D-TransConver and 3D-TransConver for 2D and 3D brain tumor segmentation tasks, respectively, and verified the performance and advantage of our model through brain tumor datasets. We trained our model on 335 cases from the training dataset of MICCAI BraTS2019 and evaluated the models performance based on 66 cases from MICCAI BraTS2018 and 125 cases from MICCAI BraTS2019. Our TransConver achieved the best average Dice score of 83.72% and 86.32% on BraTS2019 and BraTS2018, respectively. We proposed a transformer and convolution parallel network named TransConver for brain tumor segmentation. The TC-Inception module effectively extracts global information while retaining local details. The experimental results demonstrated that good segmentation requires the model to extract local fine-grained details and global semantic information simultaneously, and our TransConver effectively improves the accuracy of brain tumor segmentation.

Atypical Presentation and Neuroradiological Features of Giant Ecchordosis Physalyphora in a Seven-Year-Old Patient A Case Report.

This study presented the rare case of a seven-year-old patient with atypical presentation and neuroradiological features of giant ecchordosis physaliphora. The patient underwent cross-sectional imaging due to persistent headache without neurological or visual symptoms. CT scan imaging of the head revealed a hypodense tumor in the prepontine cistern. This lesion caused smooth scalloping of the dorsal clivus without aggressive erosion or calcification, and an osseous stalk was also identified between the lesion and the dorsal wall of the clivus. Sagittal T1 weighted image (T1WI) MRI showed a bilobed, solid and cystic, well-defined lesion, measuring 3.5 cm in terms of craniocaudal diameter, found alongside the midline within the prepontine cistern. After the evaluation of radiological images, the patient was then subjected to endoscopic transnasal complete tumor excision. Histological examination revealed sheets and lobules of clear cells with cytoplasmic globules physaliphorous cells, and myxoid stroma. There was nuclear pleomorphism associated with focal areas of necrosis. After full recovery and discharge, the patient was followed up for the first year with four-month interval brain MRI scans showing no evidence of residual tumors. On the 12 months follow-up scan, the MRI scan revealed a 1.5 x 0.7 cm recurrent mass in the retroclival right paramidline prepontine cistern, which was most notably seen on the diffusion-weighted images. Series of proton beam therapy with annual MRI scans demonstrated regression of the tumor, eventually allowing the patient to live free of neurological symptoms up to this day. Results suggest that the utilization of radiological imaging such as CT and MRI scans was successful in identifying the ecchordosis physaliphora and differentiating it from chordomas. It can also be inferred that atypical radiological and histopathological findings of ecchordosis physaliphora lesions might suggest that they are prone to recurrence, which is an atypical feature for such entities. Further studies are recommended to explore and better understand these uncommon observations in patients with ecchordosis physaliphora.

Delayed Metastasis of Clear Cell Renal Carcinoma to the Colon in the Setting of Benign Kidney Disease.

Clear cell renal carcinoma (CCRC) is a common variant of renal cell carcinoma (RCC), which presents with unpredictable features. The occurrence of RCC in those with autosomal dominant polycystic kidney disease (ADPKD) is debated. Most studies agree that ADPKD does not increase the risk of RCC however, it makes diagnosing RCC difficult due to the nature of the disease. RCC frequently metastasizes to the lungs, lymph nodes, bones, liver, adrenal glands, and brain, but rarely metastasizes to the colon. In all previous reports, primary RCC was already diagnosed in the kidneys thus, metastatic CCRC to the colon has never been described in the current literature in the absence of a primary renal tumor. Here, we report a rare presentation of metastatic CCRC wherein a patient with ADPKD presented with an obstructing sigmoid mass six years after bilateral nephrectomy for pathologically benign cysts. Despite a close follow-up after nephrectomy, our patients non-specific symptoms were attributed to underlying comorbidities and more likely etiologies of back pain, diarrhea, and anemia, thus delaying and complicating the diagnosis of CCRC which subsequently led to metastases at the time of presentation. Although past literature has described CCRC metastases to other parts of the gastrointestinal tract or even described primary clear cell carcinoma of the colon, this is the first case in which a patient with benign cystic renal disease developed CCRC presenting as metastatic disease of the colon, rectum, liver, and lung. This paper will address the manifestations of ADPKD and postulate mechanisms for the unpredictable nature of this patients RCC metastasis.

Practical guidance for telemedicine use in neuro-oncology.

While the COVID-19 pandemic has catalyzed the expansion of telemedicine into nearly every specialty of medicine, few articles have summarized current practices and recommendations for integrating virtual care in the practice of neuro-oncology. This article identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarized including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations.

Optimal timing of radiotherapy following brain metastases surgery.

There is growing evidence supporting the need for a short time delay before starting radiotherapy (RT) treatment postsurgery for most optimal responses. The timing of RT initiation and effects on outcomes have been evaluated in a variety of malignancies, but the relationship remains to be well established for brain metastasis. Retrospective study of 176 patients (aged 18-89 years) with brain metastases at a single institution (March 2009 to August 2018) who received RT following surgical resection. Time interval (≤22 and >22 days) from surgical resection to initiation of RT and any potential impact on patient outcomes were assessed. Patients who underwent RT >22 days after surgical resection had a decreased risk for all-cause mortality of 47.2% (95% CI 8.60, 69.5%). Additionally, waiting >40 days for RT after surgical resection more than doubled the risk of tumor progression adjusted hazard ratio 2.02 (95% CI 1.12, 3.64). Findings indicate that a short interval delay (>22 days) following surgical resection is required before RT initiation for optimal treatment effects in brain metastasis. Our timing of RT postsurgical resection data adds definition to current heterogeneity in RT timing, which is especially important for standardized clinical trial design and patient outcomes.

Prescription preferences of antiepileptic drugs in brain tumor patients An international survey among EANO members.

This study aimed at investigating antiepileptic drug (AED) prescription preferences in patients with brain tumor-related epilepsy (BTRE) among the European neuro-oncology community, the considerations that play a role when initiating AED treatment, the organization of care, and practices with regard to AED withdrawal. A digital survey containing 31 questions about prescription preferences of AEDs was set out among members of the European Association of Neuro-Oncology (EANO). A total of 198 respondents treating patients with BTRE participated of whom 179 completed the entire survey. Levetiracetam was the first choice in patients with BTRE for almost all respondents (90% 162181). Levetiracetam was considered the most effective AED in reducing seizure frequency (72% 131181) and having the least adverse effects (48% 87181). Common alternatives for levetiracetam as equivalent first choice included lacosamide (33% 59181), lamotrigine (22% 40181), and valproic acid (21% 38181). Most crucial factors to choose a specific AED were potential adverse effects (82% 148181) and interactions with antitumor treatments (76% 137181). In the majority of patients, neuro-oncologists were involved in the treatment of seizures (73% 132181)). Other relevant findings were that a minority of respondents ever prescribe AEDs in brain tumor patients without epilepsy solely as prophylaxis (29% 53181), but a majority routinely considers complete AED withdrawal in BTRE patients who are seizure-free after antitumor treatment (79% 141179). Our results show that among European professionals treating patients with BTRE levetiracetam is considered the first choice AED, with the presumed highest efficacy and least adverse effects.

Epidemiology of pineoblastoma in the United States, 2000-2017.

Pineoblastoma (PB) is a rare malignant brain tumor originating in the pineal gland. Here, we provide a comprehensive epidemiological analysis of PB in the United States from 2000 to 2017. Data on 1133 patients with PB were acquired from the Central Brain Tumor Registry of the United States, in collaboration with the Centers for Disease Control and Prevention and the National Cancer Institute, from 2000 to 2017. Age-adjusted incidence rates (AAIRs) per 100 000 and incidence rate ratios (IRRs) were reported for age, sex, race, and ethnicity. Using the National Program of Cancer Registries survival database, median survival and hazard ratios (HRs) were evaluated for overall survival from 2001 to 2016. Incidence was highest in ages 0-4 years (AAIR 0.049, 95% CI 0.042-0.056), decreasing as age increased. Incidence was higher among patients who are Black compared to patients who are White (IRR 1.71, 95% CI 1.48-1.98, PB incidence is highest among children and patients who are Black, and there may be a potential interaction between these factors. Survival is worse among males, young children, and elderly adults, and those who received no surgery. Comprehensive, population-based statistics provide critical information on PB characteristics that could be useful in impacting patient care and prognosis.

Induction of IDO1 and Kynurenine by Serine Proteases Subtilisin, Prostate Specific Antigen, CD26 and HtrA A New Form of Immunosuppression

Several serine proteases have been linked to autoimmune disorders and tumour initiation although the mechanisms are not fully understood. Activation of the kynurenine pathway enzyme indoleamine-2,3-dioxygenase (IDO1) modulates cellular activity in the brain, tolerogenesis in the immune system and is a major checkpoint in cancer development. We now report that

Tenascin-C can Serve as an Indicator for the Immunosuppressive Microenvironment of Diffuse Low-Grade Gliomas.

The development and progression of glioma are associated with the tumor immune microenvironment. Diffuse low-grade gliomas (LGGs) with higher immunosuppressive microenvironment tend to have a poorer prognosis. The study aimed to find a biological marker that can reflect the tumor immune microenvironment status and predict prognosis of LGGs. The target gene tenascin-C (TNC) was obtained by screening the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) databases. Then samples of LGGs were collected for experimental verification with immunohistochemistry, immunofluorescence, immunoblotting, quantitative real-time PCR. ELISA was employed to determine the content of TNC in serum and examine its relationship with the tumor immune microenvironment. Eventually, the sensitivity of immunotherapy was predicted on the basis of the content of TNC in LGGs. In the high-TNC subgroup, the infiltration of immunosuppressive cells was increased (MDSC r0.4721, Treg r0.3154, etc.), and immune effector cells were decreased NKT, γδT, etc. (p<0.05), immunosuppressive factors were elevated TGF-β, IL10, Our data suggested that TNC could serve as an indicator for the immunosuppressive microenvironment status and the prognosis of LGGs. Moreover, it could also act as a predictor for the effect of immunotherapy on LGG patients.

Observation of Clinicopathologic Features of Pituitary Adenoma With Neuronal Differentiation.

To investigate the clinicopathologic features of pituitary adenoma with neuronal differentiation. Four patients with mixed gangliocytoma-pituitary adenomas between January 2011 and January 2021 and 111 new-onset patients with adenomas between January 2019 and June 2021 who attended the First Affiliated Hospital of Fujian Medical University were included in the study. The histological and immunohistochemical findings were analyzed. Neuronal differentiation marker staining was performed on new-onset adenomas, and the related literature was reviewed. Altogether, more than 100 mixed gangliocytoma-pituitary adenoma cases have been reported in the literature until now, of which pituitary-specific POU-class homeodomain transcription 1 (PIT1) positive adenomas are more frequently observed. In the present study, all 4 patients we described were female, aged 29 to 53 years (mean 39 years). Clinically, 34 patients presented with acromegaly, and 12 patients presented with headache. Histologically, the tumor was composed of two distinct mixed components. The one was a population of neoplastic ganglionic cells with large nuclei, prominent nucleoli, and abundant basophilic cytoplasm embedded in a fibrillary background. Stains of chromograninA (CgA), synaptophysin (Syn), Calretinin (CR) were positive. Axotomy-like expression was observed in neurofilament (NF) staining. PIT1 was expressed in partial ganglionic cells in all cases. The other component was a population of small uniform cells with round nuclei and acidophilic cytoplasm. Prolactin (PRL) and growth hormone (GH) were positive in all 4 cases. PIT1 was positive in the nuclei of adenomas. Although adenomas and ganglionic regions varied in histology, there was a population of cells with neuronal differentiation expressing PIT1. Additionally, axotomy-like expression of NF staining could be seen in a distant area of adenoma regions. A total of 111 cases of adenomas without ganglionic cells were included in this study, including 7 cases with neuronal differentiation. Among them, 4 cases were prolactinomas, 2 cases were somatotroph adenomas, and 1 case was corticotroph adenoma. 67 cases were PIT1-positive adenomas. And the remaining one case is T-PIT-positive adenoma. Mixed gangliocytoma-pituitary adenomas are rare tumors with neuronal differentiation. The majority of MGAs are associated with endocrinopathies, mainly acromegaly. Our results suggest that PIT1-positive pituitary adenomas may have neural differentiation potential, which may not be unusual. This indication supports the possibility that the neuronal transdifferentiation of adenomatous cells is a possible mechanism, and the underlying mechanism requires further elucidation.

Emerging MR Imaging and Spectroscopic Methods to Study Brain Tumor Metabolism.

Proton magnetic resonance spectroscopy (

Construction and Validation of an Immune-Related Risk Score Model for Survival Prediction in Glioblastoma.

As one of the most important brain tumors, glioblastoma (GBM) has a poor prognosis, especially in adults. Immune-related genes (IRGs) and immune cell infiltration are responsible for the pathogenesis of GBM. This study aimed to identify new tumor markers to predict the prognosis of patients with GBM. The Cancer Genome Atlas (TCGA) database and ImmPort database were used for model construction. The Wilcoxon rank-sum test was applied to identify the differentially expressed IRGs (DEIRGs) between the GBM and normal samples. Univariate Cox regression analysis and Kaplan-Meier analysis was performed to investigate the relationship between each DEIRG and overall survival. Next, multivariate Cox regression analysis was exploited to further explore the prognostic potential of DEIRGs. A risk-score model was constructed based on the above results. The area under the curve (AUC) values were calculated to assess the effect of the model prediction. Furthermore, the Chinese Glioma Genome Atlas (CGGA) dataset was used for model validation. STRING database and functional enrichment analysis were used for exploring the gene interactions and the underlying functions and pathways. The CIBERSORT algorithm was used for correlation analysis of the marker genes and the tumor-infiltrating immune cells. There were 198 DEIRGs in GBM, including 153 upregulated genes and 45 downregulated genes. Seven marker genes (LYNX1, PRELID1P4, MMP9, TCF12, RGS14, RUNX1, and CCR2) were filtered out by sequential screening for DEIRGs. The regression coefficients (0.0410, 1.335, 0.005, -0.021, 0.123, 0.142, and -0.329) and expression data of the marker genes were used to construct the model. The AUC values for 1, 2, and 3 years were 0.744, 0.737, and 0.749 in the TCGA-GBM cohort and 0.612, 0.602, and 0.594 in the CGGA-GBM cohort, respectively, which indicated a high predictive power. The results of enrichment analysis revealed that these genes were enriched in the activation of T cell and cytokine receptor interaction pathways. The interaction network map demonstrated a close relationship between the marker genes MMP9 and CCR2. Infiltration analysis of the immune cells showed that dendritic cells (DCs) could identify GBM, while LYNX1, RUNX1, and CCR2 were significantly positively correlated with DCs expression. This study analyzed the expression of IRGs in GBM and identified seven marker genes for the construction of an immune-related risk score model. These marker genes were found to be associated with DCs and were enriched in similar immune response pathways. These findings are likely to provide new insights for the immunotherapy of patients with GBM.

Establishment and Characterization of Brain Cancer Primary Cell Cultures From Patients to Enable Phenotypic Screening for New Drugs.

Kif15 Is Required in the Development of Auditory System Using Zebrafish as a Model.

Kif15, a kinesin family member, is powerful in the formation of bipolar spindles. There is emerging evidence indicating that Kif15 plays vital roles in influencing the growth of axons and interference with the progression of the tumor. However, the function of Kif15 in the auditory organs remains unknown. The Western blotting test was used to examine the effect of Kif15 downregulation by specific morpholino targeting Kif15 (Kif15-MO). The development of the inner ear and posterior lateral line (PLL) system in zebrafish was under continuous observation from spawns to 96 h postfertilization (hpf) to investigate the potential role of Kif15 in the auditory and vestibular system. We uncovered that Kif15 inhibition induced otic organ deformities in zebrafish, including malformed semicircular canals, abnormal number and location of otoliths, and reduced number of hair cells (HCs) both in utricle and saccule. Furthermore, a remarkable reduction in the number of PLL neuromasts was also explored in Kif15-MO morphants compared to the normal larvae. We also detected notably reduced activity in locomotion after Kif15 was knocked down. Additionally, we performed rescue experiments with co-injection of Kif15 mRNA and found that the Kif15 splicing MO-induced deformities in otic vesicle and PLL of zebrafish were successfully rescued, and the severely reduced locomotor activity caused by Kif15-MO was partially rescued compared to the control-MO (Con-MO) embryos. Our findings uncover that Kif15 is essential in the early development of auditory and vestibular organs using zebrafish as models.

Low-grade gliomas (LGG) are primary brain tumors that often affect predominantly young adults, which usually have a painless course, and have a longer survival period compared to patients with high-grade gliomas. Relatively established treatment options include surgery, radiotherapy, chemotherapy or combination therapy, as well as individualized management based on tumor location, histology, molecular features and patient characteristics. Due to the rapid development of targeted therapies, the development of new molecular targets is now a very promising research direction. We explored the diagnostic value, clinical relevance, and molecular function of deoxynucleotidyl transferase terminal-interacting proteins 2 ( In LGG patients, This study demonstrated that DNTTIP12 had diagnostic and prognostic value in LGG patients. The biological mechanisms of

Central Nervous System Delivery of the Catalytic Subunit of DNA-Dependent Protein Kinase Inhibitor Peposertib as Radiosensitizer for Brain Metastases.

Cytotoxic effects of chemotherapy and radiation therapy (RT) used for the treatment of brain metastases results from DNA damage within cancer cells. Cells rely on highly evolved DNA damage response (DDR) pathways to repair the damage caused by these treatments. Inhibiting these repair pathways can further sensitize cancer cells to chemotherapy and RT. The catalytic subunit of DNA-dependent protein kinase, in a complex with Ku80 and Ku70, is a pivotal regulator of the DDR, and peposertib is a potent inhibitor of this catalytic subunit. The characterization of central nervous system (CNS) distributional kinetics of peposertib is critical in establishing a therapeutic index in the setting of brain metastases. Our studies demonstrate that the delivery of peposertib is severely restricted into the CNS as opposed to peripheral organs, by active efflux at the blood-brain barrier (BBB). Peposertib has a low free fraction in the brain and spinal cord, further reducing the active concentration, and distributes to the same degree within different anatomic regions of the brain. However, peposertib is heterogeneously distributed within the metastatic tumor, where its concentration is highest within the tumor core (with disrupted BBB) and substantially lower within the invasive tumor rim (with a relatively intact BBB) and surrounding normal brain. These findings are critical in guiding the potential clinical deployment of peposertib as a radiosensitizing agent for the safe and effective treatment of brain metastases. SIGNIFICANCE STATEMENT Effective radiosensitization of brain metastases while avoiding toxicity to the surrounding brain is critical in the development of novel radiosensitizers. The central nervous system distribution of peposertib, a potent catalytic subunit of DNA-dependent protein kinase inhibitor, is restricted by active efflux in the normal blood-brain barrier (BBB) but can reach significant concentrations in the tumor core. This finding suggests that peposertib may be an effective radiosensitizer for intracranial tumors with an open BBB, while limited distribution into normal brain will decrease the risk of enhanced radiation injury.

Spatiotemporal changes in along-tract profilometry of cerebellar peduncles in cerebellar mutism syndrome.

Cerebellar mutism syndrome, characterised by mutism, emotional lability and cerebellar motor signs, occurs in up to 39% of children following resection of medulloblastoma, the most common malignant posterior fossa tumour of childhood. Its pathophysiology remains unclear, but prior studies have implicated damage to the superior cerebellar peduncles. In this study, the objective was to conduct high-resolution spatial profilometry of the cerebellar peduncles and identify anatomic biomarkers of cerebellar mutism syndrome. In this retrospective study, twenty-eight children with medulloblastoma (mean age 8.8 ± 3.8 years) underwent diffusion MRI at four timepoints over one year. Forty-nine healthy children (9.0 ± 4.2 years), scanned at a single timepoint, served as age- and sex-matched controls. Automated Fibre Quantification was used to segment cerebellar peduncles and compute fractional anisotropy (FA) at 30 nodes along each tract. Thirteen patients developed cerebellar mutism syndrome. FA was significantly lower in the distal third of the left superior cerebellar peduncle pre-operatively in all patients compared to controls (FA in proximal third 0.228, middle and distal thirds 0.270, p 0.01, Cohens d 0.927). Pre-operative differences in FA did not predict cerebellar mutism syndrome. However, post-operative reductions in FA were highly specific to the distal left superior cerebellar peduncle, and were most pronounced in children with cerebellar mutism syndrome compared to those without at the 1-4 month follow up (0.325 vs 0.512, p 0.042, d 1.36) and at the 1-year follow up (0.342, vs 0.484, p 0.038, d 1.12). High spatial resolution cerebellar profilometry indicated a site-specific alteration of the distal segment of the superior cerebellar peduncle seen in cerebellar mutism syndrome which may have important surgical implications in the treatment of these devastating tumours of childhood.

Magnetic Resonance Imaging and Targeted Biopsies Compared to Transperineal Mapping Biopsies Before Focal Ablation in Localised and Metastatic Recurrent Prostate Cancer After Radiotherapy.

Recurrent prostate cancer after radiotherapy occurs in one in five patients. The efficacy of prostate magnetic resonance imaging (MRI) in recurrent cancer has not been established. Furthermore, high-quality data on new minimally invasive salvage focal ablative treatments are needed. To evaluate the role of prostate MRI in detection of prostate cancer recurring after radiotherapy and the role of salvage focal ablation in treating recurrent disease. The FORECAST trial was both a paired-cohort diagnostic study evaluating prostate multiparametric MRI (mpMRI) and MRI-targeted biopsies in the detection of recurrent cancer and a cohort study evaluating focal ablation at six UK centres. A total of 181 patients were recruited, with 155 included in the MRI analysis and 93 in the focal ablation analysis. Patients underwent choline positron emission tomographycomputed tomography and a bone scan, followed by prostate mpMRI and MRI-targeted and transperineal template-mapping (TTPM) biopsies. MRI was reported blind to other tests. Those eligible underwent subsequent focal ablation. An amendment in December 2014 permitted focal ablation in patients with metastases. Primary outcomes were the sensitivity of MRI and MRI-targeted biopsies for cancer detection, and urinary incontinence after focal ablation. A key secondary outcome was progression-free survival (PFS). Staging whole-body imaging revealed localised cancer in 128 patients (71%), with involvement of pelvic nodes only in 13 (7%) and metastases in 38 (21%). The sensitivity of MRI-targeted biopsy was 92% (95% confidence interval CI 83-97%). The specificity and positive and negative predictive values were 75% (95% CI 45-92%), 94% (95% CI 86-98%), and 65% (95% CI 38-86%), respectively. Four cancer (6%) were missed by TTPM biopsy and six (8%) were missed by MRI-targeted biopsy. The overall MRI sensitivity for detection of any cancer was 94% (95% CI 88-98%). The specificity and positive and negative predictive values were 18% (95% CI 7-35%), 80% (95% CI 73-87%), and 46% (95% CI 19-75%), respectively. Among 93 patients undergoing focal ablation, urinary incontinence occurred in 15 (16%) and five (5%) had a grade ≥3 adverse event, with no rectal injuries. Median follow-up was 27 mo (interquartile range 18-36) overall PFS was 66% (interquartile range 54-75%) at 24 mo. Patients should undergo prostate MRI with both systematic and targeted biopsies to optimise cancer detection. Focal ablation for areas of intraprostatic recurrence preserves continence in the majority, with good early cancer control. We investigated the role of magnetic resonance imaging (MRI) scans of the prostate and MRI-targeted biopsies in outcomes after cancer-targeted high-intensity ultrasound or cryotherapy in patients with recurrent cancer after radiotherapy. Our findings show that these patients should undergo prostate MRI with both systematic and targeted biopsies and then ablative treatment focused on areas of recurrent cancer to preserve their quality of life. This trial is registered at ClinicalTrials.gov as NCT01883128.

A Pan-Cancer Analysis on the Systematic Correlation of MutS Homolog 2 (MSH2) to a Malignant Tumor.

MutS homolog 2 (MSH2) is a crucial participant in human DNA repair, and lots of the studies functionally associated with it were begun with hereditary nonpolyposis colorectal cancer (HNPCC). MSH2 has also been reported to take part in the progresses of various tumors formation. With the help of GTEx, CCLE, and TCGA pan-cancer databases, the analysis of MSH2 gene distribution in both tumor tissues and normal control tissues was carried out. Kaplan-Meyer survival plots and COX regression analysis were conducted for the assessment into the MSH2s impact on tumor patients clinical prognosis. In an investigation to the association of MSH2 expression with immune infiltration level of various tumors and a similar study on tumor immune neoantigens, microsatellite instability was subsequently taken. It was found that high expression of MSH2 is prevalent in most cancers. MSH2s efficacy on clinical prognosis as well as immune infiltration in tumor patients revealed a fact that expression of MSH2 in prostate adenocarcinoma (PRAD), brain lower-grade glioma (LGG), breast-invasive carcinoma (BRCA), and head and neck squamous cell carcinoma (HNSC) posed a significant correlation with the immune cell infiltration level of patients. Likewise as above, MSH2s expression comes in a similar trend with tumor immune neoantigens and microsatellite instability. MSH2s expression in the majority of tumors is a direct factor to the activation of tumor-associated pathways as well as immune-associated pathways. MSH2s early screening or even therapeutic target role for sarcoma (SARC) diagnosis is contributing to the efficiency of early screening and overall survival in SARC patients.

Drp1-Mediated Mitochondrial Metabolic Dysfunction Inhibits the Tumor Growth of Pituitary Adenomas.

Metabolic changes have been suggested to be a hallmark of tumors and are closely associated with tumorigenesis. In a previous study, we demonstrated the role of lactate dehydrogenase in regulating abnormal glucose metabolism in pituitary adenomas (PA). As the key organelle of oxidative phosphorylation (OXPHOS), mitochondria play a vital role in the energy supply for tumor cells. However, few attempts have been made to elucidate mitochondrial metabolic homeostasis in PA. Dynamin-related protein 1 (Drp1) is a member of the dynamin superfamily of GTPases, which mediates mitochondrial fission. This study is aimed at investigating whether Drp1 affects the progression of PA through abnormal mitochondrial metabolism. We analyzed the expression of dynamin-related protein 1 (Drp1) in 20 surgical PA samples. The effects of Drp1 on PA growth were assessed in vitro and in xenograft models. We found an upregulation of Drp1 in PA samples with a low proliferation index. Knockdown or inhibition of Drp1 enhanced the proliferation of PA cell lines in vitro, while overexpression of Drp1 could reversed such effects. Mechanistically, overexpressed Drp1 damaged mitochondria by overproduction of reactive oxygen species (ROS), which induced mitochondrial OXPHOS inhibition and decline of ATP production. The energy deficiency inhibited proliferation of PA cells. In addition, overexpressed Drp1 promoted cytochrome c release from damaged mitochondria into the cytoplasm and then activated the downstream caspase apoptotic cascade reaction, which induced apoptosis of PA cells. Moreover, the decreased ATP production induced by Drp1 overexpressing activated the AMPK cellular energy stress sensor and enhanced autophagy through the AMPK-ULK1 pathway, which might play a protective role in PA growth. Furthermore, overexpression of Drp1 repressed PA growth in vivo. Our data indicates that Drp1-mediated mitochondrial metabolic dysfunction inhibits PA growth by affecting cell proliferation, apoptosis, and autophagy. Selectively targeting mitochondrial metabolic homeostasis stands out as a promising antineoplastic strategy for PA therapy.

Early Life Exposure to Tumor Necrosis Factor Induces Precocious Sensorimotor Reflexes Acquisition and Increases Locomotor Activity During Mouse Postnatal Development.

Inflammation appears as a cardinal mediator of the deleterious effect of early life stress exposure on neurodevelopment. More generally, immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life. Cytokines are also required for normal brain function in homeostatic conditions and play a role in neurodevelopmental processes. Despite these latter studies, whether pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) impact neurodevelopmental trajectories and behavior during the immediate postnatal period remains to be elucidated. To address this issue, we have injected mouse pups daily with recombinant TNF from postnatal day (P)1 to P5. This yielded a robust increase in peripheral and central TNF at P5, and also an increase of additional pro-inflammatory cytokines. Compared to control pups injected with saline, mice injected with TNF acquired the righting and the acoustic startle reflexes more rapidly and exhibited increased locomotor activity 2 weeks after birth. Our results extend previous work restricted to adult behaviors and support the notion that cytokines, and notably TNF, modulate early neurodevelopmental trajectories.

Limited field adaptive radiotherapy for glioblastoma changes in target volume and organ at risk doses.

This study aimed to investigate the tumor volume changes occurring during limited-field radiotherapy (RT) for glioblastoma patients and whether a volume-adapted boost planning approach provided any benefit on tumor coverage and normal tissue sparing. Twenty-four patients underwent simulation with magnetic resonance (MR) and computed tomography (CT) scans prior to RT (MRinitial, CTinitial) and boost treatment (MRadapt, CTadapt). For the boost phase, MRinitial and MRadapt images were used to delineate GTV2 and GTV2adapt, respectively. An initial boost plan (Planinitial) created on CTinitial for PTV2 was then reoptimized on CTadapt by keeping the same optimization and normalization values. Planadapt was generated on CTadapt for PTV2adapt volume. Dose volume histogram parameters for target volumes and organs-at-risk were compared using these boost plans generated on CTadapt. Planinitial and Planadaptive boost plans were summed with the first phase plan and the effect on the total dose was investigated. Target volume expansion was noted in 21% of patients while 79% had shrinkage. The average difference for the initial and adaptive gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) volumes were statistically significant. Maximum dose differences for brainstem and optic chiasm were significant. Healthy brain tissue V10 and ipsilateral optic nerve maximum doses were found to decrease significantly in Planadaptive. Results of this study confirm occurrence of target volume changes during RT for glioblastoma patients. An adaptive plan can provide better normal tissue sparing for patients with lesion shrinkage and avoid undercoverage of treatment volumes in case of target volume expansion especially when limited-fields are used.

Long-term Safety of Growth Hormone in Adults With Growth Hormone Deficiency Overview of 15 809 GH-Treated Patients.

Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin somatropin Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitaryhypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiacvascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathiccongenital GHD (0.64 0.43-0.91), but similar in those with pituitaryhypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipidsfasting blood glucose levels. These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.

Tetralol derivative NNC-55-0396 induces glioblastoma cell death by activating IRE1α, JNK1 and calcium signaling.

Mibefradil and NNC-55-0396, tetralol derivatives with a proven -ability to block T-type calcium channels in excitable cells, reduce cancer cell viability in vitro, causing cell death. Furthermore, they reduce tumor growth in preclinical models of Glioblastoma multiforme (GBM), a brain tumor of poor prognosis. Here we found that GBM cells treated with cytotoxic concentrations of NNC-55-0396 paradoxically increased cytosolic calcium levels through the activation of inositol triphosphate receptors (IP

Executive summary of American Radium Societys appropriate use criteria for the postoperative management of lower grade gliomas.

Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Societys brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45-54 Gy1.8-2.0 Gy, and for grade 3 gliomas is 59.4-60 Gy1.8-2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas.

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases.

Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. 10 patients were enrolled (median age-59 47-64, BM-5 1-10, 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (46 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

Surgical Resection of a Third Ventricle Nongerminomatous Germ Cell Tumor Two-Dimensional Operative Video.

Surgical resection of a pineal tumor growing into the third ventricle is difficult owing to the complex neurovascular structures, and nongerminomatous germ cell tumor is the most common malignant tumor in pediatric patients. Removing the tumor efficiently with minimal blood loss while protecting the surrounding neurovascular structure is challenging. We present a surgical case of a 9-year-old patient with a third ventricle nongerminomatous germ cell tumor (Video). Mass effect of the tumor or acute hydrocephalus is the possible reason for the coma. In this case, the reason of coma may be mass effect of the tumor, not the acute hydrocephalus. Informed consent was obtained from the patients guardian. Intraoperatively we used a modified right head-up park bench position and a linear incision. The right occipital bone flap was designed to cross the superior sagittal sinus and transverse sinus. The primary surgical approach was the occipital transtentorial approach an alternative was the supracerebellar infratentorial approach. After cutting the tentorium, a spatula was applied to retract the cerebellum and incised tentorium, with no extra brain retraction on the occipital lobe to minimize visual disturbance. The quadrigeminal cistern was opened, and the tumor was yellowish with heterogeneous consistency. Instead of rushing into the tumor debulking, we paid more attention to devascularization of the tumor from bilateral posterior medial choroidal arteries as much as possible. After debulking using an ultrasound aspirator, the tumor was removed in a piecemeal fashion, and the surgical field was inspected using an endoscope for any residue.

In situ targeting nanoparticles-hydrogel hybrid system for combined chemo-immunotherapy of glioma.

It is well known that glioma is currently the most malignant brain tumor. Because of the existence of blood-brain barrier (BBB) and tumor cell heterogeneity, systemic chemotherapy exerts unsatisfied therapeutic effect for the treatment of glioma after surgical resection and may even damage the bodys immune system. Here, we developed an in situ sustained-release hydrogel delivery system for combined chemo-immunotherapy of glioma by combined chemotherapy drug and immunoadjuvant through the resection cavity local delivery. Briefly, glioma homing peptide modified paclitaxel targeting nanoparticles (PNP

Long-term health outcomes of children born to mothers with hyperemesis gravidarum a systematic review and meta-analysis.

Hyperemesis gravidarum is characterized by severe nausea and vomiting in pregnancy, frequently resulting in severe maternal nutritional deficiency. Maternal undernutrition is associated with adverse offspring health outcomes. Whether hyperemesis gravidarum permanently affects offspring health remains unclear. This review aimed to evaluate the effects of maternal hyperemesis gravidarum on offspring health. MEDLINE and Embase were searched from inception to September 6, 2021. Studies reporting on health at any age beyond the perinatal period of children born to mothers with hyperemesis gravidarum were included. Two reviewers independently selected studies and extracted data. The Newcastle-Ottawa Quality Assessment Scale was used to assess risk of bias. We conducted a narrative synthesis and meta-analysis where possible. In meta-analyses with high heterogeneity (I Nineteen studies were included in this systematic review (n1,814,785 offspring). Meta-analysis (n619, 2 studies 1 among adolescents and 1 among adults) showed that hyperemesis gravidarum was associated with anxiety disorder (odds ratio, 1.74 95% confidence interval, 1.04-2.91 I Our systematic review showed that maternal hyperemesis gravidarum is associated with small increases in adverse health outcomes among children, including neurodevelopmental disorders, mental health disorders, and possibly testicular cancer, although evidence is based on few studies of low quality.

A novel peptide encoded by N6-methyladenosine modified circMAP3K4 prevents apoptosis in hepatocellular carcinoma.

Circular RNAs (circRNAs) regulate various biological activities and have been shown to play crucial roles in hepatocellular carcinoma (HCC) progression. However, only a few coding circRNAs have been identified in cancers, and their roles in HCC remain elusive. This study aimed to identify coding circRNAs and explore their function in HCC. CircMAP3K4 was selected from the CIRCpedia database. We performed a series of experiments to determine the characteristics and coding capacity of circMAP3K4. We then used in vivo and in vitro assays to investigate the biological function and mechanism of circMAP3K4 and its protein product, circMAP3K4-455aa, in HCC. We found circMAP3K4 to be an upregulated circRNA with coding potential in HCC. IGF2BP1 recognized the circMAP3K4 N6-methyladenosine modification and promoted its translation into circMAP3K4-455aa. Functionally, circMAP3K4-455aa prevented cisplatin-induced apoptosis in HCC cells by interacting with AIF, thus protecting AIF from cleavage and decreasing its nuclear distribution. Moreover, circMAP3K4-455aa was degraded through the ubiquitin-proteasome E3 ligase MIB1 pathway. Clinically, a high level of circMAP3K4 is an independent prognostic factor for adverse overall survival and adverse disease-free survival of HCC patients. CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, circMAP3K4 encoded circMAP3K4-455aa, protected HCC cells from cisplatin exposure, and predicted worse prognosis of HCC patients. Targeting circMAP3K4-455aa may provide a new therapeutic strategy for HCC patients, especially for those with chemoresistance. CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, IGF2BP1 facilitates circMAP3K4 peptide translation, then the circMAP3K4 peptide inhibits AIF cleavage and nuclear distribution, preventing HCC cells from cell death under stress and promoting HCC progression.

Utility of indocyanine green videoangiography with FLOW 800 analysis in brain tumour resection as a venous protection technique.

In regard to central nervous system tumour resection, preserving vital venous structures to avoid devastating consequences such as brain oedema and haemorrhage is important. However, in clinical practice, it is difficult to obtain clear and vivid intraoperative venous visualization and blood flow analyses. We retrospectively reviewed patients who underwent brain tumour resection with the application of indocyanine green videoangiography (ICG-VA) integrated with FLOW 800 from February 2019 to December 2020 and present our clinical cases to demonstrate the process of venous preservation. Galen, sylvian and superior cerebral veins were included in these cases. Clear documentation of the veins from different venous groups was obtained via ICG-VA integrated with FLOW 800, which semiquantitatively analysed the flow dynamics. ICG-VA integrated with FLOW 800 enabled us to achieve brain tumour resection without venous injury or obstruction of venous flux. ICG-VA integrated with FLOW 800 is an available method for venous preservation, although further comparisons between ICG-VA integrated with FLOW 800 and other techniques of intraoperative blood flow monitoring is needed.

MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma - An evaluation of the multicenter prospective skin cancer registry ADOREG.

Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAFMEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4-7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

Analysis of U87 glioma cells by dielectrophoresis.

Glioblastoma multiforme is the most aggressive and invasive brain cancer consisting of genetically and phenotypically altering glial cells. It has massive heterogeneity due to its highly complex and dynamic microenvironment. Here, electrophysiological properties of U87 human glioma cell line were measured based on a dielectrophoresis phenomenon to quantify the population heterogeneity of glioma cells. Dielectrophoretic forces were generated using a gold-microelectrode array within a microfluidic channel when 3 V

Mapping cognitive deficits in cancer patients after chemotherapy An Activation Likelihood Estimation meta-analysis of task-related fMRI studies.

Recent neuroimaging studies have reported alterations in brain activation during cognitive tasks in cancer patients who have undergone chemotherapy treatment. However, the location of these altered brain activation patterns after chemotherapy varies considerably across studies. The aim of the present meta-analysis was to quantitatively synthesise this body of evidence using Activation Likelihood Estimation to identify reliable regions of altered brain activation in cancer patients treated with chemotherapy, compared to healthy controls and no chemotherapy controls. Our systematic search identified 12 studies that adopted task-related fMRI on non-central nervous system cancer patients who received chemotherapy relative to controls. All studies were included in the analyses and were grouped into four contrasts. Cancer patients treated with chemotherapy showed reduced activation in the left superior parietal lobeprecuneus (family-wise error corrected p < .05) compared to no chemotherapy controls. No significant clusters were found in three of our contrasts. The majority of studies did not support an association between altered brain activation and cognitive performance after chemotherapy. Findings point towards a possible chemotherapy-induced alteration, which could inform targeted treatment strategies. With continued work in this field using homogenous task-related protocols and cancer populations, fMRI may be used as a biomarker of cognitive deficits in the future.

Clinical Prognostic Implications of Wnt Hub Genes Expression in Medulloblastoma.

Medulloblastoma is the most common type of pediatric malignant primary brain tumor, and about one-third of patients die due to disease recurrence and most survivors suffer from long-term side effects. MB is clinically, genetically, and epigenetically heterogeneous and subdivided into at least four molecular subgroups WNT, SHH, Group 3, and Group 4. We evaluated common differentially expressed genes between a Brazilian RNA-seq GSE181293 dataset and microarray GSE85217 dataset cohort of pediatric MB samples using bioinformatics methodology in order to identify hub genes of the molecular subgroups based on PPI network construction, survival and functional analysis. The main finding was the identification of five hub genes from the WNT subgroup that are tumor suppressors, and whose lower expression is related to a worse prognosis for MB patients. Furthermore, the common genes correlated with the five tumor suppressors participate in important pathways and processes for tumor initiation and progression, as well as development and differentiation, and some of them control cell stemness and pluripotency. These genes have not yet been studied within the context of MB, representing new important elements for investigation in the search for therapeutic targets, prognostic markers or for understanding of MB biology.

Mechanical transmission enables EMT cancer cells to drive epithelial cancer cell migration to guide tumor spheroid disaggregation.

Cell phenotype heterogeneity within tumor tissue, especially which due to the emergence of epithelial-mesenchymal transition (EMT) in cancer cells, is associated with cancer invasion and metastasis. However, our understanding of the cellular mechanism(s) underlying the cooperation between EMT cell and epithelial cancer cell migration remains incomplete. Herein, heterotypic tumor spheroids containing both epithelial and EMT cancer cells were generated in vitro. We observed that EMT cells dominated the peripheral region of the self-organized heterotypic tumor spheroid. Furthermore, our results demonstrated that EMT cells could serve as leader cells to improve the collective migration efficiency of epithelial cancer cells and promote dispersion and invasion of the tumor spheroids, which was regulated by the force transition between EMT cells and epithelial cancer cells. Mechanistically, our data further suggest that force transmission is mediated by heterophilic N-cadherinE-cadherin adhesion complexes between EMT and epithelial cancer cells. Impairment of N-cadherinE-cadherin adhesion complex formation abrogated the ability of EMT cells to guide epithelial cancer cell migration and blocked the dispersion of tumor spheroids. Together, our data provide new insight into the mechanical interaction between epithelial and EMT cancer cells through heterophilic cadherin adhesion, which enables cooperative tumor cell migration, highlighting the role of EMT cells in tumor invasion.

Protective effect of nuclear receptor related 1 (Nurr1) on nerves in rats with cerebral occlusionreperfusion injury and its mechanism.

Objective To investigate the protective effect of nuclear receptor related 1 (Nurr1) on nerves in rats with cerebral occlusionreperfusion injury and its mechanism. Methods Healthy male SD rats were chosen to construct the middle cerebral artery occlusionreperfusion (MCAOR) model. All rats were randomly divided into control group, model group, negative virus group, and Nurr1 over-expression group. Longas modified neurological severity score, Triphenyl tetrazolium chloride (TTC) staining, and immunofluorescence histochemical staining were applied respectively to detect the neurological injury, infarct volume, and density of microtubule associated protein-2 (MAP2) positive nerve cells in rats after MCAOR. Related kits were used to detect the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA). The protein levels of Nurr1, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), B cell lymphoma 2 (Bcl2), and Bcl2-assaciated X protein (BAX) were detected by Western blot. Results Nurr1 over-expression improved the neurological outcome with lower modified neurological severity scores by decreasing infarct volume, content of MDA, and expressions of inflammatory mediators including TNF-α, IL-1β, and pro-apoptosis related protein BAX. Nurr1 over-expression significantly increased the density of MAP2 positive nerve cells, activity of SOD, and the expression of anti-apoptosis related protein Bcl2. Conclusion Nurr1 may alleviate the cerebral ischemic damage by resisting oxidation, reducing inflammation, and inhibiting mitochondrial apoptotic signaling pathway-mediated cell apoptosis.

MRI assessment of glutamine uptake correlates with the distribution of glutamine transporters and cancer stem cell markers.

Glutamine provides carbon and nitrogen for macromolecular synthesis and participates in adenosine triphosphate (ATP) generation, anabolic metabolism, redox homeostasis, cell signaling, and cancer stem cell (CSC) metabolism. New treatment strategies targeting glutamine metabolism in cancer have emerged recently. We previously reported the magnetic resonance imaging (MRI) assessment of glutamine uptake by tumors and activated glutamine metabolism in CSC. In the present study, using MRI, we determined the correlation between glutamine uptake and the distribution of glutamine transporters, namely ASCT2 and SLC38A2 (SNAT2), glutaminase (GLS), and CSC markers, such as CD44 and CD166, in a mouse xenograft model of HT29 human colorectal cancer cells. MRI data revealed an obvious change in intensity following glutamine administration. Immunohistochemistry (IHC) results indicated that ASCT2 staining was stronger in regions that exhibited high glutamine uptake (p 0.0079). Significant differences were found in the IHC staining intensities of SNAT2, GLS, and CSC markers in the areas of high and low glutamine uptake (p 0.0079, p 0.0159 and p 0.0079, respectively). We also investigated the effect of an ASCT2 inhibitor on the uptake of glutamine using MRI. A statistically significant difference in the initial glutamine uptake was found after ASCT2 inhibitor administration. To conclude, glutamine uptake is positively correlated with the distribution of ASCT2 and certain CSC markers.

Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression.

Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic-based therapies. Here, we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the S

CDC42EP3 promotes glioma progression via regulation of CCND1.

Gliomas are the most common brain malignancies characterized by high degree of aggressiveness and high mortality. However, the underlying mechanism of glioma progression remains unclear. Here, we probed the role of CDC42EP3 (CDC42 effector protein 3) played in glioma development and its potential downstream mechanism. The expression of CDC42EP3 in tumor and normal brain tissues were examined through immunohistochemistry and we found the likelihood of CDC42EP3 overexpression was positively correlated with pathological grading. Patients with higher expression of CDC42EP3 were more likely to suffer from recurrence as well. Through constructing CDC42EP3-knockdown cell models, we discovered that silencing CDC42EP3 significantly restricted cell proliferation and migration but facilitated cell apoptosis in vitro. Inhibition on tumor growth mediated by CDC42EP3 depletion was further verified in vivo. Regarding downstream target of CDC42EP3, we found that it may positively regulate the expression of CCND1 through c-Myc-mediated transcription. Furthermore, our findings affirmed that effects of CDC42EP3 overexpression on cell proliferation, migration and apoptosis could be confined by depleting CCND1. In a word, this study reported the tumor-promoting role of CDC42EP3 in glioma progression which probably functioned through targeting CCND1.

Primary non-gestational mediastinal choriocarcinoma metastatic to the brainstem.

Choriocarcinoma is a highly malignant tumour emerging from the syncytiotrophoblast divided into gestational and non-gestational presentations. Primary choriocarcinoma of the mediastinum is rare. Metastases to the brain often occur however, brainstem involvement has not been reported for non-gestational choriocarcinoma. We described a middle-aged man who developed a complete left oculomotor nerve paralysis secondary to a brainstem tumour at the midbrain. The workup for the primary source of the brainstem tumour included a chest CT scan, which revealed a mediastinal mass. A mediastinal mass needle biopsy confirmed the diagnosis of primary mediastinal choriocarcinoma. Despite aggressive chemotherapy, the patient died 6 months after the initial presentation from neurological complications and multiorgan failure.

ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNFTrkB signaling.

To investigate the inhibitory effect of ANA-12 that blocks brain-derived neurotrophic factor (BDNF) tropomyosin receptor kinase B (TrkB) signaling on inflammatory pain in rats and explore the underlying mechanism. Forty-two adult SD rats were randomized into BDNF-induced acute pain group ( BDNF injection into the subarachnoid space significantly increased the number of spontaneous paw withdrawal of the rats ( ANA-12 can reduce spinal cord inflammation and relieve acute and chronic pain in rats by targeted blocking of BDNFTrkB signaling. 探讨ANA-12靶向阻断脑源性神经营养因子（BDNF）原肌球蛋白受体激酶B（TrkB）信号对炎症痛的抑制作用及机制。 将42只大鼠随机分为7组（6只组）：BDNF处理下的对照组、ANA-12处理组、BDNF处理组以及BDNF和ANA-12联合处理组（BDNFANA-12）；炎症痛模型下的对照组、CFA处理组以及CFA和ANA-12联合处理组（CFAANA-12）。给药完毕后，对各组大鼠进行痛觉行为学检测，记录ANA-12处理对BDNF-急性痛和CFA-慢性炎症痛大鼠痛觉行为的影响；采用免疫印迹法检测各组大鼠脊髓组织TrkB信号、小胶质细胞标记蛋白Iba1和促炎细胞因子TNF-α以及炎症因子IL-1β、Caspase-1、NLRP3的表达水平。 与对照组相比，BDNF增加自发缩足次数（ ANA-12靶向阻断BDNFTrkB信号可降低脊髓炎症并缓解急性痛和慢性痛。

Complications in Endoscopic Pituitary Surgery.

Pituitary surgery has undergone rapid advancements in the last 30 years, secondary to improved surgical techniques and technologies, including those that allow endoscopic approaches. Although the endoscopic endonasal approach (EEA) offers minimally invasive access to the region of the pituitary gland, complications are a significant consideration for the combined otolaryngology-neurosurgery team that is preparing for a case. In this article, we discuss various complications related to the EEA in pituitary surgery and explore ways to plan for and avoid them during surgery.

Microscopic Transsphenoidal Surgery in the Era of Endoscopy Are There Any Advantages

Developed over 50 years ago, the microscopic transsphenoidal approach is a simple, efficient technique with proven efficacy for the surgical treatment of an array of sellar and parasellar diseases. Although utilization of fully endoscopic transsphenoidal approaches has dramatically increased recently because it offers enhanced visualization, current outcomes data do not clearly favor either approach. Potential advantages of the microscope that persist in the endoscopic era include decreased operative time preservation of a single-surgeon, unobstructed, twohanded microsurgical technique and limited disruption of the nasal mucosa. Endoscope-assisted microsurgical approaches can also be used to overcome limitations in visualization while preserving the aforementioned advantages.

Giant Pituitary Adenoma - Special Considerations.

Giant pituitary adenomas (GPAs) comprise 5% to 15% of pituitary adenomas, but have higher rates of extrasellar invasion, subtotal resection, surgical morbidity, and recurrence. With the possible exception of giant prolactinomas, GPAs require surgical decompression. On review of 3 decades of case series encompassing 699 microsurgical transsphenoidal (MT), 1060 endoscopic endonasal trans-sphenoidal (EET), and 513 transcranial (TC) patients, gross total resection and recurrence rates were comparable across modalities, but the EET approach had lower perioperative mortality and superior restoration of visual function. Each approach has unique indications. Combined EET-TC approaches for minimizing residual tumor represent another area of study.

Nonfunctioning Pituitary Lesions.

Nonfunctioning pituitary lesions represent a subset of pituitary adenomas that do not manifest with clinical features of hormone hypersecretion. Because of their indolent nature, their diagnosis is elusive, often resulting in presentation after the tumors have grown large enough to cause compressive symptoms. Although they are clinically silent, the various subtypes correspond to the predominant cell line of origin and therefore are biochemically distinct from one another. This article reviews the biochemical, clinical, and histopathologic features of each of these subtypes. A rubric is provided for diagnostic work-up of these lesions and the management options available to the treating clinician.

Magnetic resonance imaging characteristics predict pituitary function in non-functional pituitary macro-adenoma undergoing trans-sphenoidal surgery.

Maintaining the pituitary function after surgery is highly important. The aim of this study was to investigate the relationship between preoperative magnetic resonance imaging (MRI) characteristics and pituitary function after surgery of non-functional pituitary macroadenoma. This retrospective study was performed between 2016 and 2018. Preoperative and postoperative MRI imaging data were retrieved from electronic registration system. The relationship between preoperative MRI characteristics and postoperative pituitary function as well as reconstruction of pituitary gland was investigated using regression models. Complete data were available for 44 patients. Before surgery, invisible normal tissue was observed in 23 patients (53.5%). Suprasellar extension and cavernous sinus invasion were seen in 36 patients (each one 49.1%). There was a significant reverse relationship between preoperative tumor size and postoperative thyroid stimulating hormone (TSH) (odds ratio (OR) - 0.99 (- 0.18, - 0.003), p 0.04). In addition, we found a significant positive correlation between prolactin level after surgery and tumor size before surgery, (OR 5.29 (1.65, 8.92), p 0006). Moreover, postoperative panhypopituitarism was observed in 25% of patients with complete morphologic reconstitution of pituitary tissue. While the rate was 50% in patients with no or partial morphologic reconstruction of pituitary tissue. Preoperative MRI characteristics predict TSH and prolactin level after operation. Furthermore, the adenoma size and volume prior to surgery are the main determinants of normal morphologic reconstruction of pituitary gland.

Five-year disease-free survival of Epstein-Barr virus-associated locoregionally advanced undifferentiated nasopharyngeal carcinoma patients treated with chemo-radiotherapy a case report.

Nasopharyngeal carcinoma (NPC) is a tumor caused by epithelial cells covering the surface of the nasopharynx. NPC only accounted for less than 1% of all cancers diagnosed worldwide. However, the global incidence rates are highest in southern China. We report a case of local advanced undifferentiated NPC specifically, vesicular nucleus cell carcinoma (VNCC) of NPC. Long-term disease-free survival (DFS) of a patient with stage IVA NPC is reported. A 42-year-old male presented with a 4-month history of rhinorrhea and a lump in the left neck. The positron emission tomography (PET) showed local invasion to the surrounding tissues, specifically, the tumor invaded the brain. The pathological diagnosis was VNCC, the Epstein-Barr virus (EBV) was positive in tumor tissues by in situ hybridization. and the clinical diagnosis was stage IVA of NPC. The patient was treated with induction chemotherapy (IC) with gemcitabine and cisplatin (GP) followed by cisplatinradiotherapy. The tumor lesions complete response (CR) after concurrent chemo-radiotherapy (CCRT). To date, the DFS time has been more than 5 years. IC with GP followed by CCRT should be the first choice of treatment for patients with locoregionally advanced NPC. In recent years, more and more studies have shown the efficacy of immunotherapy in treating recurrent or metastatic NPC patients, especially in patients or are programmed death-ligand 1 (PD-L1)-positive or have a high tumor mutation burden. In the future, immunotherapy may become a standard treatment in clinic and bring longer survival to patients.

A non-small cell lung cancer (NSCLC) patient harboring a rare epidermal growth factor receptor (EGFR) L858RV843I mutation complex benefited from osimertinib a case report.

Tyrosine kinase inhibitors (TKIs) have greatly improved the survival of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-TKI sensitive mutations such as L858R and exon 19 deletions. The third-generation EGFR-TKI osimertinib, an irreversible TKI, is approved as a therapy for advanced NSCLC with EGFR sensitive mutations. Recently, osimertinib showed antitumor activity against NSCLC in patients harboring an uncommon mutation such as an exon 20 insertion. Herein, we present a patient diagnosed with stage IV NSCLC with an EGFR L858RV843I mutation complex who benefited remarkably from osimertinib therapy. The patient was a 41-year-old Chinese female who complained of backache in October 2018. Computed tomography (CT) and magnetic resonance imaging (MRI) scans showed a mass in the right lung and brain metastasis. A whole-body bone scan revealed bone metastases. Targeted next-generation sequencing (NGS) of hydrothorax was performed and the coexistence of somatic L858RI and V843I mutations in EGFR exon 21 was discovered on November 13, 2018. Osimertinib therapy (80 mg daily) was administered for 12 months which resulted in an initial partial response (PR). At that point, the right lower lung lesion enlarged, indicating disease progression. Thus, the patient began combination therapy with osimertinib (80 mg daily) and bevacizumab (500 mg daily), leading to disease stabilisation until June 2020. Of note, during treatment, the patient achieved sustained control of metastatic brain and bone lesions. To the best of our knowledge, we report here the first known case of an NSCLC patient with a somatic EGFR L858RV843I mutation complex who responded well to osimertinib. Our findings provide theoretical guidance and expand the list of potential beneficiaries of EGFR-TKI therapy.

Effect of Dietary Exposure to Acrylamide on Diabetes-Associated Cognitive Dysfunction from the Perspectives of Oxidative Damage, Neuroinflammation, and Metabolic Disorders.

Acrylamide is a toxic compound that is produced widely during food processing, but whether the daily dietary consumption of acrylamide can impair the cognitive dysfunction in diabetic individuals and the potential underlying mechanisms are unknown. The aim of the present study was to observe the changes in cognitive and memory performance caused by chronic acrylamide exposure and to evaluate its influence on the brain morphology, oxidative damage, neuroinflammation, and brain metabolic disturbance. Goto-Kakizaki (GK) rats, a rat model of diabetes, were orally administered acrylamide at 1 mgkg body weight for 8 weeks. The results of the novel object recognition and Y-maze tests showed that the consumption of acrylamide significantly aggravated diabetes-associated cognitive dysfunction in GK rats. Acrylamide increased reactive oxygen species and malondialdehyde formation and reduced glutathione levels, catalase, and total antioxidant capacity activity, which caused a succession of events associated with oxidative damage, including glial cell activation. After the activation of astrocytes and microglia, related cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α, and lipopolysaccharide, were released, amyloid β-protein was accumulated, brain-derived neurotrophic factor was decreased, and the expression of caspase-3 and caspase-9 was increased, which aggravated neuroinflammation. Furthermore, there was perturbation of some important metabolites, including glutamic acid, citric acid, pyruvic acid, lactate, and sphinganine, and their related glucose, amino acid, and energy metabolism pathways in the brain. This work helps to demonstrate the effect of consumption of acrylamide in the daily diet on diabetes-associated cognitive dysfunction and its underlying mechanisms.

Gyriform infiltration as imaging biomarker for molecular glioblastomas.

Molecular glioblastomas (i.e. without the histological but with the molecular characteristics of IDH-wild-type glioblastoma) frequently lack contrast enhancement, which can wrongly lead to suspect a lower-grade glioma. Herein, we aimed to assess the diagnostic value of gyriform infiltration as an imaging marker for molecular glioblastomas. Two independent investigators reviewed the MRI scans from patients with newly diagnosed gliomas for the presence of a gyriform infiltration defined as an elective cortical hypersignal on MRI FLAIR sequence. Diagnostic test performance of this sign for the diagnosis of molecular glioblastoma were calculated. A total of 426 patients were included, corresponding to 31 molecular glioblastoma, 294 IDH-wild-type glioblastoma, 50 IDH-mutant astrocytoma, and 51 IDH-mutant 1p19q-codeleted oligodendroglioma. A gyriform infiltration was observed in 1631 (52%) molecular glioblastoma, 40294 (14%) IDH-wild-type glioblastoma, and none of the IDH-mutant glioma. All the 56 gyriform-infiltration-positive tumors were IDH-wild-type and all but two had a TERT promoter mutation. The inter-rater agreement was good (κ 0.69, p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the presence of a gyriform infiltration for the diagnosis of molecular glioblastoma were 52%, 90%, 29%, 96%, respectively. The median overall survival was better for gyriform-infiltration-negative patients compared to gyriform-infiltration-positive patients in the whole series and in patients with non-enhancing lesions (n 95) (25.6 vs 16.9 months, p 0.005 and 20.2 months vs not reached, p < 0.001). Gyriform infiltration is a specific imaging marker of molecular glioblastomas that can help distinguishing these tumors from IDH-mutant lower-grade gliomas.

Reproducibility of volume analysis of dynamic susceptibility contrast perfusion-weighted imaging in untreated glioblastomas.

Despite a high variability, the hotspot method is widely used to calculate the cerebral blood volume (CBV) of glioblastomas on DSC-MRI. Our aim was to investigate inter- and intra-observer reproducibility of parameters calculated with the hotspot or a volume method and that of an original parameter assessing the fraction of pixels in the tumour volume displaying rCBV > 2 %rCBV > 2. Twenty-seven consecutive patients with untreated glioblastoma (age 63, women 11) were retrospectively included. Three observers calculated the maximum tumour CBV value (rCBVmax) normalized with a reference ROI in the contralateral white matter (CBVWM) with (i) the hotspot method and (ii) with a volume method following tumour segmentation on 3D contrast-enhanced T1-WI. From this volume method, %rCBV > 2 was also assessed. After 8-12 weeks, one observer repeated all delineations. Intraclass (ICC) and Lins (LCC) correlation coefficients were used to determine reproducibility. Inter-observer reproducibility of rCBVmax was fair with the hotspot and good with the volume method (ICC 0.46 vs 0.65, p > 0.05). For CBVWM, it was fair with the hotspot and excellent with the volume method (0.53 vs 0.84, p < 0.05). Reproducibility of one pairwise combination of observers was significantly better for both rCBVmax and CBVWM (LCC 0.33 vs 0.75 0.52 vs 0.89, p < 0.05). %rCBV > 2 showed excellent inter- and intra-observer reproducibility (ICC 0.94 and 0.91). Calculated in glioblastomas with a volume method, rCBVmax and CBVWM yielded good to excellent reproducibility but only fair with the hotspot method. Overall, the volume analysis offers a highly reproducible parameter, %rCBV > 2, that could be promising during the follow-up of such heterogeneous tumours.

Early repeat resection for residual glioblastoma decision-making among an international cohort of neurosurgeons.

The importance of extent of resection (EOR) in glioblastoma (GBM) has been thoroughly demonstrated. However, few studies have explored the practices and benefits of early repeat resection (ERR) when residual tumor deemed resectable is unintentionally left after an initial resection, and the survival benefit of ERR is still unknown. Herein, the authors aimed to internationally survey current practices regarding ERR and to analyze differences based on geographic location and practice setting. The authors distributed a survey to the American Association of Neurological Surgeons and Congress of Neurological Surgeons Tumor Section, Society of British Neurological Surgeons, European Association of Neurosurgical Society, and Latin American Federation of Neurosurgical Societies. Neurosurgeons responded to questions about their training, practice setting, and current ERR practices. They also reported the EOR threshold below which they would pursue ERR and their likelihood of performing ERR using a Likert scale of 1-5 (5 being the most likely) in two sets of 5 cases, the first set for a patients initial hospitalization and the second for a referred patient who had undergone resection elsewhere. The resection likelihood index for each respondent was calculated as the mean Likert score across all cases. Overall, 180 neurosurgeons from 25 countries responded to the survey. Neurosurgeons performed ERRs very rarely in their practices (< 1% of all GBM cases), with an EOR threshold of 80.2% (75%-95%). When presented with 10 cases, the case context (initial hospitalization vs referred patient) did not significantly change the surgeon ERR likelihood, although ERR likelihood did vary significantly on the basis of tumor location (p < 0.0001). Latin American neurosurgeons were more likely to pursue ERR in the provided cases. Neurosurgeons were more likely to pursue ERR when the tumor was MGMT methylated versus unmethylated, with a resection likelihood index of 3.78 and 3.21, respectively (p 0.004) however, there was no significant difference between IDH mutant and IDH wild-type tumors. Results of this survey reveal current practices regarding ERR, but they also demonstrate the variability in how neurosurgeons approach ERR. Standardized guidelines based on future studies incorporating tumor molecular characteristics are needed to guide neurosurgeons in their decision-making on this complicated issue.

An integrated risk model stratifying seizure risk following brain tumor resection among seizure-naive patients without antiepileptic prophylaxis.

The natural history of seizure risk after brain tumor resection is not well understood. Identifying seizure-naive patients at highest risk for postoperative seizure events remains a clinical need. In this study, the authors sought to develop a predictive modeling strategy for anticipating postcraniotomy seizures after brain tumor resection. The IBM Watson Health MarketScan Claims Database was canvassed for antiepileptic drug (AED)- and seizure-naive patients who underwent brain tumor resection (2007-2016). The primary event of interest was short-term seizure risk (within 90 days postdischarge). The secondary event of interest was long-term seizure risk during the follow-up period. To model early-onset and long-term postdischarge seizure risk, a penalized logistic regression classifier and multivariable Cox regression model, respectively, were built, which integrated patient-, tumor-, and hospitalization-specific features. To compare empirical seizure rates, equally sized cohort tertiles were created and labeled as low risk, medium risk, and high risk. Of 5470 patients, 983 (18.0%) had a postdischarge-coded seizure event. The integrated binary classification approach for predicting early-onset seizures outperformed models using feature subsets (area under the curve AUC 0.751, hospitalization features only AUC 0.667, patient features only AUC 0.603, and tumor features only AUC 0.694). Held-out validation patient cases that were predicted by the integrated model to have elevated short-term risk more frequently developed seizures within 90 days of discharge (24.1% high risk vs 3.8% low risk, p < 0.001). Compared with those in the low-risk tertile by the long-term seizure risk model, patients in the medium-risk and high-risk tertiles had 2.13 (95% CI 1.45-3.11) and 6.24 (95% CI 4.40-8.84) times higher long-term risk for postdischarge seizures. Only patients predicted as high risk developed status epilepticus within 90 days of discharge (1.7% high risk vs 0% low risk, p 0.003). The authors have presented a risk-stratified model that accurately predicted short- and long-term seizure risk in patients who underwent brain tumor resection, which may be used to stratify future study of postoperative AED prophylaxis in highest-risk patient subpopulations.

Extraventricular neurocytoma at the sellar region Report of 8 cases and literature review.

Extraventricular neurocytoma at the sellar region (EVNSR) is an exceedingly rare tumor. Given the paucity of specificity and its peculiar nature, our study aimed to characterize the clinical, imaging, and pathological features, including treatment and clinical outcomes of this tumor. Eight patients with pathologically confirmed EVNSR at Beijing Tiantan Hospital from 2012 to 2020 were retrospectively analyzed. Additionally, 7 cases from the prior detailed literature were also retrieved. Among the 8 patients from Beijing Tiantan Hospital, 2 males and 6 females with an average age of 45.3 (range, 8-61). Vision impairment and headache were the most common complaints at presentation. Preoperative diagnoses were pituitary adenoma (n 6), meningioma (n 1), and oligodendroglioma (n 1). Treatment included subtotal tumor resection (n 3), partial resection (n 5), adjuvant therapy covered radiotherapy (n 2), and gamma knife surgery (n 3). The clinical outcomes of these 8 cases were stable (n 5), survival after progression (n 1), and death after recurrence (n 2). EVNSRs are extremely rare tumors, and most have benign prognoses after appropriate treatment. Due to the unique location, total removal of the tumor is challenging And adjuvant radiation therapy for eligible patients is recommended. Regular imaging review is also advised. Future studies with more patients are needed to elucidate the biological nature of EVNSRs.

Anti-inflammatory effects of B vitamins protect against tau hyperphosphorylation and cognitive impairment induced by 1,2 diacetyl benzene An in vitro and in silico study.

1,2 diacetyl benzene (DAB) penetrates the blood-brain barrier, causing neuroinflammation, tau hyperphosphorylation, and cognitive impairment. Converging evidence supports the anti-inflammatory effects of B vitamins on cognitive impairment, but the effects of B vitamins on cognitive impairment induced by DAB remain unclear. Here, we investigated the anti-inflammatory properties of B vitamins in DAB-stimulated human neuroblastoma SH-SY5Y cells. In this in-silico analysis, we investigated the genes, transcription factors, miRNAs, and sponges linked with DAB, B vitamins and the pathogenesis of cognitive impairment. We found vitamins B1, B2, and B3 had anti-inflammatory properties in DAB-stimulated SH-SY5Y cells, possibly via inhibiting NF-κB activation. Furthermore, vitamins B1, B2, and B3 inhibited GSK-3β, β-amyloid, and tau hyperphosphorylation in SH-SY5Y cells. These vitamins can also modulate genes induced by DAB (IL1B, IL6, IL10, iNOS, COX2, NFκB, GSK3B, TNF, and APP) in SH-SY5Y cells. In silico analyses, inflammatory response related pathways, Alzheimers disease, pathways of neurodegeneration-multiple disease, and prolactin signaling pathway, were highlighted. Additionally, we explored a network-based approach to identify key genes, transcription factors, miRNAs, and pathways in cognitive impairment. The transcription factors NFKB2 and BATF3 were shown to be the most important in regulating genes. We also found eight significant miRNAs related to cognitive impairment, and these miRNAs were also validated by qPCR. Finally, we developed and tested in silico miRNA sponge sequences for these miRNAs.

Management of Internal Carotid Artery Injury During Transsphenoidal Surgery A Case Series and Suggestion for Optimal Management.

Internal carotid artery (ICA) injury during transsphenoidal surgery is a rare but serious complication. We analyzed a series of ICA injuries that occurred during a transsphenoidal approach to suggest an optimal management strategy. Between January 2015 and May 2020, we enrolled 10 cases of ICA injury at our institution. Among the 10 patients enrolled, 5 had pituitary adenoma, 2 had craniopharyngioma, and 1 each had skull base chondrosarcoma, tuberculum sellae meningioma, and nasopharyngeal cancer 4 were revision surgery cases. The cavernous segment of the ICA was the most commonly injured area. The most common reason for ICA injury was a drill injury at the sellar floor opening. A direct repair was performed using a clip in only 1 patient. In the others, bleeding control of the injured ICA was achieved by packing multiple cotton pads. After angiography, 6 patients underwent immediate endovascular sacrifice of the injured ICA. In 3 patients who showed poor collateral flow from the anterior communicating and posterior communicating arteries, revascularization surgery was performed before endovascular trapping. After 6 postoperative months, 6 patients showed favorable functional outcomes, and 4 patients showed poor functional outcomes. Prompt control of bleeding, endovascular management of injured ICA, and consideration of revascularization surgery based on collateral flow may prevent catastrophic neurological sequelae.

Risk factors for renal allograft survival with China novel donation category Donation after brain death followed by cardiac arrest.

To meet the need for transplantable organs, a new donation program was initiated by the Chinese government. This novel policy created three categories for deceased organ donations donation after circulatory death cardiac death (DCD), donation after brain death (DBD), and donation after brain death followed by circulatory death (DBCD) meaning complete cardiac arrest. In fact, the DBCD method is a combination of both DBD and DCD methods. A DBCD donor meets the criteria of for brain death, but the organ procurement begins after the withdrawal of life support and the subsequent cardiac arrest death. The purpose of this study was to evaluate the long-term outcomes of kidney transplantation in our center with the DBCD policy. Potential risk factors for affecting the renal allograft survival were also analyzed based on our data. A retrospective study, involving 421 kidney transplants derived from 214 donors, was conducted between December 2011 and October 2019. In particular, 373 (88.6%) transplanted organs met the criteria for DBCD, and 48 (11.4%) for DCD. The log-rank test was used to compare the difference in survival. The Cox regression analysis was used for risk factor screening. Analysis showed that the DBCD group was better than the DCD group in terms of overall (p 0.031) as well as death-censored (p 0.026) allograft survival using the log-rank test. A Cox regression analysis revealed that increasing donor age (p 0.002, HR 1.82010 years incremental older), increasing recipient age (p 0.028, HR 1.52110 years increment older), prolonged dialysis duration (p 0.007, HR 1.018), occurrence episodes of acute rejection (p 0.016, HR 2.697), delayed graft function (p 0.012, HR 2.962), mismatch ≥4 HLA loci (p 0.038, HR 3.606), and warm ischemia time > 15 min (p 0.022, HR 2.915), were all independent risk factors affecting the graft survival. The new DBCD policy of donation produced acceptable results similar or even better than the DCD practice. Based on our analysis, the graft survival of DBCD transplants may be better than DCD transplants. The main risk factors for allograft loss included an increasing donor age, recipient age, warm ischemia time > 15 min, prolonged dialysis duration, acute rejection, delayed graft function, and HLA mismatch ≥4 HLA loci.

Adipose-derived stem cell and their extracellular vesicles ameliorates immune function, and cardiac markers in experimental model of cardiorenal syndrome type III TNF-α, IFN-γ and IL-10 cytokine production and their correlation with genotype.

Cardio-renal syndrome (CRS) denotes the convergence of heart-kidney interactions across several mechanisms. The current study is conducted to evaluate the anti-inflammatory role of adipose tissue-derived stem cells (ASCs) versus adipose stem cell-derived extracellular vesicles (ADSCs-EVs) in experimental model of cardiorenal syndrome type III. The study was conducted on 50 male rats that were equally divided to group I (control group) Group II (experimental cardiorenal syndrome group) which induced by right renal artery ligation (ICRSIII) Group III (Sham-operated control group) which underwent surgical incision without renal artery ligation Group IV (ICRSIII which received ADSCs-extracellular vesicles (ADSCs-EVs) Group V (ICRSIII which received adipose tissue stem cells (ASCs). Assessment of pro-inflammatory cytokines IL-10, IL-1α, IL-6, IL-1 β, IFN-γ, NF-α and their mRNA gene expression quantitation, (NGAL), and brain natriuretic peptide (BNP) as markers of cardiac dysfunction, as well as histopathological examination of renal tissue was examined by H E, Masson trichrome and periodic acid-Schiff stains (PAS). The ICRS group exhibited significant acute tubular injury with tubular dilation, loss of brush borders, epithelial flattening, and occasional sloughed cells in lumen. Use of either ADSCs-EVs or ASCs significantly ameliorated the histological findings of tubular injury. Proinflammatory cytokines, BNP and NGAL were significantly elevated in ICRSIII group as compared to all other studied groups. Administration of ADSCs-EVs or ASCs led to significant decrease in all proinflammatory cytokines as well as BNP and NGAL levels with no significant difference between them. In conclusion, ADSCs-EXs and ASCs exhibited significant repairing effects in experimental-induced cardiorenal syndrome type III as evidenced by amelioration of histological findings of tubular injury, anti-inflammatory effects, and the significant decrease in markers of cardiac dysfunction. ADSC-EVs reprogramed injured cardiac cells by activating regenerative processes.

Brain-targeting biomimetic nanoparticles for codelivery of celastrol and LY2157299 for reversing glioma immunosuppression.

The treatment of glioblastoma remains a huge challenge due to the lack of an efficient way to deliver drugs across the blood-brain barrier (BBB), and the pharmacotherapy options are very limited. In this work, a biomimetic BBB-penetrating albumin nanosystem modified by a brain-targeting peptide was designed for co-delivering a TGF-β receptor I (TGFβRI) inhibitor (LY2157299) and an mTOR inhibitor (celastrol). The albumin nanosystem can target nAChRs overexpressed both on the BBB and glioma cells, thereby promoting drug delivery into the glioma. The biomimetic nanoparticles could repolarize tumor-associated macrophages (TAMs) from M2 to M1 phenotype by suppressing the STAT6 pathway, thereby reducing TGF-β1 secretion and inducing cell apoptosis. In addition, the treatment also blocked TGF-βSMAD2 signaling pathway. The glioma-targeting ability and therapeutic efficacy were confirmed in an orthotopic glioma mouse model. The biomimetic nanoparticles significantly prolonged the survival rate, showing a decrease in the proportion of M2-like TAMs and the levels of TGF-β1 and lactic acid in the glioma tissues. This delivery and treatment strategy provides a new approach for the treatment of gliomas.

Molecular cloning, characterization, and expression analysis of TIPE1 in chicken (Gallus gallus) Its applications in fatty liver hemorrhagic syndrome.

Tumor necrosis factor-α-induced protein eight like 1 (TIPE1) plays important role in autophagy, immunity, and lipid metabolism. The potential role of TIPE1 in fatty liver hemorrhage syndrome (FLHS) is elusory. In the present study, the full-length coding sequence of TIPE1 was cloned, and the polyclonal antibody of TIPE1 was produced by the recombinant TIPE1 protein. The bioinformatic analysis showed that the chicken TIPE1 protein, which was predicted to be a hydrophobic and non-transmembrane protein without signal peptide was highly different from that of mammals. Furthermore, proceeded by using TIPE1 polyclonal antibody, the tissue distribution analysis showed that TIPE1 protein is ubiquitously expressed in various tissues in adult hens and chicks, with its level being higher in the liver and, spleen, moderate in intestinal, brain, and heart. Besides, immunohistochemistry and immunofluorescence observation demonstrated that TIPE1 mainly existed in the cytoplasm in liver, duodenum, and cecum cell. Notably, the TIPE1 expressions were significantly decreased in laying hens suffering from FLHS. Collectively, these results showed that the chicken TIPE1 polyclonal antibody was successfully prepared and further used to analyze the expression profiles of chicken. And the expression of TIPE1 was reduced in FLHS which provided the foundation for further investigation in FLHS.

Deciphering albumin-directed drug delivery by imaging.

Albumin is the most abundant plasma protein, exhibits extended circulating half-life, and its properties have long been exploited for diagnostics and therapies. Many drugs intrinsically bind albumin or have been designed to do so, yet questions remain about true rate limiting factors that govern albumin-based transport and their pharmacological impacts, particularly in advanced solid cancers. Imaging techniques have been central to quantifying - at a molecular and single-cell level - the impact of mechanisms such as phagocytic immune cell signaling, FcRn-mediated recycling, oncogene-driven macropinocytosis, and albumin-drug interactions on spatial albumin deposition and related pharmacology. Macroscopic imaging of albumin-binding probes quantifies vessel structure, permeability, and supports efficiently targeted molecular imaging. Albumin-based imaging in patients and animal disease models thus offers a strategy to understand mechanisms, guide drug development and personalize treatments.

Effects of prenatal opioid and alcohol exposures on immune and serotonin factors in human placenta.

Opioids and alcohol impact critical serotonin (5-HT) function in the developing placenta and fetus through the actions of immune proinflammatory factors. Yet, possible convergent effects of opioids and alcohol on human placental toll-like receptor 4 (TLR4) activation and subsequent 5-HT homeostasis remain entirely unknown. The purpose of this study was to examine the effect of prenatal exposure to opioids with or without prenatal alcohol exposure (PAE) on the expression of key placental immune and serotonin signaling factors in human placental tissue obtained from a well-characterized prospective cohort. Data were collected from a subset of participants enrolled in the prospective pre-birth Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH-1) cohort. Women were recruited and classified into four study groups 1) PAE (n 20) 2) those taking medications for opioid use disorder (MOUD n 28), 3) concurrent PAE and MOUD (n 20) and 4) controls (HC n 20) based on prospective, repeated self-report, and biomarker analysis. Placenta samples underwent tissue processing to identify mRNA for TLR4, nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), serotonin transporter (SERT), tryptophan hydroxylase (TPH1), indoleamine 2,3-Dioxygenase 1 (IDO) as well as protein concentrations of TLR4, IL-1β, TNF-α, SERT. To consider the association between study group and mRNAprotein expression of our targets, multivariable regression models were developed with inclusion of a priori selected covariates. There was a significant negative association between PAE and SERT mRNA (β -0.01 p < 0.01) and a positive association with TPH1 mRNA expression (β 0.78 p < 0.05). In addition, there was a negative association between MOUD and TNF-α protein expression (β -0.12 p < 0.05). This study provides the first evidence that PAE may inhibit SERT expression while simultaneously promoting increased TPH1 protein expression in human placenta. This may result in increased 5-HT in fetal circulation known to affect neurodevelopment. Our data suggest that opioids and alcohol may disturb the bidirectional, dynamic interaction between the placental immune and serotonin system. Given the implication for brain development and health across the life-span further investigation of these critical mechanisms in well-defined cohorts is required.

Inhibition of EGFR and MEK surmounts entrectinib resistance in a brain metastasis model of NTRK1-rearranged tumor cells.

Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology-agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1-G595R. Repotrectinib is a second-generation TRK inhibitor, which is active against NTRK1-G595R. However, its efficacy against entrectinib-resistant tumors has not been fully elucidated. In the present study, we established entrectinib-resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1-rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1-G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal-regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.

StatPearls

A craniotomy is a surgical procedure in which a part of the skull is temporarily removed to expose the brain and perform an intracranial procedure. The most common conditions that can be treated via this approach include brain tumors, aneurysms, arterio-venous malformations, subdural empyemas, subdural hematomas, and intracerebral hematomas. Specialized tools and equipment are utilized to remove the section of bone, which is called the bone flap. The bone flap is temporarily removed, held at the surgical instrument table, and then placed back after the brain surgery has concluded. In some cases, depending on the etiology and indication for the procedure, the bone can be discarded, stored in the abdominal subcutaneous space, or cryopreserved under cold storage conditions. If the bone flap is discarded or not placed back into the skull during the same operation, the procedure is called a craniectomy. In a decompressive craniectomy used for the treatment of malignant brain edema, the bone flap is placed back a few weeks after the brain swelling has improved. The surgical procedure to reconstruct and place the bone flap back into the skull during a second intervention is known as cranioplasty. From a historical context and perspective, cranial interventions varied from a single burr hole trephine to a larger craniectomy. Modern craniotomies are performed by connecting a series of burr holes. Although trephination is the oldest cranial surgical technique with ancient reports dating back to 2300 years, our current modern surgical technique for a craniotomy is the final cured result of the procedure introduced at the end of the 19th century by the self-educated surgeon Wilhelm Wagner. Although it was much later in the course of history that the transition from trephination to a tailored resection via craniotomy happened, ancient civilizations, such as the Incas in Peru, must have had some basic familiarity with anatomy and surgical interventions despite their rudimentary knowledge of pathology. Depending on the type of intracranial lesion, pathology, and the surgical approach, some craniotomy procedures can be assisted by neuronavigation guidance based on magnetic resonance imaging or computed tomographic scans to tailor the procedure to the size of the tumor using the smallest incision possible. Neuronavigation is a modern computerized technology that can help surgeons localize the pathology more precisely by merging a series of craniofacial points in the patient. Neuronavigation offers better guidance, orientation, and localization. It provides a higher level of confidence for the surgeon and an improved outcome for the patient.

StatPearls

Brain metastases are a common complication of cancer and the most common type of brain tumor. Anywhere from 10% to 26% of patients who die from their cancer will develop brain metastases. While few cancers that metastasize to the brain can be cured using conventional therapies, long-term survival and palliation are possible with minimal adverse effects to patients. Increasingly, neuro-cognition and quality of life are being recognized as important endpoints for patients as survival continues to increase.

Molecular alterations in the integrated diagnosis of pediatric glial and glioneuronal tumors A single center experience.

Tumors of the central nervous system (CNS) are the most common pediatric solid tumors, where low grade (LGG) and high grade gliomas (HGG) represent up to 55% of CNS tumors. Current molecular classification of these tumors results in a more accurate diagnosis and risk stratification, which ultimately enables individualized treatment strategies. Identifying known alterations is a suitable approach, particularly in developing countries, where NGS approaches are not easily accessible. We sought to assess molecular alterations in BRAF and histone 3 genes. FISH, IHC and Sanger sequencing were performed in a series of 102 pediatric glial and glioneuronal tumors. We also correlated these results with clinical and histological findings to evaluate their usefulness as diagnostic andor prognostic tools. We found that the KIAA1549-BRAF gene fusion was a relevant diagnostic tool for pilocytic astrocytoma, but not related to progression free survival (PFS) and overall survival (OS). BRAFV600E mutation was associated with a decreased OS in LGG, and with decreased PFS and OS among pilocytic astrocytomas. All HGG of the midline were H3K27M mutants, while H3G34R mutant cases were located in brain hemispheres. HGG harboring the H3K27M variant were associated with a decreased PFS and OS. Assessing druggable molecular markers with prognostic value is particularly important in those cases where complete resection or further radiation therapy is not possible. These potential diagnosticprognostic markers may be suitable as further screening tests to reduce the requirement on NGS, which is not available in all laboratories. Furthermore, these results broaden data on BRAF and Histone 3 alterations in children from geographic regions, other than USA and Europe.

TOR signalling is required for host lipid metabolic remodelling and survival following enteric infection in Drosophila.

When infected by enteric pathogenic bacteria, animals need to initiate local and whole-body defence strategies. Although most attention has focused on the role of innate immune anti-bacterial responses, less is known about how changes in host metabolism contribute to host defence. Using Drosophila as a model system, we identify induction of intestinal target-of-rapamycin (TOR) kinase signalling as a key adaptive metabolic response to enteric infection. We find that enteric infection induces both local and systemic induction of TOR independently of the Immune deficiency (IMD) innate immune pathway, and we see that TOR functions together with IMD signalling to promote infection survival. These protective effects of TOR signalling are associated with remodelling of host lipid metabolism. Thus, we see that TOR is required to limit excessive infection-mediated wasting of host lipid stores by promoting an increase in the levels of gut- and fat body-expressed lipid synthesis genes. Our data support a model in which induction of TOR represents a host tolerance response to counteract infection-mediated lipid wasting in order to promote survival. This article has an associated First Person interview with the first author of the paper.

A comprehensive investigation on pan-cancer impacts of constitutive centromere associated network gene family by integrating multi-omics data A CONSORT-compliant article.

The constitutive centromere associated network (CCAN) complex played a critical role in connecting the centromere with the mitotic spindle during mitosis and meiosis. Many studies have indicated that CCAN is related to the tumorigenesis and cancer development. Nonetheless, the overview of CCAN gene family in pan-cancer remain incompletely understood. We performed a comprehensive investigation on pan-cancer impacts of CCAN by integrating multi-omics data. We comprehensively investigated the expression profile, kyoto encyclopedia of genes and genomes (kegg) pathway, mutation, copy number variation, tumor microenvironment, immune cells infiltration, and drug sensitivity of CCAN in pan-cancer. MRNA expression profiles were collected from the cancer genome atlas, oncomine and ccle, the differential expression and various relevance analysis were performed with R or Perl. The results showed that the expression of CCAN was different in 33 tumors. Intriguingly, the poor survival in adrenocortical carcinoma, cholangiocarcinoma, kidney chromophobe, mesothelioma, kidney renal clear cell carcinoma, brain lower grade glioma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, thyroid carcinoma, uveal melanoma was most likely related to the kegg single transduction pathway including one carbon pool by folate, proteasome, arachidonic acid metabolism and so on. CENPC, ITGB3BP, APITD1, CENPU, and CENPW were more involved in tumor microenvironment, which more likely related to NK cells resting, T cells follicular helper, T cells CD8, neutrophils, macrophages M0, T cells CD4 memory activated. The relationship of CCAN expression with drug sensitivity showed that chelerythrine, nelarabine, and hydroxyurea maybe be potential drugs. This multidimensional study provides a valuable resource to assist mechanism research and clinical utility about CCAN.

Clinical and radiological findings of glioblastomas harboring a BRAF V600E mutation.

The aim of this study was to analyze the clinical and radiological characteristics of glioblastomas (GBMs) harboring a BRAF mutation. Sequencing analysis of BRAF, IDH12, and TERT promoters was performed on GBM samples of patients older than 15 years. The clinical, pathological, and radiological data of patients were retrospectively reviewed. Patients were classified into three groups according to their BRAF and IDH12 status BRAF group, IDH group, and BRAFIDH-wild-type (WT) group. Among 179 GBM cases, we identified nine cases with a BRAF mutation and nine with IDH mutation. The WT group had 161 cases. Age at onset in the BRAF group was significantly lower compared to the WT group and was similar to the IDH group. In cases with negative IDH1-R132H staining and age < 55 years, 15.2% were BRAF-mutant cases. Similar to the IDH group, overall survival of the BRAF group was significantly longer compared with the WT group. Among nine cases in the BRAF group, three cases had hemorrhagic onset and prior lesions were observed in two cases. In conclusion, age < 55 years, being IDH1-R132H negative, with hemorrhagic onset or the presence of prior lesions are factors that signal recommendation of BRAF analysis for adult GBM patients.

Clinical predictors of survival for patients with atypical teratoidrhabdoid tumors.

Atypical teratoidrhabdoid tumors (ATRTs) are malignant central nervous system (CNS) neoplasms of the young. Our study analyzed a large ATRT cohort from the National Cancer Database (NCDB) to elucidate predictors of short-term mortality and overall survival (OS). Information was collected on patients with histologically confirmed ATRT using the NCDB (2004-2016). Kaplan-Meier analysis indicated OS. Prognostic factors for 30-day mortality, 90-day mortality, and OS were determined via multivariate Cox proportional hazards (CPH) and logistic regression models. Our cohort of 189 patients had a median age of 1 year (IQR 1, 4) and tumor size of 4.7 ± 2.0 cm at diagnosis. Seventy-two percent were under 3 years old 55.6% were male and 71.0% were Caucasian. Fifty (27.2%) patients received only surgery (S) (OS 5.91 months), 51 (27.7%) received surgery and chemotherapy (S CT) (OS 11.2 months), and 9 (4.89%) received surgery and radiotherapy (S RT) (OS 10.3 months). Forty-five (24.5%) received S CT RT combination therapy (OS 45.4 months), 13 (17.1%) received S CT BMTSCT (bone marrow or stem cell transplant) (OS 55.5 months), and 16 (8.70%) received S CT RT BMTSCT (OS 68.4 months). Bivariate analysis of dichotomized age (HR 0.550, 95% CI 0.357, 0.847, p 0.0067) demonstrated significantly increased patient survival if diagnosed at or above 1 year old. On multivariate analysis, administration of S CT RT, S CT BMTSCT, or S CT RT BMTSCT combination therapy predicted significantly (p < 0.05) increased OS compared to surgery alone. ATRTs are CNS tumors where those diagnosed under 1 year old have a significantly worse prognosis. Our study demonstrates that while traditional CT, RT, and BMTSCT combination regimens prolong life, overall survival in this population is still low.

Direct Current Electric Field Coordinates the Migration of BV2 Microglia via ERKGSK3βCofilin Signaling Pathway.

Direct current electric field (DCEF) steers the migration of various neural cells. Microglia, as macrophage of the central nervous system (CNS), however, have not been reported to engage in electrotaxis. Here, we applied electric fields to an in vitro environment and found directional migration of BV2 microglia toward the cathode, in a DCEF strength-dependent manner. Transcriptome analysis then revealed significant changes in the mitogen-activated protein kinase cascades. In terms of mechanism, DCEF coordinated microglia movement by regulating the ERKGSK3βcofilin signaling pathway, and PMA (protein kinase C activator) reversed cell migration through intervention of the ERKGSK3βcofilin axis. Meanwhile, LiCl (GSK3β inhibitor) showed similar functions to PMA in the electrotaxis of microglia. Furthermore, pharmacological and genetic suppression of GSK3β or cofilin also modulated microglia directional migration under DCEF. Collectively, we discovered the electrotaxis of BV2 microglia and the essential role of the ERKGSK3βcofilin axis in regulating cell migration via modulation of F-actin redistribution. This research highlights new insight toward mediating BV2 directional migration and provides potential direction for novel therapeutic strategies of CNS diseases.

Maternal sleep deprivation induces gut microbial dysbiosis and neuroinflammation in offspring rats.

Maternal sleep deprivation (MSD) is a global public health problem that affects the physical and mental development of pregnant women and their newborns. The latest research suggests that sleep deprivation (SD) disrupts the gut microbiota, leading to neuroinflammation and psychological disturbances. However, it is unclear whether MSD affects the establishment of gut microbiota and neuroinflammation in the newborns. In the present study, MSD was performed on pregnant Sprague-Dawley rats in the third trimester of pregnancy (gestational days 15-21), after which intestinal contents and brain tissues were collected from offspring at different postnatal days (P1, P7, P14, and P56). Based on microbial profiling, microbial diversity and richness increased in pregnant rats subjected to MSD, as reflected by the significant increase in the phylum 孕期睡眠剥夺(Maternal sleep deprivation, MSD)已成为影响孕产妇身心健康及新生儿早期发育的全球公共卫生问题。最新的研究进展表明，睡眠剥夺(Sleep deprivation, SD)会破坏肠道微生物群，导致宿主神经炎症和精神异常。然而，尚不清楚MSD是否会影响新生儿肠道菌群的建立和神经炎症。该研究对妊娠晚期(妊娠15～21天)的Sprague-Dawley大鼠进行MSD处理，然后在出生后不同时间点(P1、P7、P14、P56)收集子代的肠道内容物和脑组织。通过菌群测序发现，受MSD影响的孕鼠粪便微生物多样性和丰富度增加，主要表现为厚壁菌门显著增加；同时我们在MSD子代中也观察到以厚壁菌门类细菌增多为标志的肠道菌群失调。进一步的qRT-PCR和ELISA检测发现，MSD成年后代脑内促炎细胞因子IL-1β和TNF-α的表达显著高于对照组(P56)。Spearman相关性分析显示，IL-1β和TNF-α与Ruminococcus1和RuminococcaceaeUCG-005这两类厚壁菌门的丰度呈正相关，从而提示肠道菌群与宿主神经发育密切相关。综上所述，MSD改变了母体肠道菌群，并影响了子代早期肠道菌群的建立，最后导致MSD后代出现特定菌群相关的神经炎症。因此，揭示肠道菌群在个体生理发育过程中的作用，将可能为治疗MSD后代的认知功能障碍提供潜在的干预措施。.

Research progress of anti-glioma chemotherapeutic drugs (Review).

Glioma is the most common primary intracranial malignancy in the central nervous system. At present, the most important treatment option is surgical resection of the tumor combined with radiotherapy and chemotherapy. The principle of operation is to remove the tumor to the maximal extent on the basis of preserving brain function. However, prominent invasive and infiltrative proliferation of glioma tumor cells into the surrounding normal tissues frequently reduces the efficacy of treatment. This in turn worsens the prognosis, because the tumor cannot be completely removed, which can readily relapse. Chemotherapeutic agents when applied individually have demonstrated limited efficacy for the treatment of glioma. However, multiple different chemotherapeutic agents can be used in combination with other treatment modalities to improve the efficacy while circumventing systemic toxicity and drug resistance. Therefore, it is pivotal to unravel the inhibitory mechanism mediated by the different chemotherapeutic drugs on glioma cells in preclinical studies. The aim of the present review is to provide a summary for understanding the effects of different chemotherapeutic drugs in glioma, in addition to providing a reference for the preclinical research into novel chemotherapeutic agents for future clinical application.

Loss of TAF8 causes TFIID dysfunction and p53-mediated apoptotic neuronal cell death.

Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo.

ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis.

A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70-85% of familial schwannomatosis and 30-40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12-14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours andor functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients psychosocial needs should be assessed annually as well as review of painpain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.

The identification of efficient and sensitive biomarkers for non-invasive tests is one of the major challenges in cancer diagnosis. To address this challenge, metabolomics is widely applied for identifying biomarkers that detect abnormal changes in cancer patients. Canine mammary tumors exhibit physiological characteristics identical to those in human breast cancer and serve as a useful animal model to conduct breast cancer research. Here, we aimed to provide a reliable large-scale metabolite dataset collected from dogs with mammary tumors, using proton nuclear magnetic resonance spectroscopy. We identified 55 metabolites in urine samples from 20 benign, 87 malignant, and 49 healthy control subjects. This dataset provides details of mammary tumor-specific metabolites in dogs and insights into cancer-specific metabolic alterations that share similar molecular characteristics.

Anti-apoptosis effects of codonolactone on cerebral ischemia-reperfusion injury.

Codonolactone is the main biologically active ingredient in

Radiomics Can Distinguish Pediatric Supratentorial Embryonal Tumors, High-Grade Gliomas, and Ependymomas.

Pediatric supratentorial tumors such as embryonal tumors, high-grade gliomas, and ependymomas are difficult to distinguish by histopathology and imaging because of overlapping features. We applied machine learning to uncover MR imaging-based radiomics phenotypes that can differentiate these tumor types. Our retrospective cohort of 231 patients from 7 participating institutions had 50 embryonal tumors, 127 high-grade gliomas, and 54 ependymomas. For each tumor volume, we extracted 900 Image Biomarker Standardization Initiative-based PyRadiomics features from T2-weighted and gadolinium-enhanced T1-weighted images. A reduced feature set was obtained by sparse regression analysis and was used as input for 6 candidate classifier models. Training and test sets were randomly allocated from the total cohort in a 7525 ratio. The final classifier model for embryonal tumor-versus-high-grade gliomas identified 23 features with an area under the curve of 0.98 the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.85, 0.91, 0.79, 0.94, and 0.89, respectively. The classifier for embryonal tumor-versus-ependymomas identified 4 features with an area under the curve of 0.82 the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.93, 0.69, 0.76, 0.90, and 0.81, respectively. The classifier for high-grade gliomas-versus-ependymomas identified 35 features with an area under the curve of 0.96 the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.82, 0.94, 0.82, 0.94, and 0.91, respectively. In this multi-institutional study, we identified distinct radiomic phenotypes that distinguish pediatric supratentorial tumors, high-grade gliomas, and ependymomas with high accuracy. Incorporation of this technique in diagnostic algorithms can improve diagnosis, risk stratification, and treatment planning.

Towards the establishment of national imaging practice guidelines A preliminary study of the basic computed tomography imaging protocols in Ghana.

There is a need to harmonize imaging practices in computed tomography (CT) imaging. This study, therefore, investigated the variability of the basic imaging protocols used for CT imaging of common indications in Ghana in order to generate recommendations for the development of national imaging practice guidelines in CT imaging. A cross-sectional study, utilizing a structured online questionnaire, was undertaken (between December 2018 to March 2019) to collect indication-based imaging protocol data (scan coverage, scan series, image quality requirement, slice thickness, reconstruction, scan mode and orientation, required window, AEC usage, scan and breath hold techniques etc.,) across the various CT facilities in the country. Data were analysed and with experts input, recommendations were made. The imaging protocols used across the CT facilities in the country were largely similar, with a few variabilities for similar examinations. These variabilities were found in scan coverages, series and slice thicknesses. In particular, for a brain tumour examination, 92% of the 25 facilities used both non-contrast and contrast phases while 8% preferred only the IV contrast phase. Seventy percent of all the facilities (n10) performing pulmonary angiograms in the country also used a two-sequence scan, and others (30%) worked with only the angiogram phase. A majority (89%) of the 19 facilities that were engaged in CT-IVU procedures also used 3-4 scan phases, while 11% preferred a split-bolus technique. None of the facilities employed the low-dose or ultra-low dose protocol for kidney stone examination. The studys outcome provides an important preliminary roadmap that could lead to the development of imaging practice guidelines to ensure harmonization of imaging practices to improve the protection and safety of patients across the CT facilities.

Study on the role of transcription factor SPI1 in the development of glioma.

Glioma is a common malignant brain tumor. The purpose of this study was to investigate the role of the transcription factor SPI1 in glioma. SPI1 expression in glioma was identified using qRT-PCR and Western blotting. Cell proliferation was assessed using the CCK8 assay. Transwell and wound healing assays were utilized to evaluate cell migration. Additionally, cell cycle and apoptosis were detected using flow cytometry. We observed that the expression level of SPI1 was up-regulated in glioma tissues, compared to normal tissues. Furthermore, we found that SPI1 is able to promote proliferation and migration of glioma cells in vitro. Flow cytometry results demonstrate that, compared to si-NC cells, si-SPI1 cells stagnated in the G1 phase, and down-regulation of SPI1 expression is able to increase rates of apoptosis. Double luciferase activity and chromatin immunoprecipitation assay results indicated that SPI1 can bind to the promoter sites and promote the proliferation and migration of glioma cells by regulating the expression of oncogenic PAICS. Our results suggest that SPI1 can promote proliferation and migration of glioma. Furthermore, SPI1 can be utilized as a potential diagnostic marker and therapeutic target for glioma.

Droplet digital PCR-based analyses for robust, rapid, and sensitive molecular diagnostics of gliomas.

Classification of gliomas involves the combination of histological features with molecular biomarkers to establish an integrated histomolecular diagnosis. Here, we report on the application and validation of a set of molecular assays for glioma diagnostics based on digital PCR technology using the QX200™ Droplet Digital™ PCR (ddPCR) system. The investigated ddPCR-based assays enable the detection of diagnostically relevant glioma-associated mutations in the IDH1, IDH2, H3-3A, BRAF, and PRKCA genes, as well as in the TERT promoter. In addition, ddPCR-based assays assessing diagnostically relevant copy number alterations were studied, including 1p19q codeletion, gain of chromosome 7 and loss of chromosome 10 ( 7-10), EGFR amplification, duplication of the BRAF locus, and CDKN2A homozygous deletion. Results obtained by ddPCR were validated by other methods, including immunohistochemistry, Sanger sequencing, pyrosequencing, microsatellite analyses for loss of heterozygosity, as well as real-time PCR- or microarray-based copy number assays. Particular strengths of the ddPCR approach are (1) its high analytical sensitivity allowing for reliable detection of mutations even with low mutant allele frequencies, (2) its quantitative determination of mutant allele frequencies and copy number changes, and (3) its rapid generation of results within a single day. Thus, in line with other recent studies our findings support ddPCR analysis as a valuable approach for molecular glioma diagnostics in a fast, quantitative and highly sensitive manner.